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Michael R.B. Evans
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Clinical Medicine
Treatment Resistance
Covertemplate
in Psychiatry
Subtitle
Risk for Biology, and
Factors,
Clinical Medicine Covers T3_HB
Management
Yong-Ku Kim
Second Edition
Editor
1123
3
2
Treatment Resistance in Psychiatry
Yong-Ku Kim
Editor
Treatment Resistance in
Psychiatry
Risk Factors, Biology, and
Management
Editor
Yong-Ku Kim
Department of Psychiatry
College of Medicine, Korea University
Seoul
South Korea
This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore
189721, Singapore
Preface
v
vi Preface
and persist for more than 1 year. Although the term “treatment-refractory TS”
is commonly used in research and clinical practice, there has been no consen-
sus regarding its definition. However, the presence of comorbidities is also
frequently associated with refractory TS. There are currently no guidelines
for the treatment of refractory TS, but emerging therapy, including transcra-
nial magnetic stimulation (TMS) and deep brain stimulation (DBS), is rec-
ommended for patients with refractory TS.
Chapter 17 provides a comprehensive review of neurobiology and man-
agement in treatment-resistant eating disorders such as anorexia nervosa and
bulimia nervosa. Treatment-resistant eating disorders are characterized with
protracted course; profoundly detrimental impact on social, vocational, psy-
chological, and physical health; and low recovery rates of less than 50%.
Neuro-adaptive changes in response to the highly disturbed eating pattern
may cause treatment resistance in eating disorders. It can be beneficial to use
treatments that directly target some of the dysregulated circuits that maintain
the disorder. New interventions targeting the neural changes such as cognitive
remediation therapy (CRT), cognitive bias modification (CBM), repetitive
transcranial magnetic stimulation (rTMS), and oxytocin therapy may improve
the response to treatment in enduring eating disorders.
Chapter 18 addresses sleep and wake problems that are often comorbid in
treatment-resistant psychiatric conditions and their causes and managements.
In chronic psychiatric disorders, the sleep and wake problems, such as insom-
nia, sleep apnea, restless legs syndrome, sleepiness, irregular circadian sleep
wake cycle, and prolonged and inappropriate hypnotic use, are commonly
comorbid and often contribute to a treatment-resistant condition if not prop-
erly managed. Insomnia is treated effectively with cognitive behavioral ther-
apy for insomnia (CBT-I), even if it is accompanied by psychiatric illness, but
it is better to modify the CBT-I modality for each psychiatric disorder.
Patients with psychiatric disorders often do not complain or conceal obstruc-
tive sleep apnea (OSA) symptoms themselves, and therapists should be more
aggressive in considering the evaluation and management of OSA during
pharmacotherapy.
Chapter 19 introduces the concept of creative, person-centered narrative
psychopharmacotherapy for treatment resistance in psychiatry. A paradigm
shift is needed from the mechanistic, formistic, and reductionistic ways of
thinking of technical, nomothetic, and impersonal psychopharmacology to
contextual, systemic, and creative thinking with a new treatment paradigm of
individualized and person-centered psychopharmacology. The best treat-
ments are those that timely utilize and integrate multiple therapeutic modali-
ties. Creative, person-centered narrative psychopharmacotherapy as a
multimodal resilience enhancing concept may significantly contribute to bet-
ter treatment effectiveness and efficiency in current psychiatry and thus over-
come treatment failures and resistance.
Chapter 20 reviews literature describing psychodynamic approaches to
treatment resistance and demonstrating the relevance of psychodynamic con-
cepts and the effectiveness of psychodynamic therapies. Despite the growth
of neurobiological research in psychiatry, the fundamental clinical problems
of psychiatry remain unresolved. Psychodynamic concepts and
Preface xi
xiii
xiv Contents
Index�������������������������������������������������������������������������������������������������������� 405
Part I
Rethinking the Treatment
Resistance in Psychiatry
Definition and Epidemiology
of Treatment Resistance 1
in Psychiatry
Table 1.1 Leading causes of global YLDs 2015 ing limited time to evaluate and treat mental dis-
1 Lower back and neck pain orders and prescription of medication in
2 Sense organ disease inadequate doses or for inadequate durations [6].
3 Depressive disorders The WHO estimates that in middle- and low-
4 Iron-deficiency anaemia income countries, between 76% and 85% of
5 Skin diseases
patients receive no treatment for their mental dis-
6 Diabetes
order. This rate is between 35% and 50% in high-
7 Migraine
8 Other musculoskeletal disorders income countries. Even in severe and often
9 Anxiety disorders persistent psychiatric disorders like schizophre-
10 Oral disorders nia, approximately one third of patients still
11 Asthma remain untreated [2].
12 Schizophrenia
13 Osteoarthritis
14 COPD 1.2 Treatment Outcomes
15 Falls in Psychiatry
16 Autistic spectrum
17 Gynaecological diseases
18 Drug use disorders
Apart from the high prevalence rates of psychiat-
19 Other mental and substance ric disorders and the significant treatment gap in
20 Medication overuse headache mental health, the efficacy of psychiatric treat-
21 Bipolar disorder ment is an important issue to address. Psychiatric
22 Congenital anomalies treatments, and psychotropic drugs in particular,
23 Haemoglobinopathies have been subject of criticism and mistrust, in
24 Chronic kidney disease spite of randomized controlled trials (RCTs) sup-
25 Ischaemic heart disease porting efficacy. This might be partly caused by
26 Alzheimer’s disease
the fact that the aetiology of many psychiatric
27 Alcohol use disorders
disorders and the mechanisms of action of differ-
28 Epilepsy
29 Other cardiovascular
ent treatment options are not fully understood.
30 Conduct disorder Other reasons could be the lack of diagnostic
31 Other unintentional tests, side effects or a commercial conflict of
32 Diarrhoeal diseases interest. Critics claim that pharmaceutical indus-
33 Intestinal nematode tries are corrupted; they would underreport side
effects and withhold evidence of clinical drug tri-
als for commercial reasons [7, 8]. Publication
health care is caused by different factors concern- bias, the interpretation of efficacy, and the effi-
ing the patients, the mental health system and the cacy of psychiatric treatments will be further
health-care providers. addressed.
Patients may fail to recognize or underesti-
mate the symptoms of a psychiatric disorder;
they could be prevented from seeking psychiatric 1.2.1 Publication Bias
care due to stigma, or they might be noncompli-
ant to treatment once it has been offered. Other It has clearly been demonstrated that publication
important factors are limited access to care and bias plays a role in the reporting of pharmaco-
financial considerations (e.g. lack of insurance therapy treatment outcomes of randomized con-
coverage). trolled trials in mental disorders. Turner et al.
Provider-based reasons include poor educa- compared the efficacy of antidepressants derived
tion about psychiatric disorders and the benefits from published literature with drug efficacy
of different supportive, psychotherapeutic and inferred from Food and Drug Administration
pharmacotherapeutic treatment approaches, hav- (FDA) reviews. Drug companies have to
1 Definition and Epidemiology of Treatment Resistance in Psychiatry 5
p reregister all trials they aim to use for marketing [13, 14]. Cuijpers et al. assessed the quality of
approval in an FDA database. In depression, they 115 randomized controlled trials examining psy-
found a bias towards publication of positive chotherapy for depression based on eight criteria.
results. The published results in scientific jour- In the high-quality studies, considerably smaller
nals overestimated the outcomes of the original effect sizes (0.22) were found than in other stud-
studies submitted to the FDA by around 30% [9]. ies (0.74), although the effects of psychotherapy
Furthermore, favourable secondary outcomes in depression remained statistically significant.
were sometimes highlighted instead of negative In a meta-analytic study of publication bias,
primary outcomes, also giving the impression of Cuijpers et al. examined funnel plots; graphs
higher clinical benefit [10]. designed to test for publication bias. Studies are
In the reporting of trials of second-generation assumed to be spread evenly on both sides of the
antipsychotics in the treatment of schizophrenia average, creating a funnel-shaped distribution.
or schizoaffective disorder, Turner et al. also Asymmetry in funnel plots is an indication for
found indications for publication bias [11]. Of publication bias. In this meta-analysis, the overall
the 24 FDA-registered trials, 4 remained unpub- effect size of studies comparing psychotherapy
lished. Three of these trials failed to show superi- and a control condition was 0.67, and the mean
ority of the study drug over placebo, and one trial effect size after adjustment for publication bias
showed inferiority of the study drug compared to was 0.42 [13]. Turner et al. identified randomized
an inexpensive active drug. However, the differ- clinical trials funded by the US National Institutes
ence between the point estimate mean effect size of Health grants and added the data of the unpub-
(the standardized mean difference) derived from lished studies to the published studies. Hereby,
published data and from FDA reviews was the point estimate effect size of psychotherapy
smaller in schizophrenia, and it was not statisti- when compared to control conditions was
cally significant (8% increase due to publication reduced by 25% (from Hedges’ g = 0.52–0.39).
bias). It seems that factors other than the commercial
In anxiety disorders, reporting bias inflated interest of pharmaceutical companies also seem
the effect size of second-generation antidepres- to play a role [10].
sants by 15% with differences between individ- Factors implicated in publication bias are a
ual anxiety disorders, ranging from 6% in possible reluctance of authors to submit manu-
generalized anxiety disorder to 25% in panic dis- scripts with negative or inconclusive results and
order. RCTs that were deemed positive by the a similar lack of willingness of journals to accept
FDA had a five times higher chance of being pub- such manuscripts. Researchers might fear a neg-
lished than non-positive trials [12]. ative influence on future grant applications or
Furthermore, reports of publication bias might feel reluctant to submit results that do not
were found for aripiprazole, lamotrigine and support their hypotheses. On the other hand,
gabapentin in the treatment of bipolar disorder. readers show a preference for positive research
The role of sponsorship became clear when it findings, and manuscripts with positive results
was shown that published efficacy results in are more likely to be accepted for publication by
industry-sponsored studies are more favourable reviewers [10]. Publication bias is not restricted
than the results in studies with other forms of to psychiatry; it is widespread throughout the
funding [10]. medical literature and other areas of science
It can be concluded that treatment outcomes (including chemistry and physics). This is
of psychotropic drugs have undoubtedly been receiving much more attention now than before,
mispresented in the literature, which is a very and a number of safeguards have been imple-
serious concern for the whole field. And this is mented by all major medical journals that should
not unique for the results of pharmacotherapy: in significantly reduce the possibility of bias in
psychotherapy there has been a similar overesti- published literature. These include publication
mation of the effects in meta-analytical studies of detailed trial protocols on websites such as
6 S. Y. Smith-Apeldoorn et al.
clinicaltrials.gov prior to study start and manda- with lithium shows average efficacy (SMD
tory reporting of primary outcomes. We fully 0.41). Furthermore, lithium may reduce sui-
agree with Ioannidis who stated that “The major cide rates in mood disorders [22, 23]. With
strength of science is not in being always per- concern to antidepressants and antipsychotics,
fect, but in correcting mistakes, fallacies, and meta-analyses found higher efficacy of antide-
misconceptions using the best evidence and crit- pressants [24, 25] and antipsychotics [26]
ical thinking” [15]. compared to placebo in relapse prevention than
in acute treatment. Many psychiatric treat-
ments do not only ameliorate symptoms during
1.2.2 Efficacy the acute episode but also prevent relapses, and
only long-term studies can demonstrate this.
Review articles considering the efficacy of anti- Therefore, the duration of the study should
depressants and antipsychotics show smaller always be taken into account. Funding issues
drug-placebo differences than we might intui- play a role in the amount of evidence that is
tively expect [16, 17]. Kirsch et al. [16] found available.
antidepressants to be effective when compared
to placebo only in patients suffering from severe 1.2.2.2 Reporting Methods
depression. This effect was attributed to a The method of reporting study results is impor-
decreased responsiveness to placebo among tant in the interpretation of the effectiveness
patients with severe depression. However, differ- (Table 1.2). In studies measuring dichotomous
ent studies have refuted this [18–21]. These outcomes, commonly used measures to quantify
studies re-analysed the available data and the effect are the relative and absolute risk reduc-
showed no relationship between drug-placebo tions (RRR, ARR) and the number needed to
differences and baseline depression severity. treat (NNT) to prevent one negative outcome.
They furthermore concluded that antidepres- Absolute risk reduction represents the change in
sants are clearly superior to placebo in achieving the risk of an outcome as a result of a therapy in
antidepressant response, also in mildly depressed relation to a comparison therapy. The relative risk
patients. Leucht et al. [17] found a relatively reduction is calculated by dividing the ARR by
small absolute difference of 18% in responder the risk in the control group (the baseline risk).
rates between placebo and antipsychotics in As an example statins have been shown to reduce
patients with schizophrenia. In their meta-analy- the risk for cardiovascular events from 18% to
sis, the pooled effect size for change of overall 14%. The absolute risk difference is
symptoms was 0.51. (18 − 14 =) 4%; however, the relative risk reduc-
Different factors contribute to the efficacy tion is ((1 − (0.14/0.18)) × 100 =) 22%. Clinicians
found and shown in studies that compare psycho- seem to overestimate therapeutic effectiveness
pharmacologic drugs to placebo, like outcome when only the RRR is presented [27]. Therefore,
variables, reporting methods, placebo effects and reporting the ARR with the baseline risk is impor-
nonspecific factors. tant for clinical decision-making.
In studies with continuous outcomes, the stan-
1.2.2.1 Outcome Variables dardized mean difference (SMD) is used to report
Primary outcomes in psychiatric treatments are effectiveness. The SMD is the difference between
not only reduction of disease severity and pre- the new treatment improvement and the compar-
vention of future episodes but also, for instance, ator treatment improvement, divided by the
reduction of suicide rates. As an example, the pooled standard deviation. Cohen’s rule states
efficacy of maintenance treatment with lithium that an SMD of 0.2 is a small effect size, 0.5
in prevention of depression is low (SMD 0.2), medium and 0.8 a large effect size. However, the
whereas the efficacy for preventing any relapse SMD should be interpreted within the context. As
is high (SMD 1.12). Acute treatment of mania it is relative to the pooled standard deviation,
1 Definition and Epidemiology of Treatment Resistance in Psychiatry 7
a large variability in scores reduces the SMD. This effect of the active placebo was superior to the
is often seen in psychiatry, when rating scales are effect of the inert placebo [30]. The physiologi-
used for heterogeneous diseases such as cal reaction to active drugs such as side effects
depression. might increase the expectation of a positive
effect and lead to clinical improvement. On the
1.2.2.3 Placebo Effects other hand, when patients do not experience any
Different factors influencing the size of placebo physiological changes in response to an inert
effects have been identified, such as the manner placebo, they are more likely to lower their
in which a treatment (active or inactive) is pre- expectations of the intervention leading to a
sented. A larger amount of pills shows better decrease in effect. In addition, early improve-
effects than fewer pills, intravenous administra- ment in patients receiving more effective drugs
tion is superior to oral administration, and the increases the expectation of receiving an effec-
cost of treatments, elaborate accompanying ritu- tive treatment and in itself produces additional
als or invasive sham conditions and the use of a placebo effects. Via these mechanisms, side
well-known brand name may also be of influ- effects and symptom reduction lead to unblind-
ence [28]. ing and may inflate the placebo effect in patients
The expectancy theory states that patients receiving active drugs [31].
who expect to receive an effective treatment Another factor influencing the size of the pla-
experience a reduction in their symptoms. This cebo effect is associated with the practitioner
was supported by the finding of higher placebo administrating the intervention. When the doc-
effects in trials with an increased change of tors have positive beliefs about the efficacy of
receiving active treatment, for instance, in trials the treatment, outcomes are better than when
comparing two active drug arms with an inert they assume the intervention is ineffective. This
placebo arm. This occurred in different psychiat- was shown in a study of analgesia in which all
ric disorders such as schizophrenia, psychosis patients received inactive placebo. Pain scores
and depression [29]. Additionally, in a trial in were significantly lower when the practitioners
which tricyclic antidepressants were compared believed the injection could contain fentanyl in
to an inactive and an active placebo arm, the comparison with pain scores when doctors
8 S. Y. Smith-Apeldoorn et al.
Table 1.4 Efficacy of medication for somatic disorders, selection from the article of Leucht et al. [50]
Disorder Therapy Outcome SMD 95% CI NNT 95% CI
Cardiovascular disease Acetylsalicylic acid Primary prevention 0.06 −0.03 to 0. 16 1429/year Unknown
of CV events
1 Definition and Epidemiology of Treatment Resistance in Psychiatry
two parts of the definition, (adequate) treatment c linical practice, and one approach to this prob-
and (inadequate) response, will be further lem is that of completing a diagnostic re-evalua-
addressed. tion, ideally with a structured clinical interview.
With concern to biological treatment, it is
important to assess whether the doses prescribed
1.3.1 Defining Treatment to the patient were in the therapeutic ranges and
to assess the duration of the treatment.
1.3.1.1 Pseudo-resistance Unfortunately, more than half of the patients
When evaluating possible treatment resistance, referred for an evaluation of insufficient thera-
one first needs to ascertain whether a patient has peutic response are assumed to have had inade-
received adequate treatment. The term pseudo- quate trials of psychiatric medication [53]. An
resistance has been used in reference to nonre- example is a study by Rasmussen et al. in patients
sponse to inadequate treatment. Patients with with unipolar depression, who found that among
pseudo-resistance, for example, did not receive patients with a psychotic depression, 95% had
the right form of treatment, the duration and dose not been given an adequate combination of an
(for medication) or intensity (for psychotherapy) antidepressant and antipsychotic agent. Among
may have been insufficient, the way the treatment patients with a nonpsychotic depression, 27%
was delivered may not have been adequate, or the had not had an adequate trial of an antidepressant
patient was non-adherent. Only after pseudo- before being referred for electroconvulsive ther-
resistance has been ruled out, true treatment apy [54]. But even when a trial meets the criteria
resistance can be considered. for adequacy in terms of dose and duration, there
are varying degrees of adequacy. For example, in
1.3.1.2 Adequate Treatment the treatment of major depressive disorder, the
Adequate treatment is often defined as treatment duration of the trial could be barely adequate
that accords with nationally and internationally (e.g. 4 weeks) or more substantial (e.g. 10 weeks).
developed professional treatment guidelines and It has been suggested that more prolonged trials,
standards. But treatment regimens are not static sometimes lasting more than 10 weeks, may lead
phenomena, as they are subject to substantial to a therapeutic response in certain resistant cases
changes over time. They also offer limited guid- [55]. Similarly, the dosing could be the minimum
ance for making specific choices, for example, effective dose or the maximum tolerated one.
when a clinician and patient have the possibility These factors can contribute to a marked variabil-
to choose between available drug treatments ity in the degree of response. For some drugs,
within one class. Furthermore, they do not take efficacy is clearly correlated with the presence of
into account the unique pathophysiology and adequate plasma levels. This is the case in, for
clinical characteristics of each individual patient. example, the TCAs imipramine, amitriptyline,
So it is clear that adequate treatment for any nortriptyline and clomipramine [56–58] and for
specific patient remains a combination of scien- (concomitant) the administration of lithium [59].
tific evidence, clinical wisdom and patient prefer- Certain pharmacokinetic factors may also
ence. Nevertheless, current guidelines provide an contribute to inadequate biological treatment.
established foundation for the working definition Given that there is an estimated 30-fold range of
of adequate treatment. drug metabolism among individuals [60], it is not
uncommon that patients who fail to respond to
1.3.1.3 Assessing Treatment Adequacy treatment may do so as a result of less than opti-
First of all, a basic requirement in assessing treat- mal plasma drug concentrations. For example,
ment adequacy is the accuracy of the diagnosis of the concomitant use of metabolic inducers (e.g.
the patient, to ensure that the treatment that is drugs that may increase the metabolism and
chosen matches the diagnosis (or diagnoses). elimination rate of co-administered agents) may
Misdiagnosis can be relatively common in be associated with a relative reduction in blood
1 Definition and Epidemiology of Treatment Resistance in Psychiatry 13
levels of psychotropic drugs. Also tobacco Table 1.5 Rates of non-adherence by psychiatric diag-
reduces the blood levels of a number of psycho- nosis, from the article of Julius et al.
tropic drugs, like the antipsychotics clozapine Diagnosis Rates of non-adherence
and olanzapine and the antidepressant fluvox- Major depressive disorder 28–52%
amine [61]. A similar problem may occur among Bipolar disorder 20–50%
patients who are fast metabolizers. The presence Schizophrenia 20–72%
Anxiety disorders 57%
of polymorphic alleles for cytochrome P (CYP)
450 may result in lack of expression, altered lev-
els of expression or altered function of CYP450 stance dependence), psychological (e.g. poor
enzymes. Some of these enzymes, for example, insight, denial of illness and negative attitude
CYP2D6, CYP1A2, and CYP3A4/5, are major towards medication), medication-related (e.g.
enzymes in the metabolism of antipsychotics. side effects and more complex dosing schedule)
Polymorphisms of alleles for these enzymes are and social and environmental (e.g. lower quality
associated with altered plasma levels of plasma of therapeutic alliance, fewer outpatient visits
drug concentrations [62]. Consequently, standard and lack of family support) [66].
dosing may result in drug plasma concentrations Unfortunately clinicians are not always very
that are subtherapeutic in some patients. accurate in estimating whether their patients
Nonresponse in the absence of any side effect actually follow their advice. Therefore, a check
should raise the possibility of less than adequate to establish treatment adequacy needs to be car-
blood levels. In such cases, determining poly- ried out to rule out the possibility of pseudo-
morphisms may be warranted, and dosage adjust- resistance. An assessment of adherence may
ments may produce a significant treatment allow for systematic monitoring through a variety
improvement. Research shows that clinicians not of methods, e.g. patients’ self-report, pill count,
always consider this. Furthermore, doctors and measuring blood levels or a diary.
pharmacists are not always aware of relevant
polymorphisms, even if they are known [63].
With concern to psychological treatment, it is 1.3.2 Defining Response
important to assess the type and quality of the
treatment [64] and the number of sessions It is important to specify response, in order to
attended [65]. Unfortunately, patients in primary understand treatment resistance as an inability to
care as well as in general psychiatry clinics most attain it. But what constitutes (in)adequate
often do not receive adequate psychological response has been an object of considerable
treatment [64]. While, for example, CBT is well debate in the field, and moreover, it is different in
known and taught in some psychology graduate a clinical context compared to a research
programmes, many more provide inadequate context.
training. At the same time, many therapists may
purport to “do CBT”, when all they do is provide 1.3.2.1 Treatment Outcome
basic education and skills [64]. in Clinical Context
Another important step towards the assess- In clinical practice, response is used to gauge
ment of treatment adequacy concerns the level of decision-making, such as when to modify, aug-
treatment adherence. Estimates of the extent of ment and switch treatment strategy. Response
non-adherence vary between 20% and 72% can be considered as a continuum that ranges
(Table 1.5). These numbers do not differ signifi- from nonresponse to partial response, to remis-
cantly from those in patients with somatic medi- sion and finally to full recovery.
cal conditions (66). The more traditional view of treatment resis-
Factors related to medication non-adherence tance has focused on nonresponse, e.g. patients
may be patient-related (e.g. younger age, male who have reported minimal or no improvement.
gender, lower education level and comorbid sub- Nowadays, most clinicians focus on remission
14 S. Y. Smith-Apeldoorn et al.
and recovery. The rationale for this approach is bipolar disorder still experience more functional
that symptom remission, as opposed to response impairments than healthy controls [73].
with residual symptoms, is consistently shown to
be associated with better outcome. For example, 1.3.2.2 Treatment Outcome
currently most experts would argue that inade- in Research Context
quate response in major depressive disorder is the In contrast with the clinical context, in research
failure to achieve remission [67, 68]. The defini- inadequate response is rarely defined as failure to
tions of inadequate response in schizophrenia achieve remission or recovery. Maybe because
and anxiety disorders comprise the failure to remission and recovery may occur weeks, months
achieve symptomatic remission as well; addition- or even years after response, it is more practical
ally, also functional criteria are often integrated to use either lack of response or the persistence of
[53, 69, 70]. clinically significant levels of symptoms, rather
Remission, unlike response, entails an abso- than the lack of remission or recovery [55, 68].
lute allowable ceiling level of symptoms. Several Response in research context is convention-
operational definitions of remission have been ally a reduction in baseline symptomatology of
proposed over the years. One of the definitions 50% or more, as measured on standard rating
that still stands is of Frank et al. [71]. They con- scales. A symptom reduction of 25–49% can be
ceptualized remission of depression as a “rela- called a partial response. Given the persistent and
tively brief (> E days but < F days) period during severe nature of some cases of treatment resis-
which an improvement of sufficient magnitude is tance, even a 25–49% reduction in baseline
observed that the individual is asymptomatic (i.e. symptom severity can provide a clinically mean-
no longer meets syndromal criteria for the disor- ingful benefit.
der and has no more than minimal symptoms)”. It is interesting that when response is deter-
They furthermore added that a “declaration of mined in research, no real distinction is drawn
remission implies that no increase in the intensity between the various symptoms of a disorder. This
of the treatment regimen is required”. In line with means that a quantitatively similar response can
this definition, according to Jakovljevic [53], reflect improvement across very different symp-
remission in general typically implies the attain- tom domains. However, these domains can clini-
ment of an asymptomatic stage or at least very cally be very different [74].
substantial improvements in symptom severity.
If remission is sustained, it may transmute to 1.3.2.3 Measuring Treatment Outcome
recovery. However, the absence of symptoms The use of measures of outcome is a necessary
does not always mean recovery. One has to make aspect of ascertaining (in)adequate response. We
a distinction between syndromal recovery (e.g. cannot be sure that response to treatment is (in)
“no longer fulfilling the formal criteria of a disor- adequate, unless we have a careful and system-
der”) and functional recovery (e.g. “return to the atic assessment of symptoms. Both in clinical
pre-illness level of functioning”). A psychiatric practice and research, the use of reliable and
disorder by definition affects functioning, but valid measures of outcome is advised [67].
also over time mental disorders are associated There are several well-established clinician-
with substantial impairment in functioning and rated and self-rating instruments, which have
quality of life, even after recovery from the syn- shown good sensitivity to assess the degree of
dromal episodes. For example, remission of response following treatment in patients with
major depressive disorder, bipolar disorder or mental disorders. With concern to clinician-rated
anxiety disorders is not associated with full resto- instruments, it should be noted though that they
ration of health-related quality of life, even are subject to clinicians’ biases, that clinicians
among those without comorbid disorders [72]. are often quite inconsistent in using instruments
And besides, even a year after syndromal recov- and that residual symptoms are not always ade-
ery, patients with major depressive disorder or quately measured.
1 Definition and Epidemiology of Treatment Resistance in Psychiatry 15
Self-rating instruments may eliminate these depressant trials required or of the need for
aspects. They also provide a useful tool to gain medication to be of similar or different classes.
insight into patients’ perceptions, their use allows Neither is there consensus about the trials that
patients to become actively involved in treatment, should be considered in the definition (i.e. those
and they provide the advantage of taking less cli- administered only during the current episode or
nician time. However, these instruments also those given as part of previous episodes too).
have some limitations. Their use might be limited Furthermore, definitions differ regarding the
in patients with significant cognitive impairment, minimum duration necessary for a previous treat-
poor motivation and limited reading skills. They ment to be considered as unsuccessful, ranging
also could be less suited to measure some aspects from 4 to 8 weeks, and in terms of the minimum
of behaviour and symptoms associated with poor required dose(s). For example, some studies
insight. require 200–300 mg/day of imipramine for con-
Another aspect concerns the timing of gather- sidering a previous treatment as adequate,
ing of information, especially in research. whereas others require 100 mg/day. Additionally,
Prospective gathering of information eliminates some authors use blood levels to determine the
the confounding effect of the patients’ recall bias, adequacy of imipramine treatment. And the same
but patients who are currently symptomatic may holds for treatment outcome: many authors use
underestimate the degree of improvement experi- “lack of response” or “failure” as their main out-
enced [67]. come, and some use “nonremission” or terms
such as “refractoriness” or “absence of signifi-
cant clinical improvement” [68].
1.3.3 W
hen Does Inadequate To cater for this lack of consensual operational
Response Become Treatment criteria, several authors have proposed staging
Resistance? models to conceptualize treatment resistance in
depression. These models range from single anti-
How many and which steps of adequate treat- depressant adequacy ratings to multidimensional
ment render an individual “treatment resistant”? and more continuous models, the latter basically
The number and sort of failed adequate steps may considering greater and lesser degrees of resis-
range from one to countless. And what role does tance. Some of these models also take into con-
non-biological treatment play? Definitions of sideration the intensity and optimization of each
treatment resistance focus predominantly on fail- trial, augmentation and combination strategies
ures of pharmacotherapy and physical treatments, and psychotherapy [78, 79].
with only modest consideration given to out-
comes following psychological therapies and 1.3.3.1 Relapse and Recurrences
social interventions, perhaps because the latter During Continued Treatment
can be less reliably quantified [74]? However, A special form of treatment resistance is repre-
since there is good evidence that psychological sented by the return of symptoms during treat-
and social interventions are effective in the treat- ment. This is a common clinical occurrence. In
ment of several mental disorders [75–77], one fact, relapses and recurrences during continued
can argue that a definition of treatment resistance treatment appear to occur at rates between 10%
without paying attention to non-biological treat- and 67% in depression [55], between 10% and
ment is too narrow. 40% in anxiety disorders [80, 81] and in 27% of
There is no consensus on when inadequate patients with schizophrenia [39]. Typically,
response becomes treatment resistance. For relapses and recurrences during treatment are not
example, concerning the mood disorders, included in the most definitions of treatment
treatment-resistant depression has many different resistance, maybe because the pathophysiology
definitions. There is no clear agreement regard- of these two clinical events is suggested to be dis-
ing either the minimum number of previous anti- tinct [55, 67].
16 S. Y. Smith-Apeldoorn et al.
society, due to patients’ more extensive and Global initiatives are in progress to delineate
costly use of medical services, both illness- functional subtypes and improve the accuracy
related and general medical, as well as to their with which patients are categorized and treated
loss of productivity associated with their func- [106]. It has been posited that, for example, bio-
tional impairment. Patients with treatment- logical markers are suitable candidates for sub-
resistant depression, for example, have a higher typing mental disorders [107].
number of medical visits, are at least twice as Another framework that might be useful in the
likely to be hospitalized, impose significantly treatment of mental disorders is clinical staging.
higher annual costs and have twice the economic Clinical staging tries to define the extent of pro-
costs for employers compared to nontreatment- gression of a disease at a particular point in time
resistant depressed patients [94, 95, 102–104]. and consequently places greater emphasis on
Furthermore, treatment resistance can lead cli- detailed description of where a person lies cur-
nicians to feel helpless and burnt out, facilitating rently along the continuum of the course of an
high rates of staff turnover and a desire to “throw illness. The fundamental assumptions of clinical
everything” at treatment-resistant patients hoping staging are twofold: patients in the early sates
for a response. Individuals with treatment- have a better response to treatment and a better
resistant illness might receive complex treat- prognosis than those in later stages, and the treat-
ments where the balance of risks and benefits ments offered in the early stages should be more
shifts perceptibly [101]. benign as well as more effective [108].
The main proposed strategy in diminishing the Measurement-based care can be defined as the
occurrence of treatment resistance is the optimi- practise of basing clinical care on client data col-
zation of treatment, for example, by the use of lected throughout treatment. It provides insight
more personalized medicine, measurement-based into treatment progress and highlights ongoing
care, combination and augmentation strategies treatment targets. Research has shown that
and experimental treatment strategies. measurement-based care can result in significant
improvement in clinical outcomes, especially for
clients identified as likely to experience treat-
1.6.1 Personalized Medicine ment failure [109, 110]. Moreover, as a frame-
work to guide treatment, measurement-based
Among the difficulties in mental health is a lack care has transtheoretical and transdiagnostic rel-
of consensus surrounding diagnostic categories evance with a broad reach [111].
that stems from an incomplete understanding of
the processes underlying mental disorders. Field
trials raise serious questions about the reliability 1.6.3 Combination
of the currently used categories [105]. By gaining and Augmentation Strategies
more understanding of what lies behind the clini-
cal symptoms of patients with (treatment- One may combine treatment strategies rationally
resistant) psychiatric disorders, we might be able to achieve a greater success. These include com-
to develop specific targeted therapies that are bination strategies and augmentation strategies.
more effective. In major depressive disorder, for example, com-
Furthermore, treatment outcomes would bination strategies involve the use of two or more
likely be improved by the discovery of homoge- different antidepressant treatments together. The
neous subtypes within and across diagnostic cat- aim of combining antidepressant treatments is to
egories, by which treatments could be stratified. combine two or more mechanisms of action in an
1 Definition and Epidemiology of Treatment Resistance in Psychiatry 19
attempt to obtain enhancement of efficacy or tol- day-to-day basis. Therefore, ongoing studies
erability. This requires some understanding of the focus on central concerns like elucidating ket-
targets of different treatments and flexibility in amine’s mechanism of action, understanding the
administration. Different antidepressants can be administration profile necessary to provide (sus-
combined, but also combinations with electro- tained) therapeutic benefit and examining ket-
convulsive therapy and psychotherapy can be amine’s safety profile, particularly with repeated
made. Combinations are found to enhance the administration [118].
rate of remission for patients suffering from In schizophrenia, accumulating data suggests
treatment- resistant depression [112], although that inflammatory processes play an important
not all combinations are found effective [113, role in the pathophysiology of the disorder. The
114]. Augmentation strategies in depression con- attractiveness of the inflammatory hypothesis lies
sist of the addition of a non-antidepressant ther- in the possibility that the shift towards a pro-
apy to an antidepressant. For example, mood inflammatory status in the brain can potentially
stabilizers and antipsychotics have been proven be corrected with anti-inflammatory agents.
to be effective adjuncts to standard antidepres- Therefore, several trials have been conducted to
sants, also in subjects who are unresponsive to investigate the potential of (augmentation with)
conventional antidepressant therapy [112]. anti-inflammatory agents to improve symptoms
In case of comorbidity, one may target the of schizophrenia. So far, there is some prelimi-
comorbid condition at the same time when pos- nary evidence for the efficacy of some of the
sible. This as well will lead to the use of multiple studied anti-inflammatory agents, like aspirin
treatments at the same time. and N-acetylcysteine [119]. At this point how-
ever, it is too early to make conclusions on the
benefits of this strategy.
1.6.4 Experimental Treatment
Strategies
1.7 Final Considerations
Nonresponse to current treatment strategies also
calls for the development of new treatment It is clear that much remains to be done to reduce
modalities. For example, a relative novel inter- the high level of treatment resistance in mental
vention that has shown rapid and robust effects in disorders. First of all early detection of potential
patients with treatment-resistant unipolar and treatment resistance is important, as is the possi-
bipolar depression [115, 116], and possibly anxi- bility to provide appropriate adaption of interven-
ety disorders [117], is the administration of the tions. This includes the possibility to offer a
N-methyl-D-aspartate (NMDA) receptor antago- range of treatments, something that unfortunately
nist ketamine. However, despite highly favour- is not the case for many patients. Furthermore,
able results, several important difficulties remain. clear definitions are needed, as terminology is
Ketamine’s therapeutic benefit quickly dissi- essential in decision-making in clinical practice,
pates. Achieving sustained remission of illness in making comparisons across studies and in
may require repeated doses of ketamine, but there identifying risk factors. Furthermore, we need to
are currently not enough data on the efficacy and improve our diagnostic accuracy using estab-
safety of continuation or maintenance treatment. lished instruments to measure and confirm pri-
Furthermore, there is paucity of information mary and comorbid mental and somatic disorders.
about other routes of administration for ketamine, We also need to ensure that our patients receive
such as the oral or intranasal routes. Given the adequate treatment, and we need to respond to
high prevalence of treatment-resistant disorders risk factors of treatment resistance. And finally,
and the foreseeable need for repeated doses of we need to optimize our interventions, for exam-
ketamine, this issue is of high importance to ple, by the use of more personalized medicine
facilitate the practical utility of ketamine on a and measurement-based care. Lastly and in line
20 S. Y. Smith-Apeldoorn et al.
with the aim of developing individualized treat- trials investigating the efficacy of second-generation
ments, our fields need to invest in deepening our antidepressants in the treatment of anxiety disor-
ders: a report of 2 meta-analyses. JAMA Psychiatry.
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Paradigm Shift in Study
of Treatment-Resistant Psychiatric 2
Disorder
Sang Won Jeon, Meysam Amidfar,
and Yong-Ku Kim
Were exposed
Treatment-
Initial diagnosis point Participation of resistant
Start of treatment study subjects (CASE)
Were not exposed A
n
a
l
y
s
i
s
treatment is given because subjects are enrolled treatment-resistant depression (TRD), numerous
into study after treatment has already been definitions were proposed in the past few decades
administered (Fig. 2.1). Biomarkers discovered [11]. It is widely accepted that TRP does not rep-
in such baseline study are not the initial risk fac- resent a diagnosis or syndrome per se. Therefore,
tors for TRP. And it is possible for initial bio- it is critical at the start of TRP research to deter-
markers to be altered during the treatment mine which of the definitions to apply. Important
process. If the study objective is to identify initial factors to consider when defining TRP are (i) cor-
biological risk factors, it is most ideal to enroll rect diagnosis and comorbidity, (ii) adequate
untreated patients (those who were diagnosed but treatment, (iii) treatment response, and (iv) the
have not yet undergone treatment) as study number and type of failed trials [1, 18].
subjects. Most common confounding factors in the post
In this chapter, the authors will review meth- hoc analysis done in TRP research are misdiag-
odological considerations to uncover initial bio- nosis, suboptimal treatments, and illness duration
logical risk factors for TRP and propose a better [1, 18]. To collect data regarding treatment dura-
study design for future research by discussing the tion and treatment dose, direct interviews are
shortcomings of the traditional study design. conducted and medical records reviewed. But, if
these processes are inaccurate, a problem arises
in which a high degree of heterogeneity is
2.2 Definition and Variables observed among subjects.
for TRP In TRP research, many variables are involved
prior to the determination of treatment resistance
Most researchers who study TRP feel the lack of or treatment responsiveness [10, 19]. Among
standardized definitions and operational criteria those, treatment variables are the most important.
from the start. For example, just focusing on The most critical among treatment variables are
2 Paradigm Shift in Study of Treatment-Resistant Psychiatric Disorder 27
undertreatment of psychiatric disease, delay in selected among those who have already been
initiating treatment predominant, and long- determined as treatment resistant and are avail-
lasting untreated illness [19]. Subject compliance able for study. Such a sample, however, may not
and tolerance should also be considered. represent all patients resistant to treatment,
Additionally, patient variables should be consid- because those whose illness is not diagnosed or
ered and analyzed. For example, people of older misdiagnosed, who are not treated, who do not
age and females show a higher risk for consent to register for study, and who are
TRD. Another factor to be considered is illness deceased (e.g., by committing suicide) are not
characteristics. In TRD, for example, unipolar included in the study.
depression vs. bipolar depression, psychotic Second, as shown above, the definition of TRP
depression, premorbid personality, and comorbid changes with time, and furthermore, several defi-
physical illness (e.g., thyroid dysfunction) should nitions are present at a given point. Hence, insta-
be considered [19]. The consideration of all such bility exists in that case groups differ depending
variables as above will exclude pseudo-resistant on which definition the researcher uses to define
cases. a case. To complement the shortcomings, the
researcher should be careful when sampling so
that the sampling ratio may be close to the ratio in
2.3 Limitation of Traditional the population of all patients with the illness of
Study Design interest and have extensive background knowl-
edge and confidence in regard to the current defi-
After the definition of TRP and variables are nitions of TRP.
under control to some extent, a study can be Third, there is a problem of differential mea-
designed to uncover TRP risk factors. Recent surement bias. This problem is caused by the use
biomarker research studies utilize multimodal of a retrospective approach in measuring a pre-
approaches such as neuroimaging, genetics, pro- dictor variable. Case and control groups are asked
teomics, and metabolomics [6]. Most traditional to recall past exposures. Recall of, and retrospec-
studies conducted to find biological risk factors tive analysis on, whether or not study subjects
of TRP use the case-control study design, which had sufficiently received adequate treatment
is a retrospective experimental study design [2, before determined to be treatment resistant is
14]. In traditional TRP studies, patient samples nothing but incomplete. In a case like this, prob-
are obtained according to some definition of lems of non-differential or differential misclassi-
treatment-resistant patients (case) and treatment- fication and recall bias arise, making it more
responsive patients (control), and the levels of difficult to find associations that are being mea-
predictor variables are compared between the sured in the study. To overcome the shortcom-
two samples to examine which predictor vari- ings, a prospective study should be conducted
ables are associated with the outcome (resistance [17]. The aforementioned problems such as recall
vs. responsiveness) (Fig. 2.1). Conducting a bias are not present in a cohort study, because the
study designed in this fashion is safe with low entire treatment process of subjects is exposed
risk and relatively less expensive, and thus, many and recorded before the diagnosis of treatment
studies are designed this way. However, there are resistance is made. Moreover, with an application
fatal flaws in studies using the design. of an experimental study design in a cohort study,
First, there is a sampling problem known as the treatment process will be controlled most
separate sampling. The ratio between subjects completely, and the involvement of extraneous
selected for treatment resistance and treatment variables will be minimized. If a prospective
responsiveness does not follow the correspond- study is impossible to conduct, the level of com-
ing ratio in the population, because the researcher parability between case and control should be
artificially determines the sampling of cases and improved by increasing the level of accuracy in
controls. For case sampling, subjects have to be recall of the treatment process before a patient is
28 S. W. Jeon et al.
determined as treatment resistant or treatment The nested case-control study design is a repre-
responsive, and a pair matching or frequency sentative case of such methodological approach
matching method should be appropriately (Fig. 2.2).
utilized. A nested case-control study costs less by
Finally, the most problematic in a study con- investigating only selected cases and controls,
ducted to find TRP risk factors that is designed as while enjoying many advantages of cohort
a post hoc experimental study is the point in time research. It is a case-control study, but has many
at which the baseline study is performed [17]. In positives of cohort research because it is designed
most existing studies, patients were registered for to survey risk factors before an outcome variable.
study after intervened with treatment, at which But, a nested case-control study is possible only
point a case-control study begins. Thus, baseline if the images and specimens obtained in the base-
data needed for risk factor analysis are obtained line study are well preserved. In TRP research,
after the primary treatment is complete. Could the starting point for a cohort should be at a time
biological markers like images and specimens when study subjects have not yet begun treat-
obtained at this point be initial risks for the TRP ment, and a cross-sectional study should have
patients? Definitely not. In biological research, a been conducted by obtaining specimens and
baseline study should be performed on the images images prior to the initiation of treatment (base-
or specimens obtained in the past. It is highly line study).
likely that the initial and unique characteristics of There may be a cohort in whom a study
the illness itself are lost in several biological objective has been minimally determined. For
markers due to the treatment intervention. To example, patients diagnosed with depression
resolve this problem, the time of study registra- for the first time may register for a study before
tion should be when “patients are diagnosed but undergoing treatment. In such case, the objec-
have not yet begun treatment.” That is, the timing tives of cohort research are to study depressed
of a baseline study to be performed should be patients only and investigate patients with
prior to the first treatment intervention, when the TRD.
subjects are untreated patients. Data gathered at Below, an illustration of the nested case-
this point have the value as true initial risk factors control study design to uncover initial biomark-
of TRP. ers of TRD is provided (Fig. 2.2).
Treatment-resistant
Initial Primary (CASE)
diagnosis Get the data treatment Baseline
point (specimens, termination Treatment-responsive study
Start of
imaging) treatment (CONTROL) analysis
Subjects
Drop out
Fig. 2.2 An illustration of the nested case-control study patients during a follow-up period (treatment-resistant
design in TRP research. (1) Determining the cohort whose patients). Sampling of the experimental (treatment-
specimens are obtained during the baseline study. (2) An resistant patient) and control (treatment-responsive
experimental study design can be included. Experimental patient) groups. (4) Investigating risk factors from the
control is provided for subjects to receive similar treat- specimens obtained in the past
ments during the cohort follow-up. (3) Determining
d epression. Here, the control group consists of a few years, not decades, for a patient to be even-
patients who responded to the treatment in the tually determined to be treatment resistant after
same cohort. A random selection method may be an illness is diagnosed and treated. As discussed
used, or patients whose treatment processes were above, if the aim of a study is to find initial risk
most close to those of the cases may be selected factors for TRP, the study must be designed as a
(matching). cohort study. If the nested case-control study
design is used, cost will be reduced compared to
typical cohort research, and the study will have
2.4.5 Measurement of Predictor the very strengths of a cohort study, in which data
Variables on predictor variables are collected before the
outcome variable (treatment resistance) is
Analyze the baseline data measured in the observed.
beginning and compare them between the case A weakness of this study design is that it is
and control groups to measure predictor vari- fundamentally a prospective study, and hence, it
ables. It is desirable for the analyst to be blinded is not easy to change the study design during the
with respect to whether a sample specimen course. If a study is not designed with accuracy
belongs to the patient group or the control and in detail, the consequence is irreversible. An
group. “The level of risk factors in the treat- additional weakness is that limited information is
ment-resistant patient group” and “the level of provided in post hoc analysis conducted after
risk factors in the treatment-responsive patient follow-up is complete, because the study popula-
group” are compared with each other. If a plau- tion begins with not all individuals of interest
sible factor is found, the importance of the pos- (e.g., patients with a potential to develop depres-
sible causal factor is finally measured. It is sion) but those whose range is narrowed in accor-
known as influence measure. It measures “the dance with the study objective (e.g., patients
size of additionally occurring treatment-resis- diagnosed with depression but having not yet
tant illness if the causal factor is entered” or begun treatment).
“the benefit obtained if the causal factor is
removed.” If the result is significant, the factor
is a powerful candidate as an initial biological 2.5 Other Considerations
risk factor for TRD which only treatment-resis-
tant patients have. A researcher planning to conduct a large-scale
It is relatively expensive to test serum and prospective study should keep in mind conduct-
other specimens and conduct imaging studies in ing analysis for a nested case-control study at a
order to confirm biological causes of TRP later time and consider storing biological speci-
patients. The nested case-control study design is mens, images, records, etc. which are expensive
particularly useful if the cost is high in conduct- to measure. If not all subjects in a cohort cannot
ing tests at the beginning of the study and storing be tested, the researcher should make an effort to
the biological data for later analysis. The cost save the data of only those who could potentially
reduction effect is greater if the measurements be used in the analysis for a nested case-control
are made just on the samples determined as cases study and ensure that the materials and image
and controls, rather than in the entire cohort, data of interest are saved until the analysis is per-
spending a large sum of cost. The cost issue may formed and pay close attention. In addition, dur-
have been the most important reason why until ing a cohort follow-up period, the researcher
now the case-control study design was preferred should frequently collect new specimens and
in TRP research. The time issue was probably not information which can be used in case-control
so critical, because it is highly likely that it takes comparison.
2 Paradigm Shift in Study of Treatment-Resistant Psychiatric Disorder 31
was associated with reduced weight gain follow- with a protective effect toward treatment intoler-
ing 8-week risperidone treatment [112]. In a ability, and rs6280 of DRD3 increased the risk
later report combining 181 young patients aged for intolerability (p < 0.04), whereas DRD5,
4–17 years from 2 previous trials evaluating MAOB, and MAOA had no effect on treatment
genetic effects of risperidone-induced side response or tolerability [212].
effects, at least 2 variants in cannabinoid recep-
tor 1 (CNR1) and 1 variant in leptin (LEP) were
significantly associated with weight gain [228]. 3.3 Attention-Deficit
The predictive impact of peripheral blood gene Hyperactivity Disorder
expressions of all exons on the behavioral (ADHD)
responses to risperidone was explored in 42 chil-
dren with ASD [189]. It was reported that mRNA Attention-deficit hyperactivity disorder is charac-
levels of a total of 89 exons significantly differ- terized by excessive inattention and/or hyperac-
entiated high responders from low responders to tivity and impulsivity as well as executive
risperidone, as evaluated by changes in ABC-I dysfunction and lack of emotional self-control
subscale scores. In particular, there were five and motivation.
genes significantly (p < 0.001) correlated with Pharmacotherapy with methylphenidate is
ABC-I percent change including guanylate- generally suggested as the first-line treatment of
binding protein family member 6 (GBP6), RAB choice in both children and adults with ADHD. A
member RAS oncogene family-like 5 (RABL5), review of ADHD pharmacogenetics in children
ring finger protein 213 (RNF213), nuclear factor demonstrated significant effects of genes associ-
of kappa light polypeptide gene enhancer in ated with neurodevelopment and noradrenergic
B-cell inhibitor delta (NFKBID), and ring finger systems in methylphenidate (MPH) response,
protein 40 E3 ubiquitin-protein ligase (RNF40, whereas negative or inconsistent results were
which is located on 16p11.2, a region implicated found in dopaminergic and serotonergic signal-
in ASD). While the genes identified in this study ing, synaptosomal-associated protein 25
did not corroborate prior pharmacogenetic find- (SNAP25), and various metabolic enzymes [48].
ings from Correia et al. [78], the authors assume In particular, the gene that encodes dopamine
that the gene expression may reflect convergent transporter (DAT) has been considered a promis-
downstream mechanisms from multiple genetic ing candidate for pharmacogenetic research due
backgrounds [189]. to the major role of the transporter in stimulant’s
Finally, the single pharmacogenetic study of action. The most studied polymorphism is the
stimulants so far has implicated monoaminergic 40-base pair (bp) variable number of tandem
genes in the therapeutic effect of methylpheni- repeats in the 3′ untranslated region (3′-VNTR)
date on ASD-related behavioral problems [212]. at the dopamine transporter gene (DAT1 or
As was demonstrated among children diagnosed SLC6A3) where the 10-repeat allele (10R) was
with autistic disorder or PDD-NOS, several associated with higher expression levels of the
genes, including the dopamine receptor DRD1 transporter [221, 257]. However, the pharmaco-
(p = 0.006), adrenoceptor alpha 2A (ADRA2A) genetic effects of DAT1 VNTR on MPH
(p < 0.02), COMT (p < 0.04), DRD3 (p < 0.05), responses were inconsistent. Several studies
and DRD4 (p < 0.05), modify the reduction of reported decreased MPH response in both adult
hyperactive–impulsive symptoms [212]. and children homozygous with either 9-repeat
Furthermore, the variants in two solute carrier allele (9R) [130, 318] or 10R [257, 267, 349],
family 6 (SLC6A) genes demonstrated border- while other reports showed better MPH response
line significant differences between responders in 10R homozygotes [154, 236], and still others
and nonresponders, SLC6A4 (p < 0.05) and reported no pharmacogenetic effect of the DAT1
SLC6A3 (p < 0.05) [212]. Additionally, the VNTR [76, 174, 214, 219, 337, 375]. Two meta-
minor allele of DRD2 (p < 0.01) was associated analyses demonstrated no significant effect for
36 E. Maron et al.
the DAT1 VNTR on both methylphenidate treat- ticular, the C allele was present in 77.1% of
ment response and specific symptom dimensions responders, whereas T allele was observed in
[38, 134] Thus, DAT1 VNTR was considered to 55.8% (P = 0.005). Regarding the pharmacoge-
be a non-reliable predictor of methylphenidate netic effects of the adrenergic alpha 2A gene
treatment outcome (see for review Bruxel et al. (ADRA2A), the G allele at SNP C-1291G
[48]). Although there are some evidences show- (rs1800544) was associated with greater MPH
ing that responsiveness to methylphenidate is response in children and adolescent [82, 100,
affected by certain DRD4 gene polymorphisms, 249], but again no effect of ADRA2A was found
the available data are insufficient and limited to in an adult sample [75].
children samples (see for review Bruxel et al. No association was observed between thera-
[48]. peutic response to methylphenidate and several
The other good gene candidate is catechol-O- serotonergic gene variations, including
methyltransferase (COMT), which modulates 5-HTTLPR, HTR1B (rs11568817, rs6296, and
catecholamine balance in the prefrontal cortex 13212041), tryptophan hydroxylase 2 (TPH2),
under methylphenidate action [65]. However, no and dopamine beta-hydroxylase (DBH) genes
strong evidence for the involvement of COMT in [74, 328]. Therefore, the serotonergic genes seem
treatment response to MPH has been showed so to be not major players in the therapeutic response
far. Previous pharmacogenetic studies suggested either in children or adults with ADHD.
a positive association between Val allele and As was earlier showed, the functional poly-
response to methylphenidate [67, 144]; however morphism of BDNF gene (Val66Met), involved
no effect was found in an adult sample [74], and in intracellular trafficking and BDNF activity-
only a trend level improvement of hyperactive– dependent secretion, may have promising predic-
impulsive symptoms with increasing doses of tive effect on methylphenidate therapeutic
MPH in COMT Val homozygous was demon- outcome in ADHD. For example, recent study
strated in a children sample [100]. showed in 102 children with ADHD that those
In terms of noradrenaline gene candidates, homozygous to Val/Val genotype achieve higher
Kim et al. [148] explored the possible association proportion of symptom remission (95.2%) than
between two single nucleotide polymorphisms Met-carrier children (74.1%) (p = 0.013).
(SNPs) at the norepinephrine transporter gene Moreover, Val-allele homozygous patients were
(NET1 or SLC6A2) and response to MPH more frequently (81%) assessed as “not ill” or
treatment
in Korean children with “very mild” according to CGI-I compared to 37%
ADHD. Improvement in CGI-I following MPH of Met-allele carriers (P = 0.0002), as well as
treatment was observed among 61.4% of T-allele more than 50% reduction in ADHD severity was
carriers as compared to 37.9% of A allele homo- observed in 95.2% of the Val-allele homozygous
zygous for the A-3081T (rs28386840) SNP patients and in contrast to 74.1% of Met-allele
(P = 0.03). However, no significant gene over- carriers (P = 0.018) [147]. It was suggested that
dose interaction effect for this SNP on MPH better methylphenidate response in Val/Val geno-
response was detected. Additionally, G1287A type carriers may probably be explained by a
(rs5569) polymorphism showed no significant lower degree of brain anatomical anomaly and
association with MPH response. Notably, the functional impairment in these individuals [147].
same research group did not replicate the associ- The other interesting candidate is the latrophilin
ation between MPH response and NET1 poly- 3 gene (LPHN3), which plays an important role
morphisms in their next study [180], and no in the regulation of neurotransmitter exocytosis
effect was found in an adult sample [159]. [259]. In a study with large sample of children
Nevertheless, Yang et al. [362] reported that with ADHD (n = 416), four of the six investi-
rs3785143 in NET1 had a nominally significant gated LPHN3 SNPs (rs1947274, rs2345039,
association with response rate to atomoxetine rs6551655, and rs6858066) showed significant
treatment in 111 Chinese ADHD children. In par- difference between responders and n onresponders
3 Genetic Factors Underlying Treatment Resistance in Psychiatry 37
[167]. Moreover, the authors found that the 3.5 Generalized Anxiety
rs6858066 G allele confers both risk to ADHD Disorder (GAD)
and better treatment response. LPHN3 polymor-
phism was also associated with combined-type The main feature of this anxiety disorder is exces-
ADHD in an independent adult sample [263]. sive and persistent worry, accompanied by
However, the G allele of LPHN3 SNP rs6551665 somatic anxiety symptoms as well as difficulty
has been paradoxically reported to be associated concentrating, muscle tension, sleep distur-
with better treatment response in the hyperactive bances, restlessness, irritability, and fatigue.
dimension [12] and poorer treatment response in Promising data have been reported by phar-
inattentive dimension [167]. It is possible that themacogenetic initiatives, where intensive search
differences in sample subtype composition and for genetic treatment predictors has revealed a
symptom dimension might be responsible for few genes, including the pituitary adenylate
these divergent results observed in LPHN3 phar- cyclase-activating peptide (PACAP), the sero-
macogenetic studies. tonin transporter (5-HTT), and the serotonin 2A
receptor gene (HTR2A), as potential markers
predicting treatment response to serotonin–nor-
3.4 Panic Disorder epinephrine reuptake inhibitors (SNRI) in
with Agoraphobia (PDA) patients with GAD [191]. Particularly, the
Asp54Gly (rs2856966) variant in the PACAP
Panic disorder is characterized by recurrent panic gene was associated with better treatment out-
attacks, which are discrete periods of intense fear come in 156 patients with GAD who have
or discomfort, accompanied by at least 4 of 13 received 6 months of open-label venlafaxine XR
somatic and psychic symptoms [6]. About two- flexible-dose treatment (75–225 mg/day) [77].
thirds of all patients with panic disorder suffer The involvement of HTR2A rs7997012 SNP in
from comorbid agoraphobia, which is defined as venlafaxine XR treatment response was also
fear in places or situations (e.g., crowds, public confirmed by individual analysis, showing that
transport) from which escape might be difficult G allele predicts better treatment response being
or in which help may not be available in the event more prevalent among responders (70%) as
of having unexpected panic attacks. compared to nonresponders (56%) at 6 months
Although the data from twin and family stud- (P = 0.05) of medication [191]. In the same sam-
ies suggest an involvement of genetic factors in ple, they also examined a possible interaction
the familial transmission of PD with the heritabil- between the serotonin transporter gene
ity estimate close to 48% [108], the genetic sub- (SLC6A4) 5-HTTLPR/rs25531 haplotype and
strate underlying treatment response is still the HTR2A SNP rs7997012. The results show
underinvestigated. Two available reports indicate that subjects with 5-HTTLPR/rs25531 geno-
that better response to selective serotonin reup- types La/La+G/G or La/La+G/A (n = 28) had
take inhibitor (SSRI) treatment is predicted by significantly lower Hamilton Anxiety Scale
the L-form of 5-HTTLPR [243] and the 5-HT1A (HAM-A) scores than those with genotypes La/
receptor -1019C/G polymorphism [366]. S+A/A or S/S+A/A (n = 12) at 6 months of treat-
Additionally, the COMT 158Val allele was asso- ment (HAM-A difference = 10.7; P < 0.0001)
ciated with greater symptom relief during [192]. This difference was larger than the single
exposure-based CBT [193], while carriers of the marker analysis of either gene alone and demon-
long MAOA-uVNTR alleles showed signifi- strated a gene–gene interaction effect. In con-
cantly worse response to CBT [262]. Recently, trast, none of the investigated polymorphisms
Trautmann et al. [330] reported preliminary evi- within dopamine receptor D2 or dopamine trans-
dence for poorer CBT treatment outcomes in a porter DAT1 genes showed impact on venlafax-
subgroup of female traumatized individuals car- ine XR treatment response in the same sample of
rying the low-active variant of the MAOA gene. patients with GAD [278]. Earlier, Perlis et al.
38 E. Maron et al.
[241] examined associations between 825 SNPs ference with functioning, or time consumption by
in 61 candidate genes and therapeutic response symptoms.
in patients with GAD receiving duloxetine Several pharmacogenetic studies have been
60–120 mg (N = 164) or placebo (N = 95). reported in OCD, but no definitive results support
Variants in corticotropin- releasing hormone a single genetic variation or gene that determines
receptor 1 (CRHR1), dopamine receptor D3 SSRI response in OCD. However, the most
(DRD3), nuclear receptor subfamily group C intriguing pharmacogenetic findings involving
member 1 (NR3C1), and phosphodiesterase 1A both pharmacokinetics and pharmacodynamics
(PDE1A) were associated with duloxetine have been reviewed in more details in very com-
response in GAD in their study. prehensive review by Zai et al. [372]. As the
authors summarized, only two cytochrome P450
liver enzyme genes, CYP2D6 and CYP2C19,
3.6 ocial Phobia (Social Anxiety
S have been studied in relation to the SSRI response
Disorder, SAD) in OCD. Nonresponders appear to be more com-
mon among non-extensive metabolizers accord-
SAD is characterized by persistent and unreason- ing to genetic status of CYP2D6, suggesting that
able fear of being observed or evaluated nega- genes regulating drug metabolism may play an
tively by others in social performance or important role in treatment efficacy [43].
interaction situations (e.g., speaking in public or Regarding the pharmacodynamic studies in
being exposed to possible scrutiny by others) and OCD, available data are still preliminary, either
is associated with somatic and cognitive anxiety inconsistent or not, yet replicated in independent
symptoms. and well-powered samples. Among various can-
Only few pharmacogenetic studies have ever didates, a number of genes in the serotonin, glu-
been conducted in SAD so far. Small study tamate, and dopamine systems and neurotrophic
reported that 5-HTTLPR genotype is associated factors have been identified as promising genetic
with reduction in social anxiety symptoms during predictors of treatment response to antidepres-
SSRI treatment [320]. However, in another study sants in OCD [372]. Furthermore, many new loci,
with a larger sample, none of the three gene can- including GRIN2B, glypican 6 (GPC6), dis-
didates including 5-HTT, COMT, and TPH2 pre- patched homologue 1 (Drosophila) (DISP1),
dicted CBT response [7]. The most powerful ankyrin repeat and fibronectin type III domain-
study to date with 346 patients with SAD has containing protein 1, and arrestin domain-
found that two of the four regulators of G-protein containing protein 4 (T-cell lymphoma invasion
signaling 2 (RGS2) SNPs predicted remission to and metastasis 1, protocadherin 10 (PCDH10),
sertraline treatment and suggested this gene may and LOCT30101), have been showed as top hits
be a genetic predictor of SSRI treatment response associated with SSRI response in OCD patients
in social phobia [319]. [258]. However, a further research is required to
clarify their functional status and their potential
role in the treatment response.
3.7 Obsessive–Compulsive
and Related Disorders
(OCRDs) 3.8 Post-traumatic Stress
Disorder (PTSD)
OCD is characterized by recurrent obsessions
(concerns involving contamination, harm, or sex- PTSD develops after a terrifying event that
ual and religious preoccupations) or compulsions involved physical harm or the threat of physical
(e.g., behaviors or mental acts such as washing, harm and is characterized by recurrent and intru-
checking, repeating, ordering, counting, hoard- sive distressing recollections of the event, night-
ing), or both, that cause significant distress, inter- mares, dissociative flashbacks, distress at
3 Genetic Factors Underlying Treatment Resistance in Psychiatry 39
exposure to cues that resemble the trauma cause, Subsequently, in a larger sample of alcoholics
avoidance of stimuli associated with the trauma, (n = 604), Anton et al. [9] found that Asp40-allele
isolation from others, disturbed sleep, difficulty
carriers treated with naltrexone (100 mg/day) had
concentrating, exaggerated startle response, irri-
a greater percentage of abstinent days and a lower
tability, and hypervigilance. percentage of heavy drinking days than Asn40-
Only few studies have been looking at the allele homozygotes. In an uncontrolled naltrex-
genetics of treatment response in PTSD. In par- one trial (50 mg/day), Kim et al. [150] reported
ticular, the LL genotype of 5-HTTLPR was that alcohol-dependent individuals with one or
related to greater response and lower dropouts two copies of the Asp40 allele maintained absti-
due to adverse events to sertraline treatment nence longer than Asn40-allele homozygotes,
among PTSD patients [224]. Additionally, Bryant whose risk of relapse was 10.6 times that of the
et al. [49] demonstrated that the S allele of Asp40-allele carrier group, but due to the small
5-HTTLPR may be associated with poorer long- sample size (n = 66), this effect did not reach sta-
term response to imaginal exposure-based CBT tistically significant level. Additionally, heavy
in individuals with PTSD. Two small studies drinkers carrying Asp40 G allele showed a sig-
indicate the possible predictive role of BDNF andnificantly greater percentage of non-hazardous
glucocorticoid receptor gene BCLI polymor- drinking days following treatment with 100 mg/
phisms on CBT treatment outcome in PTSD; day of naltrexone when compared to placebo
however due to limited sample size, these data controls or carriers of A-allele homozygotes in
need further replication [97, 365]. either treatment group [63]. Regarding other opi-
oid candidate genes, Krystal et al. [165] demon-
strated earlier that not only polymorphisms in
3.9 Substance Use Disorders OPRD1 and OPRK1, but also OPRM1, failed to
(SUDs) influence the effects of naltrexone (50 mg/day) in
alcohol-dependent male subjects. Despite the
Substance use disorders (SUDs), including abuse inconsistent findings for Asn40Asp impact on
(harmful use) and dependence, are characterized naltrexone efficacy, a meta-analysis conducted
by somatic or psychiatric problems caused by by Chamorro et al. [60] has concluded that
pathological patterns of the use of one or more alcohol- dependent Asp40-allele carriers are
substances. approximately half as likely to relapse when
treated with naltrexone as compared with pla-
cebo. However, no main effect of either naltrex-
3.10 Alcohol one or the Asn40Asp SNP was demonstrated in
the first prospective study of the Asn40Asp SNP
Several pharmacogenetic studies have investi- as a moderator of naltrexone’s effects among 221
gated the impact of opioid receptor mu subunit alcohol-dependent individuals [230]. Finally, a
(OPRM1) gene on the response to the opioid number of OPRM1, OPRD1, and OPRK1 poly-
antagonist naltrexone. The first report from a morphisms did not moderate any effect on the
placebo-controlled treatment trial demonstrated response to nalmefene 20 mg/day in a large sam-
that the Asp40 allele of Asn40Asp, encoded by ple of individuals (n = 272) with alcohol prob-
an A118G SNP, predicted a significantly lower lems [13].
relapse rate of heavy drinking in naltrexone- Among dopaminergic genes, DBH showed
treated patients [231]. Furthermore, under moderating effects of naltrexone medication on
naltrexone
treatment, European-American the primary outcome of abstinence from heavy
Asp40-allele carriers (n = 141) had a reduced drinking in alcohol-dependent individuals
likelihood of relapse to heavy drinking than (n = 107). Carriers of the DBH rs1611115 T
Asn40-allele homozygotes, whereas no genotype allele were significantly more likely to not drink
effect was observed in the placebo groups [231]. heavily than C-allele homozygotes under
40 E. Maron et al.
naltrexone treatment but responded poorer to s everity of alcohol drinking and its genetic asso-
disulfiram treatment [14]. Earlier, Lawford et al. ciation. They reported that 5-HTTLPR L-allele
[177] found that the greatest reductions in crav- homozygotes treated with ondansetron had fewer
ing were achieved in 83 alcohol-dependent inpa- heavy drinking days and more abstinent days
tients with bromocriptine (7.5 mg/day), who than those receiving placebo. In addition, indi-
were C-allele carriers (i.e., A1/A1 or A1/A2 gen- viduals who were also rs1042173*T-allele (a
otype) of the ankyrin repeat and kinase domain- SNP in the 3′ untranslated region of SLC6A4)
containing protein 1 (ANKK1; adjacent to homozygotes showed the greatest reductions in
DRD2) Taq1A polymorphism. Furthermore, the drinking outcomes compared to the remaining
impact of several polymorphisms at ANKK1 genotype by medication groups combined. In a
(Taq1A), GABRB2 (C1412T), and GABRA6 secondary analysis of the same trial, Johnson
(T1519C) on naltrexone (50 mg/day) and acam- et al. [127] revealed that individuals with one or
prosate (1.3–2.0 g/day) treatment was reported more of the following genotypes, rs1150226-AG
by Ooteman et al. [229] in alcohol-dependent and rs1176713-GG in HTR3A, or rs17614942-
patients (n = 126), although most findings failed AC in HTR3B, had significantly greater response
to reach the conventional significance level of to ondansetron than placebo. They calculated that
<0.05 and there was no effort to correct for mul- the use of these three genotypes plus the two
tiple testing, leaving the findings uninterpretable. SLC6A4 polymorphisms would identify 34% of
Additionally, 12 weeks of treatment with topira- European Americans with alcohol dependence
mate or placebo in heavy drinkers (n = 122) who are likely to respond very favorably to
revealed that only homozygote carriers of ondansetron treatment.
rs2832407 C allele in the kainate GluK1 receptor
subunit gene (GRIK1) had greater reduction of
heavy drinking days as compared to placebo 3.11 Nicotine
[162]. Earlier, Ray et al. [261] reported that this
SNP moderated topiramate’s adverse effects in To date, available pharmacogenetic studies on
non-treatment-seeking heavy drinkers. In a nicotine dependence have focused mainly on the
3-month acamprosate trial in a relatively large impact of genetic variation on the subjective
sample of alcohol-dependent subjects (n = 225), response to the drug and on treatment outcome in
the length of abstinence was significantly associ- smoking cessation trials [128]. Perkins et al.
ated with two polymorphisms (rs2058878, [237] found that during negative mood states,
rs2300272) in GRIN2B, which encode the Taq1A T-allele carriers reported greater “liking”
GluN2B subunit of the NMDA receptor. Among and consumed greater amount of nicotine ciga-
acamprosate-treated alcoholics, the minor A rettes than C-allele homozygotes. Similarly,
allele of rs2058878 was associated with a longer DRD2 C957T*C-allele homozygotes also
duration of abstinence, while the minor rs2300272 smoked more nicotine cigarettes during negative
G allele was associated with a shorter duration of mood states than during positive mood states
abstinence [137]. [238]. However, no association between smoking
Kranzler et al. [161] examined the effects of cessation and variation in a number of dopami-
the 5-HTTLPR tri-allelic genotype on the nergic genes, including COMT, DRD2, DRD3,
response to sertraline (200 mg/day) in 134 indi- DRD4, SLC6A3, and TH, was demonstrated in
viduals with early-onset or late-onset alcohol another prospective outcome trial in women.
dependence. In L′ homozygotes, later age of Furthermore, mixed results have also been
onset was significantly associated with better reported regarding the involvement of ANKK1
treatment response to sertraline, while younger polymorphisms on pharmacological treatment
age of onset demonstrated poorer response. outcome in smokers. Cinciripini et al. [70]
Johnson et al. [126] studied the effect of ondanse- reported that smokers without the Taq1 A1 allele
tron, a 5-HT-3 antagonist, on reducing the treated with venlafaxine had a substantial
3 Genetic Factors Underlying Treatment Resistance in Psychiatry 41
reduction in negative affect following smoking with poor and successful treatment outcomes in a
cessation. A1-allele carriers also quit signifi- later study with 116 subjects [25]. Crettol et al.
cantly less often than A2 homozygotes; however, [79] also failed to confirm any association
no genotype by treatment interaction was between the Taq1 A1 allele, the D1 dopamine
revealed on abstinence rates. In contrast, Taq1 A1 common variant (Ddel, −48A>G), and mu opioid
allele was not associated with withdrawal or with Asn40Asp (A118G) receptor gene and the
daily smoking abstinence rates during the 6-week response to methadone treatment in a sample of
treatment following smoking cessation [266]. 238 methadone-maintained patients, but they did
Nevertheless, the effect of ANKK1 gene was find an association with the C/C genotype of
observed on bupropion efficacy for smoking ces- DRD2 polymorphism C957T and poor response
sation in 577 heavy smokers. In particular, A1 to methadone treatment.
homozygotes treated with bupropion had a 28% Regarding opioid receptor genes, no associa-
greater likelihood of smoking cessation, com- tion between OPRM1 alleles and methadone
pared to a 12% greater likelihood of cessation treatment response was revealed [99]. The effect
among A2-allele carriers [44]. However, the of the delta opioid receptor gene (OPRD1) SNPs
opposite effect was observed by another large on the response to opioid substitution therapy
randomized, placebo-controlled study (722 was investigated in 643 patients who were ran-
smokers) in which A2 homozygotes treated with domized to receive 24 weeks of buprenorphine/
bupropion were more than 3 times as likely as naloxone or methadone maintenance treatment
placebo-treated individuals to be abstinent at the [80]. As demonstrated, an intronic OPRD1 SNP
end of the treatment and at 6-month follow-up (rs678849) predicted treatment outcome for both
[85]. Earlier, Yudkin et al. [371] found that pharmacotherapies among African-American
A1-allele carriers had less therapeutic benefit participants (N = 77). In a more recent study,
from the nicotine patch than A2-allele homozy- researchers found that two other intronic OPRD1
gotes, but no significant mediating effect of the SNPs (rs581111 and rs529520) predicted
Taq1A genotype on the efficacy of nicotine buprenorphine treatment outcomes, but in
replacement therapy (NRT) in smoking cessation females only. Particularly, females with the AA
was demonstrated by other studies [30, 86, 316]. or AG genotypes at rs581111 had significantly
In addition, smokers with at least one copy of the worse outcomes compared to carriers of the GG
DRD2 141C Del allele and two copies of the neu- genotype, while females with rs529520 AA gen-
ronal calcium sensor-1 protein FREQ A allele otype had a significantly worse outcome as com-
(rs1054879) had a significantly higher abstinence pared to females with the CC genotype [71].
rate with NRT compared to other smokers (62%
vs. 29–38%) [83].
3.13 Cocaine
p olymorphism (rs1048101) was also associated treated with donepezil for 6 months, the nonre-
with disulfiram treatment response [303]. In par- sponders had a significantly higher frequency of
ticular, the minor T allele had a significantly the G allele of the CYP2D6 rs1080985 SNP
lower percentage of cocaine-positive urines, [248]. Since it has been demonstrated that the G
while no treatment effect was observed among allele is associated with a higher enzyme activity
those homozygous for the major C allele. and, therefore, a faster metabolism, it is sug-
gested that the poorer response to donepezil is
due to lower plasma concentrations of the drug
3.14 Dementia [248]. However, another clinical trial exploring
treatment response to three cholinesterase inhibi-
Dementia is a syndrome of progressive cognitive tors (ChEIs) including donepezil, galantamine, or
decline, characterized by various central neuro- rivastigmine found no significant associations
degenerative or ischemic processes, sufficient to between CYP2D6 and BCHE (the gene coding
interfere with the activities of daily living. for butyrylcholinesterase) genotypes and
It should be noted that pharmacogenetic trials response to treatment after 1 year for all three
of dementia are still in a very early stage. To date, ChEIs [68]. The controversial results might be
apolipoprotein-E (APOE) has been the main can- explained by the difference in follow-up periods
didate gene, and the presence of the APOE-4 and the definition of treatment response.
allele has been reported to differentially influence However, since higher plasma concentrations
drug response in Alzheimer’s disease patients could be associated with a higher response rate
treated with cholinergic enhancers (such as done- but possibly also with a higher frequency of
pezil, galantamine, rivastigmine), endogenous adverse effects, further research is needed to clar-
nucleotides, neuroprotective compounds, rosigli- ify the impact of polymorphisms in CYP2D6 on
tazone, immunotrophins, neurotrophic factors, or plasma concentrations of donepezil and the clini-
their combinations [50–53, 55, 56, 265, 268, cal response. To date, no major role in the vari-
269]. Controversial results are frequently ability in donepezil metabolism has been
observed due to methodological problems, study observed for CYP3A4 and CYP3A5 genes [197].
design, and patient recruitment in clinical trials.
Nevertheless, APOE-4/4 carriers have been dem-
onstrated to be associated with the worst treat- 3.15 Schizophrenia (SCH)
ment outcome in long-term open clinical trials
with multifactorial treatment [50–53, 55, 56]. Schizophrenia is a chronic, severe, and debilitat-
Similarly, the presenilin gene has also been ing mental disorder, which is affecting about 1%
reported to interact with multifactorial treatment of the population in the world and characterized
response that PSEN1-1/1 homozygotes are the by psychotic or “positive” symptoms, including
worst responders and PSEN1-2/2 carriers are the hallucinations and delusions, as well as negative
better responders [53]. In addition, angiotensin- symptoms and various deficits, including inabil-
converting enzyme (ACE) genotype also influ- ity to pay attention, the loss of sense of pleasure,
ences multifactorial treatment response as the and social withdrawal.
ACE-D/D patients showed the poorest response, A number of pharmacogenetic studies have
ACE-I/I carriers had intermediate response, and investigated either the drug class or specific anti-
ACE-I/D carriers had the most positive treatment psychotics (e.g., clozapine, olanzapine, and ris-
response [51, 54]. peridone); however, most of the findings have not
The genetic variations in drug-metabolizing been clearly replicated in independent studies;
enzymes, including CYP2D6 and CYP3A4, were therefore the results should be interpreted with
the other promising candidates for pharmacoge- caution [23]. Numerous studies suggest the
netic research in dementia. In a prospective study involvement of dopaminergic candidate genes in
including 127 Caucasian Alzheimer’ patients the efficacy of clozapine. The finding that a 48 bp
3 Genetic Factors Underlying Treatment Resistance in Psychiatry 43
repeat in exon III of the dopamine receptor 4 (DTNPB1) [380], oxytocin (OXT) [307], and
(DRD4) gene was associated with clozapine GDNF family receptor α2 (GFRA2) [308] gene
treatment response indicates that this receptor variants; however further replications in indepen-
might be important in clozapine’s efficacy [297, dent studies are needed. In the contrary,
299, 376]. The five-repeat allele was more fre- clozapine-targeted adrenergic and glutamatergic
quently found in clozapine nonresponders; how- receptor variants [36, 37, 332] and CYP2D6
ever this evidence was not replicated in two later functional variants [17] were not associated with
studies [260, 264]. The DRD3 Ser9Gly func- clozapine response.
tional polymorphism has been demonstrated to In terms of pharmacogenetics of olanzapine
be associated with clozapine efficacy in several efficacy, once again the main target genes belong
studies. The D3 Gly9 variant, which codes for a to dopaminergic and serotonergic systems. An
higher-affinity dopamine receptor, was related to association between the DRD3 Gly9 variant with
better improvement of psychotic symptom fol- greater improvement of positive symptoms dur-
lowing clozapine treatment [280, 298]. A meta- ing olanzapine treatment was observed [2, 312]
analysis concluded that although not statistically although this association was not found in Indian
significant, a trend level of this D3 Gly9 variant patients [329]. The long allele (L) of the
association was found, and the small effect may 5-HTTLPR polymorphism [42] and several
be explained by differences in the clinical charac- 5-HT6 polymorphisms [115] were associated
teristics of different studies [120]. Dopamine D1 with better response to olanzapine. In addition,
and D2 genetic variants have also been shown to olanzapine efficacy has also been associated with
be associated with clozapine treatment response COMT [31], glutamate receptor type 3 (GRM3)
[117–119, 253]. Finally, dopamine transporter [35], multidrug resistance transporter (MDR1 or
(DAT) genetic variants have been associated with ABCB1) [41], adrenergic receptor 1A (ADRA1A)
clozapine response [356], although a previous [115], noradrenaline transporter (SLC6A2)
study did not find an association in a cohort of [216], and melacortin 2 receptor (MC2R) [115]
patients treated with a variety of second- variants. No positive association was demon-
generation antipsychotics [326]. strated between the efficacy of olanzapine and
Evidence suggesting an involvement of sero- CYP2D6 and CYP1A2 gene polymorphisms
tonergic receptor gene variants in clozapine effi- [329].
cacy has also been reported. Several 5-HT2A Lower risperidone efficacy has been reported
polymorphisms have been associated with clo- to be associated with several DRD2 polymor-
zapine response [15, 16, 21, 22, 205, 369], phisms including the D2 Ser311 allele [171] and
although these associations have not been clearly the D2 −241-G allele [122, 355]. Patients who
replicated [19, 22]. Insufficient clozapine effect are D2 Taq1 polymorphism A1 variant homozy-
on psychotic symptoms has been associated with gotes also showed superior improvement in psy-
the HTR2A 102-C and −1438-G variants, which chotic symptoms with risperidone treatment
cause reduced receptor expression, and Tyr452, [122]. Additionally, the DRD3 Ser9Gly polymor-
and as consequence decreased receptor function- phism has been associated with the efficacy of
ing [18]. In addition, 5-HT2C [20, 306], 5-HT6 risperidone in a study of Chinese patients [170],
[368] receptor, and serotonin transporter (5-HTT but this finding was not replicated in another
or SLC6A4) variants [20, 157] have also been independent study [359]. Finally, no association
reported to be associated with clozapine treat- was found with D4 variants in a small cohort of
ment effect, although negative findings also exist Israeli patients [373].
(please see Arranz et al. [23]). Significant associations with the efficacy of
In single reports clozapine efficacy has also risperidone have also been demonstrated for
been associated with histamine H2 receptor (H2) serotonergic polymorphisms. In particular, the
[199], COMT [351], CYP1A2 [93], G-protein 5-HT2A 102-C variant has been associated with
subunit 3 (GNB3) [158], and dysbindin better risperidone efficacy in Chinese [169] and
44 E. Maron et al.
Korean [145] patients but poorer response in associated with antipsychotic-induced weight
Caucasian patients [18]. In Japanese patients, gain [59] and GABA pathway genes related to
5-HT2A haplotypes also showed a trend of asso- drug-induced tardive dyskinesia [124], but these
ciation with risperidone efficacy [360]. Several results needed to be interpreted with caution due
5-HT2C polymorphisms were associated with to small sample sizes. Several GWA studies were
risperidone efficacy in Chinese patients [190]. In conducted on a subgroup of 750 subjects from
addition, better risperidone efficacy has been the CATIE (Clinical Antipsychotic Trials of
shown in patients with the 5-HT6 267-T/T [172], Intervention Effectiveness) study, and the results
5-HT3A rs14396-G/G [106], and 5-HT1A 1019-- showed association of polymorphisms in the
C/C [340] genotypes, while no association was ankyrin repeat and sterile α-motif domain con-
observed for 5-HT7 gene variants [344]. Finally, taining 1B (ANKS1B) and contactin-associated
the L allele of the 5-HTTLPR polymorphism has protein-like 5 (CNTNAP5) and the treatment
been associated with greater response to risperi- efficacy of olanzapine and risperidone in resolv-
done [341]. ing negative symptoms [210]. Polymorphisms in
In terms of other candidate genes, risperidone the proximity of ETS homologous factor (EHF),
efficacy, similar to that of clozapine and olanzap- solute carrier family 26 member 9 (SLC26A9),
ine, has been associated with COMT [98, 107] D2, G-protein-coupled receptor 137B
and MDR1 [354] variants. In addition, CYP3A4 (GPR137B), carbohydrate sulfotransferase 8
1G variant has been demonstrated to be associ- (CHST8), and interleukin-1α (IL1A) have also
ated with the degree of improvement in psychotic been demonstrated to be associated with neuro-
symptoms [92]. Finally, BDNF repeat [357], cognition improvement during treatment [211].
GRM3 rs724226 polymorphism [98], and several In terms of treatment-associated side effects,
SNPs in RGS4 [173] were reported to be associ- polymorphisms in the nitric oxide synthase 1
ated with the efficacy of risperidone treatment. adaptor protein (NOS1AP) and in the nucleotide-
There have been fewer studies of other anti- binding protein-like (NUBPL) genes were linked
psychotics where all the patients in the cohort to QT interval prolongation [1]. A Meis homeo-
have been treated with the same medication. box 2 (MEIS2) gene polymorphism was found to
Chlorpromazine and haloperidol are two first- mediate risperidone’s effect on hip and waist cir-
generation antipsychotics with high dopamine cumference [3]. Finally, EPF1, NOVA1, and
receptor binding affinity, and the efficacy of these FIGN underlined antipsychotic-induced parkin-
two antipsychotics was associated with DRD2 sonism [5]. However all these reported associa-
gene [279, 353]. Haloperidol efficacy was also tions need further confirmation in independent
associated with the number of active alleles of samples.
CYP2D6 gene [47]. Aripiprazole is a dopamine Two GWA studies performed in a sample of
D2 receptor partial agonist with high affinity for 457 patients treated with the relatively new anti-
dopamine and relatively low affinity for sero- psychotic iloperidone revealed polymorphisms in
tonin receptors. Dopamine D2 Taq1 genotypes the neuronal PAS domain protein 3 (NPAS3) and
seem to moderate aripiprazole efficacy in Chinese Kell blood group complex subunit-related family
and Korean patients [166, 300], but no significant member 4 (XKR4) genes associated with treat-
effect was observed between D3 variants and ment response [175], and polymorphisms in the
aripiprazole efficacy [66]. Finally, a single report ceramide kinase-like (CERKL) and solute carrier
associated MDR1 variants with the efficacy of organic anion transporter 3A1 (SLCO3A1) genes
the first-generation antipsychotic bromperidol associated with QT interval prolongation [339].
[363]. Implementing parallel in vivo transcriptomic
The first genome-wide association (GWA) studies and GWA studies on patient cohorts, sev-
studies on both first-generation and second- eral genes in neurodevelopment and neurogene-
generation antipsychotics identified a region in sis were demonstrated to be involved in
chromosome 12 hypothesized to contain genes risperidone action [121].
3 Genetic Factors Underlying Treatment Resistance in Psychiatry 45
[57, 223], tumor necrosis factor, interleukin 11 associated with lithium response but with contro-
[254], interleukin 1 beta [28], and melanocortin 1 versial results. The heterozygous L/S genotype
receptor [352]. Finally, although the association was associated with superior lithium response
of CYP2D6 or CYP2C19 on antidepressant [293], while the S/S genotype has been associ-
response has been demonstrated [183], the com- ated with both good and poor responses to lith-
bination of genotyping with therapeutic drug ium [87, 273]. The 5-HTTLPR S allele alone was
monitoring in certain cases has been earlier rec- associated with poor response to lithium in
ommended when exploring these genes [111]. In patients with bipolar disorder [271], but no asso-
addition, there are also recommendations for the ciation was found by other studies [201, 218]. In
initial dosage of antidepressant treatment based addition, patients with both the S allele and the
on genetic information [109, 110, 153]. BDNF Val/Val genotype were significantly more
Several GWAS have investigated genetic frequent among the poor lithium responders
effects on antidepressant response, but no vari- [275]. Association studies on serotonin receptor
ants with genome-wide significance were identi- gene did not show association between genetic
fied so far [183]. A meta-analysis utilizing the variants and lithium prophylaxis response,
data from the Genome-Based Therapeutic Drugs excluding a major involvement of serotonin
for Depression (GENDEP) project, the Munich genes in response to lithium prophylaxis in bipo-
Antidepressant Response Signature (MARS) lar disorder [89, 201, 292]. Finally, an association
project, and the Sequenced Treatment Alternatives between the TPH1 rs1800532 A/A genotype and
to Relieve Depression (STAR*D) study samples poor response to lithium was earlier demon-
revealed no variant associated with treatment strated [287].
response at a genome-wide level of significance Regarding the dopaminergic systems, the G
[103]. Future investigations conducting more in- allele of the DRD1 rs4532 polymorphism pre-
depth analyses of gene–gene and gene–environ- dicted a poor response to treatment in patients
ment interactions, pathway analyses, and with bipolar disorder [272]. Additionally, no
machine learning techniques may advance our associations between other dopamine receptors
understandings of genetic variants associated and dopamine-metabolizing enzyme (including
with antidepressant response [187]. MAOA and COMT) gene polymorphism were
reported by several studies [288, 289, 291, 333].
In terms of genetic variants of the glutamatergic
3.17 Bipolar Disorder system, several studies found no association with
lithium response [69, 271, 324]. However, two
Bipolar disorder is a debilitating mental disorder other genes coding for protein that interacts with
characterized by the recurrence of depressive and the glutamatergic receptors, the CACNG2 gene
hypomanic or manic episodes alternating with [304] and the FYN gene rs3730353 [325] and
intervals of partial or full recovery. rs6916861 [271] polymorphism, were associated
Pharmacogenetic research in bipolar disorder with lithium response.
is still in a relative nascent stage, and further In regard to BDNF gene variants and lithium
large cohorts of patients with well-characterized response, some studies have suggested that the
treatment regimen and response profiles are Val allele of the functional polymorphism rs6265
needed to advance our understanding in this (Val66Met) predicts a poor response to lithium
important field. So far, most of the pharmacoge- [89, 274]. Interestingly, Wang et al. demonstrated
netic research in bipolar disorder focused on association between the Val/Met and Met/Met
lithium. genotypes and a good lithium response in bipolar
The serotonergic system is one of the most I disorder patients, while the same genotypes
explored by pharmacogenetics in bipolar disor- were associated with a poor response in bipolar II
der. The 5-HTTLPR polymorphism has been disorder patients [343]. Furthermore, no associa-
48 E. Maron et al.
tion between five BDNF polymorphisms (includ- [202]. In addition, the NR1D1 rs2071427 and
ing Val66Met) and lithium response was observed CRY1 rs8192440 polymorphisms were associ-
in a Korean sample [234]. Finally, divergent ated with good response to lithium [209].
results were found in regard to the association Notably, the rs2071427 of NR1D1 and rs6438552
between the NTRK2 gene and lithium response of GSK3B had significant additive effects in pre-
[45, 90]. dicting lithium response [209].
Lithium has been shown to be involved in the Moreover, lithium interacts with the PKC
inositol pathway [301], and several genetic vari- pathway, which plays a crucial role in mediating
ants related to this pathway and their association a number of intracellular responses to neurotrans-
with lithium response were explored. Two poly- mitters [204]. However, PKC pathway-related
morphisms of the IMPA2 gene showed a trend to gene variants showed mostly no association with
significant association with good lithium lithium response [45, 310].
response [88]. An association between the INNP1 The involvement of lithium in the regulation
C937A polymorphism and response to lithium of various gene expressions makes the transcrip-
was found in Norwegian bipolar patients but not tion factor genes interesting targets for pharma-
in an independent Israeli sample [317]. In addi- cogenomic studies in lithium response. An
tion, INNP1 rs2067421 polymorphism was association between the G/G genotype of the
linked to lithium response in patients with bipolar XBP1 rs2269577 polymorphism and reduced
disorder [45], but this result was not replicated in response to lithium has been demonstrated [133,
another sample [218]. A dinucleotide repeat 207]. A significant association between the
allele of the PLCG1 gene related was associated CREB1 rs6740584 and rs2551710 SNPs and
with lithium-responsive bipolar disorder [195, good response to lithium was showed [198]. The
334], but other markers within the coding region AP2B gene association study with lithium
of PLCG1 did not give such evidence of a major response performed to date led to negative
role for this gene in lithium response [102]. results [218].
Finally, an Asn796Ser SNP in the BCR gene was Linkage studies carried out thus far have
found to be significantly associated with lithium suggested over 40 susceptibility regions in
response [206]. bipolar disorder (see for review [81]), but
The modulation of GSK3B activity has been available meta-a nalyses have failed to provide
demonstrated to be pivotal in the action of mood strong evidence for any of the loci [24]. To
stabilizers [184]. Lithium inhibits GSK3B by a sum up, chromosome 18 [95], 18q22.3 [335],
magnesium-competitive mechanism [156, 314]. 7q11.2 [336], 3p25 and 3p14 [194], and 14q11
Significant association between the C/C geno- [194] were identified in these linkage studies
type of -50T/C GSK3B (rs334558) polymor- focusing on lithium response. In terms of the
phism and good lithium response was reported GWAS, two did not report any genome-wide
[4, 29]. On the contrary, no association of GSK3B significant findings [242, 311]. In another
SNPs with lithium response was found in several GWAS conducted in a sample of 294 Han
other studies [218, 271, 323], although a trend for patients with bipolar disorder from Taiwan, a
association between the rs6438552 SNP of the GADL1 SNP reached genome-wide signifi-
GSK3B [4, 29] gene and good response to lith- cance [64]. However, this finding could not be
ium was reported [209]. replicated in independent samples from
A few studies have investigated circadian Taiwan and Japan so far [73, 122]. Finally, the
clock genes in relation to lithium response. The T largest GWAS to date on lithium response
allele of the Rev-Erb-α rs2314339 polymorphism totaling 2563 uniformly phenotyped bipolar
was linked to poor lithium response [58], but patients from more than 20 sites across 4 con-
another study failed to detect such association tinents has been published very recently by
3 Genetic Factors Underlying Treatment Resistance in Psychiatry 49
the Consortium on Lithium Genetics. Four ate in bipolar patients [146]. In addition, an
linked SNPs of a single locus located on association of the BDNF and NTRK2 genes
chr21q21.1, where two genes for long, non- and the response to valproate was showed [342,
coding RNAs, AL157359.3 and AL157359.4, 343]; however there was reported significant
are located, reached genome-wide signifi- association between the Met/Met COMT geno-
cance [114, 200, 281]. type and poor response to valproate and carba-
Antidepressant monotherapy for acute bipo- mazepine [179]. Finally, seven genes including
lar depression is generally not recommended ANKK1, DRD2, DRD4, DBH, HRH1, MC2R,
given the concern for mood switching [27, 364]. and NR3C1 were linked to lamotrigine
The majority of the pharmacogenetic studies of response [239].
clinical response to antidepressants in bipolar
patients have focused on the serotonergic path-
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Using Neuroimaging
and Electroencephalography 4
for Prediction of Treatment
Resistance in Psychiatric Disorders
Je-Yeon Yun and Seung-Hwan Lee
prediction of treatment response and focus on the controls. This difference was seen even
recent trends in machine learning-based studies 14 months after the completion of cognitive
in which brain-based biomarkers are applied as behavioral therapy [13].
explanatory or predictive features.
4.1.1.2 Mood Disorders
Depression is associated with diverse structural
4.1.1 Treatment-Related Changes and functional changes in brain circuits related to
in Brain MRI Measurements emotion processing and mood regulation; some
(State Markers) (but not all) of these circuitry changes occur in
response to pharmacological/nonpharmacologi-
4.1.1.1 Psychotic Disorders cal treatments for depression [14]. At the neu-
Treatment with antipsychotics for patients diag- rotransmitter level, greater elevation (or smaller
nosed with schizophrenia could be associated reduction) of gamma-aminobutyric acid levels in
with a decreased volume of the parietal lobe and the pregenual anterior cingulate cortex from
an increased volume of the basal ganglia [9], as baseline to after 3−7 days of citalopram treat-
well as reduction of the brain Glx (combined ment, measured using proton magnetic resonance
glutamate and glutamine signaling), measured spectroscopy ( H-MRS), could predict treatment
1
using proton magnetic resonance spectroscopy response after 6 weeks of citalopram pharmaco-
(1H-MRS) in the fronto-thalamo-temporal brain therapy [15]. In relation to task performance,
regions [10]. After pharmacotherapy with olan- treatment with antidepressants reduces functional
zapine, the long-range functional connectivity brain activation in response to a painful electrical
strength of the default mode network and senso- stimulation task in the medial thalamic nuclei of
rimotor network were restored (from reduced to the pulvinar in patients diagnosed with depres-
increased strength); on the other hand, sion. Moreover, the strength of the functional
pharmacotherapy-related reduction of the short- activation at the perigenual anterior cingulate
range functional connectivity strength in the cortex after pharmacotherapy correlated with the
right inferior parietal lobule (initially elevated degree of symptomatic improvement [16]
prior to pharmacotherapy) and left superior tem- (Fig. 4.1). Moreover, pharmacotherapy with ami-
poral gyrus appears to be associated with better sulpride [a D2/D3 receptor antagonist] for patients
and worse treatment outcome, respectively [11]. diagnosed with depression increases the func-
In addition, 16 weeks of pharmacotherapy with tional activation of striatum, as well as the func-
ziprasidone in patients diagnosed with schizo- tional connectivity between the nucleus
phrenia has been associated with increased accumbens and midcingulate cortex in response
functional activation of brain regions, including to monetary rewards during the monetary incen-
the anterior cingulate and ventrolateral prefron- tive delay task [17]. In terms of cognitive behav-
tal cortices (related to cognitive control) during ioral therapy for depression, longitudinal
the performance of a task involving selecting enhancement of the downregulated blood oxy-
stimuli based on their emotional valence [12]. genation level-dependent (BOLD) signal in the
On the other hand, cognitive behavioral therapy subgenual anterior cingulate−medial prefrontal−
(16−20 biweekly sessions) for patients diag- lingual cortices for tasks that require a voluntary
nosed with schizophrenia, who suffer from per- emotional regulation strategy while recalling
sistent auditory hallucinations, resulted in negative autobiographical memories was related
reduced functional brain activation in the bilat- to a better treatment response [18]. Likewise,
eral amygdalae and left superior temporal and treatment response for 5-Hz repetitive transcra-
right superior frontal cortices in response to an nial magnetic stimulation (rTMS) to the left dor-
emotional auditory paradigm, as compared to solateral prefrontal cortex in patients diagnosed
non-treated schizophrenia patients and healthy with major depressive disorder or posttraumatic
4 Brain Biomarkers of Treatment Resistance for Psychiatric Disorders 67
total sample 3
a
rmANOVA-F-test (no pain)
2
0
F
-1
0 -2
X = -14 z=4
b pretreatment posttreatment
posttreatment 15
unsure no pain > no pain
10
5
R = -0.73*
-5
0
-10
z=5 x=2
aMD 0.0 0.5 1.0 1.5 2.0
Dynamic HAM-D-Reduction
Fig. 4.1 (a) Reversal of thalamic hyperactivity after anti- and. fMRI-1. (b) Dynamic response to antidepressant
depressant treatment. Repeated measures analysis of vari- treatment: a significant negative correlation (p < 0.001,
ance (rmANOVA) comparisons between fMRI-1 and FWE, cluster-level) between dynamic HAM-D24 reduc-
fMRI-2 within healthy controls (HC), remitted depressed tion and perigenual cingulate and medial prefrontal acti-
patients (rMD), and acute depressed patients (aMD). vation was found at fMRI-2. Non-remitter (= HAM-D24
Acute patients were treated with escitalopram or venla- >8) exhibited higher activation after treatment. Activations
faxine for 12 weeks. (a) F-test results depict elevated acti- represent t-tests between remitter and non-remitter at
vation of thalamic pulvinar nuclei in acute patients, which fMRI-2. (a and b are referenced from Figure 4.2a and
reversed to baseline values of HC after treatment. Figure 4.3c and d of original article by [16] http://creative-
Activations represent difference in F-test between fMRI-2 commons.org/licenses/by-nc-sa/4.0/)
stress disorder was related to the degree of reduc- ral pole during the emotional face perception
tion in the resting-state functional connectivity tasks in patients diagnosed with social anxiety
strength between the subgenual anterior cingu- disorder or panic disorder was increased [20]. In
late and the default mode network, left dorsolat- addition, the long-term effect of cognitive behav-
eral prefrontal cortex, and insula [19]. ioral therapy in social anxiety disorder is associ-
ated with a reduced amygdalar volume at 1 year
4.1.1.3 Anxiety Disorders after the treatment in responders, as compared to
After pharmacotherapy with the serotonin-related nonresponders [21]. On the other hand, treatment
antidepressant paroxetine, the strength of the response to 10-Hz rTMS at the dorsomedial pre-
condition-dependent functional connectivity frontal cortex in treatment-resistant patients diag-
between the left hippocampus and the left tempo- nosed with obsessive−compulsive disorder was
68 J.-Y. Yun and S.-H. Lee
proportional to the reduction of resting-state derived from the source localization of oddball
functional connectivity between the dorsomedial auditory evoked potential), which spatially
prefrontal cortex and the ventral striatum (which overlap with the default mode network, changed
was initially elevated prior to the rTMS treat- after pharmacotherapy [27].
ment) [22]. In fact, regardless of the treatment
modality, posttreatment improvement of 4.1.2.2 Mood Disorders
obsessive−compulsive symptoms is accompa- Treatment-related changes in the EEG profile
nied by decreased functional activation of the could be used to predict treatment nonre-
ventral circuits of the cortico-striato-thalamo- sponders. When depressive patients who have
cortical loop during symptom provocation, as been prescribed antidepressants for 2 weeks
well as increased functional recruitment of the show hemispheric asymmetries of reduced
dorsal circuit during performance of cognitive absolute beta power and increased delta power
processing tasks [23]. in the left hemisphere relative to the right
hemisphere, they tend to show less sufficient
symptomatic improvement after 8 weeks of
4.1.2 Treatment-Related Changes pharmacotherapy with antidepressants [28].
in EEG Measurements (State From the perspective of resting- state func-
Markers) tional connectivity, the significantly decreased
alpha connectivity among the dorsolateral pre-
4.1.2.1 Psychotic Disorders frontal, dorsomedial prefrontal, and subgenual
Electroencephalography (EEG) is a noninva- anterior cingulate cortices after antidepressant
sive, inexpensive, and useful tool for investigat- pharmacotherapy—observed in male treatment
ing the neurobiology of schizophrenia and for responders—was not detected in nonre-
biotyping [24]. When patterns of the cortical sponders [29]. On the other hand, treatment
oscillatory activity in schizophrenia patients with bilateral or unilateral rTMS in the left
were explored using the auditory steady-state (10 Hz) and right (1 Hz) dorsolateral prefrontal
response, restoration of the reduced amplitude cortices resulted in a significant reduction in
and intertrial phase coherence of response in alpha, beta, and gamma frequencies in the
the lower gamma (30−50 Hz) range seen in medial-superior frontal-cingulate cortices only
non-medicated schizophrenia was found in in responders [30]. Of note, in patients diag-
patients prescribed with atypical antipsychot- nosed with depressive disorder who experi-
ics; these findings were comparable to those enced suicidal ideation, a reduction in the
observed in healthy controls [25]. Moreover, in suicidal ideation after magnetic seizure therapy
first-episode psychosis patients prior to phar- (MST) was strongly correlated with two base-
macotherapy, the effective connectivity from line measures of cortical inhibition, including
the right middle frontal gyrus to the left supe- the N100 amplitude for frontal electrodes
rior temporal gyrus during the eyes-open rest- (maximum at FC4; R = −0.64; P < 0.001) and
ing state was decreased as compared to healthy with long-interval cortical inhibition (LICI)
controls. In contrast, first-
episode psychosis values for frontal electrodes (maximum at
patients on pharmacotherapy showed improved FC6; R = 0.58; P = 0.002) [31].
effective connectivity strength between these
regions, comparable to that observed in healthy 4.1.2.3 Anxiety Disorders
controls [26]. For patients diagnosed with After cognitive behavioral therapy, patients
schizophrenia who showed a treatment response diagnosed with social anxiety disorder (SAD),
to pharmacotherapy with clozapine, a set of who tend to exhibit hypervigilance toward facial
cross-power spectral density (CPSD) features cues and show enhanced early facial processing
(comprised of a combination of brain regional as compared to healthy controls, demonstrated
source activity and connectivity measures reduced hypervigilance for facial stimuli as
4 Brain Biomarkers of Treatment Resistance for Psychiatric Disorders 69
score) at 8 weeks for antidepressant pharmaco- definition of the underlying neurobiology, since
therapy [28]. In addition, using a logistic regres- different biological origins of the same disorder
sion classifier, features of resting-state functional may require different treatments [62]. In contrast
brain activities at the frontal and temporal to the conventional brain MRI studies that
regions, constructed by way of wavelet trans- showed group-level differences, a machine-
form analysis-based time−frequency decompo- learning approach allows individual-level classi-
sition, could classify nonresponders from fications from the perspective of diagnosis and
responders to serotonin selective reuptake inhib- treatment response [63]. Application of machine-
itor (SSRI) pharmacotherapy with an 87.5% learning techniques to neuroimaging might
accuracy [57]. From the perspective of brain sig- uncover more robust and reliable biomarkers of
nal variability, a propensity toward global brain psychiatric disorders, currently under the
processing, as reflected in the reduced local mul- syndrome-based diagnostic criteria, that could be
tiscale entropy at fronto-central regions, in addi- used at an individual level [64].
tion to increased global multiscale entropy, could
indicate a sufficient treatment response to 4.1.5.1 Psychotic Disorders
12-weeks’ antidepressant pharmacotherapy [58]. Response to treatment for reducing the negative
On the other hand, patients diagnosed with symptoms of schizophrenia using 10-Hz rTMS
depression who showed lower levels of fronto- applied to the left dorsolateral prefrontal cortex
midline theta (4−8 Hz) power and theta connec- could be successfully predicted by way of neu-
tivity during a working memory task did not roanatomical pattern recognition for gray matter
show sufficient relief from depressive symptoms density reductions in the prefrontal, insular,
after 5−8 weeks of rTMS treatment [59]. medio-temporal, and cerebellar cortices and
Furthermore, weaker coupling between a faster increments in parietal and thalamic regions [65]
reaction time and a smaller late positive potential (Fig. 4.2). To predict the treatment response to
(LPP; an index of enhanced attention toward pharmacotherapy with antipsychotics only or a
aversive stimuli) at the preceding trial, revealed combination of electroconvulsive therapy and
in single-trial level analyses, could predict a pharmacotherapy, the similarity score calcu-
poor treatment response to cognitive behavioral lated from the schizophrenia vs. healthy con-
therapy for depressive symptoms [60]. trols classifier based on the selected feature of
the resting- state functional connectivity net-
4.1.4.3 Anxiety Disorders work, including the default mode network, the
For patients diagnosed with obsessive−compul- temporal lobe network, the language network,
sive disorder, a reduced amount of time spent at the cortico-striatal network, and the cerebellum
the highest level of CNS arousal, assessed using network, was used. As the similarity score
the Vigilance Algorithm Leipzig (VIGILL) dur- derived from the resting-state functional con-
ing the resting state, could be an indicator of a nectivity network at baseline is higher, a better
better treatment response to SSRIs, cognitive treatment response was found for schizophrenia
behavioral therapy, or both [61]. patients [66]. Furthermore, treatment response
to pharmacotherapy with amisulpride in allevi-
ating the negative symptoms of schizophrenia
4.1.5 Machine Learning differed according to patient subgroups (identi-
and Prediction of Treatment fied by means of probabilistic principal compo-
Response or Resistance nent analysis), biotyped using the
electrophysiological features of pre-pulse inhi-
As psychiatric diseases are extremely heteroge- bition (PPI), mismatch negativity (MMN), and
neous, both in clinical manifestation and etiol- P50 suppression (in addition to clinical and neu-
ogy, their treatment requires a more precise rocognitive variables) [67].
72 J.-Y. Yun and S.-H. Lee
-3 -6 -9
GMD CV-Ratio [NON-RESP < RESP]
GMD CV-Ratio [NON-RESP > RESP]
3 6 9
4.1.5.2 Mood Disorders more intact white matter tract integrity of the
Prediction of TRD per individual using brain anterior salience network and better preserved
T1-weighted imaging, at least as quantified by resting-state functional connectivity strength for
the Massachusetts General Hospital (MGH-S) the dorsal default mode network showed less
clinical staging, was not successful [64]. On the improvement of depressive symptoms in response
other hand, as classified using the alternating to pharmacotherapy with antidepressants [68].
decision-tree framework, among the patients Additionally, using the support vector regression
diagnosed with late-life depression, patients with model, the pretreatment volume of the subgenual
4 Brain Biomarkers of Treatment Resistance for Psychiatric Disorders 73
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Developing Therapies
for Treatment-Resistant 5
Depressive Disorder in Animal
Models
Michel Bourin
about the use of behavioral methods. There are at which enables an individual to master the rela-
least four reasons for advocating the use of tionship he establishes with its environment and
behavioral tests rather than biochemical tests. then to analyze the situation facing the individ-
First, behavioral methods are not invasive and ual, the way he sees and the interpreter and the
destructive. Second, the behavioral test is a guar- way he strives to control through the implemen-
antee that the agents tested actually act on the tation of an appropriate behavioral strategy.
brain. Third, behavioral measures are functional This approach presents an additional advantage
measures. Indeed, many biochemical indices are that focuses on processes and mechanisms that
not reliable indices of functional changes. Fourth, are less closely related to a given species. The
behavior integrates brain activity and takes into research then provides data with validity more
account any changes occurring beyond the mea- general and likely to be extrapolated, with all
surement point. So a behavioral test is less accu- the caution which applies to the analysis of the
rate to appreciate a change in functioning of the biological foundations of human behavior. The
brain than a biochemical test, but however it muricide model is among the oldest models of
gives a clearer indication of its functional signifi- depression. With this model the ability of anti-
cance. But in this case, he must demonstrate that depressant drugs to prevent the lethal activity of
the behavior taken into account is actually sensi- rats on the mouse is tested. It has been widely
tive to changes in the underlying physiological used, although it proved inefficient for detecting
variable (see using the behavior difficulties). antidepressant activity and it poses ethical prob-
Measurements taken at the behavioral level are lems [6]. This clearly isn’t a good model because
often carried out at the level of an ordinal scale it is difficult to find a resemblance between this
(storage by rank); plus such measures cannot be model and the depression: men do not kill mice,
processed validly only by nonparametric and it is difficult to see any connection between
statistics. killing a mouse and depression. This could be a
Consider a model of experimental analysis of test of screening (screening test) for antidepres-
brain mechanisms underlying the initiation of sant drugs. But that would amount to implicitly
aggressive driving [5], the muricide test: some consider the screening test is a type of animal
rats put in the presence of mouse kill them while model of depression. This conceptual confusion
other rats will kill them. At that time, the rela- may lead us to extrapolate the results to this test
tionship between behavior and brain was appre- outside its field of application and to produce
hended in terms of nervous substrates underlying spurious assertions. It is therefore clear that
closely specifically a category of behavior, the must be examined with care, in each case, the
behavior of aggression, for example, considered field for which the use of a particular model is
a natural entity. However, some experimental justified.
manipulations do not have the same effect, Models are tools whose validity must be
depending on whether they are applied to a estimated. This evaluation is more a matter of
“naive rat,” which is confronted for the first time judgment than of measurement. However, this
with the intrusion of a mouse in his cage, a judgment can be based on three categories of
“non-killer” rat confirmed who is familiar with elements: predictive validity, validity, and
the presence of a mouse in his environment, or construction validity [7]. Animal models are
even a “killer” rat which has a long experience open to criticism, but this critique may be an
of the behavior of interspecific aggression and encouragement to clinicians to apply the same
its consequences. Indeed, the mouse has not the rigor to the analysis of human behavioral dis-
same meaning for all three to type of rats. The orders [8].
fact that a same behavioral strategy be imple- One must keep in mind the following reflec-
mented does not imply that game mechanisms tion: technique, method, experience, and theory
are identical. We therefore consider that the are indissolubly linked; the great danger is that a
behavior is a means of expression and action strict method provides by itself numerous and
5 Developing Therapies for Treatment-Resistant Depressive Disorder in Animal Models 81
precise quantitative results. Considering con- These models may be interesting to develop in
struct animal models of depression, one must order to obtain one or more models of resistant
consider the biological hypothesis of depression depression.
where one or more genetic factors predisposing The most used models today are behavioral
to the disease exist. models:
Finally, there are new pathways such as neuro-
endocrinology (regulation of the hypothalamo- • The muricide model has been described above.
hypophysis axis) and biorhythms (sleep, • The forced swimming test: the immobility
temperature). Neurochemical theories explore observed after 2 min of swimming is antago-
the biochemical imbalance induced or preexist- nized by the antidepressants in doses which
ing to the disease, which is on the dosage of neu- often decrease the motor activity in a free situ-
rotransmitters in the blood, urine, and CSF of ation [15].
depressed and/or suicidal depressed patients, as • Tail suspension test: The behavioral desperate
well as the measurement of neurotransmitters in test is a rapid method of evaluating the psy-
blood, urine, and CSF before and after adminis- chotropic effects of antidepressants on the
tration of antidepressants (patients and experi- behavior of a rodent trying to escape an
mental animals). uncomfortable situation. It is a simple and fast
test (6 min maximum per cycle), causing no
pain in the animal. The principle is based on
5.3 Classical Models the measure of the force deployed during the
of Depression movements and the duration of these move-
ments [16].
Before considering strategies for developing • Chronic mild stress: The protocol for unpre-
therapies for treatment-resistant depressive dis- dictable chronic mild stress takes place over
order in animal models, it should be remem- 6 weeks during which animals are subjected to
bered which are the animal models of depression a succession of stressful events that take place
that exist [9]. Some of them may be better so unpredictable, with two to three events per
suited than others for therapies of resistant day. The disturbances applied are of a low
depression. intensity and without food or dipsic depriva-
The earliest animal models of depression are tion, the interest of the protocol being the rep-
models of pharmacological interactions: etition of weak events, in an unpredictable
way [17].
• Reserpine: measurement of antagonism of • Olfactory bulbectomy in rats is described as a
hypothermia and ptosis and measurement of procedure aiming to reproduce anhedonia, a
antagonism of reduction of locomotor activity cardinal symptom of depression. It causes
by potential antidepressants in mice [10]. various biochemical, cellular, and behavioral
• Oxotremorine: measures the antagonism of changes similar to those of the depressive state
hypothermia, akinesia, and tremor with poten- that can be reversed by chronic antidepressant
tial antidepressants in mice [11]. treatment [18].
• Apomorphine at high dose: hypothermia
induced by 16 mg/kg is antagonized by anti-
depressants, whereas at 1 mg/kg it is antago- 5.4 Are There Models
nized by neuroleptics [12]. of Resistant Depression?
• Amphetamine: potentiation of the effects of
amphetamine in the presence of antidepres- A model of resistant depression suggests that
sants [13]. classic depression models have been modified for
• Yohimbine: potentiation of the induced mor- this purpose. These simulations of normal human
tality of yohimbine by antidepressants [14]. behavior are rare in the face of simulations of
82 M. Bourin
abnormal behavior. An animal model of abnor- and reduced telomerase activity compared to
mal behavior tries to reproduce a symptom of a Flinders resistance line controls. Lithium treat-
disorder, a group of symptoms and even a syn- ment normalized TERT expression and telomer-
drome. The construction of such a model may ase activity in the Flinders sensitive line and
include various manipulations including brain upregulated β-catenin. This is the first report
injury, selective breeding, selection of particular showing dysregulation of telomeres in the hippo-
individuals, and the application of a variety of campus of a well-defined pattern of depression
factors that are assumed to be involved in etiol- and the restorative effects of lithium treatment. If
ogy of the disorder considered such as social iso- replicated in other models of mood disorders, the
lation and aging. These manipulations lead to the results will help to understand both the telomere
achievement of a behavioral state that is used as a function and the mechanism of action of lithium
tool to study the different aspects of the modeled in the hippocampus in depressed patients. It must
disorder: its etiology, its treatment, its physiolog- be a path to discover new drugs active in resistant
ical bases, and the physiological mechanisms depression.
underlying an effective treatment. A given model
may be suitable for the study of all or only some
of them. 5.4.2 A
nother Potential Model
to Discover Antidepressants
Active in Resistant Depression
5.4.1 R
esearchers Have Proposed Is Based on Genetic
Models Likely to Develop
Drugs That Can Treat Resistant A model was developed by a directed reproduc-
Depression, for Example, tion of mice with remarkably different responses
Using Telomeres in the tail suspension test, a stress paradigm used
to screen for potential antidepressants [22]. Thus,
Telomeres are protective DNA-protein com- the “resigned” mice are essentially immobile in
plexes at the ends of each chromosome, main- the tail suspension test, as well as in the Porsolt
tained primarily by the enzyme telomerase. The forced swimming test; they have a reduced con-
shortening of blood leukocyte telomeres is asso- sumption of a sucrose solution (2%) palatable
ciated with aging, several chronic diseases, and [23]. In addition, “resigned” mice exhibit sleep-
stress, for example, major depression [19]. The wake cycle changes. Compared to “non-resigned”
hippocampus is essential in the regulation of cog- mice, they have higher basal serum corticoste-
nition and mood and in the main brain region of rone levels and a lower serotonin turnover rate in
telomerase activity. It was unknown that there the hippocampus. Remarkably, stimulation of the
was telomere dysfunction in the hippocampus of serotonergic 5-HT1A autoreceptor induces
depressed subjects. Lithium, used in the treat- greater hypothermia and stronger inhibition of
ment and prevention of relapse of mood disor- electrical activity of the dorsal raphe nucleus
ders, has been shown to protect against shortening serotonergic neuron in “resigned” mice than in
of leukocyte telomeres in humans, but the mecha- “non-resigned.” Thus, “resigned” mice show a
nism has not been elucidated [20]. To answer the decrease in serotoninergic tone, which evokes
questions, if the telomeres are shortened and if that associated with human endogenous depres-
the telomerase activity has changed in the hippo- sion. Finally, both behavioral alterations and
campus and if lithium could reverse the process, serotonergic dysfunction can be improved by
it used a genetic model of depression, the Flinders chronic administration of the antidepressant
sensitive line rat, and treated animals with lith- fluoxetine. The line of “depressive mice” may
ium. The naive Flinders sensitive line has shorter provide an opportunity to approach the genes
telomere length, restricted TERT expression [21], influencing susceptibility to depression and to
reduced brain-derived neurotrophic factor levels, search for the neurophysiological and
5 Developing Therapies for Treatment-Resistant Depressive Disorder in Animal Models 83
n eurochemical substrates underlying antidepres- under basal conditions and after cocaine condi-
sant effects. tioning. To date, this genetic model has not been
For this, the authors used a genetic model of used in the development of treatments for resis-
depression in mice, the model of H/Rouen mice. tant depression, but it is a path that seems
These mice were selected, by directed reproduc- interesting.
tion, based on their immobility behavior in the
tail suspension test, much longer than in non-
resected (NH/Rouen) or control mice (I/Rouen) 5.4.3 Another Approach
having an intermediate phenotype. H/Rouen to the Treatment of Resistant
mice also have many features reflecting a Depression Is
depressive phenotype [24]. The phenotypic Co-administration of Drugs
characterization of these three mouse lines was
continued, and it was shown that the H/Rouen The biological hypothesis of depression is gener-
mice also exhibited more pronounced anxiety ally based on the insufficiency of one or more
behavior than the other two lines in a battery of monoamines. Historically, it has been attributed
standard behavioral tests. This observation led to a noradrenaline deficiency and then to a cere-
to the search for the neural mechanisms involved bral serotonin deficiency. Animal models of
in the increased vulnerability to cocaine depression also suggest a dopamine involvement
observed in female H/Rouen mice. The neuro- in pathophysiology of depression [25]. So in
anatomical study, based on the expression of the order to answer the question of the treatment of
Fos protein during the CPP test, showed stron- resistant depression, it is useful to study models
ger activation of the cingulate part of the pre- of depression if the combination of antidepres-
frontal cortex, the accumbens shell core, the sants with more or less marked dopaminergic
basolateral amygdala, and the ventral subiculum activity could have potentiating effects. Thus in
in H/Rouen female mice compared to NH/ and my laboratory, we obtained convincing results by
I/Rouen mice, which might reflect their higher increasing the effect/size of SSRS by associating
propensity to drug- conditioned research. The them with each other or especially with products
influence of this mixed phenotype of anxiety with dopaminergic components. The most impor-
and depression was studied on cocaine vulnera- tant results were obtained by co-administration
bility. We have shown that H/I and Rouen mice of bupropion with SSRIs and SNRIs in forced
are less sensitive to the acute psychomotor swimming test in mice, predictive of efficacy in
effects of cocaine than NH/Rouen mice; how- resistant depression [26]. Another very produc-
ever, all mouse lines express a similar cocaine tive work points out the augmentation of aripip-
behavioral sensitization, indicating that the neu- razole with antidepressants on forced swimming
roadaptative changes that develop during test [27].
repeated cocaine injections blur initial differ- It has been proven that SSRIs become ineffec-
ences in reactivity. tive in the FST after the animals’ brains have
On the other hand, H/Rouen female mice been depleted in dopamine by 6-OHDA [28]. It is
exhibit a robust, durable, and higher cocaine- as well another path using various strains of mice,
induced conditioned place preference (CPP) to understand which are the “resistant” strains
than in NH/ and I/Rouen mice, indicating according to the studied antidepressants [29].
greater sensitivity to background clues associ- Considering the role of dopamine in treating
ated with effects of this drug. Finally, as the resistant depression, this kind of “dopamine
BDNF (brain-derived neurotrophic factor) pres- depression” could be of interest to develop new
ent at the nucleus accumbens could be involved drugs. Repeated administration of reserpine
in both depression and drug vulnerability, the which induced in animal a more complete deple-
study of its expression was evaluated by the tion could be an interesting model of resistant
Western blot technique in the three mouse lines, depression [30].
84 M. Bourin
5.5 The Way of Ketamine repeated infusion. Beyond this duration, the data
and Glutamatergic do not show any significant residual effect of
Compounds intravenous initial treatment. This work also
revealed that the effect varied little according to
The literature reports relationships at different whether the treatment was administered once or
levels between glutamate and depressions. in several injections. But both researchers
Imaging data found an increase in glutamatergic pointed out that the number of these multiple
activity in patients with EDM in the occipital cor- injections was still too small to conclude, calling
tex, while anterior cortex activity was decreased. for additional studies to confirm this point.
Postmortem findings suggest the following: glu- Despite this short-term efficacy, the meta-analy-
tamate in the frontal cortex and decreased gluta- sis revealed a great variability of effect depend-
mate receptors 2 and 3 in patients with major ing on patient profile, ranging from 40% efficacy
depressive episodes and a decrease in the expres- on symptoms in some studies up to 70% in oth-
sion of glutamatergic receptor transcripts in the ers. While these results seem rather conclusive in
hippocampus of bipolar patients. Genetic data terms of efficacy, the authors acknowledged that
highlight the decreased expression of SAP102, another main conclusion of their work was the
NR1, and glutamate synthetase in EDM patients. lack of data on the safety of ketamine in depres-
In bipolar patients, polymorphisms of genes sive patients.
encoding GRIN1, GRIN2A, and GRIN2B [31] Very recent work shows the interest of the
are found to be associated with a higher preva- association of glutamatergic modulators such
lence of suicidal ideation. as riluzole [35] or memantine [36] in the treat-
One of the most successful research pathways ment of the resistant depression. However, it
is that of ketamine, an NMDA receptor antago- remains to refine the concept to make it
nist currently used as anesthetic, analgesic, and generalizable.
recreational compound. Recent work has shown
that an infusion of this N-methyl-D-aspartate Conclusion
(NMDA) antagonist triggers an antidepressant Considerable progress has been made in the
action within a few hours, whereas oral antide- development of treatments for resistant
pressants have a much longer onset of action depression. There are proposals of rodent
[32]. Other studies, in small groups of patients, models of treatment-resistant depression [37],
have shown that repeated infusions of ketamine or other biological paradigms [38]. The author
in cases of depression resistant to usual treat- believes, however, that the major problem is to
ments may also be effective in the short-term, or distinguish more pertinently unipolar resistant
even in the medium term in some patients, study depression from bipolar depression. Most
conducted without comparison control group developers in the pharmaceutical industry are
[33]. In a meta-analysis [34], the researchers not psychiatrists, and their concept of resistant
reviewed 21 baseline studies to determine if ket- depression is imprecise. The future in the
amine actually had an immediate antidepressant development of such treatments is to revisit
effect, if this effect was prolonged over time existing behavioral tests such as forced swim-
despite the short half-life of the molecule (3 h), ming test [39] with or without prior depletion
and if repeated injections could be more effec- [40]. Another avenue of investigation is to
tive than a single injection. After analysis of compare changes in brain neurotransmitters in
these trials, which totaled 437 patients with two behavioral tests and to study how new
major depressive episodes, with or without bipo- treatments can restore or amplify them [41].
lar disorder (with 8–47 subjects each), the Finally opening the potassium channels facili-
authors confirmed that ketamine significantly tates the action of antidepressants [42, 43];
reduced depressive symptoms during assess- this could be a new avenue of research in the
ments from 4 h to 14 days after a single or treatment of resistant depression [44].
5 Developing Therapies for Treatment-Resistant Depressive Disorder in Animal Models 85
treatment-resistant major depression. Biol Psychiatry. meta-analysis of the effects of prototypic antidepres-
2013;74:250–6. sants. Neurosci Biobehav Rev. 2018;84:1–11.
34. Coyle CM, Laws KR. The use of ketamine as an anti- 40. Dailly E, Chenu F, Renard CE, Bourin M. Dopamine,
depressant: a systematic review and meta-analysis. depression and antidepressants. Fundam Clin
Hum Psychopharmacol. 2015;30:152–63. Pharmacol. 2004;18:601–17.
35. Mathew SJ, Gueorguieva R, Brandt C, Fava M,
41. Renard CE, Dailly E, David DJ, Hascoet M,
Sanacora G. A randomized, double-blind, placebo- Bourin M. Monoamine metabolism changes fol-
controlled, sequential parallel comparison design trial lowing the mouse forced swimming test but not
of adjunctive riluzole for treatment-resistant major the tail suspension test. Fundam Clin Pharmacol.
depressive disorder. Neuropsychopharmacology. 2003;17:449–55.
2017;42:2567–74. 42. Redrobe JP, Pinot P, Bourin M. The effect of the
36. Amidfar M, Réus GZ, Quevedo J, Kim YK, Arbabi potassium channel activator, cromakalim, on antide-
M. Effect of co-administration of memantine and ser- pressant drugs in the forced swimming test in mice.
traline on the antidepressant-like activity and brain- Fundam Clin Pharmacol. 1996;10:524–8.
derived neurotrophic factor (BDNF) levels in the rat 43. Guo W, Todd K, Bourin M, Hascoet M, Kouadio
brain. Brain Res Bull. 2017;128:29–33. F. Additive effects of glyburide and antidepressants
37. Caldarone BJ, Zachariou V, King SL. Rodent models in the forced swimming test: evidence for the involve-
of treatment-resistant depression. Eur J Pharmacol. ment of potassium channel blockade. Pharmacol
2015;753:51–65. Biochem Behav. 1996;54:725–30.
38. Samuels BA, Leonardo ED, Gadient R, Williams A, 44. Heurteaux C, Lucas G, Guy N, El Yacoubi M,
Zhou J, David DJ, et al. Modeling treatment-resistant Thümmler S, Peng XD, et al. Deletion of the back-
depression. Neuropharmacology. 2011;61:408–13. ground potassium channel TREK-1 results in a
39. Kara NZ, Stukalin Y. Einat revisiting the validity of depression-resistant phenotype. Nat Neurosci.
the mouse forced swim test: systematic review and 2006;9:1134–41.
Integrated Approaches
for Treatment-Resistant Psychiatric 6
Disorders
Seon-Cheol Park and Yong-Ku Kim
suicide, and early onset, for bipolar disorder; resistance to antidepressant treatment [15–17].
severe symptoms and frequent recurrence, for ECT combined with venlafaxine has been shown
depressive disorder; and severe symptoms and to be effective for treatment-resistant depressive
comorbidity, for post-traumatic stress disorder. patients, and the combination of repetitive tran-
Thus, understanding the influence of gene-child- scranial magnetic stimulation (rTMS) with anti-
hood trauma interactions on the clinical manifes- depressant therapy has also been effective in
tations of treatment-resistant psychiatric treating patients with resistant bipolar depression
disorders can lead to improvements in therapeu- [18, 19]. Behavioral surgery has also been pro-
tic strategies [7, 8]. posed as an option for managing treatment-
In addition, environmental factors can con- resistant psychiatric disorders. For example, deep
tribute to antidepressant effects in depressive brain stimulation (DBS) may normalize
and anxiety disorders, given that placebo decreased cerebral blood flow (CBF) in the pre-
response may account for 75–82% of the effi- frontal, premotor, dorsal anterior cingulate gyrus,
cacy attributed to antidepressants in clinical tri- and anterior insula and increased cerebral blood
als [9, 10]. Strong responses to antidepressants flow in the subgenual cingulate gyrus, in patients
and high remission rates have been shown to cor- with major depressive disorder [20, 21].
relate with high socioeconomic status [11, 12]. Decreased volume and increased gray matter
Hence, interactions between the efficacy of anti- density of corticostriatal-thalamic circuits and
depressants and environmental factors are increased baseline activity of orbitofrontal cor-
thought to be an important variable in integrated tex, cingulate gyrus, and striatum have been iden-
therapeutic approaches for treatment-resistant tified as potential neurobiological correlates of
psychiatric disorder. In addition, “plasticity-aug- obsessive-compulsive disorder [22, 23]. Given
mented psychotherapy” for treatment-resistant these research findings, one might speculate that
depressive and anxiety disorders has been pro- brain stimulation techniques combined with
posed, in terms of the reconsolidation-updating pharmacotherapy may be a promising treatment
paradigm and epigenetic modification. Evidence option for treatment-resistant psychiatric
for the superiority of pharmacotherapy com- disorders.
bined with psychotherapy, relative to pharmaco- Integrated approaches to manage treatment-
therapy alone, has been supported by neural resistant psychiatric disorders are consistent with
plasticity data [13]. Thus, the corrective emo- neuroplasticity hypotheses, including gene-
tional experiences which are derived from psy- environment interactions and epigenetic mecha-
chodynamic psychotherapy can be supported by nisms. In terms of medication-only options,
increased neuroplasticity with neurotransmitter switching therapies, combination therapies, and
regulators and epigenetic modifiers. For this rea- augmentation strategies can be used to manage
son, integrative therapeutic strategies for depres- treatment-resistant psychiatric disorders [24, 25].
sive and anxiety disorders have been recently Furthermore, more comprehensive and integrated
proposed in the context of plasticity-augmented approaches for pharmacological and non-
psychotherapy [13]. pharmacological treatment options may be
Moreover, a recent clinical study concluded required to manage treatment-resistant psychiat-
that, with respect to inflammatory cytokines, ric disorders. With respect to such integrated
depressed patients treated with combined ECT approaches, psychotherapeutic approaches, brain
and pharmacotherapy show a decrease in inter- stimulation techniques, and other non-
leukin- 6 (IL-6) expression and an increase in pharmacological treatment options may be com-
tumor necrosis factor-α (TNF-α) expression, bined with pharmacotherapy to better treat
when compared to those treated with pharmaco- treatment-resistant psychiatric disorders [4, 26,
logical therapy alone [14]. Plasma IL-6 and 27]. In this chapter, integrated approaches for
TNF-α have been consistently associated with treatment-resistant psychiatric disorders are sum-
the severity of depressive disorders and also with marized and discussed.
6 Integrated Approaches for Treatment-Resistant Psychiatric Disorders 89
6.2 Treatment Resistance high level of childhood trauma have lower cog-
and Interaction Between nitive function than those patients lacking child-
Gene and Childhood Trauma hood trauma and those with the L/L version of
5-HTTLPR [33]. Moreover, psychotic patients
Evidence suggests that a synergistic interaction with a history of childhood sexual abuse who
between certain genes and childhood trauma can also carry the BDNF methionine (met) allele
increase the risk of poor outcomes for many psy- have been characterized by decreased working
chiatric disorders. As genetic susceptibility can memory, executive function and general cogni-
impact neurobiological responses to childhood tion, enlarged lateral ventricles, and decreased
trauma, thresholds for pathological responses hippocampal volume compared with patients
associated with severe clinical presentations of who are homozygous for the valine (val/val)
psychiatric disorders may be reduced. Given allele [34]. In summary, interactions between
such findings, childhood trauma and its interac- specific gene polymorphisms and a history of
tion with specific genes have been thought to be childhood trauma may contribute to poor prog-
an important factor affecting treatment resistance nosis and functioning in patients with schizo-
of psychiatric disorders [7, 28, 29]. The influence phrenia [7].
of gene-childhood trauma interactions on treat-
ment resistance is described below, with respect
to several different psychiatric disorders. 6.2.2 Bipolar Disorder
6.2.3 Depressive Disorder gene and childhood trauma that can contribute to
a greater vulnerability to PTSD in adulthood.
It has been reported that more influential effects More specifically, a “dose-dependent” genetic
on the relationship between childhood sexual effect has been described, protecting against the
abuse and adult depressive symptoms occur in severity of adult PTSD (in combination with
depressed patients who are carriers of the S-allele childhood trauma) that arises from an additive
of 5-HTTLPR, compared to those with the L/L interaction effect involving several SNPs within
genotype for 5-HTTLPR, and by depressed FKBP5 (rs9296158, rs3800373, rs1360780, and
patients who are carriers of the met allele of the rs9470080). Also, there has been a significant
BDNF val66met polymorphism rather than those association between the severity of PTSD symp-
with carry the val/val genotype, respectively toms and FKBP5 SNPs, which were associated
[40]. Another study has shown that the interac- with the total score on the Childhood Trauma
tion between C677T methylenetetrahydrofolate Questionnaire. These findings have suggested
reductase (MTHFR) variants and childhood that the greater symptom complexity of PTSD
trauma can influence the recurrence of major can be influenced by interactions between spe-
depressive disorder (MDD) and the interaction cific SNPs within the FKBP5 gene and childhood
between the T allele version of C677T polymor- abuse [45–47].
phism (rs1801133) and childhood trauma can be In addition, a study of male soldiers of
associated with an increased risk for develop- European American ancestry has shown that
ment of depressive symptoms and recurrence of interactions between the rs2400707 SNP within
MDD [41]. Moreover, an association between the adrenoceptor beta 2 (ADRB2) gene and expo-
exposure to childhood trauma and reduced ability sure to childhood adversity may be associated
to bind glucocorticoid and mineralocorticoid with the severity of PTSD symptoms. This find-
receptors can contribute to changes in the stress ing, linking rs2400707, childhood trauma, and
response in adulthood of the hypothalamic- PTSD, has also been replicated in an indepen-
pituitary-adrenal (HPA) axis which can lead to an dent, predominantly female African American
increased risk of depression [42, 43]. cohort. However, a negative result for this inter-
In terms of the interactions between gene and action has also been reported [48]. In summary,
childhood trauma, differences in the activation of these findings suggest that it is, in fact, not only
synapsin I, Erk 1/2, α-calcium-/calmodulin- adulthood trauma but also childhood trauma and
dependent protein kinase (αCaM kinase II)/syn- its interaction with ADRB2 gene variants that
taxin-1, and αCaM kinase II/NMDA-receptor may contribute to the severity of adulthood
interactions in hippocampal synaptosomes have PTSD. Thus, one might speculate that increased
been seen in rats subjected to maternal separation ADRB2 gene expression, which has been associ-
in the first 2 weeks of life. Also, some (although ated with more efficient transcription, may lead
not all) of the long-term effects of maternal separa- to negative effects of adrenergic and noradrener-
tion were reversed with escitalopram treatment. gic activation in individuals with childhood
These findings suggest that the interaction between trauma [7].
early life stress and genes encoding synaptic pro- Interactions between the pituitary adenylate
teins may influence life-long synaptic changes cyclase-activating polypeptide (PACAP) type I
which are potentially associated with reduced receptor (ADCYAP1R1) gene and childhood mal-
treatment response to antidepressants [44]. treatment have been associated with the severity
of adulthood PTSD symptoms [49]. Also, in
carriers of the C allele of the ADCYP1R1 gene,
6.2.4 Posttraumatic Stress the PTSD symptom severity can be predicted by
Disorder (PTSD) the specific gene-childhood trauma interaction
[50]. Consistent with these findings, the severity
Several studies have identified an interaction of PTSD symptoms and differential methylation
between the FK506 binding protein 5 (FKBP5) of ADCYP1R1 have been associated with levels
6 Integrated Approaches for Treatment-Resistant Psychiatric Disorders 91
of the PACAP protein in blood [51]. Moreover, EE/stress, stress/EE, and stress/stress before and
the extent of epigenetic modifications in adult- during the antidepressant treatments. Hence, the
hood PTSD patients with childhood trauma has anhedonia improved only in the antidepressant
been estimated to be 12 times higher than those treatment condition for the group with EE fol-
without childhood trauma. Hence, the differences lowing exposure to stress. In contrast, anhedonia
in epigenetic modifications associated with expo- was aggravated in the antidepressant treatment
sure to childhood trauma can lead to different condition for the group with exposure to stress
symptoms, courses, and treatment resistance in following EE. Also, there were no significant
adulthood PTSD [52]. changes in terms of the antidepressant effects for
mice exposed to continuous stress or EE para-
digms. These findings suggest that, by modulat-
6.3 Combination ing the susceptibility to the effects of
of Pharmacotherapy environmental factors, neural plasticity can be
and Psychotherapy increased by the antidepressant treatment [64].
for Treatment-Resistant In terms of the state-dependent anxiolytic
Psychiatric Disorders effects of antidepressants, consideration of fear
conditioning may be necessary. With regard to
Despite the tendency to increasingly focus on fear conditioning, extinction can be described as
pharmacotherapy for treating depressive and anx- suppressing learned fear, rather than manipulat-
iety disorders, the effectiveness of psychothera- ing the fear memory per se, which is followed by
peutic options, including cognitive behavioral several phenomena including reinstatement
therapy (CBT) and interpersonal therapy (IPT), is (exposure to the same unconditional response),
equivalent to that of antidepressant medications renewal (exposure in a shifted context), and
of these disorders [53–56]. Moreover, in terms of spontaneous recovery (passage of time). “Fear
treating depressive and/or anxiety disorders, it is erasure” refers to modification of the neural cir-
well known that the effectiveness of psychother- cuitry representing the fear memory without the
apy combined with pharmacotherapy is greater occurrence of the three phenomena above (Choi
than that of pharmacotherapy alone [4, 57–59]. and Kim 2016). A successful fear erasure associ-
Given the modest differences in the efficacies of ated with concurrent antidepressant treatment
the various antidepressant medications, the dif- during extinction training has been demonstrated
ference in the efficacy of combined pharmaco- in an animal model. Also, attenuated fear in the
therapy and psychotherapy vs. pharmacotherapy vehicle/extinction group and its degree is compa-
alone is remarkable [60]. Similarly, with respect rable to that of the antidepressant/extinction
to treating panic disorder, efficacy for the combi- group. Moreover, the vehicle/extinction group
nation of pharmacotherapy and CBT is greater exhibited the reinstatement, renewal, and sponta-
than pharmacotherapy alone [61–63]. neous recovery after the first week of extinction
training, whereas the antidepressant/extinction
group has not exhibited these phenomena.
6.3.1 Interaction Between Remarkably, in terms of the interaction between
Antidepressant Effects antidepressant and environment, the antidepres-
and Environmental Factors sant treatment without extinction training was
not associated with the attenuation of learned
As mentioned previously, environmental factors fear. In addition, the antidepressant-induced Bdnf
can influence the effect of antidepressants [13]. A induction is a critical mechanism for the phe-
preclinical investigation using the chronic mild nomena to occur based on the absence of the fear
stress model in mice supports the state-dependent erasure effect in Bdnf+/− knockout mice [65]. In
mood-elevating effects of antidepressants. The summary, the juvenile-like neuronal plasticity,
anhedonic symptoms assessed in mice randomly which represents fear erasure, can be supported
allocated to an enriched environment (EE)/EE, by fear erasure after extinction in juvenile mice
92 S.-C. Park and Y.-K. Kim
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Part II
Treatment Resistance in Specific Disorders
Treatment-Resistant Depression:
Understandings 7
on the Neurobiological Etiology
that Lead to Novel
Pharmacological Treatment
Options
the severity of TRD, with TPH2 rs1386494 A/A [12] and no difference in entorhinal cortex vol-
genotype carrier patients showing significantly ume (in males) [14], cortical thickness, or hip-
higher depression severity [6]. SLC6A2 has been pocampal volume [15] have also been reported.
associated with the treatment outcome of TRD, Such inconsistencies of the study results may be
with rs36024, an intronic single-nucleotide poly- in part due to differences in confounding factors
morphism (SNP) of SLC6A2, being associated such as medication status, early-life stress, and
with response to olanzapine-fluoxetine combina- gender.
tion treatment in patients with TRD [7]. Alterations in brain function in TRD have also
Regarding COMT, the G allele of COMT was been implicated by functional magnetic reso-
correlated to the occurrence of TRD, and homo- nance imaging (fMRI) studies. The default mode
zygous G allele carrier patients were evidenced network (DMN) has been of particular interest in
to be more sensitive to modified electroconvul- TRD, which consists of brain regions such as the
sive therapy than heterozygous G allele carriers medial prefrontal cortex, anterior/posterior cin-
[8]. However, such studies focusing on functional gulate, cuneus, and precuneus. Not only is the
variants of risk genes in TRD are considered to DMN hyperactive in patients with MDD com-
have several limitations. The majority of findings pared to healthy controls, this hyperactivity is
could not be generalized, due to factors such as even more prominent in TRD [16, 17].
ethnic variability, with the frequency of genes Furthermore, alterations in functional connectiv-
varying substantially across ethnicities. Also, the ity of specific brain regions, such as decreased
etiology of depression is complex, with multiple cerebellum–cerebellar functional connectivity
interactions of various factors underlying its eti- [17], and increased connectivity from the tempo-
ology, and the sole influence of genetic vulnera- ral gyrus to the frontal and angular gyrus, precu-
bility cannot lead to TRD. Stress has been neus, and rectus [18] have been reported. Patients
suggested to interact with genetic susceptibility with TRD have shown increased regional homo-
and contribute to the development of the disorder geneity in regions such as the temporal gyrus and
[9]. As a result, epigenetics is recently receiving insula and decreased regional homogeneity in
much attention, with early-life stress considered regions including the precuneus and inferior
to influence changes in DNA methylation and frontal gyrus [19]. Patients with TRD have also
histone modification, altering how genes are shown increased metabolism in the amygdala
expressed without changing the underlying DNA and uncus in positron emission tomography stud-
sequence [10]. The recurrence of depression is ies [20]. The underlying mechanisms of such
being associated with epigenetic changes of alterations in neural substrates may be attributed
genes such as the brain-derived neurotrophic fac- to the following etiological factors.
tor (BDNF) promoter gene in recent studies [11].
Further studies on the association between epi-
genetics and TRD are needed. 7.4 Neuroinflammation,
Neurogenesis,
and Neurodegeneration
7.3 Neural Substrates
Increased inflammation has been widely impli-
Alterations in brain structure in TRD have been cated in depression, with elevated pro-
implicated by previous imaging studies. Studies inflammatory cytokine levels, such as interleukin
on brain structure have reported decreased vol- (IL)-6 and tumor necrosis factor alpha (TNF-α),
ume of brain regions, such as the superior tempo- being observed in MDD [21]. Decreased levels of
ral gyrus, lateral inferior frontal gyrus, prefrontal anti-inflammatory cytokines have also been sug-
cortex [12], hippocampus [13], and entorhinal gested to contribute to the development of depres-
cortex (in females) [14]. On the other hand, sion [22]. The role of inflammation has also been
increased volume of the cuneus and precuneus emphasized in TRD, as previous studies have
7 Treatment-Resistant Depression: Neurobiological Etiology and Novel Treatments 101
reported TNF-α antagonists, such as infliximab, pus [34], may inhibit the process of neurogenesis
to be effective in patients with TRD with elevated [35]. The most widely reported cytokine is IL-1β,
inflammatory markers at baseline [23]. The major with its inhibition leading to a protective effect
intermediate target of pro-inflammatory cyto- against stress-induced reductions in neurogenesis
kines in the brain is microglia, with insufficient [36]. Accordingly, a continuous expression of
microglial function leading to reduced neuropro- IL-1β in the hippocampus has been shown to
tection and excess microglia activity leading to have negative influence on adult neurogenesis
neuronal cell damage [24]. Increased levels of [37]. IL-1β also has influence on other pro-
pro-inflammatory cytokines and microglia are inflammatory cytokine-induced reduction of neu-
suggested to underlie the pathophysiology of rogenesis, such as interferon-gamma (IFN-γ)
MDD, with both being synergistic to each other’s [38]. Another cytokine which has been impli-
activity [25]. Pro-inflammatory cytokines pro- cated in neurogenesis is leukemia inhibitory fac-
mote the activation of microglia, and activated tor (LIF), which shares glycoprotein 130 (gp130)
microglia, in turn, release pro-inflammatory with other IL-6 cytokine family members [39]. In
cytokines. Furthermore, activated microglia can relation to its effects on neurogenesis, LIF has
also increase glutamatergic neurotransmission been shown to have influence on neuroinflamma-
which may result in excitotoxicity and apoptosis. tion, glial cell activation, and various transcrip-
Glutamate and microglia are also interactive, and tion pathways [40]. Neuronal functioning
disruption in glutamatergic neurotransmission acquires adequate levels of LIF, with LIF knock-
may in turn lead to the activation of microglia out mice exhibiting abnormal cell activities of
[26]. Recent studies have reported pro- microglia and astrocytes and CNS insults leading
inflammatory mediators to be associated with to excessive LIF, which have been associated
treatment response in patients with MDD, such with schizophrenia-like symptoms [41]. TNF-α
as alterations in IL-6 levels being associated with also has been numerously implicated in neuro-
response to treatment [27]. genesis and neurodegeneration [42], with CNS
Neurogenesis is the process by which nervous insults leading to activation of TNF-α by glial
system cells, also known as neurons, are pro- cells [43]. There are two receptors of TNF-α,
duced by neural stem cells [28]. Neurogenesis TNF receptor (TNFR)-1 and TNFR-2, with
occurs not only prenatally but also continuously TNFR-1 mainly taking part in processes such as
in specific regions in the adult brain [29], includ- neurodegeneration and apoptosis and TNFR-2
ing the subgranular zone which is part of the den- mainly associated with processes of neurogenesis
tate gyrus of the hippocampus [30]. Adult [44, 45]. Accordingly, previous studies have
neurogenesis in the hippocampus has been asso- reported TNFR-1 to have detrimental effects on
ciated with learning and memory, conditioning, adult neurogenesis in the hippocampus [46, 47]
and investigative behaviors [31]. Numerous stud- and TNFR-2 to enhance neurogenesis [48, 49].
ies have implicated an association between adult Furthermore, the relation of TNF-α with α-amino-
hippocampal neurogenesis and MDD [32], with 3-hydroxy-5-methyl-4-isoxazolepropionic acid
decreased neurogenesis being observed in animal (AMPA) receptors is also known to greatly con-
models of MDD [33], and treatments with antide- tribute to synaptic plasticity, as AMPA receptors
pressant effects, such as medication and electro- control glutamatergic neurotransmission [50].
convulsive therapy, increasing neurogenesis.
Therefore, neurogenesis is considered to be a
fundamental process in the development and pro- 7.5 Glutamatergic
gression of the disorder. Neurotransmission
Both neurogenesis and neurodegeneration are
greatly influenced by neuroinflammation. For Glutamatergic neurotransmission is now consid-
neurogenesis, pro-inflammatory cytokine recep- ered to play an essential role in the etiology of
tors which are highly expressed in the hippocam- TRD [51]. Being the major and primary e xcitatory
102 E. Won et al.
neurotransmitter, glutamate has been the center neuronal plasticity and survival. Accordingly,
of attention when discussing calcium influx-asso- synaptic NMDAR neurotransmission has been
ciated neurotoxicity [52], but recently its role in shown to have opposite effects and activate ERK
synaptic plasticity is being emphasized through and CREB [61, 62].
N-methyl-D-aspartate receptor (NMDAR) neu- Metabotropic glutamate receptors (mGlus)
rotransmission [53]. Glutamate receptors can be can be divided into three groups, with group I
categorized as ionotropic or metabotropic including mGlu1 and mGlu5, which are situated
depending on which signal transduction mecha- alongside NMDARs. Antagonism of mGlu5 has
nism the receptor relies on [54]. NMDARs, been shown to lead to NMDAR inhibition, and
AMPARs, and kainate receptors are all iono- agonism of mGlu5 has been shown to lead to
tropic receptors, and the antagonism of extrasyn- NMDAR enhancement [64, 65]; hence mGlu5
aptic NMDARs and AMPARs is considered to has been widely studied in relation to TRD [66].
play an essential role in the etiology and treat- Groups II and III include mGlu2 and mGlu3 and
ment of TRD [55]. mGlu4, mGlu6, mGlu7, and mGlu8, respectively
Although glutamate’s activity had been once [67]. The majority of group II receptors are pres-
considered dependent on the intensity of neuro- ent in the hippocampus and prefrontal cortex and
transmission accompanied by calcium influx inhibit glutamatergic release via negative feed-
[56], the location of NMDARs is considered back [68]; hence the activation of these receptors
nowadays to be essential in the process of excito- decreases glutamatergic release and may enhance
toxicity and related apoptosis and neurodegener- neuroprotection [69].
ation [57]. Extrasynaptic NMDAR-mediated
glutamatergic neurotransmission has been shown
to have detrimental effects such as excitotoxicity, 7.6 Glial Cells
but synaptic neurotransmission has been shown
to have positive effects on synaptic plasticity Glial cells are the most abundant nonneuronal
[58]. Synaptic glutamate is transported into glial cells in the brain and include microglia, astro-
cells via excitatory amino acid transporters cytes, and oligodendrocytes [70]. Contrary to the
(EAATs) and, once converted to glutamine, is belief that glial cells only functioned as structural
then again transported to presynaptic neurons, support to neurons, glial cells are now considered
where glutamine is converted back to glutamate to play a central role in the etiology of
and then released to the synapse [59]. MDD. Astrocytes mainly express synaptic
Inappropriate uptake of the glial cells resulting in EAATs, and neuronal activity is greatly influ-
excess glutamate leads to the diffusion and uptake enced by astrocyte-released glutamate [71].
of glutamate by extrasynaptic NMDARs; hence Hence, astrocyte dysfunction can lead to a decline
insufficient activity of EAATs may lead to extra- in synaptic neurotransmission and an increase in
synaptic neurotransmission, contributing to exci- the direct binding of glutamate to extrasynaptic
totoxicity [60]. Therefore, enhanced synaptic NMDARs [72].
NMDAR neurotransmission along with dimin- Microglia cells are essential in neuroinflam-
ished extrasynaptic neurotransmission is consid- matory processes and react promptly to changes
ered to play a pivotal role in neuronal survival in the environment; hence CNS insults directly
[58]. The detrimental effects of extrasynaptic lead to activation of microglia [73]. Although
NMDAR neurotransmission have been numer- inadequate microglia activation can lead to inad-
ously reported, such as the inhibition of extracel- equate defense against insults, excess activation
lular signal-regulated kinases (ERK) [61], cyclic may also lead to neurotoxicity due to excess
adenosine monophosphate response element- amounts of inflammatory mediators being
binding protein (CREB) activation [62], and the released [25]. The increase in pro-inflammatory
increase in beta-induced nitric oxide production cytokines due to abnormal microglia activation is
[63], all of which exert opposing effects on considered a fundamental factor in the etiology
7 Treatment-Resistant Depression: Neurobiological Etiology and Novel Treatments 103
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Treatment-Resistant
Schizophrenia: Assessment 8
and Management
Sandeep Grover, Harsh Garekar,
and Anisha Agarwal
During the 1970s, chronic hospitalization (hospi- This definition paved the way for use of clo-
talization for more than 2 years) was considered zapine in a subset of patients with remarkable
one of the most important indicators of treatment results. Further, proper monitoring for agranulo-
resistance in schizophrenia. This approach was of cytosis showed that the incidence of agranulocy-
little help in ascertaining treatment responsive- tosis was lower than that reported earlier. This led
ness as reasons for chronic hospitalization varied to an expansion of clinician experience with the
from poor treatment adherence to inadequate use of clozapine, and gradually the molecule
psychosocial rehabilitation. However, deinstitu- emerged as the gold standard for management of
tionalization and the emergence of a host of anti- TRS. Since the beginning, the concept of TRS as
psychotics led to the transfer of some of defined by Kane et al. has been questioned by
symptomatic patients, who were not violent and contemporary researchers, and this has led to the
aggressive, from custodial care to the community proliferation of multiple definitions of TRS
care. Some of these patients were symptomatic (Table 8.1). Brenner et al. (1990) proposed a
but still could be managed at the community dimensional approach to TRS and described
level. Accordingly, the focus for treatment resis- seven levels of response ranging from full clini-
tance shifted to symptoms, rather than the dura- cal remission to severely refractory. This defini-
tion of hospitalization. Subsequent revisions of tion implies that some patient’s levels of response
diagnostic systems (Diagnostic and Statistical may worsen over time and also takes into account
Manual of Mental Disorders [DSM] and patients’ functional, social, and personal levels
International Classification of Diseases [ICD]) and not just the existence of active symptoms [8].
also led to a more narrow definition of schizo- Meltzer in 1992 proposed to assess treatment
phrenia. Positive symptoms were given more resistance in schizophrenia according to different
importance in diagnosis and consequently parameters, i.e., psychopathology, cognitive
became the focus of management. Accordingly, function, extrapyramidal functions, social func-
when Kane et al. (1988) defined the criteria for tioning, independence and work functioning,
TRS, persistent positive symptoms despite ade- quality of life, reinstatement, dependences, cost
quate drug therapy were the essential criterion for of the illness, as well as treatment [9]. His criteria
treatment resistance in schizophrenia. They con- are considered to be less strict and more useful in
sidered a patient to have TRS if [5–7]: clinical practice. But the disadvantage of this
approach is that all partial responders are consid-
1. Historically: Treatment with at least two dif- ered equal and not to differ qualitatively from
ferent classes of antipsychotics at doses equal patients who are completely refractory. The orig-
to 1000 mg/day of chlorpromazine for at least inal criteria proposed by Kane et al. also under-
three periods of 6 weeks in the last 5 years went modification driven by pharmacological
without significant clinical improvement evidence that doses of more than 400 mg/day of
2. Actual: BPRS score of at least 45. Score of at chlorpromazine led to blockade of 80–90% of
least ≥4 on two of the following BPRS items dopaminergic receptors [10]. Accordingly, the
of conceptual disorganization, unusual criteria were modified as [6]:
thoughts, hallucinatory behavior, and suspi-
ciousness and Clinical Global Impression 1. Historical: at least three treatments with typi-
(CGI) score of ≥4 (moderately ill) cal antipsychotic from two different chemical
Table 8.1 Various definitions of TRS
Year Author Definition of TRS
1988 Kane et al. Persistent positive symptoms (PPS) despite adequate drug therapy to be the essential criterion
[5] 1. Historical: Treatment with at least two different classes of antipsychotics at doses equal to 1000 mg/day of chlorpromazine for at least three periods of
6 weeks in the last 5 years without significant clinical improvement
2. Actual: BPRS score of at least 45. Score of at least ≥4 on two of the following BPRS items of conceptual disorganization, unusual thoughts, hallucinatory
behavior, and suspiciousness and CGI score ≥4 (moderately ill)
3. Prospective: No improvement after 6 weeks of treatment with haloperidol (up to 60 mg/day or higher); improvement is defined as reduction of at least 20%
on BPRS as compared with the level of severity defined by the actual criteria and/or a posttreatment CGI of ≤3 or BPRS ≤35
1988– Brenner Level 1 Clinical remission No need for a formal rehabilitation Rapid response to antipsychotics at recommended doses. Patient may show
1990 et al. [10] program anhedonia or another negative symptom. CGI normal and score <2 on BPRS. Good
functional level without supervision
Level 2 Partial remission No need for a formal rehabilitation Rapid reduction of psychotic symptoms. Mild signs of residual psychotic
program symptoms. CGI score of 2. None of the BPRS scale items are ≥3
Level 3 Light resistance Need for a rehabilitation program Slight or incomplete reduction of symptoms with positive and negative residual
symptoms. Alteration of social or personal functioning in at least two areas and
requiring occasional supervision. No more than one item with a score ≥4 on the BPRS
Level 4 Moderate resistance Need for a rehabilitation program Reduction of symptoms but with a clear persistence of them, affecting six or more
areas of social and personal functioning and requiring frequent supervision. CGI 4.
A score of 4 or 2 BPRS items. A BPRS score ≥45 on the 18-item version and 60
on the 24-item version
Level 5 Severe resistance Need for a continuous strategy, Reduction of symptoms but with a clear persistence of them, affecting six or more
individual and oriented toward areas of social and personal functioning and requiring frequent supervision. CGI 5.
8 Treatment-Resistant Schizophrenia: Assessment and Management
attempts with atypical antipsychotics A score of 5 on 1 BPRS item or ≥4 on 3 items. A total BPRS >50 on the 18-item
and adjuvant treatment version and 67 on the 24-item version
Level 6 Refractoriness Longer-term hospitalization with Reduction of mild or non-demonstrable symptoms and persistence of positive and
pharmacological and psychosocial negative symptoms with marked alteration in all areas of social and personal
attempts functioning. CGI 6. A score of 6 on 1 BPRS item or of ≥5 on 2 items. Total BPRS
score of ≥5 per level
Level 7 Severe refractoriness Longer-term hospitalization with No reduction of symptoms with many positive and negative symptoms associated
pharmacological and psychosocial with behavioral alterations. All areas of social and personal functioning have
attempts deteriorated, requiring constant supervision. CGI 7. A score of 7 on 1 BPRS item.
Total score of ≥5 per level
1989 Wilson Persistence of symptoms after 2.5 years of treatment with three different classes of neuroleptics (dosage of 1000 mg of chlorpromazine equivalents) for
et al. [11] 8 weeks in the last 5 years
1989 Schüssler Insufficient improvement after administering neuroleptic treatment for 4 weeks
et al. [12]
1991 Keefe There is no sufficient improvement after their neuroleptic treatment (40 mg haloperidol/day) during 6 weeks
111
et al. [13]
112 S. Grover et al.
classes at doses equivalent to 400–600 mg/ Table 8.2 Definition of TRS as per various treatment
guidelines
day of chlorpromazine for a period of at least
6 weeks, without significant relief. No period Author Criterion of treatment resistance
of good functioning within the preceding APA 2004 Insufficient response to two clinical
[14] trials of 4- or 6-week duration using
5 years. monotherapy with two different SGAs
2. Actual: A score of at least 45 in the BPRS with or two trials with FGAs, if SGAs are not
score of ≥4 in two of the following: conceptual available. It is considered that the patient
disorganization, unusual thought content, hal- is treatment-resistant and is a candidate
for clozapine
lucinatory behavior, and suspiciousness and
Maudsley Failure to respond to at least two
CGI score ≥4 (moderately ill). 2015 [15] antipsychotics (either SGA/FGA), each
3. Prospective: No improvement after 6 weeks of given for at least for 2–3 weeks. If some
treatment with haloperidol (up to 60 mg/day response detected, continue for a total of
at least 4 weeks before abandoning
or higher); improvement is defined as reduc-
treatment
tion of at least 20% on the Brief Psychiatric NICE Lack of satisfactory clinical
Rating Scale (BPRS) as compared with the 2014 [16] improvement despite sequential use of
level of severity defined by the actual criteria; the recommended doses for 6–8 weeks
and BPRS ≤35 points on the BPRS and CGI of at least two antipsychotics, at least
one of which should be SGA
score ≤3.
IPAP 2006 No period of good functioning in the
[17] previous 5 years
Over the last decade, with more experience in Prior nonresponse to at least two
the use of clozapine and reduction in the dread of antipsychotics of two different chemical
using clozapine, more and more authors rely on classes for at least 4–6 weeks each at
doses ≥400 mg equivalents of CPZ or
using modified Kane’s criteria for defining 5 mg/day of risperidone
TRS. Various treatment guidelines have also Moderate to severe psychopathology,
adopted similar definitions and diluted the same especially positive symptoms:
further (Table 8.2). In general these guidelines conceptual disorganization,
hallucinatory behavior, suspiciousness,
suggest that if a patient has a lack of satisfactory
or delusions
clinical improvement despite sequential use of
APA American Psychiatric Association, NICE National
the recommended doses of at least two antipsy- Institute of Clinical Excellence, IPAP International
chotics for 6–8 weeks, at least one of which Psychopharmacology Algorithm Project
should be an atypical, and then the patient should
be considered as having TRS.
problem, because patients with TRS experience
the worst outcomes, such as suicide and home-
8.3 Current Perspective of TRS lessness. TRS can manifest as failure to achieve
remission from the initial episode of psychosis,
Treatment resistance in schizophrenia is a con- failure to maintain remission, or gradual deterio-
cept that still holds different positions in clinical ration in the patient’s status.
settings and research areas. Categorical and
criteria-based approach with more emphasis on
positive symptoms is preferred for research, 8.4 Factors Associated with TRS
while individualized and holistic view for treat-
ment resistance seems appropriate for day-to-day Some of the studies have attempted to identify
clinical situations. Regarding pharmacological the risk factors for TRS. Studies which have
treatment of TRS, till now only clozapine has evaluated neurodevelopment predictors of
demonstrated conclusive favorable evidence. The poor response to treatment among patients of
management of TRS is a persistent public health schizophrenia have shown a link of poor
8 Treatment-Resistant Schizophrenia: Assessment and Management 113
treatment response to lower level of premorbid prefrontal cortex (DLPFC) volume in patients
functioning, presence of deficit state, male
with TRS [38].
gender, cavum septum pellucidum, higher
prevalence of obstetrical complications, lat-
eral and third ventricular enlargement, and 8.5 Pharmacotherapy
vulnerability to tardive dyskinesia [18–20]. of Treatment-Resistant
Other factors which have been linked to some Schizophrenia
degree of treatment refractoriness among
patients of schizophrenia include male gender, Treatment resistance can occur in approximately
early onset of illness, positive family history 20–30% of all patients with schizophrenia [39]. It
of schizophrenia, absence of affective symp- is vital that before classifying a patient as
toms, severe and lengthy premorbid manifes- treatment-resistant, the possibility of pseudo-
tations, longer duration of untreated psychosis, resistance be ruled out. The clinician should con-
severe negative and cognitive symptoms, pres- sider the following steps to rule out
ence of soft neurological signs, early onset of pseudo-resistance [40]:
abnormal involuntary movements, and low
level of social functioning [20–36]. A recent • Upward titration of antipsychotic medications
Danish register-based study included 8044 till effective dose range is reached. Checking
patients of which 1703 (21%) patients fulfilled serum levels if required. Assessing pharmaco-
the main proxy definition of TRS (earliest kinetic interactions with other drugs and
instance of either clozapine initiation or hospi- smoking.
tal admission for schizophrenia after having • Optimizing the duration of antipsychotic ther-
had two periods of different antipsychotic apy, typically a 4- to 6-week trial, with opti-
monotherapy) with a median follow-up period mal dosing.
of 9.1 years. The factors which were found to • Side effects of psychiatric drugs and other
be significantly associated with TRS included medications may mimic worsening positive
younger age, living in a less urban area, pri- (akathisia, delirium) or negative (hypokinesia)
mary education level, more than 30 bed-days symptoms. In such a scenario, reduction in
in psychiatric hospital in the year before first doses may be beneficial.
schizophrenia diagnosis, inpatient at first • Reevaluating the diagnosis of schizophrenia,
schizophrenia diagnosis, paranoid subtype, along with ruling out other general medical or
comorbid personality disorder, psychotropic neurologic condition that may be presenting
drug use, use of benzodiazepines, and previ- with psychotic symptoms.
ous suicide attempt [37]. • Evaluation for comorbid conditions such as
A recent systematic review evaluated the neu- substance use disorders, personality disorders,
roimaging findings among patients with mania or depression with psychotic symp-
TRS. Computerized tomography (CT)-based toms, and obsessive-compulsive disorder
studies have shown smaller prefrontal sulcal (OCD).
prominence reflecting prefrontal atrophy in • Ensuring drug compliance through pill count,
patients with TRS. Magnetic resonance imaging measuring serum levels, checking pharmacy
(MRI) studies show that, compared to healthy refill dates, and using depot antipsychotic
controls, patients with TRS have more wide- injections [41].
spread reduction in cortical thickness (frontal,
parietal, temporal, and occipital regions) than Once the clinicians have ensured that these
patients with non-TRS (frontal regions). When factors have been taken care of, the patients need
compared to patients with non-TRS, MRI studies to be considered as having true TRS and man-
suggested a greater reduction in left dorsolateral aged accordingly.
114 S. Grover et al.
evaluating the efficacy of clozapine against people with schizophrenia, at a high risk for sui-
other antipsychotics. It included data of 1131 cide. During the study period, compared to
patients enrolled in the clozapine arm and 1233 patients receiving olanzapine, lower number of
patients in the control medication arm. Of these patients on clozapine attempted suicide (34 vs.
patients, final follow-up data was available for 55%) and required hospitalizations (82 vs.
801 and 799 patients in the clozapine and other 107%) and rescue interventions (118 vs. 155%)
antipsychotic arms, respectively. This meta- to prevent suicide [51]. A population-based
analysis showed that clozapine was superior in cohort study of 2370 individuals with TRS from
reducing positive psychotic symptoms in both 1996 to 2013, extracting information from the
the short (less than 3 months) and long term Danish National Prescription Registry, found
(more than 3 months). For negative symptoms, that non-clozapine antipsychotic treatment was
clozapine was superior in the short term but not associated with an increased rate of self-harm,
in the long term. When compared to specific with hazard ratio of 1.36 compared to clozapine.
antipsychotics, clozapine was found to be supe- The results also demonstrated a nearly twofold
rior to olanzapine, haloperidol, and chlorproma- higher mortality rate among those not treated
zine in the short term, while these differences with clozapine [52].
were not significant when compared with olan- However, a recent systematic review, which
zapine and risperidone in the long term. A lack evaluated the data published during 2005–2014,
of efficacy for negative symptoms may explain showed that, with the strengthening of the restric-
this lack of difference in the long term [48]. tion in access to lethal means and school-based
awareness programs, the anti-suicidal effect of
clozapine is substantiated, but it might be less
8.7.2 Cognitive Symptoms specific than thought earlier [53]. Clozapine can
reduce violence and persistent impulsive aggres-
Several studies over the past decades have tried sion in patients with schizophrenia and other psy-
to assess the impact of atypical antipsychotics chiatric disorders, independent of their effects on
on cognitive function in patients with schizo- core psychopathology. The anti-aggressive effect
phrenia, based on their effects on cholinergic is particularly marked in those with TRS
and 5-HT2a- mediated neurotransmission. [54–56].
While all atypical antipsychotics have shown
variable levels of improvement, clozapine has
been consistently found to improve verbal flu- 8.7.4 Depressive Symptoms
ency, attention, and motor speed in patients
with TRS [49, 50]. Clozapine has also been shown to have better
antidepressant effect in patients with schizophre-
nia compared to other antipsychotic medica-
8.7.3 Suicidality and Aggression tions. A reanalysis of the CATIE trial data
showed that clozapine was as effective as olan-
There is emerging evidence to suggest that clo- zapine and risperidone but was more effective
zapine can be particularly effective in reducing than quetiapine [57].
specific behavioral problems of violence,
aggression, and suicidality in patients with
schizophrenia. Clozapine is the only FDA- 8.7.5 Catatonic Symptoms
recommended treatment for reducing suicidal
risk in schizophrenia. This was demonstrated in Although systematic studies are lacking, data in
the International Suicide Prevention Trial (Inter the form of case reports suggest that clozapine
SePT), a 2-year, multicenter, randomized study can be beneficial in patients with persistent cata-
comparing clozapine and olanzapine in 980 tonia and recurrent catatonia [58].
116 S. Grover et al.
emotional development at all time points, but than the quoted 1% risk for general population
adaptive behavior was delayed at 2 and 6 months [79]. Fatal myocarditis has also been reported in
of age [74]. In terms of pharmacokinetics, the the elderly [80]. While other common side effects
plasma concentration of clozapine can decrease of clozapine are often manageable, clozapine use
during pregnancy due to increased hepatic metab- in the elderly must be done with caution after a
olism and volume of distribution. A review of careful assessment of the risk to benefit ratio.
case reports and pharmacovigilance data of
nearly 200 patients has recommended that clo-
zapine dose should be increased during psychotic 8.7.10 Clozapine in Patients
symptom exacerbation and a typical antipsy- with Tardive Syndromes
chotic like perphenazine, trifluoperazine or halo-
peridol can be added to clozapine [75]. Tardive syndromes are delayed-onset syn-
Substitution of clozapine is not recommended as dromes, which include tardive dyskinesia, tar-
it can lead to psychotic exacerbation during preg- dive dystonia, tardive akathisia, tardive
nancy. The dual goal of reducing infant exposure stereotypy, tardive tourettism, tardive myoclo-
and controlling symptoms can only be achieved nus, tardive tremor, and tardive parkinsonism.
by an individualized risk-benefit analysis in part- They are associated with both atypical and typi-
nership with the patient. Each case must be eval- cal antipsychotic exposure, with possible patho-
uated on an individual basis by taking into genic mechanism involving hypersensitivity of
account the number and severity of previous dopamine receptors. Clozapine is associated
episodes. with the lowest risk of extrapyramidal side
effects, and current evidence suggests that clo-
zapine can significantly diminish dyskinetic
8.7.9 Elderly movements in patients with tardive syndromes.
However some reports have also suggested con-
The use of clozapine in the elderly is particularly flicting findings of development/worsening of
fraught with danger due to a high susceptibility tardive syndromes [81]. In an 18-week study of
for not just the serious adverse effects like agran- clozapine in patients with TRS, with coexisting
ulocytosis, myocarditis, seizures, and metabolic tardive dyskinesia, chronic akathisia, and par-
syndrome but also for the commoner side effects kinsonism, the use of low-dose clozapine led to
like sedation, constipation, urinary incontinence, improvement rates of 74% for tardive dyskine-
and hypersalivation [76]. Despite the potential sia, 69% for parkinsonism, and 78% for chronic
pitfalls, clozapine has been found to be an effec- akathisia [82]. In a case series including patients
tive drug for resistant cases in studies carried out with affective psychosis with tardive syndromes,
in the geriatric population. In a retrospective low-dose clozapine showed response rates vary-
chart review of 527 elderly patients, with chronic ing from 50% to 100% [83]. A systematic review
resistant schizophrenia, rehospitalization rates of 15 trials and 28 case series/reports supported
were found to be significantly lower for clozap- the beneficial effects of clozapine, taking in to
ine, and mortality was equal to that of other anti- account reports which suggested emergence of
psychotics [77]. In another review of 133 elderly tardive syndromes with clozapine [84].
patients, clozapine showed marked to moderate
improvements in psychotic symptoms at a rela-
tively low mean dose of 134 mg/day, which was 8.8 Clozapine: Prescription
well tolerated [78]. Although clozapine efficacy Practices and Barrier in Use
in treatment-resistant cases in the elderly is simi-
lar to that in the younger age group, the burden of While clozapine has maintained its place as the
side effects is higher. The risk of agranulocytosis treatment of choice in TRS and endorsed as the
has been estimated to be five to ten times higher gold standard of therapy in all practice
118 S. Grover et al.
g uidelines, its use has been found to be lower shown to be associated with favorable clinical
than recommended [85]. It has been found that response to clozapine include female gender,
clozapine accounts for <5% of the antipsychot- presence of extrapyramidal side effects, paranoid
ics prescribed, and an estimated five to ten subtype, and presence of 22q11.2 deletion [94,
times more patients could benefit from clozap- 95]. The clinical features which are associated
ine than who are now receiving it [86, 87]. with poor response include early age of onset,
Despite the available evidence in favor of clo- catatonia and deficit syndromes [23, 96–99].
zapine in treatment of TRS, it is often seen that Among the biological measures, low pretreat-
in many patients starting of clozapine is ment CSF homovanillic (HVA)/5-
delayed. Studies across the world show that hydroxyindoleaceticacid (HIAA) acid levels
starting of clozapine is often delayed, by 1.6– predict a superior clozapine response, consistent
4.5 years in patients of schizophrenia, despite with the dopaminergic and serotonergic compo-
patients fulfilling the criteria of TRS [88, 89]. A nents of its mechanism of action [100]. Clinical
survey of psychiatrists from India showed that, improvement with clozapine has also been related
in about 28% of patients, clozapine was not with the anatomy and metabolic activity of spe-
prescribed though indicated [90]. Clinicians cific brain areas. Improvement in positive symp-
resort to use of polypharmacy prior to starting toms with clozapine was directly related to
clozapine. Clinicians are reluctant to start clo- temporal gray matter volume, whereas improve-
zapine because of fear of agranulocytosis and ment of negative symptoms is seen in patients
associated blood monitoring. Other factors, with high baseline DLPF cortical volume and
which have been shown to be associated with metabolic activity [101, 102]. The effects of clo-
lower prescription of clozapine, include history zapine have also been attributed to changes in
of poor medication compliance, lower aware- regional blood flow. Responders to clozapine
ness among prescribers, and fear of side effects show a higher thalamic, left basal ganglia and
[91, 92]. In a study assessing attitude toward right prefrontal perfusion prior to starting of clo-
clozapine, in patients who are eligible for clo- zapine, while clozapine treatment increases bilat-
zapine, but not yet prescribed so, it was found eral frontal/caudate perfusion ratio; hence across
that the necessity for hospital admission was studies it seems that subcortical perfusion of the
seen as the greatest barrier to starting clozapine responders decreases when they received clozap-
(49% of respondents). In addition, concerns ine [103–106]. Despite a growing list of
about side effects were another reason for clo- laboratory-based findings, which could function
zapine refusal in 43% of respondents. Around as a predictor of response to clozapine, unequivo-
24% of the respondents felt that clozapine cal evidence of reproducibility, specificity, and
would be a useful option for them. So overall, it clinical feasibility is absent.
is apparent that the overall acceptability of clo- Oral dosage and pharmacokinetic factors
zapine can be increased by enhanced education also play a pivotal part in determining response.
about clozapine’s benefits, improving manage- A number of studies have related blood levels
ment of its side effects and initiating clozapine with clinical response, recommending a concen-
on an outdoor clinic basis [93]. tration of more than 350 ng/ml for clinical
response [107]. The plasma clozapine concen-
tration is influenced by a number of patient fac-
8.9 Predictors of Response tors such as altered cytochrome P450 1A4
to Clozapine activity, age, gender, and smoking. While piv-
otal studies have used clozapine in the dose
A number of studies have tried to evaluate the range of 100–900 mg, it is suggested that for
factors associated with good clinical outcomes clinical response, doses above 400 mg must be
with the use of clozapine. Some of the demo- used [108]. Furthermore, one study has indi-
graphic and clinical factors which have been cated a dose-response relationship, better
8 Treatment-Resistant Schizophrenia: Assessment and Management 119
clinical response with doses of 600 mg/day Table 8.3 Pretreatment assessment and monitoring for
clozapine
group than 300 mg/day and least benefit with a
dose 100 mg/day [109]. Another important point Baseline Complete blood count that includes an
evaluation absolute neutrophil count (ANC)
to note regarding the pharmacokinetics of clo-
Weight and height (body mass index),
zapine is the wide interindividual variability at a waist circumference, fasting blood sugar
given dose. In a Chinese sample of inpatients (or HbA1c), fasting lipids
with schizophrenia, eightfold variability at a Physical examination and vital signs
given dose was reported [110]. Due to these ECG
pharmacokinetic and pharmacodynamic proper- Liver function tests (LFTs)
ties of clozapine, an adequate trial with clozap- Consider troponin, CRP, beta natriuretic
peptide, ESR monitoring (if persisting
ine should last for 4–6 months, with plasma tachycardia or fever; suspected
trough levels maintained at 350–400 ng/L for at myocarditis) [120]. Not mandatory but
least 8 weeks [111, 112]. recommended in some guidelines
Pregnancy test in women of
childbearing age
Required Before initiating therapy – complete
8.10 How to Use Clozapine blood blood count that includes an absolute
monitoring neutrophil count (ANC); WBC >3500/
In view of side effects (both serious and nonseri- mm3 and ANC >2000/mm3
ous), different guidelines have been recom- Mandatory blood monitoring (country
specific) [121]
mended for starting and maintaining
USA – weekly for the first 26 weeks,
hematological monitoring while using clozapine then biweekly for 26 weeks, and then
(Table 8.3). However, occasional reports from monthly
resource poor countries have questioned very UK – weekly for the first 18 weeks,
frequent monitoring and suggest that monitoring then biweekly from 19 to 52 weeks,
and then monthly
at a frequency of 3 months after stabilization of
Japan – weekly for the first 26 weeks
the dose of clozapine may be considered [113]. and then biweekly thereafter
However, there is lack of systematic data for the
ANC absolute neutrophil count, ECG electrocardiogram,
same. Besides hematological monitoring, CRP C-reactive protein, WBC white blood cell count
another issue, which has received significant
attention, is the development of metabolic dis-
turbances like diabetes mellitus, obesity/weight Table 8.4 Monitoring of metabolic parameters while
using clozapine
gain and metabolic syndrome. In fact, as per the
Recommended Weight/BMI/waist – baseline
American Diabetes Association (ADA) and the
monitoring and then at 1, 3, 6, and
American Psychiatric Association (APA) con- 12 months
sensus statement on antipsychotic drugs, clozap- Plasma glucose and lipids – at
ine along with olanzapine has the highest month 1, 6, and 12 months
potential to cause metabolic syndrome [114]. Liver function tests – baseline
and at 6 months
Studies, which have evaluated the prevalence of
metabolic syndrome among patients receiving
clozapine, have reported it to range from 44% to ine, suggest that only about half of the preva-
64% [115–117]. However, few authors have lence of metabolic syndrome in patients with
questioned this high prevalence rate on the basis clozapine may be attributed to it and the rest of
of the fact that many patients would have ful- the patients fulfill the criteria of metabolic syn-
filled metabolic syndrome prior to starting of drome prior to starting of clozapine [118, 119].
clozapine. Few longitudinal studies, which have However, in view of the risk of m etabolic syn-
evaluated the prevalence of metabolic syndrome, drome, close monitoring of metabolic parame-
prior to starting clozapine and subsequently, and ters is recommended by the APA/ADA consensus
reevaluated the same after 3–6 months of clozap- statement (Table 8.4).
120 S. Grover et al.
8.11 S
ide Effects of Clozapine target plasma levels are reached [122, 123].
and Its Management Therefore, anticipating and addressing these
adverse side effects are vital for a clinician to
Clozapine is associated with a wide range of improve adherence. Among the life-threatening
adverse effects, some of which can be potentially adverse effects, agranulocytosis and myocarditis
life-threatening. Clozapine also has poorer toler- require careful monitoring during the first
ability compared to other antipsychotics. The 3–6 months of clozapine treatment (Table 8.6).
common side effects of clozapine include seda- Clozapine-induced agranulocytosis can occur in
tion, constipation, sialorrhea, weight gain, 1% of treated individuals and can be fatal if not
metabolic disturbances, sinus tachycardia, fever, detected early. The US Food and Drug
seizures, and nocturnal enuresis (Table 8.5). The Administration (FDA) requires a neutrophil
serious side effects of clozapine are agranulocy- count >1500/microL, to start clozapine, and
tosis, seizures and myocarditis. These usually treatment should be stopped if absolute neutro-
require discontinuation of clozapine even before phil count (ANC) falls below 1000/microL [124].
Table 8.6 Serious adverse effects with clozapine and their management
Adverse event Risk/time course Management
Neutropenia and Neutropenia Mild neutropenia (100–1500/microL)
agranulocytosis Incidence: 2.7% during first year Monitor absolute neutrophil count (ANC) three times
Incidence: 0.69% during second weekly till>1500/microL
year Moderate neutropenia (500–1000/microL)
Agranulocytosis Stop clozapine
Incidence: 0.73% during first Monitor ANC daily till>1000
year Then monitor three times/week till>1500
Incidence: 0. 07% during second Then weekly for 4 weeks
year Severe neutropenia (<500/microL)
80% of cases are seen within Discontinue clozapine
18 weeks of treatment Daily ANC till>1000/microL
Then three times weekly till ANC>1500
Use granulocyte colony-stimulating factor as a rescue
treatment after consultation with hematologist
Generally reexposure should not be attempted
Myocarditis and Incidence: 1% Careful monitoring is essential
cardiomyopathy 80% of the cases occur during Baseline – pulse, blood pressure, temperature,
the first 6 weeks respiratory rate, blood counts, ECG
Daily – pulse, blood pressure, temperature,
respiratory rate; ask about chest pain, fever, cough,
shortness of breath, exercise capacity
Weekly till 4 weeks – CRP, troponin, complete blood
counts, ECG, and echocardiography if possible
If CRP > 100 mg/L or troponin > twice upper limit of
normal – stop clozapine; repeat echo
Rechallenge with clozapine associated with high
mortality rates
Neuroleptic Few case reports Early recognition
malignant Low risk when compared to other Cessation of clozapine
syndrome neuroleptics Supportive care
Dopamine agonists/dantrolene
ANC absolute neutrophil count, ECG electrocardiogram, CRP C-reactive protein
Clozapine-treated patients are also at a higher Table 8.3. Before starting clozapine, it is impor-
risk to develop both transient and persistent ane- tant that patients and family/caregivers are given
mia, neutrophilia, and eosinophilia, but these full information about the risks and benefits of
generally do not require treatment interruption. clozapine treatment, the need for blood regular
Male patients have been found to be at a higher blood testing and the need for lifestyle changes.
risk for persistent neutrophilia and eosinophilia, There should be a discussion about the common
while concomitant treatments with mood stabi- side effects and potential medical complications,
lizers (or benzodiazepines) and antidepressants and arrangements should be made to ensure
have been associated with transient anemia and availability of the medical help, apart from the
eosinophilia, respectively [125]. A number of usual clinic hours, in case of emergency.
case reports have suggested elevated clozapine
levels during infections. A systematic review of
these reports (40 cases) has demonstrated ele- 8.11.1 Treatment Strategies Other
vated clozapine levels associated with infections than Clozapine for TRS
particularly of respiratory origin and hence
advised consideration of reduction of dose to As some of the clinicians are reluctant to use clo-
minimize side effects [126]. zapine, available data also suggest use of treat-
A summary of the suggested pretreatment ment strategies other than clozapine in the
assessment and monitoring schedule is given in management of TRS. These include the use of
122 S. Grover et al.
combination of antipsychotics other than clozap- use of two oral antipsychotics, an oral
ine, use of combination of antipsychotics other antipsychotic combined with a depot preparation,
than clozapine and ECT, and use of suprathresh- and use of combination of two depot
old doses of other antipsychotics. preparations.
Treatment resistance has been attributed to a Amisulpride binds preferentially to D2/D3 recep-
number of biological changes such as reduced tors in the limbic region and also has a high affin-
presynaptic striatal dopamine synthesis, dopa- ity for HT2B antagonism. Amisulpride
mine super sensitivity, and abnormalities in glu- augmentation has been used mainly for persistent
taminergic system. The clinical utility of these negative symptoms in clinical practice, but its
proposed mechanisms are continually being efficacy in combination with clozapine continues
investigated. From the perspective of pharmacol- to be analyzed in robust RCTs. In a placebo-
ogy, clozapine with its low D2 receptor binding controlled trial of 16 patients, partially respon-
properties can be combined with drugs with a sive to clozapine, augmentation with amisulpride
strong D2 receptor affinity, such as risperidone, (dose, 600 mg) led to improvements in subscores
amisulpride, or haloperidol, to increase response. of “activity” on BPRS and in secondary outcome
8 Treatment-Resistant Schizophrenia: Assessment and Management 125
and found a trend toward greater reduction of positive and general symptom severity com-
global symptoms, driven by hostility and anxi- pared to clozapine monotherapy, with no signifi-
ety, in the first month of adjunct treatment as cant differences in adverse drug reactions [165].
compared to clozapine monotherapy [162].
Meta-analytical studies have since showed that
while valproate augmentation is beneficial for a 8.13.2 Lithium
faster response and those with sever hostility
and aggression, its impact on core psychotic Lithium has been used effectively as an augment-
features is u nconvincing [163, 164]. However, a ing agent along with clozapine in patients with
recent meta-analysis of RCTs on the use of schizoaffective disorder, where improvements
adjunctive sodium valproate in TRS (6 RCTs, have occurred in both negative symptoms and
n = 430) has shown significant improvements in cognitive domain. However, these results have
8 Treatment-Resistant Schizophrenia: Assessment and Management 127
not been seen in those with schizophrenia [166– led to a 14% reduction in BPRS scores and a
168]. The use of lithium with clozapine is well 2.5% decrease in body weight [175]. In another
tolerated, and the usefulness of this combination 24-week double-blind, randomized, placebo-
has been highlighted in cases of clozapine- controlled trial of 43 patients with TRS on clo-
induced neutropenia. Lithium can be used to zapine, add-on topiramate was scarcely effective
increase neutrophil blood counts and prevent in reducing clinical symptomatology and also led
neutropenia recurrence after clozapine rechal- to cognitive complaints confirmed by impair-
lenge [169]. ments on certain cognitive tasks [176]. Based on
current evidence, the benefits of augmentation
with topiramate appear meager; however it can
8.13.3 Lamotrigine be particularly useful in offsetting the weight loss
induced by clozapine (Table 8.8).
Like other anticonvulsants, lamotrigine is a
voltage-gated sodium channel inhibitor, but it
has also been shown to inhibit glutamate. 8.14 Augmentation
Glutamate is an excitatory neurotransmitter, with Antidepressants
which has been implicated in the pathophysiol-
ogy of schizophrenia. Based on this probable Antidepressants can be effectively used to treat
mechanism of action, as a stabilizer of glutamate depressive symptoms in schizophrenia. In addi-
neurotransmission, lamotrigine has been studied tion, augmentation with antidepressants is being
as an augmentation agent with positive results. A increasingly done to treat negative symptoms,
meta-analysis and systematic review of five ran- comorbid obsessive-compulsive symptoms, and
domized placebo- controlled trials, of 10–24- even some psychotic symptoms and treatment
week duration, involving 161 patients, evaluated resistance.
the effectiveness of lamotrigine augmentation in
clozapine-resistant patients. It was found that
lamotrigine augmentation was effective for both 8.14.1 Fluvoxamine
positive and negative symptoms [170–172].
However, subsequent placebo-controlled studies Fluvoxamine is an inhibitor of cytochrome P450
have failed to show benefits, and the need for 1A2 and increases clozapine plasma levels. The
further investigation is evident [173]. In addi- increase in dose can increase response in
tion, current evidence also does not support the patients in whom adequate clozapine levels
use of lamotrigine in patients on antipsychotics have not been reached. Addition of 50 mg/day
other than clozapine. Lamotrigine is generally of fluvoxamine to low-dose clozapine (100 mg/
well tolerated in combination with clozapine, day) can increase clozapine levels to over
with a small but important risk of Steven- 400 ng/ml [177, 178]. Several trials have dem-
Johnson syndrome, which necessitates a slow onstrated that adjunctive use of fluvoxamine can
titration of dose. also increase clozapine efficacy by reducing
plasma norclozapine- clozapine ratios [179,
180]. A systematic review of adjunctive fluvox-
8.13.4 Topiramate amine with clozapine based on 24 case reports/
series, 7 cohort studies, and 2 randomized con-
Augmentation studies based on topiramate have trolled trials showed that the combination can
shown varied results. A 17-week, double-blind, increase the probability of response and reduce
placebo-controlled study on 80 patients failed to metabolic side effects of clozapine, but further
show significant benefits in psychotic symptoms studies are needed to explore clinical implica-
[174], while a12-week naturalistic, open study tion [181, 182].
128 S. Grover et al.
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Treatment Resistance in Bipolar
Disorders 9
Marsal Sanches, João Quevedo, and Jair C. Soares
that depressive symptoms, rather than manic or In conclusion, the concept of treatment-
hypomanic ones, tend to be more pervasive and resistant BD is not well established, and there is
associated with a higher degree of morbidity, not enough evidence to support it as a single con-
mortality, and functional impairment [8]. In addi- struct. The ISBD-proposed criteria are probably
tion to the at times limited treatment response the most appropriate for research purposes, while
observed during index episodes of bipolar depres- from a clinical standpoint, a more global concept,
sion, subsyndromal depressive symptoms are taking into consideration a number of therapeutic
common among BD patients in partial remission. agents necessary to achieve remission, degree of
Furthermore, patients with bipolar depression are response to treatment, functional impact of the
often more accessible for inclusion in controlled condition, and residual symptoms, is likely more
studies from a practical standpoint. On the other realistic and closely correlated with clinician’s
hand, most of the literature on resistant mania observations. The different definitions of resis-
comes from anecdotal reports and case series, tance as well as the multitude of therapeutic regi-
usually describing innovative therapeutic inter- mens potentially considered adequate for the
ventions, which will be discussed in the next sec- treatment of BD across its different phases make
tions of the present chapter. the comparison of different literature findings on
Finally, some authors attempted to identify the topic particularly challenging.
clinical features that seem to be associated with
treatment-resistant bipolar disorder. These stud-
ies usually utilize a retrospective approach, with 9.3 Pathophysiological Factors
different definitions of resistance. In a recently and Resistance
published naturalistic study [9], treatment resis-
tance was established based on the number of Literature data on the pathophysiological basis of
psychiatric medications and mood stabilizers treatment resistance in bipolar disorder is notori-
received. Resistance was found to be associated ously scant. Yet, it is possible to make some infer-
with female gender, older age, later onset of ill- ences from biological research addressing factors
ness, strong family history of depression, per- of poor prognosis among bipolar patients, as well
sonality traits such as irritability and as from studies assessing the possible role of
interpersonal sensitivity, employment status, degenerative processes in the pathophysiology of
benzodiazepine use, and comorbid anxiety dis- bipolar disorder. Further, some studies have ana-
orders and medical conditions. Similarly, mixed lyzed biological predictors of response to certain
states are often cited as indicators of poor therapeutic interventions.
response to treatment in BD [10]. The relation- For instance, the fact that patients with a stron-
ship between poor treatment response and sev- ger family history of depression are more likely
eral of these factors is likely bidirectional, with to display resistance to treatment [10] indicates
some of them possibly representing risk factors that the degree of genetic load for bipolar disor-
for poor response while others are probably der may impact response to treatment in bipolar
consequences of the functional and psycho- disorder. The heterogeneity of the concept of
pathological impact of the limited response to treatment-resistant BD is likely behind the lack
treatment. On the other hand, there is a certain of studies addressing genetic factors associated
consensus in the literature indicating that rapid with treatment resistance. Pharmacogenetic stud-
cycling (the presence of four or more mood epi- ies have identified several candidate genes asso-
sodes over the course of 1 year) is an indicator ciated with good response to lithium therapy
of poor response to treatment and worse prog- among bipolar patients [12], although the evi-
nosis [10]. Similarly, the number of mood epi- dence is less strong when it comes to other mood
sodes has been described as associated with stabilizers. Some of these findings may conversely
higher severity and worse prognosis among be seen as possible indicators of treatment
bipolar patients [11]. resistance.
142 M. Sanches et al.
Similarly, the finding that the number of epi- based options for the treatment of bipolar disor-
sodes is a factor of poor response to treatment in der in a stepwise fashion, therefore indirectly
bipolar disorder suggests that, over the course of targeting some of the resistant-to-treatment cases.
the illness, the bipolar brain suffers some degree Yet, no specific guideline focusing on those cases
of desensitization and possibly neurodegenera- is currently available.
tion. The kindling theory hypothesizes that,
while in early phases of the disease, environ- 9.4.1.1 Resistant Bipolar Depression
mental factors play a major role in triggering According to the ISBD guidelines, published in
mood episodes among bipolar patients, as the 2009 and updated in 2013 [7], lithium, lamotrig-
disease progresses, the threshold for triggering ine, quetiapine, and quetiapine ER should be
of a mood episode decreases, with sometimes considered as first-line monotherapy medications
minor stressors being associated with relapses for the treatment of bipolar depression. Based on
and recurrence in mood symptoms [13]. It has available evidence, divalproex and lurasidone are
been recently hypothesized that, in early phases listed as second-line agents, while carbamaze-
of the disease, putative endogenous compensa- pine and olanzapine appear as third-line mono-
tory mechanisms are able to counterbalance the therapy agents. A large number of combinations
negative impact that mood episodes seem to are listed as alternative treatments as first-, sec-
have on the brain of bipolar patients. However, ond-, and third-line agents. Despite the contro-
as the disease progresses, the compensatory versy regarding use of antidepressants in patients
mechanisms become overwhelmed, resulting in with bipolar depression (due to concerns about
neuroprogression and, likely, in resistance to the risk of manic-induced switch, rapid cycling,
treatment [13]. Evidence suggests that, among and possible lack of efficacy), they are listed
bipolar patients, intensity and chronicity of ill- among the recommendations, although not rec-
ness are associated cognitive impairment in the ommended as monotherapy. The guidelines state
inter-episode period, and neuroimaging studies that SSRIs (except for paroxetine) and bupropion
point to correlations between illness progression may be used in the acute treatment of bipolar
and the volume of several brain structures [14]. depression, in combination with a mood stabi-
These findings support the possible involvement lizer, with an ultimate goal of having the antide-
of neurodegenerative processes among bipolar pressants tapered off 6–8 weeks after remission
patients. At a biochemical level, evidence sug- of the depressive episode [7]. Venlafaxine and
gests that factors such as inflammatory process, tricyclic antidepressants should be avoided,
mitochondrial dysfunctions, and abnormalities although they (as well as MAOI inhibitors) do
in the gene expression on brain-derived neuro- appear as third-line option in combination with
trophic factors are involved in these neurodegen- mood stabilizers. Current evidence does not sup-
erative changes [13]. port the use of ziprasidone in the treatment of
bipolar depression. Similarly, randomized clini-
cal trials failed to demonstrate a significant effect
9.4 Therapeutic Approaches of aripiprazole in the treatment of depression in
for Treatment Resistance BD, although some open-label trials did suggest
in BD possible improvement among depressed bipolar
patients treated with that medication. Finally,
9.4.1 Pharmacological Agents augmentation with modafinil, as well as prami-
pexole (the latter, in combination with lithium),
While certain agents have been identified as of is listed as second- and third-line option for the
particular interest for the treatment of resistant treatment of bipolar depression [7].
patients, no particular medications have received On the other hand, the International College of
specific FDA approval for that purpose. Several Neuro-Psychopharmacology (CINP) recently
currently available guidelines offer evidence- published its own guidelines for the clinical
9 Treatment Resistance in Bipolar Disorders 143
management of BD, including bipolar depression Yet, the studies in question largely differ as for
[15]. It adopted a stepwise process similar to the several methodological issues (e.g., patient pro-
proposed by the ISBD, including however a file, use of saline versus midazolam in the control
broader range of agents and a higher number of group).
steps. According to the CINP guidelines, quetiap- In the only study to specifically address
ine and lurasidone should be considered as first- treatment- resistant, depressed bipolar patients,
line agents in the treatment of bipolar depression, ketamine infusions were found to produce a rapid
and monotherapy with aripiprazole does appear and significant improvement in anhedonia, even
as a treatment option for the treatment of bipolar when controlling for the total antidepressant
depression, as a step 3 strategy. Curiously, mono- effect, suggesting that the medication had an spe-
therapy with some antidepressants (including cific anti-anhedonic effect in resistant bipolar
imipramine, phenelzine, and tranylcypromine) is depression [18]. Also of notice, improvement in
listed as a viable option for the treatment of bipo- anhedonia was more pronounced among patients
lar depression, although the authors do state that, who were receiving lithium than among those
at the therapist’s discretion, an antimanic agent receiving valproic acid, and there was a direct
may be added as a prophylactic measure against correlation between the anti-anhedonic effect and
manic switching [15]. The CINP recommenda- increase in glucose metabolism (as observed
tions include several alternative agents as possi- through PET) in the dorsal anterior cingulate cor-
ble augmentation strategies, including tex and in the putamen, following the ketamine
pioglitazone (second step), lithium in combina- infusion. Given the mechanism of action of ket-
tion with oxcarbazepine or sulpiride (third step), amine (an NMDA receptor partial agonist), the
and mood stabilizers in combination with levo- finding above suggests that dysfunctions in the
thyroxine, armodafinil, or ketamine (fourth step). glutamatergic system are likely involved in the
Very few trials addressed the treatment of pathophysiology of anhedonia among resistant,
resistant bipolar depression. As part of the depressed bipolar patients. In a small, open-label
STEP-BD study, a randomized, open-label study study, patients with treatment-resistant bipolar
analyzed the effects of add-on inositol (compared depression were treated for 8 weeks with
to lamotrigine and risperidone) in the treatment D-cycloserine, an antibiotic with NMDA antago-
of resistant bipolar depression [16]. Participants nism properties, following a single ketamine
were receiving an optimized mood stabilizer reg- infusion [19]. Acute improvement was a predic-
imen (lithium, valproic acid, carbamazepine, or tor of response at 8 weeks, with five patients hav-
lithium plus valproic acid) in addition to either ing completed the study and four (out of a total of
one or two antidepressants. The overall recovery seven participants) achieved remission at
rate was low, and no differences were observed 8 weeks.
across the three treatment groups. The potential role of other alternative agents
Among the alternative agents mentioned in the treatment of resistant bipolar depression is
above, ketamine is considered a promising agent less clear, although several novel agents seem to
for the treatment of bipolar depression, although be promising. Scopolamine, a muscarinic recep-
the strength of the evidence is not as high as it is tor antagonist, seems to produce rapid improve-
in regard to the treatment of unipolar patients. ment in depressive symptoms, not only in
Nevertheless, at least four randomized clinical unipolar patients but also in BD [20]. Similarly,
trials have analyzed the efficacy of ketamine riluzole, a glutamatergic modulator, has been
infusions in patents with bipolar depression [17]. found to produce improvements when utilized as
Evidence suggests that the antidepressant an augmentation to lithium in depressed bipolar
response associated with that medicine in bipolar patients unresponsive to lithium as monotherapy
patients is similar to the one observed among uni- [20]. Omega-3 fatty acids have been extensively
polar patients, with improvements observed from studied in regard to their role in the treatment
40 min to several hours following the infusion. of mood disorder, including bipolar disorder.
144 M. Sanches et al.
Evidence suggests that they may be effective in role of these agents in the treatment of depressed
the treatment of bipolar depression, in contrast patients with bipolar disorder still demands fur-
with their role in the treatment of manic symp- ther investigation.
toms, which is not clear at this point [21].
Furthermore, given the large amount of 9.4.1.2 Resistant Mania
research pointing to the possible role of inflam- The management of treatment-resistant mania/
mation in the pathophysiology of BD, the effi- hypomania has been a neglected area of study.
cacy of agents with anti-inflammatory properties The ISBD guidelines for the treatment of BD list
in the treatment of BD (particularly bipolar monotherapy with lithium, valproic acid, and
depression) is of high interest. These agents several atypical antipsychotics (risperidone, que-
include nonsteroidal anti-inflammatory drugs tiapine, quetiapine XR, aripiprazole, ziprasidone,
(especially cox-2 inhibitors such as celecoxib, asenapine, and paliperidone) as first-line option
cimicoxib, and rofecoxib), N-acetylcysteine for the treatment of mania [7]. Monotherapy with
(which also seems to have antioxidant and anti- carbamazepine, carbamazepine ER, or haloperi-
glutamatergic effects), and minocycline, an anti- dol appears as second option, while third option
biotic with important anti-inflammatory includes chlorpromazine, clozapine, oxcarbaze-
properties, which seem to be independent of its pine, tamoxifen, and cariprazine as monotherapy.
antimicrobial effects [22, 23]. Pioglitazone, an Several medication combinations are presented
antidiabetic medication, has also recently been as alternatives to monotherapy, usually involving
tested in the treatment of bipolar depression, with a mood stabilizer and an antipsychotic.
positive results [24]. In contrast, in the CINP guidelines (which
Nevertheless, in a recent meta-analysis, the combine recommendations for manic and mixed
possible role of different agents (including anti- states), monotherapy with lithium appears as a
inflammatory drugs, N-acetylcysteine, omega-3 second-step strategy, while valproic acid or an
fatty acids, and pioglitazone) in the treatment of atypical antipsychotic (aripiprazole, quetiapine,
bipolar depression was addressed [25]. When cariprazine, paliperidone, quetiapine, risperi-
findings regarding all agents with anti- done, or asenapine) should be considered as first-
inflammatory properties were pooled and com- line therapy [15]. The recommendations
pared to conventional treatments, a moderate emphasize that past history of psychotic symp-
antidepressant effect was observed. However, toms should be taken into consideration.
when considered separately, the effect sizes of Adjunctive treatment with allopurinol, medroxy-
omega-3 fatty acids, pioglitazone, and nonsteroi- progesterone, and celecoxib, which are not
dal anti-inflammatory drugs were not considered included in the ISBD guidelines for mania, is
to be statistically significant. N-acetylcysteine listed as second-step option, while tamoxifen,
was the only agent that seemed to have indepen- either as monotherapy or an adjunct to lithium or
dent positive effects as an adjunctive treatment valproic acid, is listed as a fourth-step strategy.
for bipolar depression, although the effect size The strength of the evidence supporting the
resulted from one single study. The authors con- use of some of the alternative agents mentioned
cluded that, despite their promising role, it is not above varies. The role of clozapine in the man-
yet possible to recommend the use of any specific agement of resistant mania has been well
agents in question for the treatment of bipolar established by several studies and was
depression, in light of the available evidence. addressed in a recent systematic review [27]. A
Finally, despite its popularity in the treatment case series described the potential benefits of
of unipolar depression as an augmentation strat- clozapine rapid titration in patients with resis-
egy, the efficacy of thyroid hormones as augmen- tant mania [28]. To our knowledge, however,
tation agents in the treatment of bipolar depression no randomized clinical trials have analyzed the
is not clear at this point [26]. To date, studies usefulness and safety of clozapine under those
seem to have elicited conflicting results, and the conditions.
9 Treatment Resistance in Bipolar Disorders 145
Similarly, a recent meta-analysis supports the reducing subsyndromal mood symptoms of bipo-
use of tamoxifen, a protein-kinase C inhibitor, in lar disorder in children [32]. Given the benign
the treatment of patients with manic symptoms side-effect profile of these agents and their appar-
[29]. Allopurinol has been found to be effective ent safety as a long-term maintenance medica-
as an adjunctive agent in the treatment of acute tion, further research should assess their
mania in at least four randomized clinical trials, usefulness as a maintenance agent among BD
but its side-effect profile limits the use of that patients, especially those with partial remission
medication [30]. In the ISBD guidelines, allopu- and residual symptoms.
rinol is mentioned only as an alternative treat- Similarly, the role of cognitive impairment in
ment for patients that are “refractory to other euthymic bipolar disorder patients has been the
first-, second-, and third-line treatments.” object of several studies, although limited evi-
Celecoxib, a Cox-2 inhibitor previously assessed dence supports the use of medications in the
in regard to its possible role in the treatment of management of those symptoms [33].
bipolar depression, also seems to have potential Cholinesterase inhibitors seem to have limited
benefits in the treatment of mania. In a recent ran- value in the management of cognitive deficits in
domized clinical trial, celecoxib was found to be bipolar disorder. Anecdotic reports suggest
superior to placebo when combined with valproic memantine may have some role in the treatment
acid in the treatment of nonpsychotic mania [31]. of acute mania, but there is no evidence support-
ing its role in the treatment of cognitive impair-
9.4.1.3 Resistance During Maintenance ment during the maintenance phase. In one study,
Treatment mifepristone, a glucocorticoid receptor antago-
There is limited evidence on the pharmacological nist, seemed to produce some improvements in
treatment of resistant bipolar disorder during the the cognitive performance of depressed bipolar
maintenance phase, likely due to the difficulties patients, but to our knowledge, no study has
in characterizing refractoriness during that addressed its efficacy during the maintenance
period. The ISBD guideline recommendations phase of BD [33]. Another study showed
for maintenance include a large number of agents improvements in executive functioning associ-
as first-, second-, and third-line options, empha- ated with the use of intranasal insulin among
sizing that antidepressants should not be used as bipolar patients, possibly due to neuroplastic
maintenance agents as monotherapy [7]. Of effects of that agent on the dorsolateral prefrontal
notice, omega-3-fatty acids are mentioned as cortex [34].
adjunctive agents, as a third-line medication. The Finally, given the growing evidence support-
CINP guidelines emphasize the need to take into ing the conceptualization of BD as a chronic and
consideration the predominant polarity of each potentially disabling condition, psychosocial
patient (based on number of previous depressive interventions seem to play a prominent role in its
versus manic or hypomanic episodes) when management during the maintenance phase. This
deciding what medication regimen to be utilized issue will be addressed in the section “psychoso-
during maintenance [15]. It also recommends cial approaches” of this chapter (see below).
that the medications utilized during the index epi-
sode should be kept for at least 2 months follow-
ing remission, before changes are made to the 9.4.2 Neurostimulation
medication regimen.
As mentioned above, the use of omega-3 fatty Although electroconvulsive therapy (ECT) is
acids in bipolar disorder remains a controversial generally considered an effective option in the
issue. In addition to its apparent positive effects management of treatment-resistant mood disor-
on the treatment of bipolar depression, there is ders, the efficacy of ECT in the treatment of
also evidence suggesting that dietary supplemen- refractory bipolar disorder comes mostly from
tation with omega-3 fatty acids may be useful in anecdotic or open-label studies. Yet, the ISBD
146 M. Sanches et al.
guidelines list ECT as a third-line option in the that allows the electrical stimulation of the brain
treatment of bipolar depression and a second- through magnetic fields produced by a coil [38].
line option for the treatment of mania [7]. It is considered a noninvasive technique, and its
Among depressed patients, the guidelines efficacy in the treatment of unipolar depression
emphasize that early consideration should be has been widely demonstrated. Yet, few studies
given to ECT among patients with psychotic have specifically addressed its role in the man-
symptoms, at high suicide risk, and in those agement of bipolar disorder. Most of the evidence
with ongoing medical complications due to poor available comes from case reports or small, open-
ingestion of fluids and food. ECT is also men- label studies, often without a sham group.
tioned as a third-line option for the maintenance Nevertheless, these results point to possible ben-
treatment of BD, as an adjunctive agent. On the efits from excitatory TMS targeting the prefrontal
other hand, in the CINP guidelines, ECT is men- cortex in patients with bipolar depression [38].
tioned as a fifth step option in the management Two other studies analyzed the efficacy of inhibi-
of mania, bipolar depression, and also in the tory TMS targeting the right dorsolateral prefron-
maintenance phase [15]. tal cortex in bipolar depression, with positive
In a recent naturalistic, observational study results, although the conclusions were limited by
with 522 patients, ECT was found to be effec- the small sample size in one of the studies [39]
tive in approximately two-thirds of the patients and lack of a sham group in the other [40].
with depressed manic or mixed features and Similarly, the efficacy of TMS in mania has been
80% of those with catatonic features [35]. addressed in a small number of studies, and evi-
Predictors of nonresponse included length of the dence points to possible benefits of right prefron-
index mood episode and global severity of the tal cortex excitatory TMS in the treatment of
illness. Despite the promising results displayed mania [41]. Last, there is not clear evidence
above, the several methodological issues inher- regarding the possible role of traditional TMS in
ent to the nature of the study limit the general- the maintenance treatment of BD, although a
ization of its conclusions. In a meta-analysis, recent study pointed to decreases in the rates of
the rates of response to ECT were found to be depressive relapses among unipolar and bipolar
similar among patients with bipolar and unipo- patients treated with deep TMS, a novel modality
lar depression. In a randomized study, ECT was of TMS [42]. TMS is not mentioned in the ISBD
compared to an evidence-based pharmacologi- guidelines for the treatment of BD and is listed
cal algorithm for the treatment of resistant bipo- by the CINP guidelines as not recommended for
lar depression [36]. Results indicated a higher the treatment of mania or acute bipolar depres-
response rate in the ECT group than in the algo- sion [15].
rithm-based pharmacological treatment group, Similar to TMS, vagus nerve stimulation (VNS)
but no statistically significant differences is a well-studied therapeutic modality, widely
between groups were found with respect to the accepted for the treatment of resistant unipolar
remission rate. Concerns regarding the use of depressive disorder. It consists of an implanted
ECT in BD are related to the risk of manic stimulator that transmits electrical pulses to the
switch (among patients with bipolar depression) left vagus nerve [43]. Evidence regarding the effi-
and worsening cognitive impairment. In one of cacy of VNS in bipolar patients is scant and usu-
the studies mentioned above, though, the risk of ally comes from studies that pooled unipolar and
manic switch was found to be “almost nonexis- bipolar depressed patients under the label “resis-
tent,” and, in another study, ECT was found as tant depressive disorder.” A small, open-label
not being associated with worsening in the cog- study assessing the efficacy of VNS in the treat-
nitive function when utilized in the treatment of ment of rapid cycling bipolar patients pointed to
resistant bipolar disorder patients [37]. benefits over a period of 12 months [44].
Transcranial magnetic stimulation (TMS) is a Finally, there is very limited efficacy regard-
different modality of neurostimulation technique ing the efficacy of other neurostimulation
9 Treatment Resistance in Bipolar Disorders 147
techniques in BD. A noninvasive technique, tran- patients with bipolar disorder. Yet, psychosocial
scranial direct current stimulation (TDCS), interventions may be of benefit in the manage-
involves the application of a weak direct electric ment of treatment-resistant bipolar disorder,
current through two scalp electrodes [38]. specially in the maintenance phase. These
Literature findings suggest it may be promising interventions may include psychoeducational
in the treatment of bipolar depression, although approaches aiming at improving adherence to
very few studies, usually with small sample sizes, treatment, as well as other interventions focusing
specifically analyzed its role in the management on improving coping strategies and eventually
of depression in bipolar disorder, and there are decreasing the risk of a mood relapse associated
concerns about the possible risk of manic switch- with stressors. Studies support the role of
ing associated with the treatment [45]. Moreover, psychoeducation, cognitive-behavioral therapy
deep brain stimulation (DBS), another technique, (CBT), mindfulness-based interventions, family
has been used in the treatment of severe, resistant therapy, and interpersonal and social rhythm
unipolar depression. In DBS, an electric stimula- therapy (IPSRT) in BD [48].
tor sends pulses to specific brain areas through Yet, systematic reviews and meta-analysis
implanted wires [38]. Due to concerns about pos- focusing on the effects of psychosocial interven-
sible DBS-induced manic or hypomanic symp- tions in the treatment of bipolar patients have
toms, patients with bipolar depression are usually reached inconsistent conclusions. For example,
excluded from these studies, although a case the efficacy of CBT as an adjunctive treatment in
report of a bipolar patient treated with DBS sug- BD has been questioned in regard to its impact on
gested that the risk of a manic switch can be min- relapse prevention [49]. In a recent meta-analysis,
imized by concomitant use of mood stabilizer CBT was associated with mild-to-moderate
and decreases in the intensity of the stimulation effect sizes in regard to improvement not only in
[38]. Magnetic seizure therapy (MST), an experi- depressive symptoms but also in mania severity
mental therapeutic intervention, combines and psychosocial functioning [50]. Group psy-
aspects of ECT and TMS, aiming at producing choeducation has been found to produce positive
improvement in mood symptoms by inducing effects in terms of reducing frequency and num-
seizure activity, with a lower risk of cognitive ber of relapses, as well as duration of acute epi-
impairment when compared with ECT [46]. Very sodes and length of hospitalizations.
few studies with MST included bipolar patients, On the other hand, in a recent systematic
and the actual advantages and disadvantages of review focusing on the impact of different psy-
that therapeutic modality when compared to ECT chosocial treatments in BD, psychoeducation
in the management of treatment-resistant bipolar seemed to be effective only on a very specific sub-
disorder are still not clear. group of bipolar patients, with optimized mood
Last, a prospective study analyzed the longitudi- stabilization and full (or “very good”) remission
nal effects of a psychosurgical intervention (subcau- [51]. The same review presented a rather guarded
date tractotomy and cingulotomy) in the treatment scenario when it comes to the efficacy of other
of patients with severe, refractory bipolar disorder psychosocial interventions in the management of
[47]. Results over a 7-year period of follow-up BD, with family interventions displaying possible
pointed to significant reductions in the depressive benefits primarily for caregivers and unclear
symptomatology, while no apparent effects were effects in regard to patient’s outcomes. Studies
observed in regard to manic symptoms. focusing on interventions aiming at improving the
cognitive performance of bipolar patients, such as
cognitive remediation and functional remediation,
9.4.3 Psychosocial Interventions were found to display basically negative results.
In the review in question, mindfulness-based
There is a consensus as for the recommendation interventions seem to be effective only in reduc-
for long-term pharmacological treatment for ing anxiety symptoms, while in another recent
148 M. Sanches et al.
disability across mood states in bipolar disorder. Psychopharmacology (CINP) treatment guidelines for
Value Health. 2010;13(8):984–8. Bipolar disorder in adults (CINP-BD-2017), part 3:
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Sinyor M, Kessing LV, et al. Epidemiology, neuro- 2017;20(2):180–195.
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150 M. Sanches et al.
o utcomes. For example, when a meta-analysis by A clinical staging strategy utilises on the sub-
Benish et al. [20] concluded that CBT was no stantial body of research on the longitudinal
more effective than other active non-trauma- course of PTSD and the progressive sequential
focused therapies, this evoked strong counter- shifts in its neurobiology following traumatic
claim by a group of senior therapists from the stress exposure [25]. This methodology has been
cognitive behavioural school [21, 22]. This type advocated as a valuable framework to better
of dialectic has not encouraged a questioning of define the unpredictable treatment response and
the effectiveness of trauma-focused therapies as course of disorders, such as bipolar disorder and
should have occurred. schizophrenia [26, 27]. The staging approach is
More recent research has confirmed the lack thought to permit the identification of clear and
of differences between trauma-focused therapies detectible inflexion points in the course of a dis-
and a present-centred approach [23]. Furthermore, ease process that inform severity, prognosis and
a meta-analysis by Steenkamp et al. [24], founded treatment [28]. Staging moves away from a reli-
approximately two thirds of veterans continue to ance on cross-sectional descriptions and high-
retain their PTSD diagnosis following treatment lights the importance of studying illnesses
with cognitive processing therapy and prolonged longitudinally. The advantage of a longitudinal
exposure. Trauma-focused therapy is the only approach is that it offers the potential for the
marginally superior compared with non-trauma- early prediction of a range of later outcomes that
focused approaches. These findings highlight the reflect different trajectories and phenotypes. The
need to have more effective interventions, the increasing recognition of the prevalence of
extent of treatment resistance and the predictors comorbidity with PTSD and the lack of specific-
of treatment response. ity of most intervention strategies across psychia-
try highlight the need for more sophisticated
diagnostic reasoning.
10.2 C
onceptual Issues About PTSD is no different. The lack of utilisation of
Treatment Resistance a longitudinal perspective is reflected in the study
and PTSD of the way the biology of PTSD is lumped
together without consideration of the differences
In addressing the issue of treatment resistance due to duration of illness and earlier treatment
and PTSD, there are several bodies of literature interventions. In this regarded, PTSD tends to be
that have been relevant to this discussion. Critical seen as a unitary entity without consideration that
issues are the existence of a series of phenotypes it may reflect a series of stages in the progression
and the progression of the disorder. These are of the disorder, and this is necessary to better
underpinned by the increasing body of evidence characterise treatment nonresponse. The litera-
about the role of delayed onset in post-traumatic ture about delayed-onset disorder highlights the
stress disorder. Longitudinal studies that have imperative of this approach.
been highlighted are significantly more prevalent
than had previously been anticipated [25].
10.2.2 The Issue of Delayed Onset:
M/L Paper Trajectory ADF
10.2.1 The Utility of a Staging Model
of PTSD The importance of the impact of the longitudinal
course on the responses to traumatic events is
Advances in improving treatment resistance in highlighted by the increasing recognition that
PTSD requires a more sophisticated classification of delayed-onset PTSD is much more common than
PTSD that takes account of the heterogeneity of this previously thought. Delayed-onset PTSD was
condition and the progressions which occur with initially recognised in the DSM-III formulation
chronicity that impact on treatment responsiveness. published in 1980 [29]. DSM-IV specifically
10 Treatment Resistance in Post-traumatic Stress Disorder 153
defines that delayed-onset PTSD should be diag- much longer time periods has only limited exami-
nosed if “…the onset of symptoms is at least 6 nation literature. For example, a 20-year follow-up
months after the stressor” [30, Page 468]. A his- of a group of veterans with combat stress reactions
torical review about the delayed-onset PTSD and a group of veterans without stress reactions
emphasised how much of the confusion about indicated that in the latter group, the total number of
this construct has arisen from different defini- symptoms was greater 20 years after combat than at
tions of delayed-onset PTSD [31]. For example, any of the previous assessment points. This study
different interpretations of the construct included was of Israeli veterans of the 1982 Lebanon War
whether or not an individual who has had subsyn- and found that the rates of delayed-onset PTSD
dromal symptoms who has subsequently crossed emerged relatively soon in the aftermath of the war
a threshold of clinical severity has a delayed but again 17 years after the period of military ser-
onset or whether the term should be preserved for vice [35]. In fact, 23% of the Israeli veterans who
individuals who have been asymptomatic and did not develop an immediate acute stress disorder
then at some later point developed a disorder. subsequently went on to develop a delayed-onset
The existence of the delayed form of PTSD PTSD. Furthermore, in the Australian Vietnam
emphasises how a traumatic experience can Veterans Study, rates of lifetime PTSD were found
apparently lie relatively symptomatically dor- to increase over a decade, going from 20% in the
mant within an individual only to become mani- 1990s to 28% in the 2000s [37]. These studies high-
fest at some future point. This raises important light the long-term and continual increase in PTSD
questions about the mechanism of how a subclin- morbidity following trauma. In other words, the
ical state is triggered into a full-blown syndrome degree of symptomatic distress even in those with-
and how these switches may impact on treatment out PTSD does not seem to decrease with time. In
responsiveness. There is a broad body of scien- those without combat stress reactions, 14% of indi-
tific literature available that can assist in answer- viduals had PTSD in the 1st year in contrast to 26%
ing these questions. at the 20th year assessment [35].
There is substantial literature highlighting the These studies have been of populations who
risk of subsyndromal symptoms and the later have access to treatment services. If treatment was
emergence of full-blown disorder in the form of effective, there would be an expectation that with
delayed-onset PTSD [32–35]. One of the difficul- the passage of time, the rates of disorder would
ties summarising this literature is the variable decrease. The findings suggest the opposite,
periods of follow-up. One meta-analysis [36] namely, that the combination of age and time,
indicated that most studies have followed popula- despite the effects of treatment, leads to increasing
tions for less than 2 years, which provides little rates for disorder highlighting the importance of
information about the longer-term cumulative considering the issue of treatment resistance.
risk. Specifically, Smid et al. [36] found that the Given the interest in the longitudinal course of
mean duration of longitudinal studies was PTSD, it is surprising that there has not been a
25 months and the maximum range of 60 months. more systematic examination of this critically
In the combined study population, 24.8% (95% important clinical issue. Hence the literature sug-
CI = 22.6–27.2%) had delayed-onset PTSD. A gests that PTSD passes through a series of stages
regression analysis of this data showed that the as well as different subtypes where treatment
proportion of individuals with delayed-onset response should not be assumed to be unitary.
PTSD was larger when the duration of follow-up
was longer. They also found that traumatic expo-
sures in military populations were associated 10.2.3 The Impact of Cumulative
with a greater proportion of delayed-onset PTSD Stress Exposure
and when the cumulative incidence was lower.
One important limitation of the literature is that A further related issue that has not been system-
the probability of symptoms increasing across atically addressed in the treatment literature for
154 A. C. McFarlane
risk factors as is now increasingly the case with pain. Given the significant interrelationship
PTSD. One meta-analysis [52] concluded that between PTSD and somatic symptoms, these
the first onset of major depression was more shared mechanisms are of particular relevance in
likely to be preceded by severe life stress than assessing the importance and contribution of
were recurrent episodes of depression. In other stress exposure to conditions such as chronic
words, milder events can trigger the onset of back pain and fatigue-like syndromes and their
depressive episodes as the number of episodes role in treatment refractoriness [55, 56]. The role
of depression increases. Ultimately this process of these somatic symptoms in the treatment
can reach a point where the illness becomes responsiveness in PTSD has received remarkably
relatively autonomous of stress in situations little attention in the literature.
where the stressors are not required to trigger
the onset or what to an outside observer would
be regarded as a stressor is absent [53]. It is 10.2.5 The Model of Allostatic Load
important to examine whether a similar process
is occurring with PTSD and leading to increas- A further body of evidence highlights the under-
ing treatment resistance. lying mechanisms by which stress exposure can
Kendler et al. [54] have concluded that kin- modify subsequent reactivity to challenge, with
dling is particularly important in people who do exposure to stress leading to modification of a
not have a major genetic predisposition to depres- range of biological systems. This results in
sion, and this is a model likely to be applicable to increasing allostatic load due to the up-regulation
PTSD. Furthermore, this kindling effect has been of the inhibitory systems [57–59]. The allostatic
shown to disappear after approximately nine epi- load model has been used to refocus the stress
sodes when the process becomes increasingly disease literature, emphasising that their multiple
autonomous and may provide a model for emerg- biological systems are vulnerable to a temporal
ing treatment resistance in PTSD. This is in keep- cascade of dysregulation [55]. These progressive
ing with the kindling hypothesis that suggests dysregulations lead to the emergence of a range
that there is a threshold beyond which there can of disease trajectories as well as treatment resis-
be no additional sensitisation to the depressive tance. This approach provides a broader construct
state as maybe the case with PTSD. This implies than traditional models used in biomedical prac-
a transitioning to a pattern of increasingly auton- tice for understanding how repeated challenges
omous illness, where an increasing number of from the environment lead to increasingly mal-
episodes have been correlated with relative treat- adaptive disruptions of homeostatic mechanisms.
ment refractiveness [47]. The essence of the allostatic load model is that
In the case of PTSD, once the disorder has the body is subject to wear and tear with repeated
developed, triggers play a particularly important activation during stressful situations [60].
role in reinforcing the intrusive memories and At a neurobiological level, these inhibitory
the associated psychophysiological activity. systems are reflected in the prefrontal/amygdala
These memories increasingly become more and circuitry [60, 61]. Similarly, the HPA axis and
more spontaneous as a consequence of a kin- other neurohormonal systems are vulnerable to
dling-like progression. The support for the com- these mechanisms of sensitisation [57, 58].
monality of this mechanism also comes from Hence, when individuals who has suffered a
the role of serotonin in the rate of development major trauma exposure and then attempts to adapt
of amygdala kindling and the role of serotonin to day-to-day life including the normal stressors
reuptake inhibitors in the treatment of all of that occur within the community, the dysregula-
these conditions. tion of these underlying regulatory systems mod-
Sensitisation is also likely to play an impor- ifies their adaptability. Progressively, they react
tant role via kindling-like mechanisms in the to the presence of stressors with greater ampli-
somatic symptoms associated with PTSD such as tude or intensity and ultimately develop an
156 A. C. McFarlane
o vergeneralised reactivity to a range of stimuli the lack of investigation of this domain in the
that remind them of the traumatic event [62]. PTSD is surprising as it is highly probable that
This cycle of increasing reactivity to a widening similar observations would be made.
range of cues serves to further reinforce the dis- This effect is related to the sensitivity of the
tress response. This may, however, only become hippocampus to stress, a critical issue in PTSD. In
manifest as frank disorder after the passage of depression, it has been found that the length of
time and also logically lead to decreased treat- past depression impairs memory performance and
ment responsiveness as the disorder becomes that there is a significant toxic link between the
more chronic. Again, the lack of examination of burden of depression and cognition [9]. The role
this question in the treatment literature is of the hippocampus in the aetiology of post-
surprising. traumatic stress disorder has been similarly exten-
sively researched with several meta- analyses
concluding that individuals with post-traumatic
10.2.6 Shared Neural Circuitry stress disorder have a smaller hippocampal vol-
ume than individuals without this condition who
The models of sensitisation, kindling and allo- are trauma exposed and that this difference cannot
static load in PTSD highlight the importance of be solely attributed to a pre-existing vulnerability
the biological mechanisms of the onset and chro- as suggested by the study of [69].
nicity of this disorder. The underlying circuitry There is now a range of literature which sug-
neural regions which have been identified as gests that the hippocampus is one structure that is
being relevant to the aetiology of PTSD are vulnerable to morphological damage caused by
equally those involved in depression and the untreated illness such as in depression and
emergence of treatment resistance. For example, schizophrenia. This issue has been investigated in
amygdala reactivity has been identified as a pri- PTSD. It has been found that the longer the dura-
mary area of interest in PTSD, and this nucleus tion of illness, the greater degree of hippocampal
plays a central role in determining fear reactivity atrophy in post-traumatic stress disorder.
[63, 64]. The amygdala has also been extensively Importantly, the hippocampus is part of a neural
involved in the investigation of depression [65]. network associated with the dorsolateral prefron-
For example, Ramel et al. [66] highlighted tal cortex and the anterior cingulate whose activa-
how amygdala reactivity is an important issue in tion is critical to the outcomes of cognitive
people with a history of depression in contrast to behavioural therapy. Hence the damage to this
those without such a history. These results indi- network diminishes the probability of an ade-
cate how the amygdala plays a central role in quate treatment response in cognitive behavioural
modulating mood congruent memory, particu- therapy. Logically, the longer the illness goes
larly during the induction of sad states of mind in untreated and the greater the degree of the disrup-
individuals who are vulnerable to depression. tion of these networks, the less the probability
Hence, a known risk for individuals with PTSD is that the individual will have an adequate treat-
further exposure to environments that have trau- ment response. Furthermore, changes in the hip-
matic triggers because the obvious risks of acti- pocampus have been associated with insomnia
vation of fear-related circuitry are similar to the severity in PTSD. The importance of this finding
risks for individuals with depression to activate is that the structural abnormalities and the pro-
the neural systems associated with the vulnera- gressive disruption of hippocampal function at
bility to negative emotion and the onset of depres- the time of post-traumatic stress disorder have
sive episodes [67, 68]. Further evidence suggested also been specifically tied to the phenomenologi-
the underlying biological mechanisms of how the cal outcomes that are of clinical relevance [70].
duration of depression impacts on cognitive func- These findings have been studied in the
tioning and disability. Against this background, aftermath of a number of different types of
10 Treatment Resistance in Post-traumatic Stress Disorder 157
traumas [71]. In this sample, the severity of the that the duration of disorder did not influence the
re-experiencing symptoms was greater in those effectiveness, i.e. the time that had elapsed since
officers with smaller total and left hippocampal the traumatic exposure. However, people who
volume. They highlighted how the chronic present late for treatment cannot be presumed to
stress of having PTSD symptoms can contrib- have a disorder that has the same severity or
ute to smaller hippocampal volume [72]. In course as those presenting to closer proximity to
this study, the PTSD subjects had had their the trauma. The Gillespie et al. study [75] was an
symptoms for approximately 3 years highlight- effectiveness study following the Omagh bomb-
ing the possibility that these changes had ing, and the outcomes of those who presented
occurred. early for care were compared with those present-
Finally, further neuroimaging studies have ing in the latter period of the treatment service.
demonstrated increased activation of these Again those presenting in the immediate after-
regions of interest in patients who have success- math of bombing cannot be presumed to be the
ful outcomes from cognitive behavioural therapy. same as those presenting later. In particular, those
Therefore, factors that lessen the probability that presenting later may have a delayed-onset PTSD
these neural networks can be recruited in the where the high levels of acute distress in those
course of treatment are likely to lessen the prob- without a delayed onset may be indicative of dif-
ability of effective treatment outcomes. This lit- ferential risk factors. A study of sertraline [2] in
erature highlights the characteristics of these combat veterans where the mean duration of
predictors of treatment outcome that have been treatment was 17 years found no effect of the
examined in PTSD but have not led to more gen- duration of treatment, but this is not surprising,
eral consideration of the issue of treatment resis- given that sertraline was not demonstrated to be
tance in PTSD. an effective intervention in this population.
In contrast, the study of Duffy et al. [74] of
patients with PTSD in the context of terrorism in
10.3 T
he Relevance of Other Northern Ireland did find that the longer the delay
Issues from the General for presenting for treatment, the worse the
Literature outcome.
Hence, these studies do not provide an ade-
10.3.1 Duration of Illness quate scientific investigation of this question, and
the lack of investigation of this issue in PTSD in
There is no direct research that has examined the contrast to major depression, bipolar disorder and
impact of duration of illness on treatment outcome GAD is in fact surprising. Furthermore, there is a
in PTSD, despite the extensive research into this general consensus reflected in the general psychi-
question with other disorders. However, the major- atric literature about the gains that are obtained
ity of the naturalistic studies concluded that it did from the early intervention of psychiatric disor-
not impact on the effectiveness of interventions, der [76–78].
but these were substantially flawed from a meth- Given the commonality of the underpinnings
odological perspective. The studies that have con- of the aetiology in depression and PTSD, it is rea-
sidered this question of the impact of a delay in sonable to extrapolate from the factors that have
implementation of treatment in PTSD [2, 73–75] been identified as influencing treatment response.
have done this by re-examining existing treatment Kravitz et al. [79] reviewed the evidence and in a
studies. None were specifically designed to answer study of a further sample identified that recovery
this question; rather, this is being addressed in sec- from a major depressive episode was most
ondary analyses. strongly correlated with the length of the current
The Resick et al. [73] study compares CBT episode. Similar findings have been identified in
and cognitive reprocessing treatment and found a number of other studies where the longer the
158 A. C. McFarlane
illness length, the greater the delay in the remis- clinical stages as described above [27]. Similarly
sion onset [10–12]. It is improbable that the dura- in PTSD, it is necessary to identify which early
tion of illness is not a substantial determinant of symptoms are the likely markers of the risk to
treatment responsive of PTSD. chronic illness. Clinically and theoretically, there
has been a propensity to normalise the early symp-
toms of distress following traumatic stress expo-
10.4 Partial Remission sure [80, 81], thereby depriving the field of
to Treatment as a Protector important prognostic indicators for those who may
of Relapse be en route to a chronic course of illness.
Fortunately, biological studies of the acute stress
There is a substantial body of research that has response in those who develop PTSD at a later
examined the impact of partial remission follow- time have shown that there are important predic-
ing treatment in the course of a major depressive tors that differentiate these individuals from those
disorder on longitudinal course and recurrence. who demonstrate minimal reactivity [82, 83].
This perspective is of equal relevance to PTSD The question becomes, if trauma survivors
but has received virtually no systematic examina- have different biological alterations at early stages
tion. Pintor et al. [13] followed up a population of illness that appear to predict symptoms later
suffering from unipolar depression and identified on, even if they do not seem to have particularly
that the relapse rate in patients with partial remis- different symptomatic presentations in the early
sion was 67%. This study emphasised the impor- aftermath of trauma, should the biological infor-
tance of complete remission as an issue required mation be used to determine further treatment?
to decrease the rates of short-term relapse. This is Staging may be of considerable benefit if it is able
an important finding in the context of the fact that to differentiate patients who are likely to have
in the order of 80% of individuals have second good treatment outcomes with early intervention
episodes. These findings about major depressive from those who are less likely to benefit. The
episodes are pertinent particularly to individuals probable adverse effect of duration of illness is
who have a comorbid major depressive disorder one important predictor of prognosis. In PTSD,
and PTSD but are also likely to be applicable to like other psychiatric disorders, the need to docu-
those without the secondary comorbidity. ment the continually evolving dysregulation that
has a substantial probability of impacting on treat-
ment outcome is highlighted [84]. This worsening
10.5 T
he Utility of a Staging treatment outcome with increasing duration of
Approach to Addressing untreated illness is a further argument for a stag-
Treatment Resistance ing model. There needs to be more attention to
in PTSD defining the phenotypes and neurobiology of
those who are treatment resistance to allow a sys-
A staging approach to PTSD as with other disor- tematic examination of second-order treatments.
ders would provide a framework for addressing Specifically, if the course of PTSD rests on the
the changing patterns of treatment response if it fact that post-trauma neurobiological alterations
was systematically applied in treatment studies. It reach a point that results in persistent or progres-
requires an acknowledgement of the inadequate sive illness [4], then staging would have consid-
outcomes that current treatments, psychotherapeu- erable clinical utility. To test this hypothesis,
tic and pharmacological alike provide for a signifi- disease markers that have a direct clinico-
cant percentage of those with PTSD. The staging pathological correlation to the underlying patho-
approach highlights the need to characterise the physiology need to be characterised, and these
biological progression of the disease and how this need to reflect the emerging increasing severity
impacts on treatment response. This has been of the disorder [5, 85–90]. The research strategy
characterised in major depressive disorder, with has to involve longitudinal investigation of the
particular emphasis on the early treatment of pre- relationship between the biological characteris-
10 Treatment Resistance in Post-traumatic Stress Disorder 159
tics of PTSD and its stages. This approach also cal guidance regarding risks and benefits. A num-
needs to consider the related somatic comorbidi- ber of potential strategies such as the atypical
ties that have a shared biology. The aim of the antipsychotics [95], anticonvulsants [96], ket-
staging approach is to identify biomarkers that amine [97, 98] and prazosin [99, 100] have not met
have an adequate degree of specificity for PTSD up to their initial promise in the outcomes from
and to differentiate those that act as disease mark-clinical trials. MDMA-assisted psychotherapy is
ers from indicators of risk and vulnerability currently receiving considerable attention [101].
across the different stages, markers of disease However, other agents that have been trialled to
progression and epiphenomena [26]. assist cognitive behavioural interventions such as
The staging model further allows a framework propranolol [102] and d-cycloserine [103] have
for examining different biological models for not provided substantial evidence of benefits.
PTSD and how they overlap [25]. This requires a Perhaps the strategies that should be utilised to
long window of observation to investigate mod- further the knowledge about treatment resistance
els such as stress-induced sensitisation and should be adapted from the depression literature.
increasing inflammatory reactivity [91]. The neu- There is an increasingly sophisticated literature
robiology of the secondary adaptations of chronic about the role of inflammation in PTSD, and this
hyperreactivity and associated numbing in the may be a target for intervention [25]. Trials that
context of emerging mood disorder is likely to be investigate the potential augmentation benefits of
of particular importance in understanding chro- minocycline and aspirin that have been shown to
nicity and treatment resistance. In essence, time have benefit in major depressive disorder should be
is a critical dimension in dissecting the interplay considered [104]. Equally raised C reactive protein
of the matrix of biological phenomena that has has been found to be a predictor of improved
been examined in PTSD and treatment respon- response in depression to different types of antide-
siveness [92, 93]. The development of a model of pressants [105]. When the C reactive protein is
clinical stages of PTSD has much to recommend greater than one, targeting both noradrenergic and
itself to inform future possible novel treatments. serotoninergic neurotransmission leads to better
treatment response [105]. In contrast, medications
targetting serotoninergic neurotransmission alone
10.6 Candidate Strategies showed better treatment response when C reactive
protein levels were less than one. Hence inflamma-
The substantial body of the treatment studies in tion is another domain worthy of examining in deter-
PTSD has trialled interventions as a primary mining treatment response to medications in PTSD.
intervention for PTSD. The literature has very Also, the cognitive deficits in PTSD are an
few studies that consider the issues of augmenta- important cause of impairment and disability in
tion or second-line interventions that address PTSD [106]. The use of medications such as dex-
treatment resistance. amphetamine, donepezil and rivastigmine has
some promising findings but has not been subject
to large systematic trials [107].
10.6.1 Medication Approaches The lack of interest of the pharmaceutical
industry in funding such trials highlights the
A recent consensus statement about psychophar- importance of treatment resistance needing to be
macological approaches for PTSD statement high- addressed by organisations such as the Departments
lighted the paucity of treatment alternatives. It of Veterans Affairs and organising registries that
concluded that there was no visible horizon for assist in improving treatment outcomes. The per-
advancements in PTSD treatment [94]. The SSRIs sonalised medicine approach where interventions
remain the only FDA-approved treatments for are trialled in settings where there is a substantial
PTSD [8]. In clinical practice, a variety of off- neurobiological database collected on patients
label usages underpin the polypharmacy that is prior to the commencement of treatment has much
frequent. Hence most prescribing has little empiri- to recommend itself.
160 A. C. McFarlane
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Treatment Resistance
in Obsessive-Compulsive Disorder 11
Rachel Middleton, Michael G. Wheaton,
Reilly Kayser, and H. Blair Simpson
many patients reduce their OCD symptoms and patient to prematurely discontinue the medica-
about half achieve minimal symptoms [6–9]. tion [18]. Therefore, it is recommended that
However promising, these results indicate that patients begin at low doses and increase their
these treatment options are not universally effec- dose to the maximum tolerated. The maximally
tive, as up to 40–60% of individuals fail to tolerated dose should be maintained for a mini-
respond to these first-line treatments [10, 11]. A mum of 6 weeks to be considered an adequate
“treatment response” in OCD clinical trials has therapeutic trial [3, 16].
historically been operationalized as a decrease of Several clinical factors can also predict poor
25–35% in OCD symptoms, typically assessed response to SRIs. Higher levels of symptoms at
with the YBOCS, and often combined with a rat- baseline have been associated with lower levels
ing of “improved” or “very much improved” on of SRI response in multiple trials [12, 19, 20].
the Clinical Global Impressions-Improvement Comorbid tic disorders, such as Tourette’s, have
Scale (CGI-I) [12]. Individuals who fail to also been linked to poorer SRI outcomes. For
achieve a sufficient response, and those who con- example, in a study of 33 OCD patients on flu-
tinue to experience clinically significant symp- voxamine, 52% of OCD patients without a his-
toms despite a 25–35% decrease, are often tory of tic disorders achieved a significant
referred to as “treatment-resistant” [13]. When a decrease in symptoms (assessed by the YBOCS),
first-line treatment is not enough, several alterna- compared to only 21% of OCD patients in the
tives are available, depending on the type and comorbid tic group [21]. These findings have
degree of treatment resistance (i.e., resistance to been replicated in children and adolescents with
SSRIs, ERP, or both), as discussed below. the SSRIs sertraline and paroxetine [22, 23].
However, in a small pilot study, comorbid tics did
not appear to adversely impact response to clo-
11.2 Treatment Resistance mipramine [21]. One issue complicating the
with Pharmacotherapy interpretation of these data is that higher rates of
comorbid tic disorders have been linked to earlier
11.2.1 Predictors of SRI Response OCD onset [24]. Early age of OCD onset has also
been linked to treatment nonresponse across sev-
In the Cochrane review [14] meta-analysis of 17 eral SRIs [25–29], including fluvoxamine, parox-
RCTs (comprising more than 3000 participants), etine, citalopram, and clomipramine [28, 29].
researchers found SRIs to be associated with sig- Patients with OCD often present with comor-
nificant reductions in OCD symptoms, with an bid psychiatric conditions, most frequently anxi-
average YBOCS reduction for patients who ety disorders (e.g., panic disorder, social anxiety
respond to SRIs to be 30–60% from baseline. In disorder, generalized anxiety disorder, specific
this analysis, no individual medication emerged phobias), which appear in about 75% of OCD
as more efficacious. However, because the side patients [30]. However, the impact of comorbid
effects associated with clomipramine can be anxiety disorders on SRI response remains
more severe [5, 14, 15], treating clinicians typi- unclear. Most OCD studies have not found
cally begin with an SSRI. comorbid anxiety disorders to interfere with SRI
Ineffective dosages or insufficient duration response [17, 31], though an earlier review of this
may be responsible for poor response to SRI literature came to a different conclusion [32].
treatment, the so-called technical failure. Studies Unexpectedly, some reports have found that
show that higher doses yield, on average, higher comorbid PTSD predicts better responses in indi-
rates of improvement in symptoms [16]. viduals with certain OCD symptoms (hoarding,
Similarly, data suggest that doses should be contamination fears, illness concerns, mental rit-
maintained for at least 8–12 weeks for maximum uals, and/or superstition) [33]. A “post-traumatic”
therapeutic effects [17]. However, higher doses OCD subtype has been proposed as a potential
of SSRIs produce more side effects, leading some explanation for these findings, though further
11 Treatment Resistance in Obsessive-Compulsive Disorder 167
research on this area is warranted [34]. Although practice (e.g., fluoxetine up to 120 mg/day, fluvox-
panic disorder has not been shown to impact amine up to 450 mg/day, paroxetine up to 100 mg/
SSRI response in OCD, higher doses of SSRIs in day, sertraline up to 400 mg/day, citalopram up to
these individuals have been linked to increases in 120 mg/day, and escitalopram up to 60 mg/day)
panic attacks in multiple studies [17]. [17]. As noted above, since higher SRI doses may
Medication adherence has also been linked to increase the risk for side effects in some patients,
the likelihood of responding to SRI treatment, dosing should begin on the lower end after which
with nonadherent patients at risk for treatment dosages can be increased every 1–2 weeks to
failure [28]. Unwanted medication effects are a determine the maximally tolerated dose. Only fol-
barrier to adherence for many patients. Common lowing 6 weeks at this dose should a patient be
side effects with SRIs include gastrointestinal considered treatment-resistant [16].
problems (nausea, constipation, and diarrhea), Switching SSRIs or exploring monotherapy
weight gain, tremors, apathy, sleep disturbances with clomipramine are both alternatives for
(insomnia and/or vivid dreams), fatigue and som- patients who have experienced little to no
nolence, dry mouth, and sexual dysfunction response to an initial SSRI trial. It has been esti-
(decreased libido, trouble ejaculating, anorgas- mated that less than half of patients will benefit
mia) [16, 35], the latter three of which have been from switching from one SSRI to another, and
found to be the most predictive of medication dis- the likelihood of response diminishes as the
continuation for patients beginning pharmaco- number of failed adequate trials increases [16,
therapy [35]. Other patients may have difficulty 25]. Switching to clomipramine, a tricyclic anti-
with adherence to medication due to particular depressant that inhibits the reuptake of both
aspects of their presentation of OCD (e.g., those serotonin and norepinephrine, is often tried after
with contamination fears may be concerned two different SSRIs have not produced a signifi-
about what they ingest, making them more hesi- cant relief from symptoms. Although not typi-
tant to take medicine [36]). cally a first-line agent due to its side effect
A patient’s degree of insight may also impact profile (e.g., sedation, dry mouth, constipation,
his or her adherence to medication. Insight can be urinary delay, orthostatic hypotension, and car-
defined as the degree to which an individual recog- diac conduction delay), some meta-analyses
nizes the maladaptive nature of their symptoms. find that clomipramine can lead to larger effects
Several studies have reported poor insight as a sig- than SSRIs [39].
nificant predictor of poor SRI response [37, 38]. When patients experience a partial response to
serotonergic medication but continue to have clini-
cally impairing symptoms, SRI augmentation is
11.2.2 Management of Resistance often considered. In general, augmentation strate-
with SRIs gies involve the addition of either psychotherapy
(ERP) or an antipsychotic medication such as ris-
Patients who do not experience an adequate peridone. In our recent trial, we found ERP aug-
response to SSRIs may explore several different mentation to be more efficacious than risperidone,
options. If they do not have dose-limiting side even among patients who preferred medication
effects, a practical first step is to increase their over ERP [7, 40]. Given this result, as well as the
dose. The FDA has approved the following SSRI side effect profile of antipsychotics, augmentation
dose ranges for OCD: fluoxetine 20–60 mg/day, with ERP is the best to try first [41, 42].
fluvoxamine 100–300 mg/day, paroxetine However, ERP is not available to all patients,
40–60 mg/day, sertraline 50–200 mg/day, citalo- and not all are willing to try it. Therefore, anti-
pram up to 40 mg/day (20 mg/day in patients older psychotic augmentation remains a viable strategy
than 60), and escitalopram 10–20 mg/day [39]. for some patients. Haloperidol, risperidone,
However, higher doses are recommended in prac- quetiapine, olanzapine, and aripiprazole have all
tice guidelines and are commonly used in clinical been shown in RCTs to enhance response to
168 R. Middleton et al.
SRIs, though not all trials with these agents have patients discontinue treatment prematurely, and
had positive results [41–43]. It is unclear if mixed of those who complete, a subset does not respond
responses found across antipsychotic trials reflect [8]. Substantial effort has been made to describe
true differences in efficacy between these agents predictors of ERP outcomes in order to identify
or methodological issues with specific trials. patients at risk for poor outcomes. Both patient
Meta-analyses across all of these trials [42, 44, factors (e.g., patient adherence, comorbidity,
45] suggest that around one third of OCD patients degree of insight) and treatment factors (e.g.,
on an SRI will have a treatment response when an treatment intensity and duration) can influence
antipsychotic medication is added. Some data outcome [49].
suggest that OCD patients with comorbid tics are Patient adherence is the strongest predictor of
more likely to respond, particularly, to risperi- ERP outcome. ERP requires patients to confront
done and haloperidol [44]. Although effective for fears and refrain from compulsive rituals, both in
some, antipsychotics are associated with weight therapy sessions (under therapist supervision)
gain, metabolic syndrome, and a variety of extra- and between therapy sessions (as homework
pyramidal side effects including acute dyskine- assignments). Several studies have shown that
sias and dystonic reactions, tardive dyskinesia, the degree to which patients adhere to ERP
parkinsonism, akinesia, akathisia, and neurolep- assignments robustly predicts acute outcomes
tic malignant syndrome [44]. Patients starting an [50], and also outcomes 6 months later [51].
antipsychotic should be monitored closely for Monitoring patient adherence, particularly adher-
side effects, and the medication should be dis- ence to ritual prevention instructions, has also
continued if no benefits are observed after an been shown to prospectively forecast who will
adequate therapeutic trial of 1 month [16]. benefit from treatment, allowing treating clini-
There is some evidence from case studies to cians to make individualized treatment predic-
support augmentation with other pharmacologi- tions [40].
cal agents such as lithium, buspirone, and clonaz- Some studies have found that higher initial
epam. However, none were found to outperform OCD symptom severity and severe comorbid
placebo in small clinical trials, which may sug- depression can also predict poor ERP outcomes
gest that these drugs are only effective for a sub- [52]. However, other studies have not replicated
set of patients [46]. these findings, and a recent meta-analysis found
Monotherapy with other medications has also no relationship between either baseline OCD
been explored, including venlafaxine and mir- severity or depression severity and ERP effect
tazapine. Venlafaxine had robust effects on OCD size [53]. One potential explanation for these
symptoms in both open-label and double-blind mixed results is that it may only be severe depres-
comparator studies. However, these effects were sion that predicts ERP response, which has been
not replicated in a placebo-controlled trial [47]. excluded in many ERP trials. Severe depression
In one small study, mirtazapine was shown to be can also impact patient adherence to treatment,
effective in patients who have had no more than which may mediate the link with poor outcomes.
one failed SSRI trial [48]. Similarly, other common comorbid disorders
found in OCD populations (e.g., obsessive-
compulsive personality disorder and comorbid
11.3 Treatment Resistance anxiety disorders) warrant clinical attention when
with ERP they impact a patient’s ability to adhere to treat-
ment [17].
11.3.1 Predictors of Treatment Some studies have reported that patients with
Resistance poor insight are less likely to experience an ERP
treatment response compared to patients with
Although the evidence supporting ERP is sub- good or fair insight [30, 54]. However, other
stantial [17], not all patients benefit. Some studies have found no association between insight
11 Treatment Resistance in Obsessive-Compulsive Disorder 169
and treatment response [17, 50, 55]. One possible terms of strength, with patient adherence to the
explanation for these different outcomes is ERP playing a major role and showing a consis-
restriction in range of insight, as few patients tent relationship with ERP outcomes [58]. Given
with the poorest insight present for treatment. how effective ERP is for individuals with OCD,
The link between insight and outcome may also further study is warranted and should include
be via patient adherence. For example, early both therapist and patient factors as well as bio-
studies found that approximately 25–30% of logical, psychological, behavioral, and sociocul-
patients who begin ERP drop out due to the tural variables.
nature of ERP (i.e., ERP requires the patient to
confront their anxiety [56]). Thus, the APA rec-
ommends that clinicians gauge patient insight as 11.3.2 Management of Treatment
a preliminary step to the establishment of a treat- Resistance with ERP
ment plan [17]. Assessing insight before treat-
ment selection can inform the clinician of their When a trial of ERP does not yield a sufficient
patient’s motivation and willingness to adhere; treatment response, therapists should consider
this information can in turn be factored into the increasing exposure intensity (i.e., utilize stimuli
patient’s treatment plan. that induce higher levels of anxiety) and/or
Therapist fidelity to ERP is another factor that increasing the duration and frequency of sessions
may play a role in treatment outcomes. If ERP is before considering a different type of therapy or
not administered effectively, patients may not exploring pharmacological options. There is
respond [57]. Effective ERP administration some evidence that ERP sessions are more effec-
involves exposing patients to distress-provoking tive when administered intensively (at least twice
stimuli and then persisting in the exposure for a weekly); however, this benefit may plateau at five
sufficient amount of time in order for the patient sessions per week in outpatient treatment [10,
to learn that the situation can be managed without 17]. Increasing dose and intensity may be partic-
giving into compulsive rituals [52]. Therapist ularly helpful for patients who need extra support
failure to follow these treatment procedures dur- in adherence outside of session ERP assignments,
ing sessions may interfere with patients’ ability including those with poor insight [10, 62].
to benefit from ERP. Some data also suggest that Residential treatment is another option when
the frequency of sessions also can affect treat- outpatient ERP does not succeed. In the United
ment outcomes, as reviewed below. States, several specialty residential programs
Finally, other factors have also been identified have been established focusing on OCD, includ-
in individual studies to affect ERP outcomes, ing programs at Rogers Memorial Hospital and
including gender, marital status, and baseline the McLean Institute at Massachusetts General
quality of life/functioning. For example, some Hospital. Even though these programs tend to
studies have reported that females have poorer enroll patients with high illness severity, who
ERP response as compared to males [58], while often also have multiple comorbidities, both pro-
others have found that married/partnered patients grams have reported positive results in terms of
fare better than single patients [59]. Similarly, reducing OCD and depressive symptoms [63–
Maher et al. reported that individuals with worse 65]. Residential programs allow patients to
quality of life at baseline had poorer ERP receive multiple hours per day of ERP work,
responses [58], while Wheaton et al. found that delivered in both group and individual formats.
greater problems in functioning at baseline pre- When ERP does not succeed as a monother-
dicted poorer ERP response [60]. However, for apy, it can be combined with either medica-
each of these variables, multiple other studies tions or other techniques from other forms of
have reported null results [61]. It may be that psychotherapy. For example, psychotherapy
many factors each play a small role in ERP out- incorporating cognitive therapy may offer an
comes which can vary from sample to sample in alternative or an augmentation strategy to
170 R. Middleton et al.
standard ERP [66]. Cognitive therapy involves implanted electrodes. Recent literature has
identification and modification of distorted or focused on the CSTC circuit as a target for this
dysfunctional beliefs, and some trials have treatment modality [71], with a double-blind
found it to be effective at reducing OCD symp- trial and several case reports/series focusing on
toms, although these trials have not been as the anterior limbs of the internal capsules
extensive those for ERP [46, 67]. (ALIC) and the subthalamic nucleus. A case
series investigation in which the ALIC was tar-
geted using DBS found a greater than 25%
11.4 Treatment Resistance decrease in YBOCS scores in 73% of partici-
to Both SRIs and ERP pants. Studies using the subthalamic nucleus as
a target have not reported significant decreases
SRIs and ERP alone, or in combination, can help in YBOCS scores [72, 73]. While DBS is
up to 50% of OCD patients become well [7, 9]. reversible (in the sense that the stimulation can
However, any of the aforementioned factors can be turned off and the electrodes removed from
interfere with achieving wellness, and thus many the brain), risks include brain hemorrhage,
continue to suffer. After thoroughly exploring the infection, and new onset of seizures. For these
treatment options outlined above, the use of more reasons, DBS is only used in treatment-refrac-
experimental therapies may be warranted. These tory populations [17].
include neuromodulatory treatments and even Neurosurgical lesions can be produced
neurosurgery. either surgically or using radiosurgical
Transcranial magnetic stimulation (TMS) is a (“Gamma Knife”) techniques. Different lesions
noninvasive method for either stimulating or have been tried: subcaudate tractotomy, capsu-
inhibiting neural transmission. Greenberg et al. lotomy, cingulotomy, and limbic leucotomy
(1997) found that a single session of stimulation [74, 75]. Case series find that 30–70% of
of the right lateral prefrontal cortex (PFC) led to patients have at least minimal improvement
a decrease in compulsive urges that lasted for symptoms following these procedures [10, 76].
8 hours. Since then, there have been several trials The first RTC of gamma knife capsulotomy
of repetitive TMS (rTMS) targeting different was conducted in 2014. The final report found
brain regions [46]. Meta-analyses of existing tri- that two of the eight patients who received the
als of rTMS studies suggest that rTMS of pre- procedure responded at the 12-month follow-
frontal regions (specifically the dorsolateral PFC) up and an additional two responded at the
may not be effective in OCD, but low-frequency 54-month follow-up [77]. A second report dur-
rTMS targeting the supplemental motor area ing an open phase of the same study found sig-
appears to be promising [68–70]. nificant improvement in two out of four patients
Patients deemed treatment refractory (i.e., who were elected to undergo the procedure
failed at least three adequate SRI trials, several after initial randomization to the sham condi-
augmentation trials (e.g., with an antipsychotic or tion. No patients in the sham condition of
clonazepam), and at least one adequate CBT either phase reported an improvement in symp-
trial) are potential candidates for neurosurgical toms [78]. Ablative procedures are irreversible
interventions. These interventions include either and can lead to serious adverse events (SAEs)
making targeted lesions in cortico-striatal- including seizures, increased executive dys-
thalamic- cortical (CTSC) circuits or altering function, apathy, disinhibition, suicide, weight
activity within these circuits using deep brain gain, brain hemorrhage, stroke, edema, hydro-
stimulation (DBS). cephalus, and personality change [75, 79].
DBS involves delivering electrical impulses Thus, ablation is only used in treatment-refrac-
to various areas of the brain via surgically tory populations.
11 Treatment Resistance in Obsessive-Compulsive Disorder 171
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Treatment of Opioid Dependence
12
Michael Soyka
For many substance use disorders, such as support alone than in those who receive opioid
cocaine, amphetamine and cannabis use disorder, agonist therapy [10].
there are no approved medications or standard In recent years, the USA in particular has
therapy. This is not the case for opioid depen- experienced an epidemic of misuse of opioid
dence, however, for which some gold standards prescription drugs (painkillers), such as oxyco-
for treatment have been defined [1] and novel done. In the USA, 2.6 people per 1000 use her-
medications are available for otherwise treatment oin [11] and in Europe, 4 per 1000 [9]. In 2015,
refractory individuals and for those with side about half of the 33,091 opioid overdoses
effects or severe adverse events. involved opioid prescription drugs [12], and
In ICD-10 [2] and DSM-IV [3], opioid about two million individuals in the USA had
dependence is defined by various somatic, psy- an opioid use disorder associated with prescrip-
chological and behavioural symptoms (three tion opioids [13]. Prognosis and treatment
out of six or seven criteria must be fulfilled). It adherence are often poor in opioid use disor-
is a chronic, relapsing disorder [4] with high ders, with only about a third of patients suc-
mortality rates from comorbid psychiatric and cessfully completing treatment [14]. Apart
physical diseases (hepatitis, HIV, carcinoma, from psychosocial therapies, which often have
etc.), particularly in untreated individuals [5, only a limited effect on abstinence rates in opi-
6]. The rates of cardiovascular and respiratory oid dependence, opioid maintenance treatment
disorders, suicide and traffic accidents are also is a well-proven, first-line approach [15]. Oral
high [7]. Worldwide, 33 million people misuse methadone (MET), buprenorphine (BUP) and a
opioids [8]. In the European Union, the num- combination of BUP and the opioid antagonist
ber of opioid users is estimated at 1.3 million naloxone (BUP/naloxone) are frequently used
people. Opioids account for and can be detected for treatment [1, 16–18]. All three treatments
in 82% of fatal drug intoxications [9]. Mortality have been studied extensively in opioid depen-
from overdose is high and was found to be dence [1, 15, 19–21], and numerous studies and
higher in patients who receive psychosocial meta-analyses have demonstrated the efficacy
of both MET and BUP [17, 22, 23]. For com-
M. Soyka prehensive reviews, see Mammen and Bell [16]
Medical Park Chiemseeblick, Bernau, Germany and Yokell et al. [24]. Meanwhile, a number of
Psychiatric Hospital, University of Munich, pharmacological options are available or on the
Munich, Germany horizon for the treatment of opioid dependence
e-mail: m.soyka@medicalpark.de (see Table 12.1).
Table 12.1 Available and potential pharmacotherapies for at least a day. BUP is available in two tablet
for opioid dependence
forms: BUP only and BUP/naloxone. Because nal-
Drug name Method of administration oxone has poor sublingual but good parenteral bio-
Available treatments availability, it precipitates opioid withdrawal only
Methadone Oral, i.m.
when administered intravenously. Thus, the com-
Buprenorphine/naloxone
bination tablet aims to prevent patients from dis-
Buprenorphine film Sublingual
Buprenorphine Depot (implant) solving and injecting the tablet and consequently
Naloxone i.v., nasal to reduce the risk for misuse and diversion.
Naltrexone oral, Depot Naloxone has a short elimination half-life in
Morphine sulphate oral plasma of about 30 min [31]. Further information
Diacetylmorphine i.v. on the emergency treatment of opioid overdose
Potential treatment with naloxone is given below (under “Alternative
Hydromorphone i.v. Treatments in Treatment-Refractory Patients”).
The induction phase is important for and pre-
dictive of treatment outcome, especially for BUP,
Most studies on MET and BUP have been and thus requires special attention [32].
short or medium term (of several months of dura- MET is orally absorbed and basically metabo-
tion), but a few long-term studies have also been lized in the liver by CYP3A4 (demethylation) to
performed [25, 26]. Studies comparing MET and the inactive metabolite EDDP. There is a strong
BUP have shown that both drugs have compara- genetic variability of CYP3A4 activity among
ble effects on opioid use, but the retention rate is individuals. CYP2D6 and possibly CYP1A2 also
somewhat lower in BUP-treated patients [27–29]. play a role. CYP3A4 inducers such as many anti-
In our large naturalistic 6-year follow-up study retrovirals may reduce methadone concentrations
[30], we found high overall retention rates in both possibly causing withdrawal symptoms.
MET- and BUP-treated patients and no differ- BUP is absorbed sublingually; CYP3A4 and
ences in retention rates between the two to a lesser extent CYP2C8 convert and
medications. N-dealkylate it in the liver to the active metabo-
lite norbuprenorphine. Both BUP and norbu-
prenorphine are metabolized further by uridine
12.1 Methadone and diphosphate glucuronosyltransferases (UGTs).
Buprenorphine Pharmacology: Similar to MET, BUP does not significantly
induce or inhibit P450 enzymes, but it may com-
MET is a long-acting synthetic opioid that, in pete with drugs that are metabolized by the same
combination with psychosocial interventions, pathways. BUP is only a weak inhibitor of
effectively treats opioid dependence [15]. It CYP3A4.
addresses symptoms of opioid withdrawal and
reduces craving and opioid-induced euphoria. It
is a full agonist at the mu- and all other opioid 12.2 Dosage
receptors, whereas BUP is an agonist at the mu-
opioid receptor and an antagonist at the kappa- The usual dosage of MET is 60–120 mg/day, but
opioid receptor. higher dosages may be given, especially in rapid
MET can be ingested in a liquid form or as a metabolizers. BUP is usually started at 2–4 mg/
tablet and is orally active. BUP, on the other hand, day [15] and can be increased by 2–4 mg/day.
has low bioavailability after oral administration The typical BUP dosage for maintenance treat-
because it is subject to extensive first-pass metabo- ment is 8–16 mg/day, and the Food and Drug
lism in the liver. Consequently, BUP tablets are Administration (FDA) limits the dose to a maxi-
administered sublingually. Both MET and BUP mum of 24 mg/day [15]. A dose of 16 mg/day of
have a long half-life and bind to opioid receptors BUP suppresses 80% of the opioid receptor. The
12 Treatment of Opioid Dependence 181
BUP/naloxone tablet contains BUP and naloxone Both drugs cause typical opioid-related side
in a 4:1 ratio, i.e. BUP 2 mg/naloxone 0.5 mg or effects. The side effects of MET include sedation,
BUP 8 mg/naloxone 2 mg. respiratory depression, constipation, decreased
Dosing issues are critical for treatment reten- appetite, sweating (which may be a reason for
tion and outcome, and numerous studies have switching to other medications) and fatigue [38].
shown the extreme importance of administering Caution is required when MET is taken in combi-
an adequate dose in opioid-dependent individu- nation with other CNS “downers”, such as alco-
als. Many patients are underdosed and may expe- hol and psychotropic drugs. In addition to
rience opioid withdrawal or craving as a respiratory depression, BUP can also cause anxi-
consequence. A meta-analysis of 21 randomized ety, sweating, constipation, headache, insomnia,
clinical studies showed that the retention rate for nausea, dizziness, asthenia and somnolence.
BUP is better at a higher dose (16–32 mg/day) Liver enzyme elevations or hepatotoxic effects
than at a lower one (<16 mg/day). Similar results may occur with buprenorphine [39], although
have been published for MET [33]. The results of they are rare [40].
a 24-week randomized multicentre study com-
paring the effects and treatment retention rates of
MET and BUP in 1267 patients [34] found a 12.3.1 Cardiotoxicity
higher retention rate with MET than with BUP
(74% vs 46%) and a retention rate of up to 80% Opioid-induced QT prolongation or arrhythmias
in the MET group when the maximum dose (torsade des pointes) have been repeatedly
reached or exceeded 60 mg/day. In BUP patients, described in opioids [41], especially with MET
the completion rate also increased and reached a and other full opioid agonists when given at
60% retention rate at doses of 30–32 mg/day. A higher doses [42, 43], and may limit clinical use.
lower dose (BUP <16 mg/day, MET <60 mg/day) The cardiac side effects increase the risk of sud-
was associated with dropout. The induction phase den cardiac death.
for BUP is crucial: in patients with more severe The first step in patients with cardiotoxic side
withdrawal symptoms, a lower dropout rate was effects is to reconsider the dosage and possible
found if the dose was increased more rapidly in interactions with other drugs; the second step is
the induction phase [35]. to change the opioid being given. With respect to
cardiotoxicity, BUP appears to be safer than
MET and to have fewer or no cardiotoxic effects
12.3 Safety and no risk of cardiac arrhythmias [44, 45].
Another alternative is to use morphine sulphate
A comprehensive review on 58 prospective stud- (see below).
ies of people with opioid dependence [36] indi-
cated high mortality rates (all-cause mortality:
2.09 per 100 person-years [PY]) but confirmed 12.4 Alternative Treatments
that maintenance treatment significantly lowers in Treatment-Refractory
rates compared with untreated heroin depen- Patients
dence The review found that most patients died
from overdose and the risk was higher in males The first approach in treatment-resistant patients
and in patients during out-of-treatment periods. is to switch from MET to BUP or vice versa. No
Both MET and BUP may cause respiratory precautions are necessary when switching from
depression, but at higher concentrations, BUP BUP to MET, but switching MET to BUP may be
has a ceiling effect for respiratory depression more difficult. Because BUP can induce precipi-
[37], i.e. higher doses of BUP >24–32 mg/day do tated withdrawal, opioid-dependent patients
not further increase its respiratory depressant should wait until they experience mild to moder-
effect. ate opioid withdrawal (tremor, mydriasis,
182 M. Soyka
r estlessness, vomiting, anxiety, rhinorrhoea, etc.) MET and therefore requires “more clinical atten-
before taking the first MET dose. Many guide- tion to manage greater safety issues” [54]. In
lines suggest reducing the MET dose to most countries, significant regulatory restrictions
30–40 mg/day before initiating treatment with limit the use of diacetylmorphine, and it is avail-
BUP [15]. able only in special supervised treatment
settings.
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Disclosure For the past 5 years, MS has worked as a con- treatment for opioid use disorder: a national, five-
sultant or has received research grants from Lundbeck, year, prospective, observational study in England.
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Treatment-Resistant Panic
Disorder 13
Mu-Hong Chen and Shih-Jen Tsai
Panic disorder is one of the most frequently national reports were able to suggest the severe
observed mental illnesses with a chronic or a disease burdens due to panic disorder, panic dis-
remitting-relapsing condition [1–3]. Panic disor- order treatments in the real world remained frus-
der includes two symptomatic domains: somatic/ trating. Only about one-third of the patients with
physical domain and cognitive domain. The panic disorder have treatment contact in the first
somatic/physical domain expresses repetitive year of onset [12, 13].
panic attacks with various somatic/physical Increasing evidence indicated that panic disor-
symptoms, such as palpitation, dyspnea, chest der is a remitting-relapsing or a chronic or mental
pain, sweating, numbness, nausea, and dizziness; illness, significantly interfering with the individ-
as for the cognitive domain, panic disorder mani- ual’s functions and life qualities [14–19]. With
fests in the development of phobic avoidance, recommended treatment methods from current
behavioral changes due to panic attacks, and per- clinical guidelines [20–25], only about one-third
sistent worries and concerns for the future attacks of the patients with panic disorder could be
[1–5]. In the human population, the prevalence of symptom free at long-term follow-up, and yet
panic disorder is approximately 2.7% at over 50% of patients did not achieve remission,
12 months and 4.7% during one’s lifetime [6–8]. with threshold or subthreshold panic symptoms,
An American national survey reported that particularly in terms of cognitive and phobic
panic disorder individuals had around a doubling avoidance [14, 15, 17, 18, 26, 27]. A recent cross-
risk of 1-month work impairment than that of national study further reported that, among indi-
mood disorders, causing 1.7 working day absence viduals with experiences of panic attacks, the
[9]. The World Health Organization survey dem- majority (66.5%) had recurrent panic attacks
onstrated that around 1% of all disability-adjusted [28]. Relapses of panic disorder commonly occur
life years and 3.5% of all years lived with disabil- in life among half of the panic disorder patients
ity worldwide were due to anxiety disorders, [15, 16, 18, 19, 29–31]. However, the definition
including panic disorder [10, 11]. Although inter- of treatment-resistant panic disorder (TRPD)
remains unclear despite that several studies stated
M.-H. Chen · S.-J. Tsai (*) the need to elaborate this clinical phenomenon in
Department of Psychiatry, Taipei Veterans General this decade [32–35]. In this chapter, we wish to
Hospital, Taipei, Taiwan address the concept, psychopathology, pathogen-
School of Medicine, National Yang-Ming University, esis, and potential treatment strategies for TRPD.
Taipei, Taiwan
practice, we should assess the panic disorder con- der indicated that approximately 1/3 of panic
dition from symptomatic and functional views. patients would be free from panic disorder with
The symptomatic criteria (i.e., HAM-A or PDSS) the standard treatments, another 1/3 would
and the functional criteria (i.e., Sheehan improve and partially respond to treatment, and
Disability Scale score or CGI) should be inte- yet the last 1/3 would be considered the TRPD
grated together for defining the remission of group by the current treatments [15, 17–19,
panic disorder [47, 48]. In addition, the symptom 33, 49].
severity should be positively correlated to the
functional impairment, indicating a greater
symptom severity correlating with higher func- 13.2 F
actors Related to Treatment
tional impairment and vice versa [47, 48]. For Resistance
example, the HAM-A score ≤7–10 is approxi-
mately equal to a CGI-severity score <2 [47, 48]. Factors associated with the failure to achieve
The scores of 2–5 and 0–1 in PDSS corresponds response and remission in panic disorder could
to the CGI-S score of “borderline mentally” and be the representatives of factors associated with
“not at all ill,” respectively [41]. TRPD. We proposed five major risk factors for
TRPD should be defined as the failure to TRPD, including the characteristic essence of
achieve remission according to the previously panic disorder, personal demographic character-
mentioned criteria after at least 9–12 months of istics, comorbid medical illnesses, comorbid psy-
optimal treatment [43, 44]. The follow-up studies chiatric disorders, and psychosocial factors, in
assessing the long-term prognosis of panic disor- the following text (Table 13.2).
13.3 T
raits Defining Panic higher impulsivity, the more neuroticism, the
Disorder lower extraversion, the higher levels of harm
avoidance, the lower levels of persistence, and
Symptomatic manifestations of panic disorder, borderline personality traits may be related to
such as severe panic and anxiety symptoms, TRPD [73–76, 78, 79]. Furthermore, the higher
greater severity in panic-related distress, higher the expectations for the treatment effect, the
panic attack frequency, higher degree of agora- higher the confidence in the treatment rationale
phobic avoidance, more persistence of anticipa- and the stronger the beliefs about the manage-
tory anxiety and phobic avoidance, panic attacks ability of panic disorder contributing to the better
with fear of dying or going crazy, nocturnal panic therapeutic response [54, 80]. On the contrary,
attacks, and non-respiratory subtype of panic dis- the psychological and behavioral resistance to
order, were associated with TRPD. Furthermore, therapy and the therapeutic alliance increased the
earlier panic disorder onset age, longer clinical likelihood of treatment resistance of panic disor-
course, relapse of panic attack, greater residual der [72, 73, 77]. In addition, sensitivity toward
functional and social difficulties, and continued personal anxiety was another predicting factor
use of anxiolytics have also been suggested as the for the treatment response of panic disorder [81–
susceptibility to TRPD [14, 16, 17, 19, 26, 30, 86]. Reduced anxiety sensitivity indicated treat-
50–60]. ment response of panic disorder, but high anxiety
sensitivity was linked to subsequent panic attacks
and relapse of panic disorder [83].
13.4 Personal Demographic
Characteristics
13.6 Psychiatric Comorbidities
Sex and ethnicity may have a role in the treat-
ment responses or resistance of panic disorder. Comorbid psychiatric diseases, such as bipolar
Low social economic status or ethnic minority disorder, obsessive-compulsive disorder, major
had been reported to be associated with treatment depression, agoraphobia, other anxiety disorders
resistance in panic disorder [52, 61–63]. Women (social phobia, generalized anxiety disorder),
reported a later onset and achieved significantly personality disorders, as well as substance use
greater improvement than men [14, 16, 19, 30, disorders, would be associated with increased
53, 62, 64]. Age may be another factor. Both symptom severity of panic disorder and decreased
pharmacotherapy and psychotherapy for anxiety individual functioning. The psychiatric comor-
disorders, including panic disorder, may not be as bidities were also related to the deterioration in
effective for older patients as they are for younger the clinical course and poor prognosis of panic
patients [65]. Furthermore, family history of disorder [1, 14–18, 30, 53, 64, 87, 88]. Psychiatric
bipolar disorder, major depression, and anxiety comorbidities would increase the risk of treat-
disorders may be also related to treatment resis- ment resistance in panic disorder.
tance of panic disorder [66–69].
heart disease and cerebrovascular diseases [96, disorder who had more psychosocial stresses
98–100]. Previous studies reported that panic dis- would be more severely ill, with higher severity
order may worsen in postpartum and menopause of panic disorder, increased medical and psychi-
[101–103]. In addition, panic disorder occurred atric comorbidity, and also greater disability and
less frequently in the aged than in younger adults functional impairment [52, 53, 110–117].
and rarely had onset in old age [104]. Panic
attacks that began in old age should prompt a
detail search for physical diseases or medications 13.9 Potential Pathophysiology
that could be contributing to their presence [104]. of TRPD
Some symptoms of medical comorbidities were
very similar with symptoms of panic attacks, 13.9.1 Genetic Factors
such as palpitation, dyspnea, chest tightness, nau-
sea, and dizziness. In addition, some medical Several monoamine-related neurotransmitter
comorbidities may induce the onset of panic pathway genes, such as serotonin transporter and
attacks and disrupt the clinical course of panic monoamine oxidase A (MAOA) genes, have been
disorder and were also associated with the found to be related to the onset age, persistence,
impaired individual functions. When atypical and therapeutic response of panic disorder [40,
panic symptoms, such as changes in conscious- 119–123]. Individuals who carry the high-
ness, additional physical symptoms, and longer expression alleles of a promoter repeat polymor-
panic attack, are noted during panic attack, phism in MAOA (MAOA-uVNTR) were
prompt intervention for medical comorbidities susceptible to panic disorder, had greater panic
should be suggested. Furthermore, some medica- symptom severity, and poorly responded to stan-
tions, such as rifampin, Vicodin, interferon, dard antidepressant treatment [40, 122]. The
mefloquine, isotretinoin, rimonabant, corticoste- inhibitory anterior cingulate cortex-amygdala
roids, and trimethoprim-sulfamethoxazole, may coupling during fear conditioning was modulated
trigger or worsen the panic attacks [105–109]. by the L/L genotype of the serotonin transporter-
The comprehensive scrutiny for physical condi- linked polymorphic region (5-HTTLPR) and has
tions and medication use was warranted. Panic been regarded as a biomarker to predict treatment
patients with a greater burden of physical disease responses in panic disorder [121]. The 5-HTTLPR
were more psychiatrically ill, with higher sever- S allele was related to poor treatment responses
ity of anxiety symptoms, greater disability, and in panic disorder patients [123]. Homozygote GG
more psychiatric comorbidities [94]. carriers of serotonin 1A receptor (HTR1A)
-1019C/G polymorphism responded poorly to
treatment with antidepressants and were more
13.8 Psychosocial Factors likely to become resistant to medication treat-
ment [123, 124]. In addition, several serotonin
Stressful life events and childhood adversities transporters and HTR1A and MAOA polymor-
may be related to the age of onset, persistence, phisms have been found to modulate activity in
and the relapses of panic disorder [52, 53, 110– specific brain regions, such as amygdala and pre-
117]. Psychosocial stressors included issues in frontal cortex, which play significant roles in
social support, social environment, occupation, panic disorder and its treatment response [125,
economy, personal loss, legal issues, and instabil- 126]. Furthermore, the genetic variants affecting
ity in interpersonal relationships, as well as child- pharmacodynamics or pharmacokinetics of med-
hood adversities including sexual abuse and ications for panic disorder may have a potential
physical and/or emotional ill-treatment. Early role in the treatment response of panic disorder
childhood adversities would increase likelihood [127, 128]. For example, CYP2C19 genetic poly-
of developing panic disorder after exposure to morphism *1/*1 as an extensive metabolizer was
stressful life events [118]. Patients with panic associated with poor outcome of escitalopram
194 M.-H. Chen and S.-J. Tsai
treatment for panic disorders [128]. However, from cortical level (i.e., prefrontal cortex), and
pharmacogenetic studies investigating the genetic the modulation of the hippocampus for the above
contribution to treatment response of panic disor- brain circuits, which played a critical role in
der were still limited and thus require further TRPD.
genome-wide association studies to clarify this
issue.
13.9.3 Hypothalamus-Pituitary-
Adrenal (HPA) Axis
13.9.2 Brain Circuit Dysfunction Dysregulation
A number of specific brain regions, such as the HPA axis plays a crucial role in the physiology of
prefrontal/orbitofrontal region, cingulum, hippo- fear conditioning and fear- and anxiety-related
campus, amygdala, striatum, and insular cortex, behaviors, which are the core psychopathology
play crucial roles in anxiety sensitivity and are of panic disorder [141–146]. Several studies sug-
implicated in the gating, processing, and integra- gested that dexamethasone, which suppressed the
tion of threat information based on functional cortisol levels in a negative feedback manner,
neuroimaging studies [1, 33, 86, 129–133]. The may facilitate the fear extinction and reduced
chronic anticipatory anxiety and phobic avoid- fear-associated physical symptoms [147, 148].
ance in panic disorder were mediated by intero- Panic disorder patients demonstrated increased
ceptive fear conditioning of internal physical overnight cortisol secretion and greater ampli-
cues such as palpitation and dyspnea of panic tude of ultradian secretory episodes relative to
attack and have been found to be a predictor for healthy controls, and those with high frequent
poor therapeutic response [1, 33, 86, 131–134]. panic attacks had shifted corticotropin circadian
The decoupling processing between amygdala cycles [141, 142]. The hypercortisol state was
and anterior cingulate cortex and increased acti- still noted in the remitted, drug-free panic disor-
vations in the anterior insula, orbitofrontal cor- der [149]. In addition, similar with the findings in
tex, dorsal anterior cingulate cortex, amygdala, post-traumatic stress disorder patients and much
and dorsomedial prefrontal cortex may contrib- different with the findings in major depressive
ute to the threat anticipation of somatic symp- patients, panic disorder patients showed a corti-
toms and anxiety sensitivity and were associated sol hypo-responsiveness after the Trier Social
with the treatment outcome of panic disorder Stress Test, independent of comorbid depression
[130–132, 135–138]. Enhanced activation in the [150]. Furthermore, panic disorder patients who
anterior cingulate cortex, the amygdala, and the had the non-suppression of dexamethasone sup-
hippocampus in response to a safety signal was pression test had more anxious symptoms, more
noted in panic disorder patients who have poor work and social dysfunction, and more likely to
response to cognitive-behavioral therapy (CBT) develop major depression as well as a more dis-
[137], and on the contrary, increased activation in abling chronic panic conditions [151]. Those
dorsolateral prefrontal cortex and insula during patients who had complete remissions after med-
threat processing was related to improved ication treatment had less evidence of overactiv-
response [133]. Voxel-based morphometry stud- ity of HPA axis at baseline than those who did not
ies determined a relative increase in insula and a achieve remission [152]. Another hypothesis for
reduction in anterior cingulate cortex in panic the influence of HPA axis in patients with panic
disorder [139, 140]. disorder was the dissociation between the HPA
In summary, the persistence and maintenance axis response in panic disorder and the subjective
of conditioning fear and cognitive and phobic stress response, which might be the outcome of
avoidance were mediated by the dysregulation in an overfocused self-monitoring leading to an
bottom-up excitement of the limbic system (i.e., increased stress perception in spite of normal or
insular cortex, amygdala), top-down inhibition only mild HPA axis activation [145].
13 Treatment-Resistant Panic Disorder 195
The modulation of HPA axis may be one of the Acute and chronic stresses may induce alterations
critical treatment strategies for panic disorder. The
in sensitivity of inflammatory pathways to multi-
levels of cortisol and corticotropin significantly ple stress signals [170, 171, 174]. Previous reports
decreased after cognitive intervention in panic dis-have demonstrated the link between systemic
order patients who were treated with cholecystoki- inflammation and anxiety disorders [173, 175].
nin-B agonist pentagastrin (a pharmacological Higher level of interleukin (IL)-6 was associated
trigger of panic attacks) [153]. However, antide- with current panic disorder compared to remitted
pressant treatment had no substantial effect on cor-panic disorder and was related to higher scores of
tisol response to cholecystokinin tetrapeptide PDSS [176]. Increased level of C-reactive protein
(CCK-4), although antidepressants could also (CRP) was found in the late-onset anxiety disor-
reduce 50% of full panic attack frequency induced ders [173]. Particularly, higher levels of CRP,
by injection of CCK-4 in panic disorder patients tumor necrosis factor (TNF)-α, and IL-6 were
[154]. The above findings may implicate the differ- related to the somatic symptoms of anxiety disor-
ent underlying mechanisms for treating panic disor-der, whereas only CRP level was associated with
der between pharmacotherapy and psychotherapy. cognitive anxiety symptoms [177].
Stress axis dysregulation, including autonomic
nervous system imbalance and alternation in HPA
13.9.4 Brain-Derived Neurotrophic axis, was related to panic disorder and would fur-
Factor (BDNF) ther support systemic inflammation and contribute
to increased panic symptoms by having effects on
BDNF plays an important role in the amygdala- fear- and anxiety-related brain regions (i.e., the
dependent fear conditioning [155–159] and may prefrontal cortex, hippocampus, amygdala, and
play a role in the pathophysiology of panic disor- insula) [172]. Furthermore, interferon treatment
der [159–163]. Animal studies suggested that may reduce and interfere with the panic disorder
BDNF had a panicolytic-like effect [164, 165]. treatment response of cognitive therapy [108].
Subjects who had a lower serum BDNF level had Therapeutic cell-mediated immunity intervention
an increased risk of developing panic disorder may relieve the anxiety symptoms [178]. The
and were more likely to have a poor therapeutic treatment-resistant panic disorder may be associ-
response [159, 161]. In addition, individuals who ated with the cumulative impacts of systemic
had BDNF 196G-1175C haplotype were prone to inflammation due to psychiatric comorbidities,
developing panic disorder [161, 166]. Potential psychosocial stressors, and physical disease.
effects of BDNF in the pathophysiology and
treatment prognosis of panic disorder may moti-
vate further studies to clarify the role of other 13.9.6 Biopsychosocial Model
neurotrophic factors in the clinical manifestation, Hypothesis
course, and prognosis in panic disorder.
Bringing the above evidences together, we pro-
posed a biopsychosocial hypothesis to explain
13.9.5 Chronic Systemic the potential pathophysiology of the treatment-
Inflammation resistant panic disorder. Individuals who carry
some risk alleles (i.e., serotonin transporter and
Chronic systemic inflammation and related HTR1A and MAOA genes) for panic disorder and
changes of inflammatory cytokines may play cru- have family members having panic disorder or
cial roles in the mental illnesses (including panic other major psychiatric disorders may exhibit an
disorder) as well as in many physical diseases, early onset, a higher symptom severity, and a
including metabolic diseases and cardiovascular poor prognosis of panic disorder, further suffered
diseases [167–173]. Low-grade systemic inflam- from some psychosocial stresses and childhood
mation was also related to psychosocial stresses. adversities, and also manifested the dysregulated
196 M.-H. Chen and S.-J. Tsai
Perception of
change in
bodily state
Brain circuit
Insular dysfunction
cortex
Sensory
cortex Conditioning
Cin- Pre- fear & panic-
Genetic gulate frontal related phobia
susceptibility cortex cortex
Thalamus
Systemic
inflammation
Periaqueductal Hypothalamus
grey
Stresses
Locus Autonomic HPA axis Trauma
caeruleus pathway
Panic symptoms
Fig. 13.1 Biopsychosocial and cognitive model for treatment-resistant panic disorder
top-down inhibition from cortical levels and one with antidepressants has shown a better
increased bottom-up excitement of the limbic therapeutic response in patients with panic dis-
system, as well as the long-term systemic inflam- order compared with antidepressant treatment
mation, resulting in a higher propensity for the alone [179–186] (Table 13.3), despite a recent
treatment resistance (Fig. 13.1). meta-analysis which failed to support the medi-
Because the definition of remission and treat- cation augmentation in treatment-resistant anxi-
ment resistance in panic disorder did not achieve ety disorders [187]. However, atypical
a clinical consensus, the underlying mechanisms antipsychotics-related metabolic syndrome and
for treatment-resistant panic disorder were less benzodiazepine-associated risk of dependence
investigated and remained unclear. Here, we should be thoroughly taken into consideration,
proposed the potential biopsychosocial model to and a comprehensive risk and benefit assess-
explain the treatment resistance in panic disorder, ment should be made for the combination treat-
but the exact pathophysiology required more ment [188, 189]. The chronic use of
investigation in the future. benzodiazepines may indicate a poor treatment
response of panic disorder. Antidepressants are
usually the preferable agents than benzodiaze-
13.10 Therapeutic Strategies pines as the first-line treatment for elderly
for TRPD patients with panic disorder [104]. Other poten-
tial agents for TRPD included GABA-ergic
13.10.1 Pharmacological anticonvulsants (i.e., gabapentin, pregabalin),
Intervention anti-inflammatory agents, antihistamine, low-
dose ketamine infusion, xenon, metabotropic
Combination treatment of atypical antipsychot- glutamate II receptor agonists, and D-cycloserine
ics, benzodiazepines, or buspirone and azapir- [190–197].
13 Treatment-Resistant Panic Disorder 197
above strategies still failed. Of course, the 7. Kessler RC, Chiu WT, Demler O, Merikangas KR,
Walters EE. Prevalence, severity, and comorbid-
patients’ individual characteristics may be related ity of 12-month DSM-IV disorders in the National
to the clinical decision-making to select the most Comorbidity Survey Replication. Arch Gen
favorable treatment option for patients. For Psychiatry. 2005;62(6):617–27.
example, CBT may be used as first choice for a 8. Kessler RC, Chiu WT, Jin R, Ruscio AM, Shear
K, Walters EE. The epidemiology of panic attacks,
patient who concerned or cannot withstand the panic disorder, and agoraphobia in the National
medication’s side effects, and pharmacotherapy Comorbidity Survey Replication. Arch Gen
may be the first-line treatment strategy for Psychiatry. 2006;63(4):415–24.
patients who have more physical symptoms 9. Kessler RC, Greenberg PE, Mickelson KD,
Meneades LM, Wang PS. The effects of chronic
rather than cognitive symptoms, such as persis- medical conditions on work loss and work cutback.
tent worries for additional panic attacks. J Occup Environ Med/Am Coll Occup Environ Med.
2001;43(3):218–25.
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Ferrari AJ, Erskine HE, et al. Global burden of dis-
Panic disorder, in its chronic, remitting, ease attributable to mental and substance use disor-
relapsing, and treatment-resistant forms, sig- ders: findings from the Global Burden of Disease
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Treatment Resistance in Anxiety
Disorder: Generalized Anxiety 14
Disorder and Social Anxiety
Disorder
Kang Soo Lee and Sang Hyuk Lee
factors in treatment resistance can be classified as attention deficit hyperactivity disorder, which
treatment- and patient-related factors. Treatment- can lead to non-compliance and maladapted
related factors include incorrect diagnosis and behavioral coping strategies.
inappropriate treatment such as inadequate dos-
ing schedules and insufficient maintenance dura-
tion. Patient-related factors include such 14.3 Strategies for Treatment
comorbidities as personality disorders, substance Resistance
abuse, and poor adherence. Factors associated
with treatment resistance according to Bystritsky Correct and complete diagnostic workup of anxi-
are divided into aspects related to the pathology ety disorders and comorbidities, as well as the
(lack of knowledge on the pathophysiology, inac- appropriate delivery of pharmacological and psy-
curate diagnosis, limitation of the biological chological treatment, is crucial to maximize ther-
treatment), patient (symptom severity, comorbid- apeutic benefits for anxiety disorders. For patient
ities, nonadherence), professional (lack of CBT engagement, psychoeducation, including the
skills, cost), and environment (stress, childhood clinical course of the illness and the conse-
experiences, life cycles) [9]. Pollcak listed fac- quences of optimal treatment, is important.
tors associated with treatment resistance as Finally, comprehensive assessment and appropri-
related to the patient (comorbidity, lack of adher- ate targeted interventions are needed to achieve
ence), related to the treatment (incomplete diag- remission or recovery [13].
nosis, inadequate treatment), and related to the The first step in overcoming treatment resis-
logistics (lack of training, inadequate health sys- tance is reassessment of diagnosis and reevalua-
tem) [10]. tion of the treatment effectiveness [9]. Patients
The exact biological mechanisms of who fail to respond to at least two SSRIs, one
treatment-resistant GAD and SAD are unknown. serotonin-norepinephrine reuptake inhibitor
GAD shares substantial genetic variation with (SNRI), and cognitive behavior therapy (CBT)
major depression and the personality trait neu- should be reappraised, and the presence of
roticism. An alarm reaction mediated by activa- comorbidities, including personality disorder,
tion of neuronal circuits including amygdale should be reevaluated. Treatment compliance and
and other limbic structures is most often found adequacy of medication treatment must be
in neuroimaging studies of GAD. Right hemi- explored. In terms of pharmacotherapy, augmen-
spheric involvement and a variety of abnormali- tation or combination strategies have been
ties in the amygdala and superior temporal attempted in treatment-resistant anxiety disor-
gyrus were also observed in GAD. Abnormalities ders. Examples of augmentation or combination
in the limbic-medial prefrontal circuit shown in strategies for treatment resistance include using
functional neuroimaging studies may be critical buspirone, lithium, or other mood stabilizers as
for the pathophysiology of SAD which has dys- add-on therapy, combining two SSRIs or an SSRI
functional emotion regulation by reappraisal of with an SNRI, or using tricyclic antidepressants
social criticism. Some studies suggested that with SSRIs. Although the scientific data do not
reduced resting-state functional connectivity report any good efficacy for polypharmacy, the
between the amygdala and orbitofrontal cortex use of multiple drugs with different mechanisms
predicted treatment resistance in SAD [11, 12]. is not unusual in treatment-resistant anxiety
Psychosocial theories of treatment resistance in patients. Augmentation with medication is one of
GAD and SAD underestimate environmental the best strategies for patients who are
factors associated with severe persistent stress- treatment-resistant. Antipsychotics, anticonvul-
ors. Another important factor of treatment resis- sants, and other novel medications have been
tance in GAD and SAD is comorbidity such as studied for patients who fail to respond to stan-
major depressive disorder, personality disorder, dard treatment. The use of long-term benzodiaz-
bipolar disorder, substance use disorder, and epines for treatment-resistant anxiety disorder is
14 Treatment Resistance in Anxiety Disorder: Generalized Anxiety Disorder and Social Anxiety Disorder 209
debated due to high comorbidity rate of anxiety Although a study conducted for resistant SAD
disorders with substance use disorders. The use did not show the superiority of combination treat-
of g-aminobutyric acid (GABA)-ergic anticon- ment over either treatment modality alone [23],
vulsants involving gabapentin, pregabalin, and the most common first action by most clinicians
tiagabine leads to less dependency but also is less when a patient does not respond to one of the two
effective [14, 15]. Several medications show bet- initial treatment modalities is to combine two
ter efficacy than SSRI monotherapy. One of the treatment modalities. A newer approach to com-
most valuable findings was the combination bined treatment for treatment of anxiety disor-
treatment of SSRI and atypical antipsychotics for ders is that pharmacotherapy is used not to
anxiety disorders, including social anxiety disor- attenuate symptoms but to enhance extinction
ders without psychotic symptoms. learning [24]. The N-methyl-D-aspartate
Several pharmacological agents with novel (NMDA) partial agonist D-cycloserine contrib-
mechanisms of action such as substance P, NK, utes consolidation of conditioned fear and extinc-
and corticotropin-releasing factor (CRF) antago- tion memory in animal models [25]. In a
nists have recently been tested but have failed to proof-of-concept study, 28 patients with phobia
prove their efficacy [16, 17]. The most attractive were randomized to exposure therapy plus
targets for new anxiolytic development include D-cycloserine or placebo, administered before
non-serotonin, dopamine, norepinephrine, and each of two weekly exposure sessions.
non-GABA neurotransmitters that have been D-Cycloserine resulted in significantly fewer
implicated in the development of anxiety disor- anxiety symptoms compared with placebo during
ders as shown in preclinical studies. the trial as well as long-term follow-up. In a rep-
Neuropeptides are short-chain amino acids that lication study of the D-cycloserine effect, it has
act as neurotransmitters and are involved in a shown better treatment effectiveness in 27
wide range of brain functions, including reward, patients with SAD [26].
food intake, social behaviors, mood, and stress
response. The most prominent groups of these
small neuropeptide receptor ligands are sub- 14.4 Generalized Anxiety
stance P, CRF-1, CRF-2, neuropeptide Y, chole- Disorder
cystokinin (CCK)-2, and galanin [18, 19]. A
CCK-B antagonist which has known reduced Most of the patients with GAD follow the chronic
potentiated states of anxiety has been studied in wax and wane course. Effective management of
patients with GAD but was not more effective treatment-resistant GAD has not yet been deter-
than a placebo [20]. mined, and there are few studies suggesting
Recently, psychotherapeutic modalities such available options for treatment-resistant
as mindfulness, meditation, interpersonal, and GAD. Some evidence-based pharmacological
psychodynamic therapies have been tested in and psychotherapeutic treatments for GAD
various anxiety disorders [21, 22]. It is apparent include SSRIs, SNRIs, and CBT. However,
that a complicated patient may require long-term despite appropriate treatments, many patients
consistent treatments. Combining CBT and phar- with GAD fail to achieve remission in both short-
macotherapy for patients who do not respond to and long-term follow-up studies [27, 28], and as
either treatment alone indicates the need for an few as 38% of patients have achieved remission
alternative treatment strategy. Few randomized at 5 years [29]. Treatment options for patients
trials comparing combined pharmacotherapy and who failed to respond to pharmacotherapy
CBT, with either modality alone or with a pla- suggest the need for augmentation with other
cebo, have been conducted with treatment- antidepressants, benzodiazepines, or pregabalin,
resistant anxiety disorders. A more definitive despite their own limitations [30]. Until now, few
advantage for combined treatment has been studies have investigated the efficacy of pharma-
shown in SAD and other anxiety disorders. cological treatment and/or psychotherapeutic
210 K. S. Lee and S. H. Lee
[55]. It is remarkable that in some patients, drug done with SSRIs or benzodiazepines [66]. In
response occasionally starts only after both studies, the augmentation strategies were
8–12 weeks [56]. proven to be successful, although placebo-
Although there are few studies about SAD, controlled studies are necessary to confirm those
there is weak evidence that other SSRIs or venla- observations. Further, in one small randomized
faxine may be effective in patients with SAD controlled trial, olanzapine monotherapy also
who have failed to achieve a remission to an ini- showed a possible option for SAD [63].
tial SSRI treatment [57–59]. Despite the adverse Delivering CBT for treatment-resistant SAD
effects and dietary restrictions, monoamine oxi- seems to be a reasonable strategy, as supported by
dase inhibitors (MAOIs) are also thought to be studies suggesting that the combination of MAOI
alternative agents in the treatment-resistant SAD and CBT is superior to either treatment alone [71,
[60]. A number of open studies have suggested 72]. A partial NMDA agonist, D-cycloserine, was
preliminary efficacy of MAOIs in treatment- studied as a newer treatment option with exposure
resistant SAD. The use of escitalopram and cita- therapy in anxiety disorders [25]. Preliminary evi-
lopram in patients who have failed to respond to dence has suggested that D-cycloserine signifi-
other SSRIs showed also positive results [34, 61]. cantly enhances the effectiveness of an attenuated
In open studies describing the use of SNRI or exposure therapy for SAD [73]. Although meta-
MAOIs in treatment-resistant SAD patients, ther- analyses have demonstrated significant effects of
apeutic outcomes have also been improved [60, CBT, as well as pharmacotherapy, a significant
62]. Based on evidence suggesting anxiolytic proportion of patients does not achieve remission
properties of the olanzapine, an olanzapine from these treatments [74]. Treatment-resistant
monotherapy warrants new approaches for the SAD may be very common in clinical practice but
treatment-resistant patients with SAD [63]. currently has no systematic studies [75].
Likewise, efficacy was suggested for an anticon-
vulsant topiramate, valproic acid, and levetirace-
tam in open-label trials in SAD [64–67]. References
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Treatment Resistance in
Attention-Deficit/Hyperactivity 15
Disorder
15.1 Introduction 5.3% for children and adolescents [5]. The male
to female ratio becomes more evenly distributed
Attention-deficit/hyperactivity disorder (ADHD) in adulthood [6]. Inattention symptoms tend to
is one of the most common and widely researched persist, while hyperactivity symptoms decline
disorders of childhood [1]. According to the with age [3]. ADHD persists into adulthood for
DSM-5, it is a neurodevelopmental disorder up to 60–65% of cases [7, 8]. In both children and
characterized by at least six of nine inattention adults with ADHD, a larger percentage of females
symptoms and/or at least six of nine hyperactiv- are diagnosed with ADHD-inattentive type than
ity/impulsivity symptoms. Specifiers include males, but males are more likely to be diagnosed
predominantly inattentive presentation and pre- with ADHD-combined presentation, as well as
dominantly hyperactive/impulsive presentation, with ADHD overall [9].
and the disorder can be categorized as mild, mod-
erate, or severe. Symptoms must interfere with
functioning or development and must be present 15.3 Impact
prior to the age of 12 to qualify for ADHD (Table
15.1) [2]. The economic and psychosocial costs of ADHD
are significant for patients, their families, and
the society. In 2000, the annual estimated eco-
15.2 Epidemiology nomic cost of ADHD in the United States alone
was estimated to exceed $30 billion [10]. ADHD
US prevalence estimates of attention-deficit/ is associated with a higher risk for substance use
hyperactivity disorder in youth ages 4–17 range disorders and other comorbid psychiatric disor-
from 5% to 11% [3], with the childhood male to ders, increased mortality due to accidents,
female ratio estimated to be 3–4:1 in epidemio- unwanted pregnancies, lower academic achieve-
logical samples [4]. Worldwide prevalence of ment and occupational performance, adult anti-
ADHD/hyperkinetic disorder is estimated to be social behavior, and poor social functioning,
including higher divorce rates [1, 11, 12].
A. D. Hunt · D. W. Dunn (*) · H. S. Blake Bernardi et al. presented the results from the
J. Downs National Epidemiological Survey on Alcohol
Indiana University School of Medicine, and Related Conditions and reported that adults
Indianapolis, IN, USA
e-mail: adhunt@iupui.edu; ddunn@iupui.edu; with ADHD were more likely to be diagnosed
hcstanle@iupui.edu; downsjl@iupui.edu with histrionic, borderline, narcissistic, schizo-
the CDC’s National Health Statistics Report, half defiant disorder, conduct disorder, and substance
of children with ADHD are diagnosed by pri- abuse. Social factors such as bullying, familial
mary care physicians, and three quarters of conflict, rigorous academic and extracurricular
patients with ADHD were diagnosed by age 9 schedules, and frequent changes in school can lead
[31]. The assessment and diagnosis of ADHD to academic problems and confound the ADHD
requires a thorough history, ideally from multiple diagnosis [35].
sources, including caregivers, teachers, and other Further complicating the picture is the fact
relevant adults in the child’s life, and mental sta- that ADHD is associated with a wide variety of
tus examination. As much as possible, the patient psychiatric comorbidities. In a study of US chil-
should also be included in providing history, dren ages 6–17 years with ADHD, about a third
keeping in mind that young children provide less of subjects had at least one comorbid psychiatric
reliable history. Diagnosis should be based on disorder [36]. Oppositional defiant disorder is the
DSM-5 criteria and incorporate data from at least most common comorbidity, with some estimates
two settings. ranging from 54% to 67% [35]. The comorbidity
There are currently no medical tests or bio- of learning disorders can reach as high as 45%
markers that can definitively diagnose ADHD. As when writing disorders are included with reading
mentioned above, ADHD is a highly heteroge- and math disorders [37]. Other common comor-
neous disorder, and there is a wide variety of core bidities include mood disorders, anxiety disor-
symptom presentation, degree of severity, and ders, tic disorders, sleep disorders, substance
psychiatric comorbidities. The AAP recommends abuse disorders, autism spectrum disorder, post-
standardized rating scales be used as part of a traumatic stress disorder, circadian rhythm disor-
comprehensive diagnostic assessment. Several ders, and sleep disorders [38–41].
rating scales with good sensitivity and specificity
include the Conners’ Rating Scale-Revised
(CRS), the Conners Abbreviated Symptom 15.6 Treatment of ADHD
Questionnaire (ASQ), the Child Behavior
Checklist-Attention Problem (CBCL-AP) [32], The treatment of ADHD should involve a system-
and the Vanderbilt Parent and Teacher Rating atic approach targeting the predominant clinical
Scales [33, 34]. Screening scales are best used in symptoms with the goal of minimizing the nega-
conjunction with a thorough history taking and tive impact on social and academic functioning.
mental status examination and are most helpful An evidence-based risk-benefit analysis should
when used to assess response to treatment over always be undertaken when choosing pharmaco-
time. Review of academic records, such as psy- logic and/or nonpharmacologic intervention(s).
choeducational testing and reports cards, may The original Multimodal Treatment Study of
also be useful in evaluating school functioning. Children with ADHD study examined the short-
An essential component of assessment for term (14 months) outcome of different arms of
ADHD includes evaluating for differential diagno- treatment, including intensive behavioral, medi-
ses and psychiatric comorbidities. Several disor- cation, and multimodal treatment versus commu-
ders include symptoms that overlap with the core nity care only. The study found superior outcomes
symptoms of ADHD and can cloud the clinical for medication versus other treatment arms.
picture. For example, children and adolescents However, a more recent analysis of long-term
with anxiety disorders can present with psycho- outcomes suggests the superiority of medication
motor agitation, inattention and distractibility, is diminished over time and indicates superiority
externalizing behaviors, and poor academic func- of combined treatment for long-term positive
tioning. Depressive disorders can likewise cause outcomes, such as academic and social function-
poor attention and concentration and psychomotor ing and parenting styles [42]. Parents of subjects
agitation. Other mental illnesses that can mimic in the combined treatment group showed the
ADHD include learning disorders, oppositional greatest reduction in negative/ineffective disci-
15 Treatment Resistance in Attention-Deficit/Hyperactivity Disorder 219
Initial
dose (mg/ FDA max dose (mg/ Duration of
Class Generic name Brand name Age (years) day) day) action (hours) Dosage formulation
Stimulants Amphetamine mixed Adderall 3–5 2.5 40 4–6 Immediate-release tablet
salts 6+ 5–10
Adderall XR 6–12 5–10 30 10–12 Extended-release capsules, can be
13+ 10 opened
Adzenys ER* 6+ 6.3 18.8 10–12 Extended-release suspension
Adzenys XR 6+ 6.3 18.8 10–12 Extended-release ODT, orange
Evekeo 3–5 2.5 40 4–6 Immediate-release tablet
6+ 5
Dyanavel XR 6+ 2.5 20 12 Extended-release suspension,
bubblegum
Mydayis 13+ 12.5 25 16 Extended-release capsules, can be
opened
Dextroamphetamine Dexedrine 3–5 2.5 No approval for age 4–6 Immediate-release tablet
3–5
6+ 5 40
Dexedrine Spansule 6+ 5 40 6–10 Extended-release capsule
ProCentra 3–5 2.5 40 4–6 Immediate-release suspension,
6+ 5 bubblegum
Zenzedi 3–5 2.5 40 4–6 Immediate-release tablet
6+ 5
Lisdexamphetamine Vyvanse 6+ 30 70 12–14 Extended-release capsule
Methylphenidate Ritalin 3–5 2.5 No approval for age 3–4 Immediate-release tablet
3–5
6+ 5 60
Ritalin SR 6+ 20 60 6–8 Sustained-release tablet
Ritalin LA 6+ 20 60 8–10 Extended-release capsule, can be
opened
Metadate ER 6+ 10 60 6–8 Extended-release tablet
Metadate CD 6+ 10 60 8–10 Extended-release capsule, can be
opened
Methylin 6+ 5 60 3–4 Immediate-release chewable and
suspension
A. D. Hunt et al.
Methylin ER 6+ 10 60 6–8 Extended-release chewable, grape
Concerta 6–12 18 54 10–14 Extended-release capsule
13+ 18 72
Daytrana TD 6+ 10 30 8–12 Transdermal patch
Aptensio XR 6+ 10 60 8–12 Extended-release capsules, can be
opened
Cotempla 6+ 17.3 51.8 6–8 Extended-release ODT
Quillivant XR 6+ 20 60 6–8 Extended-release suspension, banana
QuilliChew ER 6+ 20 60 6–8 Extended-release chewable, cherry
Dexmethylphenidate Focalin 6+ 2.5 20 3–4 Immediate-release tablet
Focalin XR 6+ 5 30 8–10 Extended-release capsule, can be
opened
Non-stimulants Atomoxatine Strattera 6+ 100 24 Capsule
Clonidine Catapres 0.05 No approval for 3–6 Immediate-release tablet, transdermal
ADHD patch
Kapvay 6+ 0.1 0.4 12–16 Extended-release tablet
Guanfacine Tenex 0.5 No approval for age 6–12 Immediate-release tablet
< 18
Intinuv 6+ 1 4 14–18 Extended-release tablet
Sources: Stahl [20]; Adesman A. The ADHD Medication Guide [53]; Spencer et al. [54]
15 Treatment Resistance in Attention-Deficit/Hyperactivity Disorder
221
222 A. D. Hunt et al.
than is clonidine [20, 21, 56]. Table 15.2 contains treated first, and the secondary disorder is treated
the non-stimulant pharmacologic treatments and if remission does not occur for both disorders
dosing guidelines. Table 15.3 lists commonly with monotherapy. Anxiety and ADHD are
occurring adverse effects with non-stimulants and treated by using atomoxetine to treat both disor-
best practice in managing them. ders or first treating ADHD with a stimulant and
then adding an SSRI for anxiety. In stage 2 the
15.6.1.3 Treatment Algorithm alternative strategy is chosen. ADHD and tic dis-
In 2006, the Texas Children’s Revised Medication orders are treated with stimulant monotherapy in
Algorithm Project (TMAP) [64] outlines an stage 1 and in stage 2 adding an alpha agonist for
evidence-based approach to stepwise treatment continued impairing tics. In stage 3, an atypical
of ADHD in children and adolescents. An open antipsychotic is added, although more recent data
trial of the feasibility of and adherence to the first suggests using HRT and C-BIT prior to antipsy-
algorithm developed in 1998 showed physicians chotics [65]. If this fails, stage 4 consists of add-
demonstrated good adherence to the first two ing haloperidol or pimozide only if an atypical
stages of the algorithm and that adherence to the antipsychotic fails. In aggression and co-
algorithm predicted better outcomes and less occurring ADHD, it is recommended to follow
polypharmacy than historical controls. However, the ADHD treatment algorithm first, and if
developing a treatment algorithm, the authors aggression does not resolve, stage 2 stipulates
noted, is difficult due to expanding knowledge in adding behavioral intervention to a stimulant. In
the field of child and adolescent psychiatry [64]. stage 3 an atypical antipsychotic is tried, and in
The TMAP algorithm is based on a well- stage 4, lithium or divalproex sodium is sug-
established diagnosis of ADHD, and entry into the gested. The agent not used in stage 4 is tried in
algorithm excludes certain psychiatric disorders stage 5 [64].
such as a manic episode, psychotic disorders, and
autism spectrum disorder. Stage 1 includes trialing
a stimulant from the methylphenidate or amphet- 15.6.2 Nonpharmacologic
amine and stage 2 involves choosing from the
alternative stimulant category or changing the for- In addition to medication management, studies
mulation (short-acting versus long-acting formu- have shown that behavioral therapy further
lation) within the same category. In stage 3, improves ADHD symptoms and ADHD-related
atomoxetine should be trialed. Families should be impairments such as oppositional and defiant
cautioned that it may take 2–6 weeks for beneficial behavior [66, 67], conduct problems, poor social
effects [56]. Substage 3 was added for low-dose skills [67, 68], and academic achievement [68].
atomoxetine combined with a stimulant (if atom- Behavioral interventions can be implemented at
oxetine monotherapy is not as effective as stimu- home and/or school, each with the goal of
lants but stimulants could not control evening or increasing desirable behaviors and decreasing
early morning symptoms) based on clinical con- problem behaviors.
sensus. It should be noted that atomoxetine com-
bined with a stimulant significantly increases the 15.6.2.1 Behavioral Parent Training
risk of adverse effects such as appetite loss, insom- Behavioral parent training is an empirically sup-
nia, and irritability [35]. Stage 4 stipulates trial of ported treatment to address ADHD symptoms
bupropion or a tricyclic antidepressant (nortripty- [66, 67, 69, 70], where parents learn behavior
line or imipramine), and stage 5 is the alternative modification techniques [69]. Typically, BPT is a
not used in stage 4. The alpha agonists are trialed manualized treatment that ranges from 8 to 12
in stage 6 [64]. sessions [71]. It can be implemented in a group or
The TMAP review also outlines treatment of individualized treatment [70, 72]. During BPT,
ADHD and comorbidities. For ADHD and parents are provided instruction by his/her thera-
comorbid depression, the most severe disorder is pist, the therapist models the skills, and then the
224 A. D. Hunt et al.
parent practices the skill with his/her child while 15.6.2.4 Skills Training for Executive
receiving feedback from the therapist. Problem- Functioning Deficits
solving, using behavioral techniques outside the Children with ADHD often have poor executive
home, and planning for future misbehavior is functioning, resulting in difficulty with organiza-
also covered during BPT [70, 72, 73]. tion and planning [84]. Impaired executive
functioning results in misplacing homework
15.6.2.2 Behavior Classroom assignments, failure to turn in completed assign-
Management ments [85, 86], forgetting to bring materials home
Teachers should implement behavioral strategies [85], careless mistakes, poor planning for tests
in their classroom to reduce ADHD symptoms [86], difficulty tracking assignments, poor time
and ADHD-related behaviors [74]. Classroom management, and forgetting class materials which
management increases academic productivity, in turn negatively impacts academic performance
peer relations, and adaptive behavior while [82]. A combination of skills training and behav-
decreasing oppositional behavior and aggression ioral techniques has been shown in the literature to
[75]. Behavioral classroom interventions are sim- improve organizational and planning skills.
ilar to those implemented with BPT. Specifically, In addition to having planning and organiza-
teachers implement classroom rules, time-outs, tional problems, individuals with ADHD often
and other response cost interventions to decrease have deficits in their working memory, which is
negative behaviors [75, 76]. Additionally, teach- the ability to hold information in one’s mind and
ers use positive reinforcement strategies such as a manipulate it [87, 88]. Working memory deficits
point system, token economy, and positive praise are associated with lower academic achievement
[77]. Clinicians can provide consultations with and behavioral problems [88]. As such, studies
teachers in order to assist with implementing have examined how to improve working memory
classroom management procedures [68, 72]. deficits through working memory training
(WMT). The most common working memory
15.6.2.3 Social Skills Training training program used in studies, Cogmed, has
Children with ADHD often have poor social been shown to improve working memory [89–
skills and are rejected by their peers [78]. Studies 91]. However, long-term studies suggest that the
indicate that behavioral treatments help improve increase in working memory do not persist past
social skills in individuals with ADHD [65, 79, 24 months [89]. Despite the improvement in
80]. Social skills training are often taught in a working memory, studies indicate that Cogmed
group setting [80]. In social skills training, chil- does not increase academic achievement [89, 90]
dren are taught skills such as good sportsman- or improve ADHD symptoms of inattention,
ship, assertiveness, dealing with teasing, making impulsivity, or hyperactivity [90, 92].
friends, playing with others [81], conversational
skills [82], contacts with adults at home and 15.6.2.5 Multimodal Treatments
school, handling problem situations [82], shar- When children with ADHD do not respond to
ing, listening skills, giving and receiving compli- BPT, behavior classroom management, organiza-
ments, and accepting negative consequences tion skills training, or social skills training alone,
[80]. After children are taught these skills and clinicians can combine multiple behavioral treat-
instructors model how to use them, children prac- ments in order to target treatment-resistant
tice these skills in session and receive feedback ADHD. In fact, multimodal treatments are the
from the instructor and/or peers [80, 83]. To most effective treatment for ADHD [74]. The
assist with generalization, children are assigned most well-known multimodal treatment is the
homework. Some programs implement reinforce- summer treatment program (STP). STP is an
ment such as point systems, positive praise [82], intensive program that combines behavioral ther-
and tangible rewards [79] to further increase uti- apy and medication management that has strong
lization of skills. empirical support to reduce symptoms of ADHD
15 Treatment Resistance in Attention-Deficit/Hyperactivity Disorder 225
[67, 68, 77, 93]. STP ranges from 6 to 9 weeks erals such as iron, magnesium, and zinc and
and is for individuals between the ages of 5 and vitamins such as vitamin D. Review of data from
16 years old. the US Department of Agriculture suggests that
the average American consumes less than the rec-
ommended daily intake of vitamin E, calcium,
15.6.3 Investigational/ folate, vitamin A, and magnesium. If a defi-
Complementary ciency/insufficiency of vitamins and minerals is
suspected, a careful dietary history should be per-
Current conventional treatments for ADHD in formed, especially in children who do not have
children and adolescents have limitations. well-balanced diets and/or stimulant-related
Although stimulants are known to be signifi- appetite suppression. If a thorough history, physi-
cantly efficacious, it is estimated that 10–30% of cal examination, and laboratory testing indicate
patients will not respond or cannot tolerate deficiencies/insufficiencies, supplementation is
adverse effects [94, 95]. Stimulants also do not recommended with careful monitoring for
provide 24-h coverage. Non-stimulants can pro- adverse effects such as constipation and
vide all-day coverage but are generally less effec- diarrhea [99].
tive [96]. Additionally, many geographic areas Dietary treatments have been commonly used
lack availability of behavioral therapy providers, by parents and families in treating children with
or families and teachers have difficulty commit- ADHD. Two common therapies include restricted
ting the amount of time required for behavioral elimination diets (RED) and artificial food color
interventions [97]. These limitations have elimination (AFCE). These diets rely on careful
prompted research to identify additional thera- control of dietary ingestion of food ingredients to
pies. Parents, families, and patients are often which the child may have demonstrated hyper-
interested in nontraditional therapies and may be sensitivity with worsening of ADHD symptoms.
utilizing one or more without physician aware- The results of the efficacy of RED are somewhat
ness. One study found 54% of parents reported promising, but more large-scale trials using
using complementary and alternative medicines unselected (those not already suspected of being
to treat their child with ADHD, but only 11% of responders) subjects and blinded assessments
parents reported discussing CAM use with their and examining long-term outcomes will need to
child’s physician. The most frequent CAM thera- be performed before recommending this therapy.
pies were expressive therapies (sensory integra- Similarly, the evidence for AFCE is currently
tion, occupational therapy, art, music, etc.), limited, but further research using unselected
vitamins, and dietary restrictions such as the subjects and blinded assessments is required
elimination of sugar and food additives [98]. before using as a standardized treatment [100].
Families and patients not using CAM may often
be curious about such therapies but reluctant to 15.6.3.2 Natural Supplements/Herbal
broach the subject with the physician. Information Remedies
that is not always accurate is widely disseminated A number of systematic reviews have found
through the Internet and social media. It behooves small to moderate effect sizes for polyunsatu-
the practitioner to be prepared to discuss the topic rated fatty acids (PUFA), with the thought
of CAM and be well-informed regarding the that omega-3 fatty acids protect against
potential benefits and risks of investigational and neuro-
inflammation and by the modulation of
complementary treatments. dopamine and serotonin neurotransmission in the
frontal cortex [101]. In these reviews, eicosapen-
15.6.3.1 Dietary/Nutritional taenoic acid (EPA) was highly associated with
A 2014 review by Hurt et al. found that some efficacy [102]. Limitations in studies looking at
children with ADHD have documented deficien- omega-3 fatty acids include many studies being
cies, or more commonly insufficiencies, of min- underpowered and the lack of consistent dosing
226 A. D. Hunt et al.
and formula [103]. Efficacy with PUFA is still hydrochloride (H1 agonist and H3 antagonist),
inferior to conventional medications. The current V81444 (adenosine A2a antagonist), and tipepi-
data suggests use of PUFA for treatment of dine hibenzate (inhibits G-protein coupled
ADHD should be limited to mild cases and as inwardly rectifying potassium [GIRK]-channel
adjunct treatment with conventional pharmaco- currents) [96].
logic agents in severe cases [99, 102, 103].
Although a number of studies have examined 15.6.3.4 Noninvasive Brain
the safety and efficacy of natural supplements Stimulation
and herbal remedies, the results are mixed. Ahn Noninvasive brain stimulation consists of tran-
et al. reviewed clinical studies evaluating the scranial magnetic stimulation (TMS) and tran-
safety and efficacy of a variety of nutritional and scranial direct current stimulation (repetitive
herbal supplements. This review of studies transcranial magnetic stimulation [rTMS]) and
included botanical agents, vitamins, minerals, has potential diagnostic and therapeutic applica-
amino acids, essential fatty acids, and emerging tion in a number of neuropsychiatric disorders in
natural product-derived treatments from preclini- children, including Tourette’s syndrome and
cal studies. A major limitation of comparing autism spectrum disorder [105]. However, there
these agents to standard medications in clinical are limited well-designed trials examining the
trials is the lack of standardization of herbal sup- safety and efficacy of noninvasive brain stimula-
plements that make it difficult to determine tion in children and adolescents with
purity, safety, and toxicity profiles. Although ADHD. Although the highly neuroplastic devel-
many of the botanical agents showed promise, oping brain has the potential for responding to
the authors conclude that due to the complexity neuromodulation, there are potential risks associ-
and heterogeneity of ADHD, a combination ther- ated with this intervention, including seizure risk,
apy of standard pharmacologic agents, a botani- as well as potential for commercial misuse [106].
cal or nutritional supplement, and behavioral In 2009, a consensus conference committee
therapy may yield the most positive outcomes. It reviewed safety and ethical issues in TMS clini-
should be noted that naturally derived supple- cal use and recommended that single- and paired-
ments can still have bothersome side effects, and pulse TMS is likely safe in patients aged 2 and
some agents, such as St. John’s wort, can have older, but there is not enough data to recommend
significant interactions with psychotropic medi- safe use of rTMS in pediatric patients [107].
cations [97, 102]. Further research will need to be performed before
noninvasive brain stimulation becomes a stan-
15.6.3.3 Investigational Drugs dard treatment for ADHD in children and
A number of novel stimulant and non-stimulant adolescents.
drugs are currently being examined. New stim-
ulant delayed- and extended-release prepara- 15.6.3.5 Neurofeedback
tions being investigated are designed to improve Neurofeedback training (NFT) is gaining support
early morning symptoms and extend coverage after a number of clinical trials have demon-
throughout the day [96], including HLD200, a strated improvement in behavior, attention, and
methylphenidate formulation with combination neuropsychological test performance [108]. NFT
delayed- and extended-release delivery allow- involves self-regulation of brain activity patterns
ing for evening administration with release by utilizing EEG biofeedback of brain waves.
beginning in the morning (after an 8- or 9-h The improvement with neurofeedback training
delay) and occurring throughout the day [104]. rests on theorized neurophysiological changes
Investigational non-stimulants include drugs occurring in children and adolescents with
that target reuptake and transportation of sero- ADHD. These trials have been criticized, how-
tonin, norepinephrine, and dopamine and agents ever, for lack of control groups and low power
targeting novel receptors such as betahistine [109]. Despite this, neurofeedback training
15 Treatment Resistance in Attention-Deficit/Hyperactivity Disorder 227
appears to be a promising and valid option for period of time [114]. Many factors impact adher-
treating ADHD, but further studies illuminating ence including, but not limited to, adverse effects,
treatment protocol and predictors of response are parent-child dynamics, comorbid oppositional
necessary [110]. defiant disorder, and perceived lack of effective-
ness, and these factors will need to be addressed
before progressing in the treatment algorithm.
15.7 Treatment Resistance Diversion or misuse of stimulants should also
be considered in cases of apparent treatment
ADHD is considered to be one of the most highly resistance. In a recent study, 16% of parents
treatable psychiatric disorders. Approximately reported diverting their child’s stimulants, pre-
75–90% of patients will respond to some form of dominantly to themselves but sometimes to other
pharmacotherapy, although not necessarily on household family members, and another 13%
the first trial [111]. However, despite the wealth reported being tempted to self-administer their
of evidence of a number of treatments for chil- child’s stimulant medication [117]. The preva-
dren and adolescents with ADHD, not every child lence of nonmedical use of stimulants is believed
or teen will respond. There is no standard defini- to be approximately 5–10% of high school stu-
tion of ADHD treatment resistance in the litera- dents [118]. If parent or peer diversion is a strong
ture, but as noted previously, it is estimated that concern, it is recommended that the prescriber
10–30% of patients may not respond to any stim- closely monitor prescription refills or switch to a
ulant treatment [94]. Although it is difficult to long-acting stimulant or non-stimulant [61, 119].
define “inadequate response” to treatment in clin- If a patient is deemed to be adherent to med-
ical research, it may best be thought of as a ications, the dosing may need to be optimized
response that does not sufficiently improve core for weight, and, if a patient is on an IR formu-
ADHD symptoms to the point of improving over- lation, the number of administrations may need
all functioning [112]. Additionally, treatment to be increased. Table 15.2 lists dosage guide-
failure may best be defined as failure to reach lines per weight and administration schedule
treatment goals despite the maximum, therapeu- for each ADHD medication, including stimu-
tic dose of medication or experiencing intolera- lants and non-stimulants. Considering duration
ble side effects [63]. If the treating physician of treatment time is also important, especially
determines that a patient is not responding well to if the patient is using atomoxetine. One review
pharmacologic treatment, a few factors may need of open-label studies found a median response
to be addressed before moving forward. time of 4 weeks of treatment with atomoxetine
Firstly, the issue of adherence should be dis- with full remission (defined as an ADHD-
cussed. Child nonadherence to ADHD medica- RS-IV score ≤18) having a median response
tions can range from 15% to 87% [113]. A time of 8 weeks and probability of remission
different review found that in community sam- reaching 85% at 52 weeks [120]. Although
ples, only a third to two-thirds of children and stimulants can provide relatively immediate
adolescents with ADHD consistently take stimu- benefits, observation of symptoms should take
lant medications and that, on average, families do place over at least a week to fully assess any
not persist in medication use beyond 1 year [114]. pattern changes in behavior. Again, core symp-
Rates of adherence appear higher in clinical tom rating scales completed by caregivers and
research samples. For example, in the 3-year fol- other adults across settings can provide a more
low-up of the NIH MTA study, 71% of the sam- objective appraisal of medication response. If
ple continued immediate-release stimulant not already done so, it may also be beneficial to
medication for up to 3 years [115]. Long-acting educate families regarding realistic expecta-
stimulants are generally associated with higher tions for improvement and developmentally
rates of adherence [113, 116], but more research appropriate symptoms versus pathological
is needed to assess adherence over an extended symptoms.
228 A. D. Hunt et al.
If symptoms have not responded to a thera- data found only 10% of patients with the combi-
peutic medication dose and/or schedule, it may nation of parental depression, lower IQ, and
be worthwhile at this point to reassess diagnosis higher symptom severity achieved an excellent
and rule out alternative causes of symptoms [30]. response to treatment [121]. Emotional lability
ADHD, and even more, ADHD plus stimulants, has also been linked with worse outcomes and
may impair sleep, and sleep deprivation can neg- multiple modality treatments [122].
atively affect attention. Other behavioral effects Despite the use of medication and behav-
may occur such as irritability with amphetamines. ioral treatments, some youth with ADHD and
Possible comorbid diagnoses may also need to be comorbid disruptive behavior disorders will
reconsidered as co-occurring conditions can have continue to exhibit aggressive behaviors. In
an impact on response to treatment. For example, patients with comorbid ODD, a stimulant plus
a review of the literature suggests fewer subjects behavioral therapy is considered first-line
with autism spectrum disorder are considered treatment, and alpha agonists may be added if
“responders” to stimulant medication, treatment symptoms persist [35]. Several studies have
effects are slightly smaller, and adverse effects shown the combination of a stimulant with the
are more common than in the non-ASD popula- extended-release formulations of clonidine and
tion [38]. However, effect sizes with stimulants guanfacine was significantly effective for
are still statistically significant. If ADHD is the patients with complicated ADHD [94]. For
predominant, established diagnosis, treatment ADHD with comorbid conduct disorder, multi-
can proceed in a stepwise progression, preferably systemic therapy is the only behavioral inter-
with only one medication change at a time. vention determined to be effective [35].
Several factors have been identified in Atypical antipsychotics should only be consid-
treatment-refractory patients including caregiver ered for ADHD with disruptive behavior disor-
psychiatric illness. In a study examining modera- ders if behavioral interventions plus standard
tors of treatment response in the MTA, parental ADHD treatments (stimulants, atomoxetine,
depression was associated with decreased and alpha agonists) have failed and significant
response in the medication management group aggressive behaviors are present [123].
but not combined or behavioral treatment only There has been much interest in examining
[121]. The authors theorize that since the behav- pharmacogenetic factors in ADHD treatment
ioral treatment groups involve group and indi- resistance, and a relatively large number of
vidual parent training, parental depression is, in a studies have examined ADHD pharmacogenom-
sense, treated. For patients in families requiring ics compared to other mental health disorders
public assistance, the MTA data suggests [124]. Bruxel et al. performed a systematic
evidence- based medication management plus review of ADHD pharmacogenetics studies.
intensive home- and school-based behavioral Most genes studied involved the catecholamine
therapy may be necessary to see benefits in social pathway and have focused on methylphenidate
skills and peer relationships [43]. response. The most studied polymorphism
Patient characteristics such as subaverage IQ, involves the dopamine transporter gene (DAT1
higher baseline symptom severity, and medical or SLC6A3) [123]. The authors found that there
comorbidities that impair fronto-striatal function were conflicting results and that, overall, find-
(e.g., TBI, epilepsy, etc.) are also associated with ings did not consistently support a gene-drug
treatment-resistant ADHD. For patients with interaction for this polymorphism. Other genes
higher baseline symptom severity, early nonphar- studied in the child population included the
macologic intervention, such as parent training dopamine receptor D4 (DRD4), the COMT
programs through Head Start or other public pre- enzyme, the norepinephrine transporter (NET1),
kindergarten programs, may help reduce ADHD the adrenergic alpha-2A receptor, the serotonin
symptom severity [30, 121]. However, the MTA transporter (5HTT), the synaptosomal-associ-
15 Treatment Resistance in Attention-Deficit/Hyperactivity Disorder 229
– switch to atomoxetine
Mild: adequate (suspect comorbid
grades at school, anxiety/depression)
parents tolerating Coordinate with OR
hyperactivity, no school to develop – add alpha agonist
safety concerns from any needed (hyperactivity and
impulsivity accommodations impulsivity prevailing)
(IEP/504)
Define
Severity
If third line
treatment fails,
Moderate: grades Prescribe If original stimulate
consider
dropping, parental- stimulate– fails after 2 weeks at
bupropion / TCA
child relationship methylphenidate goal dose or side effect
dysfunction, formulations is intolerable, switch to
dangerous preferred alternate class of
impulsivity stimulate with same
dosing parameters
d ivalproex sodium can sometimes be used to treat studies are needed to incorporate these tools as
the aggression separately. part of a standardized treatment plan.
Standard pharmacologic and nonpharmaco-
logic treatments will not benefit a minority of
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Treatment Resistance in Tourette
Syndrome 16
Renata Rizzo and Mariangela Gulisano
maladaptive behaviour and decreased cognitive subscale, highlighting the importance of social
functioning [18]. Additional studies have indi- communication impairments when diagnosing
cated that the presence of comorbidities associ- ASD in children with TS.
ated with poorer quality of life (QoL) [19]. Eddy
et al. [20] reported that high ADHD symptom
scores were associated with poorer QoL within 16.4 Neurobiology
the Self and Relationship domains, whereas high
OCD symptom scores were associated with more TS represents a complex and heterogeneous dis-
widespread difficulties across the Self, order with an equally heterogeneous aetiology.
Relationship, Environment, and General Previous studies have suggested that several
domains. Significant differences in QoL may be genes associated with multiple neural systems—
most likely when both comorbidities are present, including the dopaminergic, serotonergic, and
and features of OCD and ADHD may exert a histaminergic pathways—are involved in the
differential impact on QoL across individual
pathogenesis of TS (DRD2, DRD4, 5-HT2C,
domains [20]. SERT). More recent studies have identified sev-
The endophenotype of OCD in the context of eral new candidate genes, such as SLITRK1,
tic disorders differs from that of OCD without IMMP2L, CNTNAP2, and NLGN4 [25].
tics: The former is associated with more frequent Although abnormal dopaminergic transmis-
counting, aggressive thoughts, symmetry, and sion is involved in the aetiology of tics, it does
touching, while the latter is associated with more not explain the presence of comorbidities, sug-
frequent contamination compulsions. Indeed, gesting that the noradrenergic and serotoninergic
such obsessive-compulsive tic disorders are asso- systems are also involved. Neuroimaging studies
ciated with earlier symptom onset, male sex, sen- involving heterogenous patient groups as well as
sory phenomena, and ADHD [21]. animal studies support the pathological involve-
Self-injurious behaviour occurs in a minority ment of cortico-striato-thalamo-cortical circuits
of patients with TS and has been associated with TS. Recent studies have identified alterations in
obsessive tendencies. Likewise, non-obscene several brain regions in patients with TS, includ-
socially inappropriate behaviours are more com- ing the lateral prefrontal cortex (inferior, middle,
mon in adult TS and may be associated with and superior frontal gyri), anterior cingulate cor-
impulse control disorder [7]. In addition, conduct tex, lateral premotor cortex (precentral gyrus),
disorders and other disruptive behaviours, such supplementary motor area (SMA), posterior
as those associated with oppositional defiant dis- superior temporal sulcus, supramarginal gyrus,
order, are strongly linked to comorbid ADHD retrosplenial cortex, secondary somatosensory
and impulsivity [22, 23]. cortex (postcentral gyrus), and lingual gyrus [26].
Chou et al. [24] reported that patients with TS Such studies have indicated that premonitory
have a significantly higher risk of developing urges likely result from altered structure and
depression than individuals without TS. More functional connectivity in the cortico-striatal-
recently, Rizzo et al. [22, 23] demonstrated that thalamic-cortical loop. Evidence from volumet-
depression is common among patients with TS ric MRI studies, functional MRI (fMRI), and
(41.8%) and is associated with tic severity, isotope neurochemical ligand studies also sug-
comorbid ADHD, coexisting anxiety, CDs, and gests that TS is associated with structural and
behavioural problems. functional abnormalities in the basal ganglia.
ASD has been diagnosed in 5–15% of TS However, functional imaging and postmortem
cohorts [22, 23]. In a recent study, Darrow et al. studies have failed to identify dopaminergic dys-
[8, 9] utilized the Social Responsiveness Scale to function in patients with TS [27, 28], leading
demonstrate that 2.8% of patients met ASD crite- some researchers to speculate that imbalances in
ria, although this was primarily due to higher the serotoninergic, glutamatergic, GABAergic,
scores on the repetitive and restricted behaviours cholinergic, and opioid systems may be involved.
240 R. Rizzo and M. Gulisano
16.5 Pharmacological Therapy ment options with different efficacy profiles and
side effects.
The current treatment guidelines for the manage- The efficacy of typical antipsychotics (e.g.
ment of TS first recommend psychological edu- haloperidol and pimozide) is supported by ran-
cation and supportive management, followed by domized controlled trials (RCTs), as well as
the addition of psychological therapy. Cognitive broad clinical experience in treating TS with
behavioural therapy (CBT) should be considered dopamine-blocking agents [32–34]. However,
as first-line treatment for patients with their use is limited due to severe side effects such
TS. Psychopharmacological treatments for TS as sedation, somnolence, metabolic disturbances,
aim to diminish the frequency of tics and improve dystonic reaction, hyperprolactinaemia, and
psychosocial functioning while minimizing menstrual disorders. RCTs have revealed that the
adverse effects. Practical management of TS atypical antipsychotics risperidone and aripipra-
should focus on evaluating tics as well as comor- zole are as effective in reducing tics as typical
bidities and coexistent conditions (ADHD, OCD, antipsychotics [35], with fewer adverse effects
ASD, depression, anxiety, etc.), as these may be [36]. Indeed, a meta-analysis of antipsychotics
more disabling for the patient than the tics them- used for the treatment of TS reported no differ-
selves. Moreover, it is important to discuss treat- ences in efficacy among risperidone, haloperidol,
ment priorities with patients and families to pimozide, and ziprasidone [37]. More recently, a
ensure appropriate, individualized treatment for comprehensive systematic review of four trials
the most disabling symptoms. investigating treatments for tics in children and
The 2011 European guidelines for the phar- young people with TS and persistent tic disor-
macological management of TS recommend the der found no significant differences in effect
use of the second-generation antipsychotic ris- sizes among specific antipsychotic drugs
peridone as a first-line treatment option [29]. (aripiprazole (SMD = −0.62), haloperidol
However, despite their efficacy, Canadian and US (SMD = 0.50), pimozide (SMD = −0.81),
guidelines only weakly recommend the use of risperidone (SMD = −1.18), ziprasidone
antipsychotics due to their high rates of adverse (SMD = −0.74)) [35].
events, instead recommending first-line treat- Research has indicated that tics also respond to
ment with alpha-2 (α2) adrenergic agonists [30]. neuroleptic drugs, often using smaller dosages
To date, three classes of drugs have exhibited than required for antipsychotics. However,
efficacy in the treatment of TS: (i) dopamine responses vary among patients, and treatment with
receptor blockers, which include both typical several agents may be necessary before the most
and atypical antipsychotics (e.g. haloperidol, appropriate drug is identified. Pharmacological
tiapride, sulpiride, pimozide, risperidone, treatment of tics should be initiated at the lowest
aripiprazole, etc.), (ii) non-dopaminergic agents doses possible and increased slowly.
(α2-adrenergic agonists (e.g. clonidine and
guanfacine), baclofen, and topiramate), and (iii)
vesicular monoamine transporter-2 (VMAT2) 16.5.2 Non-dopaminergic Agents
inhibitors (tetrabenazine, deutetrabenazine, val-
benazine) [31]. Non-dopaminergic agents such as α2-adrenergic
agonists, clonidine, and guanfacine are often
preferred over neuroleptics for first-line treat-
16.5.1 Dopamine Receptor Blockers ment in children with TS. Several RCTs have
demonstrated that such agents exhibit similar
Antipsychotics such as dopamine-blocking efficacy to that of risperidone [38] and haloperi-
agents and partial agonists have been used in the dol [35]. In a meta-analysis regarding the effi-
treatment of TS for several decades. Both typical cacy of α2-adrenergic agonists on tic suppression
and atypical antipsychotics are effective treat- in patients with TS, Weisman et al. [37]
16 Treatment Resistance in Tourette Syndrome 241
Table 16.2 (continued)
Daily/dosage
Drug mg Efficacy Adverse events
Guanfacine 0.5–3 Level A Sedation, bradycardia, hypotension, dry mouth, irritability,
headache, stomach ache, sleep disturbances
Baclofen 10–60 Not Sedation, constipation, nausea, anxiety, and depression
provided
Topiramate <200 Not Weight loss, paresthesias
provided
Tetrabenazine 12.5–50 Not Sedation, fatigue, nausea, insomnia, parkinsonism, depression,
provided drowsiness
Modified from Ganos et al. [44]
a
Efficacy based on the level of evidence established from the European Society for the Study of Tourette Syndrome
Treatment Guidelines
Valbenazine is the only VMAT2 inhibitor specifi- peutic priorities according to functional
cally investigated for its role in the treatment of impairment.
TS. One open-label phase Ib study, one open-label ADHD is the most common comorbid disor-
phase II study, and one randomized placebo- der in children and adolescents with TS. The
controlled phase IIc study were completed in the most effective treatment for ADHD and related
USA (NCT02679079, NCT02581865, and oppositional and aggressive behaviours involves
NCT02256475), although their results have yet to be the use of psychostimulants. Psychostimulants
reported. A phase II placebo-controlled study is now block the reuptake of dopamine and norepineph-
recruiting in the USA (NCT03325010). Preliminary rine into presynaptic neurons (methylphenidate)
results indicate that valbenazine treatment signifi- or increase the release of these monoamines into
cantly improves tic symptoms as measured using the the extraneuronal space (amphetamine). One
YGTSS, as well as Clinical Global Impression. No research group in the USA has demonstrated that
serious or severe adverse events have been reported. methylphenidate is effective in the treatment of
These preliminary findings suggest that deutetra- ADHD in patients with tics. Although 20% of
benazine and valbenazine are preferable to tetraben- patients exhibited worsening of tics, no signifi-
azine with regard to side effects, although further cant difference was observed between methyl-
studies of safety and efficacy are required. phenidate and placebo treatment [50].
Psychostimulants should be used as second-line
treatment for ADHD symptoms in children with
16.6.4 Histamine H3 Receptor tics, although literature regarding the efficacy of
Antagonist: AZD5213 dexamphetamine in patients with tics is lacking.
Clonidine or guanfacine rather than psychostim-
AZD5213 was developed following the identifi- ulants can be given as first-line treatment because
cation of the brain’s histaminergic dysregulation the α2 agonists are effective in alleviating symp-
in TS [49]. The H3R receptor, which is expressed toms of both disorders, as well as related opposi-
primarily in the central nervous system, repre- tional behaviour (Rizzo et al. 2017).
sents a promising pharmacotherapeutic target. In First-line treatment for anxiety, depression,
one recently completed placebo-controlled study and OCD involves CBT, followed by the addition
(NCT01904773), AZD5213 significantly reduced of selective serotonin reuptake inhibitors (SSRIs)
total YGTSS scores in patients treated with high if necessary. Treatment recommendations are
doses (2.0 mg), while no significant effects were similar for children with OCD alone. However,
observed in patients treated with low doses patients with TS and comorbid OCD may also
(0.5 mg). Mild adverse events including palpita- benefit from the addition of atypical antipsychot-
tions, gastrointestinal disorders, headache, dizzi- ics [51].
ness, constipation, nausea, fatigue, asthenia,
vomiting, and irritability have also been associ-
ated with AZD5213 treatment (NCT1904773). 16.8 Definition of Treatment
Novel pharmacological treatment options for Resistance
TS are summarized in Table 16.3.
Although the term treatment-refractory TS is
commonly used in research and clinical practice,
16.7 Treatment of Comorbidity there has been no consensus regarding its defini-
tion. Storch et al. [52] defined optimal treatment
When present, comorbid symptoms are often response as a decrease in total YGTSS score of at
more disruptive than tics, and screening for least 35% or a reduction in raw total tic severity
comorbidity is essential for determining thera- score of six to seven points [52]. Severe tics may
244
not only lead to serious social problems but also even when treatment reduced the baseline YGTSS
represent a danger to the patient’s health, as they severity sub-score by ≥20%, suggesting that
may cause repeated trauma to the involved body other clinical measures should be considered
parts. Several life-threatening TS symptoms have when evaluating treatment efficacy. Indeed, in
been reported in the literature: death following some patients, seemingly relevant decreases in
subdural haematoma due to head banging, paral- tic severity as indicated using an assessment tool
yses secondary to neck jerking, infections of the may be insufficient for improving QoL and func-
oral muscles secondary to biting, and perma- tioning [55].
nently impaired vision due to self-inflicted Over the last 10 years, several guidelines for
injuries. defining refractory TS and selecting candidates
However, the presence of comorbidities is also for deep brain stimulation have been proposed by
frequently associated with refractory TS. Cheung expert medical associations.
et al. [53] reviewed data from a series of 333 In 2006, the Tourette Syndrome Association
patients with TS, 5% of whom had ≥2 emergency (TSA) suggested that the term refractory should
room visits or ≥1 hospitalization. Such patients be applied to patients in whom the following
were described as having “malignant TS”. When have failed or produced severe side effects: (1)
prescribing treatments for TS, clinicians should alpha-adrenergic agonists, typical and atypical
emphasize the achievement of adequate function- antipsychotics, and benzodiazepines, (2) con-
ing in the social, occupational, and educational comitant CBT for at least 6 months, and (3) 12
domains, despite the presence of residual tics consecutive sessions of habit reversal training
[54]. It is important to identify patients with (HRT) or exposure prevention (EP). However,
refractory TS, as the condition may represent a the dosage and duration of therapy were not
significant source of disability. A standardised reported. The TSA also recommended adequate,
definition of refractoriness to pharmacological stable, and optimized treatment of concomitant
treatment of tics in TS and persistent tic disorder disorders for at least 6 months [56].
would aid in making decisions regarding medica- The Dutch/Flemish guidelines recommend
tion use, psychological treatment, or invasive that at least three medications (including typical
treatments such as functional surgery [55]. In a and atypical antipsychotics) should be tried at
European survey by Macerollo et al. [55], a panel adequate doses for 12 weeks, while other groups
of seven expert clinicians judged the following have suggested a minimum treatment period of
items as “essential” for the definition of refracto- 6 months for TS to be considered medication-
riness: dichotomous judgement of improvements refractory. Porta et al. [57] defined “treatment
in tic severity (improved/not improved), docu- refractoriness” in potential candidates for DBS as
mented changes in the YGTSS severity score, failure of the following drugs or severe adverse
maximum dose reached and reasons for dose events after at least 2 years of psychological
increases, and number of single doses missed on treatment: typical or atypical antipsychotics,
average over a 10-day period. In addition, the SSRIs, and catecholamine-depleting agents. The
panel argued that refractoriness should primarily Müller-Vahl KR et al. [58] suggested that TS can
be judged based on lack of efficacy at the highest be considered “treatment resistant” upon the
tolerated dose or lack of tolerability at the initial occurrence of adverse events or failure of at least
or effective dose. This survey provides prelimi- three appropriate pharmacological treatment
nary information that may aid in the development options (including both typical and atypical anti-
of a consensus-based definition of refractoriness psychotics) after at least 12 sessions of CBT.
to tic treatment. Lack of tolerability at the initial Recently, the Tourette Syndrome Association
or effective medication dose resulted in a judge- International Deep Brain Stimulation (DBS)
ment of refractoriness in at least a third of cases. Database and Registry Study Group [59] pro-
The authors also reported that a minority of vided updated opinions and recommendations
patients could be judged as treatment refractory for the definition of “refractory patient”,
246 R. Rizzo and M. Gulisano
Treatment
correctly Good response
performed
Evaluation
No/poor response
conditions that
could affect
Second line
treatment Good response
correctly
performed
No/poor response
activity and nerve conduction. Such mechanisms were predominantly male and within the age
explain the efficacy of rTMS in reducing tic range of 13–58 years, although they presented
symptoms (as measured using the YGTSS) in with complex phenotypes. OCD was the most
both children and adults [67] and in improving frequent comorbidity, followed by depression,
comorbid behavioural and depressive symptoms. anxiety, and ADHD. High rates of side effects
were reported: dysarthria (6.3%, due to stimula-
tion), paraesthesia (8.2%), and haemorrhage
16.10 Deep Brain Stimulation (1.3%). However, rates of adverse events were
lower than those reported in previous studies,
DBS is a good, established chirurgical interven- likely due to the relatively short follow-up period
tion for patients with severely impairing motor [70]. Implanted patients exhibited higher rates of
and vocal tics that have been refractory to medi- infection and hardware-related complications
cal and behavioural therapy. Although DBS is [71]. Common adverse events associated with the
advantageous in that it is non-destructive, revers- surgical procedures for DBS included intracere-
ible, and adjustable [59], data obtained from bral haemorrhage (1%) [72], infection (18%)
patients with TS may be difficult to interpret. (most commonly Staphylococcus aureus), and
Given the great phenotypic variability of TS, the seroma/haematoma (19.3%) [73].
selection of the DBS target is particularly com- Adverse events due to stimulation vary depend-
plicated and heterogeneous. The potential for ing on the target of stimulation. The most com-
DBS to improve patient QoL should be deter- monly reported adverse events include changes in
mined on a strictly individual basis while bearing sexual behaviour (centromedial nucleus, substan-
in mind the natural course of the disease as well tia periventricularis nucleo ventro oralis internus)
as the risk/benefit ratio [68]. Although DBS (Temel and Visser-Vandewalle 2003); weight loss
seems an appropriate treatment solution for (anteromedial globus pallidus internal) [74]; nau-
refractory patients affected by TS, critical ques- sea, vertigo, anxiety, and social avoidance (ventro-
tions remain regarding the following: medial globus pallidus internus) [75]; and transient
paresthesias (thalamus) [70]).
• Definitions of medication-refractory TS and Although there are multiple ongoing studies
the selection of candidates for DBS treatment investigating the most effective DBS targets for
• Patient age improving tics and comorbid symptoms in patients
• Brain regions to be targeted based on different with TS, further large-scale multicentre studies are
clusters of symptoms required to increase statistical power. Such studies
• Stimulation parameters should include systematic assessment of social
• Post-operative complications outcomes as well as longer follow-up periods. The
first-year data within the multinational DBS regis-
In order to reach a consensus, experts on DBS try support the notion that DBS represents a surgi-
in TS have created the International Tourette cal treatment option for select patients with
Syndrome Deep Brain Stimulation Public TS. Clinicians should remain aware of the high
Database and Registry to share pertinent infor- number of stimulation- related adverse events,
mation regarding DBS. One year after the devel- most of which are likely reversible [70].
opment of this database, the authors reported that
the most effective DBS targets were the (i) ante- Conclusions
rior globus pallidus internus within the thalamus Although several studies and meta-analyses
and the (ii) centromedian-parafascicular complex have reported moderate-to-high efficacy in
(both with level A evidence) [69]. Moreover, reducing tics and comorbid symptoms in
decreases of 50.5% and 46.3% were observed in patients with TS, there are limitations associ-
YGTSS scores following DBS, respectively. The ated with treating patients with refractory
study revealed that patients treated with DBS TS. To date, evidence- based studies have
16 Treatment Resistance in Tourette Syndrome 249
failed to identify reliable neurobiological fac- Lifetime prevalence, age of risk, and genetic relation-
tors or clinical markers that contribute to or ships of comorbid psychiatric disorders in Tourette
syndrome. JAMA Psychiat. 2015;72(4):325–33.
may aid in the prediction of treatment- 7. Robertson MM, Eapen V, Singer HS, Martino D,
refractory TS. The efficacy of treatment for Scharf JM, Paschou P, Roessner V, Woods DW, Hariz
refractory TS is related to several factors: M, Mathews CA, Črnčec R, Leckman JF. Gilles
pharmacological efficacy and tolerability, de la Tourette syndrome. Nat Rev Dis Primers.
2017;3:16097.
therapist ability, and the patient’s capacity to 8. Darrow SM, Grados M, Sandor P, Hirschtritt ME,
adhere to the treatment. Understanding the Illmann C, Osiecki L, Dion Y, King R, Pauls D,
differences between patients with TS who Budman CL, Cath DC, Greenberg E, Lyon GJ,
experience better treatment outcomes and McMahon WM, Lee P, Delucchi KL, Scharf JM,
Mathews CA. Autism spectrum symptoms in a
those with treatment-refractory TS may aid in Tourette’s disorder sample. J Am Acad Child Adolesc
elucidating the heterogeneity of the disorder. Psychiatry. 2017a;56(7):610–7.
Additional studies should focus on identifying 9. Darrow SM, Hirschtritt ME, Davis LK, Illmann C,
genetic or neuroimaging factors that can be Osiecki L, Grados M, Sandor P, Dion Y, King R, Pauls
D, Budman CL, Cath DC, Greenberg E, Lyon GJ, Yu
used to determine the most appropriate medi- D, McGrath LM, McMahon WM, Lee PC, Delucchi
cations and on developing novel pharmaco- KL, Scharf JM, Mathews CA, Tourette Syndrome
logical interventions to optimize the treatment Association International Consortium for Genetics.
of patients with TS. Among these novel strate- Identification of two heritable cross-disorder endo-
phenotypes for Tourette syndrome. Am J Psychiatry.
gies, rTMS and DBS represent valid therapeu- 2017b;174(4):387–96. https://doi.org/10.1176/appi.
tic options for improving QoL in patients with ajp.2016.16020240.
refractory TS. 10. Scharf JM, Miller LL, Gauvin CA, Alabiso J,
Mathews CA, Ben-Shlomo Y. Population prevalence
of Tourette syndrome: a systematic review and meta-
Acknowledgements and Conflicts of Interest Prof. analysis. Mov Disord. 2015;30(2):221–8.
Rizzo has nothing to disclose. Dr. Gulisano has nothing to 11. Robertson MM. The prevalence and epidemiology
disclose. of Gilles de la Tourette syndrome. Part 1: the epide-
miological and prevalence studies. J Psychosom Res.
2008;65(5):461–72.
12. Freeman RD, Fast DK, Burd L, Kerbeshian J,
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Treatment-Resistant Eating
Disorders 17
Youl-Ri Kim and Jione Kim
Fig. 17.2 The
development of severe AN predisposing factors
and enduring anorexia (Childhood anxiety, sensitivity to punishment, obsessive-
nervosa (AN) and compulsive and/or autistic traits, increased fear learning)
bulimia nervosa (BN)
based on Treasure’s
BN predisposing factors
maintenance model (Abnormalities in appetite regulation, childhood
Anxiety, reward sensitivity and inhibitory control)
AN symptoms
(Restriction, weight loss, food, weight, shape-related
preoccupations)
BN symptoms
(Cycles of restriction and loss of control, food,
weight, shape-related preoccupations)
Secondary consequences of AN / BN
(Neuroprogressivechanges)
Abnormal eating
habits and food.
[19]. The concept of food addiction [20] in obe- given a new meaning for recovery [24]. The
sity and overeating is controversial [20], but it “new” recovery does not require amelioration of
might explain why bulimia nervosa persists. As symptoms or other deficits and does not simply
shown in Fig. 17.2, Treasure’s maintenance involve a return to a previous state; it is also not
model of bulimia nervosa illustrates that similar synonymous with cure and does not constitute a
changes provide the mechanism for chronicity in return to normal functioning. Rather, it is a life-
bulimia nervosa [13]. Within the addiction model, long process that involves an indefinite number
impulsive behaviors become compulsive habits of incremental steps in various life domains. It
particularly in the context of the rebound low, views mental illness as only one aspect of an
anxious mood in the withdrawal state [21, 22]; otherwise whole person. This new recovery
urge impulsivity overrides cognitive control, and emphasizes accepting and living well with the
so binge eating persists. In Fig. 17.2, a simplified illness; assuming responsibility in treatment
diagram illustrates Treasure’s maintenance model goals and plans; expanding and redefining sense
of bulimia nervosa. of self, renewed hope, meaningful activity, and
autonomy; overcoming stigma; becoming
empowered and exercising citizenship; and
17.4 T
he Recovery Approach rebuilding personal, social, and environmental
for Treatment-Resistant connections.
Eating Disorders There have been discussions about how to
define and measure recovery from EDs. Studies
There has been a shift toward recovery-based in of patient perspectives on recovery highlight hav-
mainstream psychiatry, in particular for schizo- ing a relaxed attitude toward the body and food,
phrenia [23]. This recovery approach moves having a functioning social environment, accept-
beyond the focus on a cure or absence of symp- ing oneself, and seeing oneself as an individual.
toms to how patients can be helped to build Crucially, these studies’ authors have also high-
meaningful and valued lives across a number of lighted that patients’ common view is that recov-
life domains. This approach has guiding prin- ery does not depend entirely on symptom
ciples that emphasize treatments that promote absence. Despite these findings in other domains
autonomy, self-management, and the reclaim- of mental illness, there have been very few stud-
ing of identity, and it supports patients in mean- ies on the recovery from EDs. Because of the
ingful activity. Thereby, it could reduce the long illness durations and poor outcomes in some
stigma of mental illness and increase self- individuals, there might exist questions whether
awareness, self-esteem, and self-acceptance; in recovery can apply to EDs.
the process of this approach, patients are not Turton et al. [25] conducted an interview-
discouraged if they are not “cured” after their based study of adults with an ED to investigate
first treatment episode; this approach might be the meaning of recovery. In the project, analysis
useful for all people with ED but of most ben- of interviews generated ten broad domains: the
efit and relevance to those with long-standing future, process, social inclusion, treatment, self,
disorders. “clinical” recovery, ambivalence, physical health,
From a traditional clinical perspective, recov- practical matters, and rights. That study’s fi
ndings
ery was described as remission of symptoms and showed that recovery is meaningful and relevant
other deficits associated with psychiatric disor- to people with eating disorders. However, themes
ders to a sufficient degree that they no longer also emerged that corresponded to a move con-
restrict daily functioning. Moreover, recovered vention understanding of recovery such as
patients are expected to resume daily personal, ambivalence or “clinical.” The authors empha-
social, and vocational functioning within what is sized acknowledging the struggles of recovery as
regarded as a normal range. More recently, the well as the positives and understanding how pain-
mental health consumer/survivor movement has ful the recovery process can be. In that study,
17 Treatment-Resistant Eating Disorders 257
“conventional” recovery and patients’ desire to and adding adjunctive treatments such as cogni-
be symptom-free were also important, and the tive remediation therapy [30]. This approach has
value of peer support programs was highlighted. guiding principles including seeing treatment as
part of a recovery journey; improving quality of
life; working on specific issues; supporting the
17.5 Treatments decision to engage in other treatments; maintain-
ing hope; emphasizing reassurance, support, and
17.5.1 Treatment Approaches at encouragement; being aware of medical concerns
the Different Stages of Illness and possible risk of destabilization; accepting
that pace of change may be slow; emphasizing
There is limited evidence from high-quality trials engagement and reducing premature ending; col-
to answer questions on the enduring state of eat- laboratively agreeing on goals; and acknowledg-
ing disorders regarding which treatments are ing losses and gains as a result of long-term
effective and how much treatments can be benefi- illness [31]. In the research conducted by Touyz
cial [6]. Currently, there are few recommenda- et al. [11], patients with severe and enduring
tions for first-line therapy for patients in the later anorexia nervosa participated in one of the tai-
stages of anorexia nervosa [26], although the lim- lored therapies for long-standing eating disorders
ited evidence on patients with severe, enduring for 30 sessions. Patients in each group experi-
illness suggests that remission rates are modest enced improvements in quality of life, depres-
and treatment effectiveness is poor [66]. sion, social functioning, and eating-related
Additional research is needed that explores treat- pathologies. New treatment approaches are rec-
ment approaches for less responsive patients. For ommended that could target the neuro-progressive
eating disorders, many treatments have been changes that occur with EDs.
adapted from those used to treat other illnesses,
whereas it is possible that a more targeted
approach to treating key ED symptoms can 17.6 Cognitive Remediation
improve outcomes [6]. Therapy
focused on anorexia nervosa. Although there is ing, mood, symptom plasticity, and inhibitory
evidence that suggested CRT can enhance treat- control [13]. Repetitive transcranial magnetic
ment for obesity, adapting it for other eating dis- stimulation (rTMS) was described as a therapeu-
orders such as bulimia nervosa or binge eating tic approach that stimulates the brain areas [35,
disorder needs additional research. 36]. Unlike electroconvulsive therapy, rTMS is
noninvasive and already used in depression,
obsessive-compulsive disorder, and schizophre-
17.7 Cognitive Bias Modification nia. It can be helpful for improving feeding
behaviors, controlling serotonergic processing,
Cognitive bias modification (CBM) aims at adjust- and augmenting brain-derived neurotrophic fac-
ing maladaptive cognitive biases in interpretations tor [6]. Thus, rTMS can be a novel form of ther-
and attention among clinical populations such as apy for eating disorders because of its possibility
affective disorders, obsessive-compulsive disorder, for improving maladaptive eating patterns and its
and substance abuse. CBM is composed of two regulation. In one study, rTMS for 20 sessions
computerized main variants, one of which was aimed at the dorsolateral prefrontal cortex
developed for the purpose of shifting negative (DLPFC) improved eating-related pathologies
biases in attention with a modified visual version of and affected severe and enduring AN [37]. rTMS
the dot-probe task [34]. On the dot-probe task, pos- also showed promising findings for the DMPFC
itive or negative valenced stimuli appear onscreen; treatment-resistant patients with BN [38].
a probe then appears briefly onscreen and patients
must press a computer key as soon as possible. The
other CBM approach can be useful for improving 17.9 Oxytocin
negative biases in interpretation; patients listen to
ambiguous scenarios that can be interpreted nega- Oxytocin, a neuropeptide, plays an important role in
tively but are given positive decisions. neural circuits associated with social behavior,
Some studies suggested that CBM can ame- appetite, anxiety, and stress [39, 40]. Because these
liorate negative biases toward emotional stimuli features are core characteristics of people with eat-
or stimuli associated with anxiety or depression, ing disorders, anomalies in oxytocin functioning
and there is also evidence that a CBM interven- might be involved in these disorders [41, 42].
tion to remediate maladaptive self-beliefs was Study authors have found that the bias toward
associated with a decrease in eating-related attention on food-related stimuli and body image
pathologies in subclinical and clinical samples improved [43], as did biases toward negative emo-
[35, 36]. Furthermore, a recent study on therapy tional expression [44]. These results indicate that
that combined trainings for attentional and inter- oxytocin can be helpful for moderating fear and
pretation bias showed improvements in attention avoidance related to a protracted trajectory in
to smiling faces and fewer biased interpretations anorexia nervosa. Intranasal oxytocin led to a
of ambiguous social stimuli. This finding indi- reduction in caloric intake in the 24 h after admin-
cates that CBM may improve negative cognitions istration in patients with bulimia nervosa [45].
in eating disorders [6]. These results indicate that intranasal oxytocin can
change abnormalities in attentional processes to
specific and general aversive stimuli in anorexia
17.8 Repetitive Transcranial nervosa and may change eating behaviors.
Magnetic Stimulation ED symptoms produce neuro-adaptive
changes that cause chronicity and severely
Anorexia nervosa is associated with changes in impaired quality of life. Oxytocin is a key central
the brain; in particular, alterations have been regulator of appetite, stress, and social functions,
found in systems implicated in reward process- and translational pilot work suggests that it can
17 Treatment-Resistant Eating Disorders 259
moderate the automatic processes that underpin 10. Schmidt U, Treasure J. Anorexia nervosa: valued and
visible. A cognitive-interpersonal maintenance model
treatment resistance. and its implications for research and practice. Br J
Clin Psychol. 2006;45:343–66.
Conclusion 11. Touyz S, Le Grange D, Lacey H, et al. Treating severe
and enduring anorexia nervosa: a randomized con-
Evidence from epidemiological studies, neuro- trolled trial. Psychol Med. 2013;43(12):2501–11.
psychological findings, treatment responsivity, 12. Treasure J, Schmidt U. The cognitive-interpersonal
and prognosis supports a specific staging tra- maintenance model of anorexia nervosa revisited:
jectory for anorexia nervosa in that there is a a summary of the evidence for cognitive, socio-
emotional and interpersonal predisposing and per-
longitudinal trajectory with evidence of neuro- petuating factors. J Eat Disord. 2013;1(13):1–10.
biological progression and evidence that inter- 13. Treasure J, Cardi V, Schmidt U. Moving to establish the
ventions matched to stage of illness may mechanisms underpinning the biopsychiatric models
optimize the treatment benefits. Early and of eating disorders with brain-based translational treat-
ments: from paradigm clash to paradigm complementar-
effective interventions appear crucial because ity. Adv Eat Disord: Theory, Res Pract. 2014;2(2):171–9.
the prognosis sharply declines the longer the 14. Zabala MJ, Macdonald P, Treasure J. Appraisal of
illness persists. There is little information at caregiving burden, expressed emotion and psycho-
the moment to support such a model for buli- logical distress in families of people with eating
disorders: a systematic review. Eur Eat Disord Rev.
mia nervosa and binge eating disorder [8]. 2009;17(5):338–49.
15. Sepulveda AR, Kyriacou O, Treasure J. Development
and validation of the accommodation and enabling
scale for eating disorders (AESED) for caregivers in
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Comorbid Sleep and Wake
Problems in Treatment-Resistant 18
Psychiatric Conditions
ing REM sleep, and sometimes, they have the 18.3 Hypnotic Abuse Problems
side effect of insomnia. Psychostimulants, such
as methylphenidate and modafinil, can cause Hypnotics are effective for insomnia in the short
insomnia as a side effect, and mood stabilizers, term, but they induce shallow sleep, tolerance,
such as lamotrigine, may cause insomnia. and dependency with long-term use. Dependence
Cognitive behavioral therapy for insomnia on benzodiazepines and nonbenzodiazepine
(CBT-I) is a very effective and clinically neces- GABAA agonists is already well known, and
sary therapy for most other mental disorders as patients are also aware of this [28–30].
well as primary insomnia. In the case of depres- Nonbenzodiazepine GABAA agonists, such as Z
sion, CBT-I can be applied except for very drugs, have been reported to have a low misuse
severe depression. In the case of bipolar disor- rate in some studies [31], but in the United States,
ders, CBT-I is modified because the sleep insuf- Z drugs are classified as Class IV Drug
ficiency due to strict sleep restriction and Enforcement Administration (DEA) restricted
stimulus control might induce mood elation or agents, which belong to the same group as benzo-
irritability and sometimes trigger manic symp- diazepines [32].
toms [23]. The bipolar disorder-specific modifi- In addition, benzodiazepines, especially long-
cation of CBT-I was developed by integrating acting benzodiazepines, inhibit respiration, dis-
interpersonal and social rhythm therapy, chro- rupt sleep quality, and increase the risk of sleep
notherapy, and motivational interviewing, and apnea [33]. Occasionally, sleepiness due to ben-
positive effects have been reported [7]. In recent zodiazepines might cause disturbances in the
years, the use of wearable devices and mobile sleep-wake cycle and, ultimately, might cause
applications in insomnia patients has increased, insomnia at night. These patients should be
and interest in them has continued to increase. observed with caution because some of them ask
CBT-I studies using mobile applications and doctors to prescribe more sedative drugs while
wearable devices have been performed, and the sleeping during the daytime. We need to pay
efficacy of these devices has been reported more attention to patients with substance use dis-
recently [24–27]. orders, such as alcohol use disorder, regarding
Pharmacotherapy is widely used for insomnia the abuse of hypnotics. Sometimes they take
when it is difficult to apply CBT-I in clinical set- sleeping pills, such as benzodiazepine receptor
tings. The following drugs have been indicated agonists, during the daytime as well as at night
for primary insomnia: benzodiazepine agonists, [22]. This is thought to be self-medication to
named Z drugs (zolpidem, zopiclone, eszopi- minimize daytime physiologic hyperarousal [34].
clone, zaleplon), benzodiazepines (quazepam, Doctors should be particularly cautious to pre-
flurazepam, triazolam, temazepam); doxepin; scribe hypnotics in cases of drug use disorders,
melatonin receptor agonists (ramelteon); orexin such as alcohol, because these patients often mis-
receptor antagonists (suvorexant); and prolonged- use hypnotics or take alcohol and hypnotics at the
release melatonin (Circadin). In psychiatric dis- same time. This might promote accidents and
orders, not only hypnotics with indications for more serious side effects.
insomnia but also off-label hypnotic medications
with sedative effects are commonly used consid-
ering the symptoms that are comorbid with other 18.4 Sleep Apnea
psychiatric disorders. Typical off-label sedatives
include the following: antidepressants, including According to previous studies, many mentally ill
mirtazapine, trazodone, amitriptyline, imipra- patients have sleep apnea, suggesting a high asso-
mine, clomipramine, and agomelatine; antipsy- ciation between mental disorders and sleep
chotics, including quetiapine, olanzapine, and apnea. Major depression patients have an
chlorpromazine; and anticonvulsants, including increased risk (1.6-fold) for OSA, and those with
gabapentin and pregabalin. sleep apnea have an increased risk (1.8-fold) of
264 S.-G. Kang et al.
developing major depression [35]. Treating OSA OSA symptoms, including snoring, obesity, and
results in the improvement of depressive symp- weight gain, secondary to antipsychotics [18].
toms [36]. Schizophrenia patients with comorbid OSA can
Attention deficit hyperactivity disorder be treated effectively with nasal continuous air-
(ADHD), one of the most common psychiatric way pressure with relatively good compliance
disorders in children and adolescents, is also and clinical improvement in OSA and schizo-
associated with OSA. A recent meta-analysis phrenia [48–50].
found a higher apnea-hypopnea index (AHI) in Second-generation antipsychotics appear to
children with ADHD than in healthy children decrease sleep onset latency and improve sleep
based on polysomnography [37]. There is contro- efficiency, but they also commonly cause weight
versy over the prevalence of sleep-related breath- gain, which can increase the risk of OSA [10].
ing disorders (SRBDs) in children due to the Therefore, when antidepressants or antipsychot-
debate over whether the current AHI criteria are ics with weight gain-inducing potential are pre-
appropriate, but symptoms of SRBD, such as scribed, side effects should be explained to the
snoring, seem to be common in children with patient in advance, and attention should be paid
ADHD or ADHD-like behaviors [38]. to OSA development.
Approximately 20–66% of children with ADHD
have been reported to habitually snore [39–41].
Meanwhile, data from previous studies suggest 18.5 R
estless Legs Syndrome
that treatments such as adenotonsillectomy for and Periodic Limb
SRBD improve ADHD symptoms [42]. Movement During Sleep
Therefore, expert consensus recommends that all
children undergoing evaluation for ADHD should Previous literature has reported that 44% of
be screened for symptoms of SRBD, particularly ADHD patients have RLS or RLS symptoms
snoring [43]. If the child snores, then polysom- [51]. Recent, less-biased studies have reported an
nography is recommended [43]. If the child has approximately 10–20% RLS prevalence in
AHI >1 on polysomnography, large tonsils, and a patients with ADHD [39, 52]. Although the
small airway, adenotonsillectomy should be con- mechanism of the association between the two
sidered [43]. diseases is unclear, a nigrostriatal deficit may
Due to the nature of psychotic disorders, the underlie RLS and periodic limb movements dur-
prevalence of OSA among antipsychotic-naïve ing sleep (PLMS) in ADHD [53].
schizophrenic patients has not been reported. The association between RLS and major
Schizophrenic patients treated with antipsychot- depression is not well established [10]. Several
ics demonstrated a high prevalence rate (17– studies have shown inconsistent results regarding
25%) for sleep-disordered breathing [44–46], the association between the two diseases, pre-
although Takahashi et al.’s study did not show a sumably due to the bias of RLS induced by sero-
higher SRBD prevalence in schizophrenia than in tonergic antidepressants [54].
the control group [45]. In addition to this, more It is unclear how RLS and periodic limb move-
than 46% of schizophrenia patients with sus- ment disorder (PLMD) are related to schizophre-
pected sleep disorder had a respiratory distur- nia because few prevalence studies exist for sleep
bance index (RDI) greater than 10, and the mean disorders in antipsychotic-naïve patients [18].
RDI was 64.8 [47]. The most powerful predictor However, our previous study reported that the
of OSA was obesity in that study [47]. Although prevalence of RLS in schizophrenia patients tak-
somnolence is a common side effect of antipsy- ing antipsychotic medication was 21.4%, twice as
chotics, clinician must consider the possibility of common as in normal controls [55]. Because anti-
comorbid OSA in patients with schizophrenia psychotics have a dopamine antagonist effect,
who show significant somnolence. Therefore, the drug-induced dopamine deficiency appears to
clinician should evaluate whether patients have cause RLS or PLMS symptoms [55]. In addition,
18 Comorbid Sleep and Wake Problems in Treatment-Resistant Psychiatric Conditions 265
the severity of RLS symptoms is correlated with reactivity, weight gain, and hypersomnia symp-
the severity of psychopathology, suggesting that toms [10]. Approximately 10% of general adults
RLS might play an important role in the deteriora- with hypersomnia have major depression [15, 64].
tion and improvement of symptoms of schizophre- Depressive patients with severe fatigue or hyper-
nia [55]. Symptoms of RLS are often confused somnia may experience an improvement in hyper-
with akathisia. The most important difference is somnia as well as depressive symptoms when
the circadian pattern: RLS symptoms are aggra- treated with antidepressants, and some patients
vated at night, but there is no circadian pattern in may benefit from adjunctive use of stimulant
akathisia symptoms [18]. Previous studies have medication with antidepressants [10, 65]. Light
reported that 13–14% of schizophrenia patients therapy is also effective for patients with seasonal
taking first-generation antipsychotics show PLMS depression and hypersomnia [10].
in nocturnal polysomnography [44, 56]. Sleepiness and hypersomnia are also common
The management of RLS/PLMD in psychiatric symptoms of bipolar disorder. In particular, bipo-
disorders, such as schizophrenia, depression, and lar disorder patients with depressive episodes
ADHD, includes the elimination of the cause (e.g., complain of hypersomnia, prolonged time in bed,
stopping the antidepressants or antipsychotics, and excessive sleepiness, and 25% of patients
which might trigger secondary RLS), nonpharma- with bipolar disorder complain of hypersomnia
cologic strategies, and, if necessary, pharmaco- in the inter-episode period [66, 67].
logic strategies. In particulary, the RLS symptoms First-line treatment medications for psychiat-
in psychiatric patients should be assessed for the ric disorders may also cause sedation [7]. The
probability of medication-induced symptoms such CATIE study reported significantly prevalent
as SSRI and antipsychotics should be examined antipsychotic-related somnolence [68]. The rate
[57, 58]. In this case, adherence to pharmacother- of somnolence in antipsychotic-treated schizo-
apy deteriorates, and psychiatric disorders often phrenic patients was 24–31% among
relapse; therefore, ultimately, a reduction or dis- antipsychotic-treated schizophrenic patients [68].
continuation/replacement of the medication is Sedation can be an adverse reaction due to the
necessary for the fundamental solution [59]. direct effect of antipsychotics, sometimes due to
Nonpharmacologic strategies include sleep negative symptoms or secondary SRBD due to
hygiene therapy, physical exercise, and avoiding antipsychotic-induced weight gain [18]. Typical
aggravating factors, such as iron deficiency, pain, low-potency antipsychotic drugs have antihista-
caffeine, nicotine, and alcohol [60]. minergic and anticholinergic side effects, includ-
In pharmacotherapy, dopaminergic drugs are ing sedation [18]. The sedative effect of clozapine,
used as off-label drugs in children with ADHD quetiapine, and olanzapine in second-generation
[61, 62]; however, there is no established data on antipsychotics is remarkable [18]. If the patient’s
their long-term efficacy and tolerability [38]. In discomfort or side effects are severe, dose reduc-
cases of low ferritin or iron levels, oral iron sup- tions of antipsychotics should be considered to
plementation is recommended [63]. In patients improve patient’s quality of life and compliance,
with schizophrenia, dopamine agonists, such as even if the medication is needed therapeutically
ropinirole and pramipexole, may exacerbate psy- [69]. Quetiapine is often used off-label for insom-
chotic symptoms and should be administered nia symptoms. The extended release form of que-
with caution [18]. tiapine was originally developed to reduce the
side effects of the immediate release form;
however, the hangover from quetiapine’s
18.6 Sleepiness and Hypersomnia extended release form may persist longer through
the next morning. In this case, considering the
In addition to insomnia, hypersomnia is also a pharmacokinetics of the drug, changing to an
common and important symptom in major depres- immediate release form may be helpful in sleep
sion. Depression’s atypical features include mood induction and reducing hangover the next day.
266 S.-G. Kang et al.
The results of previous studies on modafinil com- 18.8 REM Sleep Behavior Disorder
bination therapy to improve antipsychotic-asso-
ciated sedation or fatigue did not show RBD or RBD-like symptoms frequently occur
significantly favorable results compared to a pla- during pharmacotherapy for psychiatric disor-
cebo combination [70, 71]. ders. In particular, the antidepressants that
inhibit REM sleep are closely associated with
the RBD occurrence. SSRI, SNRI, and mir-
18.7 Disturbances tazapine often cause RBD symptoms [84, 85].
of the Circadian Sleep-Wake Antidepressant-associated RBD symptoms may
Cycle be caused by a mechanism distinct from synu-
cleinopathy, but others insist that antidepres-
In bipolar disorder, sleep and circadian rhythms sants tend to unmask RBD symptoms in people
are unstable due to the inadequate and irregular with subclinical synucleinopathy [86].
timing of the exposure to light and dark and irreg- Withdrawal from barbiturates and ethanol is
ularities in social rhythms. In addition, the clock known to trigger RBD symptoms and caffeine
gene function is also involved in circadian rhythm abuse, and beta-blockers may also cause RBD
disturbances [7]. The medication used to treat [87–90]. If RBD symptoms are suspected,
bipolar disorder also has the effect of delaying or patients and their families should be educated to
advancing circadian rhythm [72]. be cautious of accidents and injuries caused by
Although circadian rhythm abnormalities abnormal behavior during sleep. When the
are common in schizophrenia and there have symptoms of RBD are suspected to develop due
been many studies on them, the results are to medication, it is advisable to reduce the dos-
largely inconsistent on the proportion of each age of antidepressants or to switch to other anti-
sleep-wake pattern (e.g., delayed phase, depressants (e.g., bupropion) that are less likely
advanced phase, irregular pattern, and free-run- to cause RBD symptoms, considering their psy-
ning pattern) [19, 73–77]. A disturbed pattern chiatric symptoms. Although benzodiazepines,
of melatonin secretion was reported in both such as clonazepam, may be effective in this
schizophrenic patients with phase-advanced case, they are not a fundamental solution for the
[78] and phase-delayed [79] disease. These problem and are likely to cause sleep apnea. In
inconsistent results may be due to a variety of situations where clonazepam is not advisable,
circumstances, such as the methodological het- 3–15 mg of melatonin can be used [91]. If there
erogeneity of the studies and environmental/ is a suspicion of comorbid sleep apnea or if it is
lifestyle factors (sunlight exposure, decreased necessary to distinguish RBD-like symptoms
activity, effective time cues, and lifestyle from other parasomnias or seizures, nocturnal
choices involving preferences for staying awake polysomnography should be performed.
at night, etc.) [18].
Circadian rhythm abnormalities occur fre- Conclusions
quently in ADHD patients. The common area Treatment resistance or residual symptoms in
of the brain regions identified as a cause of many psychiatric disorders are often caused by
ADHD and circadian rhythm disorder is the sleep and wake problems. In long-term treat-
locus coeruleus [80]. A clinical study of the ment situations, sleep-wake disturbances, such
melatonin secretion pattern of patients with as insomnia, become more important problems
ADHD shows that delayed sleep phase syn- than the initial chief complaint of psychiatric ill-
drome is common in that population [81, 82]. ness. Sleep and wake problems in major psychi-
According to the recommendations of the atric disorders, such as depressive disorders,
expert consensus group, melatonin, light ther- anxiety disorders, bipolar disorders, schizophre-
apy, and chronotherapy can be used for sleep nia, and ADHD, impair the quality of life of
induction difficulties due to delayed sleep patients and deteriorate their therapeutic prog-
phase syndrome [43, 83]. ress. Sleep problems, such as insomnia, sleep
18 Comorbid Sleep and Wake Problems in Treatment-Resistant Psychiatric Conditions 267
apnea, RLS, hypersomnia, hypnotic use and 7. Harvey AG, Soehner AM, Buysse DJ. Bipolar dis-
misuse, and circadian disruption, are quite com- order. In: Principles and practice of sleep medicine.
Philadelphia, PA: Elsevier; 2017. p. 1363–9.e4.
mon, and the treatment of psychiatric disorders 8. Harvey AG, Schmidt DA, Scarna A, Semler CN,
is jeopardized when they are not properly man- Goodwin GM. Sleep-related functioning in euthymic
aged. Occasionally, sleep and wake problems patients with bipolar disorder, patients with insomnia
that occur during the treatment of psychiatric and subjects without sleep problems. Am J Psychiatry.
2005;162(1):50–7.
illness often require changes in the treatment 9. Reynolds CF 3rd, Kupfer DJ. Sleep research in
strategy, including pharmacotherapy. Insomnia, affective illness: state of the art circa 1987. Sleep.
which is the most common sleep-wake symp- 1987;10(3):199–215.
tom, is usually treated effectively with CBT-I, 10. Minkel JD, Krystal AD, Benca RM. Unipolar major
depression. In: Principles and practice of sleep medi-
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69–70.
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Acknowledgment This research was supported by Basic the United States: results of the 1991 National Sleep
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Part III
Therapeutic Intervention for
Treatment Resistance
Creative, Person-Centered
Psychopharmacology 19
for Treatment Resistance
in Psychiatry
Miro Jakovljevic
19.1 Introduction ness from the other side is a very complex one
and circular in its nature. Many psychiatric
Among the leading topics in contemporary psy- patients suffer from post-episode residual symp-
chiatry, treatment resistance is a very hot one, not toms and have a lower quality of life followed by
only from practical clinical perspective but also increased relapse risk and poorer long-term out-
from research, theoretical, and epistemological comes associated with illness chronification.
points of view. It has always been an important Major mental disorders are typically chronic dis-
topic in psychiatry, but concerns about increasing orders with a waxing and waning course and ill-
costs of psychiatric treatments and high mortality ness progression. Even mental disorders, episodic
rates have put this topic in hot focus of interest. at the onset, turn chronic with shortening inter-
Despite the introduction of significant number of vals between episodes. It is always important to
new mental health medicines since “the decade have in mind that patients who do not achieve a
of the brain,” outcomes of mental disorders in our good symptomatic remission and personal
“century of mind” remain poor in both short-term recovery after the first or repeated episode of ill-
and long-term course of the treatment. Inadequate ness have higher probability of relapse or of a
treatment in psychiatry seems to be more com- new episode of illness, and by extension, of
monly the rule than the exception, and a huge developing treatment decrement or resistance
number of patients do not respond in a satisfac- and chronic mental disorder. The high rate of
tory way, in terms of the magnitude of therapeu- treatment failures, the low effectiveness of men-
tic response and/or the persistence of the tal health medicines, and the rigid and mechanis-
remission [1]. Insufficient treatment response, tic pharmaco-centric treatment are currently in
treatment decrement, and treatment resistance contention, both outside and within the field of
are commonly associated with chronification of psychiatry. Some classes of mental health medi-
many mental disorders. Relationship between cines, for example, antidepressants, are wrongly
relapses, recurrent episodes, and illness chronic- depicted as noneffective, but harmful, and noth-
ity from one side and partial remission, treatment ing more than “placebos with adverse effects.”
decrement, and treatment resistance/refractori- These negative and wrong views significantly
contribute to vilification and condemnation of
Parts of the chapter were previously published in Person contemporary technical and impersonal psycho-
Centered Psychiatry, pp. 235–245, Springer 2016. pharmacotherapy and to stigmatization and fear
M. Jakovljevic of psychiatry. There has been an increasing
Department of Psychiatry, University Hospital Centre concern that clinical psychopharmacology has
Zagreb, Zagreb, Croatia
lost its right way and biological psychiatry its applications, and implications. There are no gen-
soul, so commonly called “mindless psychiatry.” erally accepted definitions of what defines treat-
What causes a good therapeutic outcome and ment resistance and refractoriness, as well as
how to prevent or overcome treatment resistance treatment nonresponsiveness and ineffectiveness
are the fundamental questions from the perspec- for any of the individual mental disorders.
tive of transdisciplinary integrative psychiatry Unfortunately, studies claiming that certain
(see [2–4]). The challenge for contemporary markers could predict treatment response or dif-
thinking about treatment resistance in psychiatry ferentiate treatment-responsive from treatment-
arises from the way we understand and treat men- resistant mental disorders have not been still
tal disorders. Treatment outcome is strongly replicated (see [7]). Full and clear understanding
associated with person-centered approach in of neurobiology and psychopathology of major
therapy and the level of resilience (lat. resilare – mental disorders has been still elusive. The prac-
to rebound), creativity, patient-doctor partner- tice of evidence-biased instead of true evidence-
ship, and positive therapeutic narratives. In order based medicine may significantly contribute to
to increase treatment efficiency, including pre- treatment pseudo-resistance. Early differentia-
venting and overcoming treatment resistance, the tion of real treatment resistance from pseudo-
author has been trying to develop the concept of resistance and insufficient treatment response is
creative, person-centered pharmacotherapy [2– of the great importance because a starting false
5]. The key terms of this concept are the focus on resistance commonly becomes the real one. The
person in treatment instead of blockbuster and misdiagnosis or rapid labeling of patients as
stratified medicine approaches, synergistic drug treatment resistant can have very deleterious
combinations, enhancing resilience and saluto- nocebo effects on treatment outcome. According
genesis, decreasing general psychopathology or to the very popular, but not precise definition,
p factor (see [6]), reconstructing disease and ther- treatment resistance “refers to the occurrence of
apeutic narratives, and promoting creativity and an inadequate response following adequate ther-
partnership. apy among patients suffering from a defined psy-
chiatric disorder” [1]. Treatment resistance is a
negative and pessimism provoking term which
19.2 Reframing Pessimistic may have double nocebo meaning: that the
Paradigm: Insufficient patient is resisting treatment and that the mental
Treatment Response Is Not disorder is resistant to treatment. It implies dis-
Always Treatment Resistance couraging and disappointing message that remis-
sion or recovery is not possible which inhibits
The ways in which we define problems often hin- patients from continuing treatment long enough
der their solutions. Paul Watzlawick (1989)
or from further searching to get competent treat-
Our everyday clinical experience confirms ment. Having in mind this pessimistic connota-
Watzlawick’s claim that the ways in which we tion, which implies incurability and bad
define problems with biases and blunders regu- prognosis, it is better to use more neutral terms
larly hinder their solutions. It is also the case like insufficient or unsatisfactory treatment
with the treatment resistance in psychiatry. response to avoid, among other negativities, the
Treatment resistance is a metaphor which possible nocebo effects on patients. As it is
implies negative and frightening connotations sometimes possible in good clinical practice to
and augments therapeutic pessimism and com- achieve favored or even optimal treatment out-
plicates treatment as well as living of patients come after previous several unsuccessful
with the so-called treatment-resistant mental dis- attempts, several and long treatment failures in
orders. For the time being, treatment resistance fact mean “more-difficult-than-usual treatment.”
is unfortunately a badly defined and understood Therefore, instead of treatment resistance, it is
phenomenon with differing conceptualizations, better to speak about “for a time being treatment
19 Creative, Person-Centered Psychopharmacology for Treatment Resistance in Psychiatry 275
Table 19.2 Factors contributing to insufficient or negative therapeutic response and treatment failure (see [11],
revised)
Illness-related factors: poor knowing of pathophysiology, unrecognized and undiagnosed psychopathology,
unrecognized comorbid medical disorders, comorbid psychiatric disorders (dual disorders), personality/character
pathology, and deficiencies in thiamine, vitamin B6, vitamin B12, folates, copper, and zinc
Treatment-related factors: non-adequate treatment, unimodal treatment not covering some important pathological
mechanisms, rigid dogmatic treatment approach, the so-called “wait-and-see strategy,” inadequate treatment of
earlier episodes, and drug therapy as a sole form of treatment with the message to patients: “you don’t have to
change anything, you just have to take your medication on time and for a long time enough”
Medication-related factors: delayed treatment onset, intolerance to the medication, adverse events and toxic side
effects, monotherapy non-covering all important pathological mechanisms, medications with opposite effects,
irrational polypharmacy and toxic drug combinations, adverse drug and food interactions
Patient-generated factors: partial adherence or nonadherence to treatment, rapid or slow drug metabolism,
pessimism and negative beliefs and expectations, recent psycho-traumatization, reactivation of suppressed
psycho-trauma, lack of faith in doctor and treatment, nocebo response, negative meaning response, preoccupation
with side effects and negative reactions, negative treatment conditioning, negative therapeutic reaction related to
unconscious sense of guilt, self-defeating behavior, strong need to be in charge, pharmacophobia, prejudice, and
bad nutritional status
Clinician-related factors: non-adequate communication style; poor fit between type of psychological approach and
personality type of patient; nonconscious nocebo induction; lack of optimism; lack of empathy, compassion, and
guidance skills; low level of experience and professional knowledge; discomfort with uncertainty; negative
countertransference (anger, guilt, dislike, disappointment, helplessness, and powerlessness) and negative emotional
reaction to the patient; unsatisfactory self-management; and accusing the patient of being problematic or difficult
Factors associated with doctor-patient relationship: anti-therapeutic relationship, lack of therapeutic alliance,
psychiatric care experienced as impersonal, unconcerned and uncaring, lack of rapport, and power games
Patient’s family-related factors: stigma, lack of support and care, rejection, high negative emotional expression, and
family psychopathology
life story is and narrative about illness and its ered as a treatment reserved only for nonadherent
treatment. and non-compliant patients with frequent
Some general principles for the management relapses or who pose risk for others. Recently,
of treatment failures may be helpful in overcom- with regard to the schizophrenia staging and crit-
ing the problem (Table 19.3). First and foremost, ical period concept, the interest of using SG (sec-
clinicians should be rethinking their definition of ond generation)-LAIAs in the early stage of
treatment goals and treatment strategy, always schizophrenia has increased [9]. Rethinking
having in mind that the best treatments are those schizophrenia as a neurodevelopmental disorder
that utilize and integrate multiple modalities at with psychosis and neurodegeneration as a late,
the right time and in good treatment context potentially preventable stage of illness [14] yields
accepted by patients. For example, rethinking the new perspective on SG-LAIAs utilization in
strategy of long acting injection or depot antipsy- early stages of illness aimed to prevent treatment
chotics application could significantly improve resistance.
treatment response and outcome in patients with Creative, person-centered psychopharma-
schizophrenia. cology is called upon to denounce the metaphor
Despite the evidence-proved advantages of treatment resistance and to support patients
offered by long-acting injections of antipsychotics and their families in enhancing their resilience
(LAIAs), they are widely underused in many and healthy parts of personalities, thus promot-
countries all over the world [12, 13]. The LAIAs ing their positive mental health. At the end of
have long been considered and still are consid- the day, it means to change an inadequate and
19 Creative, Person-Centered Psychopharmacology for Treatment Resistance in Psychiatry 277
Table 19.3 General principles for the management of treatment failure ([11], revised)
Assess factors contributing to treatment failure and formulate and implement a new treatment plan
Ensure accurate diagnosis, including the subtype of mental disorder
Identify patient’s strengths and weakness and opportunities and threats (SWOT analysis)
Assess psychiatric and somatic comorbidity
Evaluate psychosocial stressors and enhance social support
Ensure appropriate dose and duration of treatment (e.g., long-acting injectable antipsychotics)
Monitor and treat adverse events
Check and monitor drug concentrations in blood
Evaluate pharmacokinetic parameters
Assess possible undesired drug interactions
Assess drug-induced neurotransmitter dysbalance syndrome, neurotransmitter receptor supersensitivity syndrome
(e.g., dopamine supersensitivity psychosis), and drug tachyphylaxis
If applicable assess DHEA/cortisol ratio, thyroid hormones, homocysteine blood level, inflammatory biomarkers
like CRP (c-reactive protein), candidate genes ABSB1, FTD7, and WNT2B on antidepressant drug resistance, etc.
Ensure the psycho-education of patient and his or her family
Assess cultural beliefs
Ensure treatment adherence (e.g., LAIAs in schizophrenia and recurrent psychotic disorders) and therapeutic
alliance
Ensure integrative and complementary treatment approach
Evaluate and redefine treatment goals and therapeutic narratives
Enhance resilience and placebo response
Integrate treatment from multiple clinicians
Aim for clinical remission, social rehabilitation, and personal recovery
fragmented therapy for a proper and integrative With regard to treatment resistance in psychiatry
one. and association between health, resilience, and
disease, an essential question arises: Does resil-
ience enhancing help and how in preventing and
19.3 From Treatment Resistance overcoming treatment resistance in psychiatry? It
to Resilience and Positive seems that many major mental disorders may be
Mental Health understood as a limitation of primary resilience
[6], while treatment failure or treatment resistance
Our greatest glory is not in never falling, but in ris- may be associated with limitations of secondary
ing every time we fall.
Confucius
and tertiary resilience. Resilience is a relatively
new psychobiological concept which refers to
Following the quote of Confucius, resilience individual’s capacity to overcome therapeutic
may be defined as an ability to rise every time we failure and hard-treated mental disorders. The
fall, to bend but not to break, and to adapt well concept of resilience and resiliency promotes pos-
when face to adversity, threats, trauma, disease, or itive psychology and positive mental health by
tragedy. The term resilience refers to the process increasing individual and collective sense of well-
of bouncing back and overcoming adversity, while being which may be an important component of
resiliency means personality traits related to resil- favorable treatment outcome [15]. Well-being as
ience. Resiliency refers to personality traits like “the capacity to live a full and creative life, and
adaptability, hardiness, self-directedness, coopera- the flexibility to deal with life’s inevitable chal-
tiveness, self-transcendence, and invincibility. lenges” [16] is closely related to resilience.
278 M. Jakovljevic
come, distress, and burden of mental illness (see ranging from surviving to thriving, positive trans-
[15]). Tertiary resilience enables patients to formation and personal growth. Enhancing
develop a healthy and productive way to live with patients’ resilience by emphasizing their strength
their illness, helps them to adapt to limitations in and covering up their weakness is an ambitious
life associated with illness, and has positive and goal that aims to promote positive mental health
creative life attitudes. Proactive and more effica- in spite of the presence of symptoms [25] and
cious participation of patients with chronic ill- drug treatment failure. Good news is that resil-
ness and residual symptoms in their medical ience can be enhanced through learning and train-
treatment is also an expression of tertiary ing. Resilience training can result in augmented
resilience. neuroplasticity and balance of neural circuits that
modulate reward and motivation, emotion regula-
tion, cognitive reappraisal and executive function,
19.4 Enhancing Resilience: novelty seeking, harm avoidance and fear
Creative response, self-directedness, cooperativeness and
Psychopharmacotherapy adaptive social behavior, and self-transcendence.
May Overcome Treatment A variety of internal and external events can influ-
Resistance ence our genes triggering epigenetic reactions,
e.g., methylation which turn gene on or turn them
It is more important to know what kind of a patient off [26]. When a gene is “turned on,” it governs
has a disease than what kind of a disease a patient
has. William Osler
the making of gene products, e.g., proteins, and
when a gene is “turned off,” these products are no
The model of primary, secondary, and tertiary longer produced. Genes found to be associated
resilience explains how appropriate resilience- with different aspects of resiliency include the
enhancing interventions may help in overcoming monoamine oxidase A (MAO-A), neuropeptide Y
the lack of therapeutic response. The level of and (NPY), brain-derived neurotrophic factor
pace by which recovery is established is a func- (BDNF), corticotrophin-releasing hormone
tion of brain resilience, external resources like receptor (CRHR1), oxytocin receptor gene
support, nature of the mental disorder, and chosen (OXTR), FK-506 binding protein 5 (FKBP5),
drug treatment. However, resiliency as a treatment serotonin-transporter promoter polymorphism
target has been largely neglected in the field of (5-HTTLPR), catechol-O-methyltranspherase
therapeutics [23], so the lack of favorable treat- (COMT), nerve growth factor inducible
ment outcome may be commonly related to the (NGFI-A), and calcium channel, voltage-
treatment focus only on symptoms and illness. dependent, L type, alpha1C subunit (CACNA
The route of clinical, functional, and personal 1C), apolipoprotein E (ApoE) genes [27–31].
recovery lies not only in decreasing illness but Some authors speak about resilience promoting
also in enhancing resilience and increasing well- molecules like DHEA, neuropeptide Y, galanin,
ness [24]. Full personal recovery does not mean serotonin, oxytocin, testosterone, estrogen, HDL
only the absence of symptoms of mental illness and benzodiazepine receptors, and resilience
but also the presence of resilience and wellness. undermining molecules like corticotropin-
The concept of resilience enhancing focuses also releasing hormone (CRH) and cortisol [32–34].
on strengths and potentials for wellness which are The methylation of certain genes, e.g., the gluco-
present in patients, not only on their weakness and corticoid gene promoter, could mediate the long-
pathology. Each patient is a unique, responsive, term effect of adversity (see [6]). It is interesting
and responsible person, and within every person that low DHEA/cortisol ratio was suggested as
there is a force that drives them to strive to self- useful biological resilience marker in patients
realization, self-understanding and self-transcen- with PTSD [32, 34]. According to some studies,
dence and a sense of cohesion and control over resilience may be affected by pharmacological
their own life. Resilience is a complex process treatments like antidepressants [35].
280 M. Jakovljevic
Antidepressant effects have been reported to be tions of different classes (e.g., adding antide-
related to reversing hippocampal atrophy by the pressant to antipsychotic drug in patients with
stimulation of neuronal proliferation and synaptic schizophrenia), while polypharmacy is defined
plasticity as well as that the candidate genes as the use of two or more medications of the
ABCB1, FZD7, and WNT2B can be biomarkers same group such as antipsychotic medications
for antidepressant drug resistance [36]. (see [41]). Polypharmacy (lat. multiple drugs)
Antidepressants may have resilience-enhancing refers to the concurrent use of multiple medica-
or saliostatic properties [37] and vice versa; high tions by a patient for the same illness or different
resilience might contribute to better treatment illnesses in the case of comorbidity. It usually
response in depressed patients [38]. The specific implies a negative connotation of too many med-
role of resilience in mental disorders like depres- ications which is a wrong apprehension. Within
sion, personality disorders, and schizophrenia the concept of creative psychopharmacotherapy,
spectrum disorders is not fully understood; as creative drug combinations mean as many medi-
suggested by literature, it may contribute to the cations as needed, each for a specific target of
determinism of illness onset, duration, severity, illness, to obtain optimal therapeutic response
frequency relapses, treatment compliance, and and personal recovery. Medications which
effectiveness [39]. Our growing understanding of become not-needed or un-tolerable over time are
the psycho-neurobiology of resilience could have discontinued.
significant implications for predictive, preventive, In the case of treatment failure, first and fore-
and person-centered psychopharmacotherapy. most, clinicians should be rethinking their treat-
ment philosophy and strategy. The best treatments
are those that utilize and integrate multiple com-
19.4.1 Rethinking Treatment plementary modalities aimed to clear defined
Strategy: Multidimensional therapeutic goals addressing all presenting
and Integrative Therapeutic important syndromes. The concept of creative,
Approach person-centered narrative psychopharmacother-
apy gives a hope for overcoming treatment non-
The rational use of multiple medications simulta- response and failure (Table 19.5).
neously to treat difficult illnesses places p sychiatric The concept of creative psychopharmacother-
pharmacotherapy on a par with treatment in other apy offers an overarching theoretical framework
medical specialties. Bernstein (1993) [40]
that permits the integration of different levels of
In the literature one can identify several, explanation from neuroscience, clinical psycho-
mainly empirically supported, recommendations pharmacology, psychodynamics, evolutionary
to relieve treatment nonresponse or failure and to psychobiology, and positive psychology in order
prevent developing a real treatment resistance. to predict and prevent or identify and resolve
These recommendations commonly contradict treatment resistance. It represents an art and prac-
with one another and are changeable as the ever- tice of the learning organization (see [43]) in the
increasing influx of new information appears frame of transdisciplinary, integrative, narrative,
and novel therapies are made available. The most person-centered, and neuroscience-based psy-
popular pharmacological strategies are switch- chiatry [5, 2, 3, 11]. Each therapy is a learning
ing, augmentation, and drug combination from process which involves systemic thinking, cre-
the treatment beginning (see Table 19.4). ative mental model, personal mastery, therapeutic
However, these terms have different meaning for vision, and therapeutic dialogue (see [43]). The
different people which is not good for the scien- more complicated the treatment case is, the more
tific image of psychiatry. According to some art and learning with the patient are needed for a
authors, augmentation is usually defined as the successful therapeutic outcome. Creative psy-
simultaneous administration of the two medica- chopharmacotherapy is much more than pre-
19 Creative, Person-Centered Psychopharmacology for Treatment Resistance in Psychiatry 281
Table 19.4 Management strategies for overcoming insufficient treatment response ([11], modified)
Pharmacological strategies
Increasing the dosage of medication to the maximal recommended dose
Switching strategies: stopping the medication to which the patient is not responding and prescribing another
medicine, usually from an another group of the same class
Augmentation strategies: adding another agent to an ongoing medication that has been insufficient in order to
augment or maximize its effectiveness
Adjunctive, adjuvant, or add-on therapy: another treatment used with or added to the primary treatment with an
ancillary role in treating an illness (in addition to drugs also horticultural, art, music, recreation therapy)
Neoadjuvant therapy: in contrast to adjuvant therapy, it is applied before the application of the main therapy
Supplementations (brain-healthy diet, vitamins, omega-3 fatty acids, amino-acids, S-adenosyl-L- methionine
(SAM-e), dehydroepiandrosterone (DHEA), Saint John’s wort, Ginkgo biloba, etc.)
Combination strategies (COMBOs): adding another compound very soon or starting with two or more
compounds of the same or different class with a well-established efficacy as a single agent for the treatment of
the mental disorder
Off-label indication drugs: ketamine, oxytocin, memantine, armodafinil, thyroid hormones, riluzole,
minocycline, COX-2 inhibitors, etc.
Non-pharmacological strategies
Electroconvulsive therapy (ECT): better term is electroneuromodulatory therapy
Vagus nerve stimulation
Repetitive transcranial magnetic stimulation (rTMS)
Cognitive enhancement therapy based on the brain neuroplasticity model
Psychotherapy and psychosocial treatments, assertive community treatment
Psycho-education and cooperation with family and social skills training
Individual resiliency training
The health belief dialogue and improving treatment adherence and proactivity
Psychological strategies: respecting the patient, being nonjudgmental, careful active listening, validating feelings
and behaviors, supportive and understanding attitude, framing a clear treatment strategy and contract, enhancing
motivation for change (motivational enhancement therapy)
Creating favorable therapeutic context
Partnership-based guidance of the patient and building a stable therapeutic alliance
Increasing placebo and decreasing nocebo responses
Creating positive treatment narrative: narrative psychopharmacology
Psychodynamic pharmacotherapy
Life coaching strategies
Enhancing resilience and resiliency: cognitive restructuring and improving coping strategies
Promoting patients’ creativity
Improving illness self-management skills and coping with persistent symptoms
Supporting patients to achieve personal goals
Complementary medicine: therapeutic disciplines that are used together with conventional medicine as add-on
therapy
Acupuncture, homeopathy, spiritual healing, yoga, tai chi, etc.
Integrated strategies
-Use of mental health medications together with other modes of treatment like psychotherapy, family therapy,
narrative therapy, risk management strategies, complementary, and alternative medicine
Creative, person-centered narrative psychopharmacotherapy
health problems, resilience enhancing, and fos- nations (COMBOs), if treatment fails again.
tering patients’ creativity and personal mastery. It Although many of the evidence support
is an alternative to dogmatic, rigid, and authori- “COMBOs as soon as needed” strategy (see [45,
tarian application of official treatment guidelines 46]), international consensus treatment guide-
and marketing-based practice. lines for all major mental disorders strongly rec-
ommend single drug of choice as the first-line
treatment in spite of the fact that many psychiat-
19.4.2 Tailoring the Best Drug ric patients do not recover after their initial mono-
Combinations as Soon therapy trial. The so-called treatment
as Possible for Specific Mental pseudo-resistance may be commonly a result of
Disorders on Individual Basis this treatment strategy. The use of a single mental
health medication is always the simplest and saf-
Good clinicians practice rational poly-pharmacy, est, but very often not the most effective or suffi-
and those who do it expertly are leaders in their
field. Doran [44]
cient treatment [44]. Approximately half of
depressed patients, for example, show an insuffi-
Dr. Jonathan Cole (1925–2009) coined the cient response to monotherapy, and every fifth
term creative psychopharmacology in 1992 refer- patient has chronic depression despite multiple
ring to “the rational use of multiple medications interventions. In general, creative COMBOs with
simultaneously to treat difficult illnesses” (accord- an additive, synergistic, and therapeutic effect
ing [40]). Rational and safe combinations of mul- between two and more medicines make the over-
tiple medications are usually recommended to all treatment benefit greater than that achieved by
achieve clinical improvement when simpler regi- either of the medications alone. Patients with
mens have failed [40, 44]. Drug treatment guide- panic disorder, for example, respond better and
lines mainly promote a next decision- making sooner to the COMBO of an SSRI antidepressant
procedure: (1) single drug treatment of the first and a high potent benzodiazepine than to either of
choice; (2) switching, if there is no treatment the medications alone. When panic attacks disap-
response; and (3) augmentation or drug combi- pear soon, the benzodiazepine is excluded, while
19 Creative, Person-Centered Psychopharmacology for Treatment Resistance in Psychiatry 283
maintenance treatment is continued with the anti- stable and free from depression. Comorbidity
depressant. Individual antipsychotics are not increases risk of treatment failure, and because of
effective in treating the entire range of symptoms that it is also an important reason supporting the
in schizophrenia as well as antidepressants in rationale of polypharmacy. For example, patients
monotherapy which do not cover all the aspects of with comorbid depression and anxiety disorder,
psychopathology in depression. It is quite rational like panic disorder, treated with antidepressant
to treat depressed patients with two or more anti- alone, may become overstimulated or respond
depressants simultaneously if they have different only partially, while treated with a high potent
mechanisms of action and synergistic therapeutic benzodiazepine alone may have breakthrough
effects, e.g., stimulating one in the morning and depressive symptoms or breakthrough panic
sedating one in the evening (see Table 19.6). It is attacks (see [44]). Combination of these two
similar with combinations of mood stabilizers, classes of drugs together (COMBOs) may elimi-
antipsychotics, etc. Many bipolar patients simply nate both depression and panic attacks.
cannot be stabilized with one mood stabilizer As mental disorders contribute enormously to
alone but improve considerably or achieve a full psychological, social, and economic suffering of
recovery when treated with a combination of patients and their families, the achievement of
mood stabilizers from different drug families. A complete remission as soon as possible is a very
common example of monotherapy ineffectiveness important goal of creative psychopharmacother-
may be seen in bipolar depressed patients, when apy. Rapid remission and complete recovery,
patients on a mood stabilizer alone have break- what is the best prevention of treatment failures
through depressions but when on an antidepres- and resistance, can be achieved in majority cases
sant alone have lack of response, manic only with rational drug combinations and cre-
overstimulation, or erratic, unpredictable response ative polypharmacy. Creative and rational
[44]. Rational combination of two or more mental polypharmacy means multiple drug treatment
health medicines may help patients to be mood with “only as many drugs as necessary, each for a
284 M. Jakovljevic
Table 19.7 Some interesting evidence-based and practice-based COMBOs according to Stephen Stahl [45, 46]
Combos for unipolar depression
Triple-action combo: SSRI/SNRI+NDRI
California rocket fuel: SNRI + mirtazapine
Arousal combos: SNRI + stimulant or modafinil
Lithium combo: 1st line agent + lithium
Thyroid combo: 1st line agent + T3/T4
Serotonin 1A combo: 1st line agent + buspirone (?pindolol)
Insomnia anxiety combo: 1st line agent + eszopiclone/zolpidem or benzodiazepine
Serotonin 2A combo: 1st line agent + SARI + mirtazapine + SDA/DPA
Dopaminergic combo: NDRI/NRI + stimulant + modafinil + DA agonist (e.g., pramipexole)
Heroic combo: high-dose SNRI/SSRI + alfa2 antagonist + NDRI/NRI + stimulant
Bipolar combos
Atypical + lithium (evidence-based)
Atypical + valproate (evidence-based)
Li-Vo: lithium + valproate (practice-based)
La-Vo: lamotrigine + valproate (practice-based – caution)
La-Li: lamotrigine + lithium (practice-based)
La-Li-Vo: lamotrigine + lithium + valproate (practice-based – caution)
Lami-quel: lamotrigine + quetiapine (practice-based)
Boston bipolar brew: any combo but antidepressant
California careful cocktail: any combo + antidepressant
Tennessee mood shine: atypical + antidepressant
Walt Disney’s combo: any combo containing ziprasidone
California sunshine: ziprasidone + lithium + transdermal selegiline or ziprasidone + lithium + venlafaxine
Schizophrenia combos
The second-line treatment of positive symptoms: clozapine or conventional AP + SDA or DPA
The third-line treatment: first line AP + mood stabilizer
AP antipsychotic, DPA dopamine partial agonist, NDRA noradrenalin dopamine reuptake inhibitor, NRI noradrenaline
reuptake inhibitor, SDA serotonin dopamine antagonist, SNRI serotonin noradrenaline reuptake inhibitor, SSRI selective
serotonin reuptake inhibitor
specific target symptom, each evaluated individu- ties in the complex interactions between several
ally for efficacy and side effects and adjusted neurotransmitter and psychobiological systems
optimally, with the elimination of each one that is rather than in the abnormalities of any only one
no longer necessary” [47]. Creative COMBOs simple system. In clinical practice it is very dif-
provide synergistic benefits and mitigate or ficult to achieve a full remission or recovery with
eliminate adverse effects by using lower doses of drug monotherapy, so polypharmacy of mental
each medication and targeting complementary health medicines should be rather a rule than an
physiological (compensatory) mechanisms. exception.
General strategy “monotherapy before poly- In general, creative COMBOs (see Tables
therapy” is one of the significant causes of treat- 19.6 and 19.7) with an additive, synergistic
ment resistance or better to say pseudo-resistance. therapeutic effect between two and more medi-
It is evident that finding the right medication for cines, make the overall treatment benefit greater
an individual in serial mono-pharmacy approach than that achieved by either of the medications
is not so easy. Many patients usually try several alone. Rapid remission and complete recovery
different medicines before finding the right one. can be achieved in a majority of cases only with
In addition, we are now confronted with the fact rational drug combinations and creative
that mental disorders are the result of abnormali- polypharmacy.
19 Creative, Person-Centered Psychopharmacology for Treatment Resistance in Psychiatry 285
responsibility, and commitment can significantly Narrative psychiatry is predicated on the concep-
contribute to overall positive response to pharma- tualization of human beings as narrators who live
cotherapy, but in the other way round, drug treat- their lives in relationships and connect and coop-
ment can contribute to creation and fostering erate with one another through the stories they
hope, meaning, personal responsibility, spirit of create, tell, and live. Human beings are immersed
optimism, and commitment. Hope, which in narrative; the stories they tell about themselves
includes perceived external resources, perceived not only describe themselves but also shape their
internal resources and positive expectations, is lives [50]; telling and listening stories, they rec-
recognized as the starting point for treatment suc- ognize themselves in the stories of others, and
cess and personal recovery. Hope is not hype or others in their stories. One’s ability to create, live,
only wishful thinking so that the treatment con- and tell a coherent, hopeful, and self-actualizing
text of hope refers to creating appropriate ways story of his or her life is a fundamental compo-
for overcoming treatment failures and achieving nent of mental health and well-being. Creative
positive treatment goals. Incenting hope makes person-centered psychopharmacotherapy is
patients invest energy and activities toward treat- based on a deep and empathic understanding of
ment goals and personal recovery. Personal the patients’ as persons with unique individual
recovery involves a journey from disengagement life stories, and therapy involves their re-
to engagement and from surviving to living and authoring and retelling the stories of their lives in
growing; it has many routes, and each patient’s a creative and hopeful way. Patients simply have
journey is unique with taking back control over a fundamental need for narrative because human
one’s own life and finding hope for a better future life itself is structured narratively and narratives
(see [49]. are strongly associated with personal understand-
ings, purpose, and meaning, in health as well as
in illness.
19.4.4 Deconstructing All therapies from psychopharmacologic
the Therapeutic Narratives: ones to all kinds of psychotherapies involve a
Person-Centered Narratives therapeutic narrative and start with therapist lis-
of Therapeutic Benefit tening to the patient’s story and then helping
him to recognize a new perspective on the prob-
The good physician will treat the disease, lem and gain new coping and resilience skills
but the great physician will treat the patient.
William Osler
[51]. Mental health medications have diverse
physical and neurochemical as well as rhetorical
Treatment resistance may be associated with and symbolical effects, both of which are
diverse iatrogenic hopeless nocebo tales within responsible for treatment outcome. In addition
losing life scripts or destructive unconscious life to their diverse pharmacodynamic mechanisms,
scenarios. Lack of hope in positive treatment out- they work also on account of meanings, expec-
come is both demoralizing for patients and con- tations, and relationships which may modify
tributing to their pessimistic self-fulfilling neurobiological effects of medications.
prophecies as well as influencing negatively on Treatment failure may be related to the inconve-
psychiatrists and their devotion to the patients nient drugs biological effects as well as to the
well-being [13]. Repeated treatment failures can negative meanings the patient ascribes to the
reflect the negative ways on how patients define medicine and its effects. Deconstructing narra-
and explain their mental disorder (lifelong last- tives that fuel mental health problems and treat-
ing, uncurable), how they are defined by diagno- ment failures is essential whenever desired
sis (stigmatization), and how community treatment goals are not obtained. Through ill-
responds to them (secondary gain) as well as how ness narratives patients form their own explana-
they imagine their treatment and future life (situ- tions about the causes of their illnesses, in a
ating in a nowhere-land or in a losing game). useful or harmful way. Deconstructing hopeless
19 Creative, Person-Centered Psychopharmacology for Treatment Resistance in Psychiatry 287
and harmful into hopeful and useful narratives change losing into winning life story, and to
may help in overcoming treatment failure. regain control over their life to get more love,
Therapeutic narrative refers to explanations on freedom, power, joy, and sense of life [9, 11, 49,
how mental health medications work. These 53]. Psychopharmacotherapy is one essential
explanations are different during acute, stabiliz- external support, alongside a whole range of
ing, and maintenance phase of treatment. other types of transformation and resilience-
Treatment failure may be related to an promoting supports, skills, and strengths.
inappropriate narrative in specific situations.
The restitution narrative presumes the illness to
be cured or overcome so that the patient becomes 19.4.5 Enhancing Placebo
the same or healthy again. While restitution and Eliminating Nocebo
story “yesterday I was healthy, today I am sick, Responses
but tomorrow I’ll be healthy again” may work
for some illness experience, it can be problem- The doctor-patient relationship is critical to the
placebo effect. Irwing Kirsch
atic in the context of some other mental disor-
ders for which cure, or return to previous health Placebo (Latin, I shall please) and nocebo
as it was once, may not be forthcoming [52]. So, (Latin, I shall harm) phenomena are a part of
patients with severe major mental disorders every treatment procedure and thus require care-
need alternative narrative resources to preserve ful approach by all clinicians [21]. These phe-
or reinstate sense of self, meaning, identity, nomena of positive “pleasing” and negative
hope, well-being, and mental health. In chaos “harming” response of patients to any kind of
narrative, the illness destroys the life of the treatment have potential to powerfully improve
patient. The quest narrative is characterized by or worsen mental and/or somatic symptoms and
the patient’s search for meaning and the idea can significantly modify the overall treatment
that something can be learned or gained from outcome. However, they have been usually
the illness experience [52]. The recovery narra- viewed in pharmacology through reductionist
tives involve the four component process: rec- lenses. Some treatment failures may be predicated
ognizing the problem, transforming the self and predicted on nocebo response. As causal fac-
through recovery narratives, reconciling with tors of some mental disorders are linked to
the system, and reaching out to others. adverse life experiences and negative beliefs,
Establishing a personal relationship with the views, and expectations, they can be described in
patient should help the patient to find a new self some way as nocebo responses to stressful and
as a person with a mental disorder who can important life events. Many psychiatric patients
recover from that disorder with a new perspec- are characteristically engaged in a negative view
tive on life. The main focus is on the person, not of themselves, in a negative view of the world,
on the symptoms and problems. This approach and in a negative view of their future and prone to
allows the patient to reconnect with his or her pharmacophobia, negative self-fulfilling proph-
true healthy self. Finding a new, true self is asso- ecy, or nocebo response. For proper understand-
ciated with a re-authoring life story, personal ing of placebo and nocebo phenomena in
growth, self-actualization, and reaching one’s pharmacology, it is of great importance to be
full potential. Person-centered psychopharmaco- familiar with quite a number of explanatory mod-
therapy supports hope, self-actualization, and els which can be identified in scientific literature
self-directed growth focused on patients’ (Table 19.8). The creative use the potential of
strengths and resources. Narrative psychophar- these mechanisms to master strategies on how to
macology combines the resources of re-author- manage these phenomena to increase the quality
ing conversations and mental health medications. of clinical practice [54, 55] may help in prevent-
The purpose of psychopharmacotherapy is to ing and overcoming treatment failures. Goal-
empower the patients’ to control their disease, to oriented utilization of placebo responses may
288 M. Jakovljevic
Table 19.8 Explanatory models of placebo and nocebo effects and responses [8, 21, 56–61] modified
The individual, personality differences model: placebo and nocebo responsiveness may be related to the certain
types of personalities so that one can speak about placebo reactors and nocebo reactors (placebo-prone and
nocebo-prone personality). Factors such as dispositional optimism, hypnotic suggestibility, somatic focus, empathy,
neuroticism, altruism, social desirability, dopamine-related traits, fear of pain, locus of ego-resilience, anxiety,
pessimism, pain catastrophizing, harm avoidance, and persistence have been linked to placebo and nocebo effects
The interpersonal dynamics model: placebo and nocebo responsiveness should be understood in terms of the
complex dynamics of the physician-patient relationship. Some physicians are themselves powerful placebos:
central components in all healer-patient relationships such as hope, trust, caring, empathy, and compassion play an
important role in placebo response
The perceptual filtering model: placebo and nocebo responsiveness can be explained in terms of patients’ positive
or negative perceptual filtering and misattribution. Patients with placebo response are typically motivated to get
better and to please their physicians, and in doing so they tend to foreground beneficial changes. In addition, they
frequently filter out negative changes and outcomes
The neurobiological model: placebo and nocebo responsiveness can be understood in neurobiological terms as the
activation of the different psychophysiological and neurotransmitters systems. For example, placebo and nocebo
phenomena are related to the opposite responses of dopaminergic and endogenous opioid neurotransmissions in
various brain areas, as well as of the brain reward – punishment system; oxytocin increases trust and placebo
response by binding to its receptors in amygdala
The conditioning model: placebo and nocebo responsiveness can be explained in terms of classical conditioning
theory because they resembles to a positive or negative conditioned stimulus. They can be related to nonconscious
associative learning processes and priming effects
The meaning making model: placebo and nocebo responsiveness can be understood in terms of cultural practices of
positive and negative meaning making. Placebo is positive, and nocebo is negative meaning response
The logic of expectation model: placebo and nocebo responsiveness can be explained in terms of a logic of
expectation in which cultural conceptions of the effectiveness of medications, or imagined expectations, can
override their pharmacological action. Patients’ knowledge about and expectations of a treatment may affect the
treatment outcome
The narrative pharmacology model: the patient’s beliefs and stories concerning the origin of symptoms and
medicines action may contribute positively (placebo) or negatively (nocebo) to drug treatment response
The resilience model: beliefs, actions, and behavior may have salutogenic or pathogenic effects. Resilience is a
protective collection of thoughts, actions, and behavior that can be developed and improved by everybody. Thus,
placebo effect can be understood as a form of resilience activating or enhancing by treatment
The multidimensional integrative model includes all of the above models based on transdisciplinary systemic
approach
contribute to overall drug treatment effectiveness by diverse procedures like medications, talking
and while having in mind and preventing nocebo psychotherapies, music therapy, dancing therapy,
responses may provide a useful possibility to psychodrama, etc.
reduce adversary events and prevent treatment The placebo and nocebo phenomena represent
failures. It seems that psychiatric patients with a very good model for our better understanding
good treatment response are likely to possess a of the role of treatment context and how the
common biological, psychological, and/or spiri- words, thoughts, meanings, images, beliefs,
tual resilience component that largely controls anticipations, and expectancies act on our brain
recovery from mental disorders. Some authors, and mind producing positive or negative health
for example, suggest “a common resilience effects [62]. Placebo and nocebo might be con-
mechanism underlying antidepressant drug sidered as the personal responses to any kind of
response” because “once triggered recovery treatment; they are universal phenomena in
appears to follow a pattern similar to the course human communication and so very important
observed with placebo, despite marked pharma- from the perspective of the person-centered med-
cologic differences of triggers” [56]. This antide- icine. Patients are always subjects who give sense
pressant resilience mechanism can be activated and respond more or less actively to meanings
19 Creative, Person-Centered Psychopharmacology for Treatment Resistance in Psychiatry 289
that disease, illness, and treatment have for them selves and their lives. Creativity involves new
and their physicians. While the physician is an perspective improvement and creation, it asserts
expert with specialized knowledge about drug life, frees human spirit, and helps to overcome
treatments, the patient is the expert on his or her both mental disorders and somatic diseases [4].
life and the best judge of the treatment outcome. Everyday creativity is an ability to cope effec-
Patients always bring into treatment unique char- tively with life problems and adversaries and find
acteristics related to their sensibility, vulnerabil- new solutions. In this spirit the creative, person-
ity, resilience, narration, and potential for centered psychopharmacotherapy may be defined
personal growth as well as proneness to placebo as an art and practice of learning organization
or nocebo responsiveness. Disease has to be [11, 42, 43] aimed to increase resilience, foster
treated, illness has to be healed, and the needs of creativity, and help patients to reset their own
the suffering person have to be met and satisfied. selves. The patient is a person, a body-mind-
There are many placebo-inducing psychological spirit unit, capable of resilience which involves
interventions which involve creating and foster- self-regulation, self-healing, and salutogenesis or
ing hope, meaning, personal responsibility, spirit health maintenance (see [64]). The idea of foster-
of optimism, and commitment. Patients just need ing resilience and creativity of patients who
to learn specific skills of positive psychology: experienced treatment failure is an issue of grow-
how to have more positive thinking and emo- ing interest. The concept of resilience and cre-
tions, more novelty seeking and engagement, ativity explains us why one person differs from
more gratitude, love, and sense of life, more another, and what makes each of patients the per-
accomplishment, and better human relations (see son they are. Resilience of each individual is
[63]). Properly choice of drug treatment can con- based on intrinsic and extrinsic protective factors
tribute to the creation and fostering hope, mean- promoting strength and compensating for weak-
ing, and personal commitment. Hope is an ness of patients as well as maximizing opportuni-
important part of an effective coping or treatment ties and protecting against threats. Extrinsic
strategy which involves a positive perspective of factors operate indirectly modifying exposure to,
future, the expectation of achieving a favorable or the impact of, adverse events or illness, while
outcome, and an inner power that helps one to intrinsic protective factors are the accumulated
overcome treatment failure. physiological, psychological, social, and spiritual
capital that patients can mobilize [65]. Resilience
can be both built and maintained through life
19.4.6 Individual Resilience coaching the proactive efforts of patients using
and Creativity Enhancing self-help resources [66]. Enhancing resilience
Training involves the protective and salutogenic processes
aimed to (1) reduce the impact of risks; (2) reduce
The great thing, than, in all education, is to make the negative chain reactions that follow adversi-
our nervous system our ally instead our enemy. ties; (3) establish and maintain positive mindset,
William James: The Principals of Psychology,
self-esteem, and self-efficacy; (4) create opportu-
1892
nities to revert the damaging effects and change
Treatment failures may appear due to diminished circulus viciosus into circulus virtuosus; and (5)
secondary or tertiary resilience and lack of cre- help finding new meaning and constructing new
ativity, on both clinician’s and patient’s side. pathways in the face of adversity (see [67]).
Creativity and resilience are qualities that exist Adversities and failures are inevitable in life, and
more or less in all people, and they are strongly it is very important to recognize and learn the les-
related to each other. Resilience is in a way an sons they offer. Resiliency known as “the hard-
ability to learn from failure, whereas therapy in resilient style” appears as (1) a strong sense of
psychiatry is also a complex learning process in commitment and self-esteem, a belief that indi-
which patients learn new dimensions of them- vidual can control or influence outcomes; (2) an
290 M. Jakovljevic
open-minded and exploring approach to living, a ergistic quality of all three character dimensions”
sense of challenge and novelty seeking; (3) a represents “creativity and the healthy personality
strong future orientation and optimism, living at configuration, called the creative character pro-
the present and learning from the past; and (4) a file.” Resilience is not about just to survive but
sense of humor and joy [33]. also to thrive. Improving self-directedness
All treatments in general may be roughly involves promoting disposition attributes of the
divided into creativity-promoting and creativity- patient such as personal mastery and healthy life-
killing ones. Creativity promoting means resil- style, growth and learning, physical condition
ience enhancing. Psychopharmacotherapy may and robustness, vitality, optimism, positive cog-
preserve, foster, or damage patients’ creativity in nitive reappraisal, and affiliative behavior. It
ways that significantly influence their resilience, means also cultivating a positive mindset and liv-
quality of life, and personal recovery. Many psy- ing life from a creative and proactive as opposed
chiatric patients commonly discontinue medica- to passive and reactive viewpoint. Interestingly
tion due to complaints of creativity blocking and enough research showed that nonresponders to
cognitive impairments caused by drug treatment antidepressant medication scored low in self-
[68]. The programs of individual resiliency and directedness, both before and after treatment, in
creativity training focus on positive mental health comparison with responders who had scored
and individual improvement and recovery goals, normally after treatment [71]. A high capacity
improving illness management skills, making for cooperativeness is one of the pillars of resil-
progress toward a meaningful life, and finding ience. Improving cooperativeness refers to learn-
new pathways [4, 69]. Treatment failure may be ing successful communication skills and
associated in a circular way with despair, help- assertiveness as well as to practicing positive
lessness, meaninglessness, isolation, resentment, mutual interaction and forming attachments and
and sorrow, while favorable treatment outcome is bonds with supportive resources. Being kind,
associated with a state of resilience which empathic, and compassionate and working in the
involves love (attachment, connecting, belong- service of others enhances physical, mental,
ing, communion), personal mastery (power, inner social, and spiritual well-being and improves
peace, learning, achievement, control), freedom different aspects of mental health and health in
(choice, independence, autonomy), happiness general. Mindful meditation and contemplation
(gratitude, joy, fun, play, pleasure, enjoyment), effectively increase the total well-being of previ-
and purpose (meaning, sense of life, personal ously treatment-resistant patients too. Improving
life’s mission). Person-centered creative psycho- self-transcendence is related to existential per-
pharmacotherapy has included varied combina- sonal journey and transcendent relationship with
tions of resilience-enhancing and an entity that is beyond physical, psychological,
creativity-fostering interventions in addition to or social dimensions of life. Self-transcendence
psychopharmacologic treatment. Resilience-means growing in spirituality and awareness of
enhancing and creativity-fostering techniques on right purpose and meaning life beyond limita-
a therapeutic journey of healing and transforma- tions of mental disorders and material
tion enable patients with a mental disorder to live possessions.
a meaningful life in their community while striv- At the end of the day, creative, person-centered
ing to achieve their own potential of self- psychopharmacotherapy may be represented as a
actualization. It helps them to live a satisfying, therapeutic journey of evolving therapeutic chal-
hopeful, and contributing life even with the limi- lenges and treatment goals by enhancing second-
tations caused by illness. Resilience-enhancing ary and tertiary resilience and creativity that
training is aimed to improve functional expres- promotes the flourishing of healthy, happy, and
sion of character dimensions: self-directedness, virtuous life and thus changes treatment resis-
cooperativeness, and self-transcendence (see [64, tance into treatment response. With regard to
70]). According to Cloninger et al. [70], “the syn- achieving successful treatment outcome, the
19 Creative, Person-Centered Psychopharmacology for Treatment Resistance in Psychiatry 291
motto is “better late than never, but never late is 8. Jakovljevic M. The placebo-nocebo response:
better.” controversies and challenges from clinical and
research perspective. Eur Neuropsychopharmacol.
2014a;24:333–41.
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12. Jakovljevic M. Long-acting injectable (depot) anti-
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19 Creative, Person-Centered Psychopharmacology for Treatment Resistance in Psychiatry 293
not led to adequate improvements in treatment or Despite the increasing importance of “patient-
understanding of illness. “The boundaries of centered medicine” in primary care [15], there
these categories have not been predictive of treat- has been relatively less focus on patient-centered
ment response. And, perhaps most important, care in psychiatry. The term “patient-centered
these categories, based upon presenting signs and medicine” derives from the work of Michael and
symptoms, may not capture fundamental under- Enid Balint, [16] who were both psychoanalysts
lying mechanisms of dysfunction [11].” While and who worked with primary care physicians to
this statement was made to advocate for increased integrate psychotherapy into ordinary medical
focus on basic neuroscience, it is also the case care. Patient-centered medicine has been judged
that focusing on neuroscience has not resulted in to be a priority central to the development of
interventions that consistently predict treatment high-quality medical care by the Institute of
response. Moreover, neuroscience has not yet Medicine [17]. Central features of patient-
explained in a satisfactory manner the mecha- centered care, as described by Mead and Bower
nisms underlying psychiatric illness or the resis- [18], include practice grounded in the biopsy-
tance of illness to treatment. As Insel later said in chosocial perspective, awareness of the “patient-
an interview with Wired magazine [12], “I spent as-person” and the “doctor-as-person,” attention
13 years at NIMH really pushing on the neurosci- to the therapeutic alliance, and a stance in which
ence and genetics of mental disorders…. I don’t power and responsibility are shared. It is an
think we moved the needle in reducing suicide, irony of current psychiatric practice that it has
reducing hospitalizations, improving recovery been slow to embrace this approach, even as it
for the tens of millions of people who have men- becomes increasingly valued by general medi-
tal illness.” A psychodynamic approach offers a cine. Enid and Michael Balint emphasized the
significant opportunity to reframe the problem of importance of assessing psychological and social
treatment-resistant psychiatric conditions. factors as well as the use of psychotherapy in the
The psychodynamic approach takes as its treatment of “fat envelope patients,” [19] that is,
starting point the experience of the individual the treatment-resistant patients with very large
patient and seeks to understand the meaning of charts. The comprehensive biopsychosocial,
the patient’s illness. This approach does not by alliance-based approach of psychodynamic psy-
any means reject the findings of neuroscience or chiatry is consistent with patient-centered prac-
biological intervention but accepts these findings tice, allows for the assessment of psychosocial
in the context of awareness that the human brain complexity and adversity, and supports a treat-
changes in response to life experience and to ment approach appropriate for work with com-
medical manipulation, that our brains and our plex, treatment-resistant patients.
minds are constantly responding to and accom- The effort to define mental illness as a brain
modating more environmental and biological fac- disorder or a medical illness “like any other” in
tors than we possibly can identify, and that part was intended to reduce stigma [20, 21] but in
awareness of neurology does not diminish the fact has either not affected or has increased rejec-
central importance of lived experience. While tion of those with mental illness [21, 22]. Assuming
this approach acknowledges the contributions of that mental illness is entirely due to genetics or
other fields, such as neurobiology and cognitive immutable biological deficits can contribute to the
science, the integrative nature of psychodynamic sense that the patient has no capacity to learn or to
thought offers new possibilities for treatment. change. Rather than taking sides in a “nature ver-
Moreover, there is increasing evidence that psy- sus nurture” debate, an informed perspective
chodynamic treatments can be as effective in the favors investigating the complex interplay between
treatment of mental illness as other evidence- genetic and environmental influences. In this con-
based treatments, challenging the dominance of text, a psychodynamic approach includes the use
biological and cognitive-behavioral interventions of appropriate biological interventions—while
[13, 14]. attending to their meaning.
20 A Psychodynamic Approach to Treatment Resistance 297
pies, and recommendations focus on medication. Efforts to describe patients with treatment-
As noted by Thase et al. [29], psychotherapy is resistant depression have yielded a picture of a
not created or funded by profit-oriented corpora- complex population, more likely to suffer from
tions, and cannot compete with the corporate personality pathology and trauma than treatment-
interests and funding that ensures that medication responsive patients. Kaplan and Klinetor [55]
marketing is supported by research evidence as studied outpatients treated for major depressive
soon as it becomes available. For this reason, it is disorder, and found that non-responders differed
not likely that psychotherapies can achieve the from responders in being significantly more
same evidence base as medication yet may be functionally impaired, more likely to have comor-
essential in achieving clinical response for bid anxiety diagnoses, more likely to show per-
treatment-resistant patients. In particular, patientssonality pathology, and were more likely to show
with histories of early adversity respond better to evidence of chronic post-traumatic stress disor-
psychotherapy than to medications, though the der. Moreover, childhood trauma in one study
combination is superior to either alone [47]. appeared to moderate preferential response to
Second, although there is evidence that trauma psychotherapy [47]. In this study, CBASP
and childhood adversity can contribute to mood, (cognitive-behavioral analysis system of psycho-
anxiety, psychotic, personality disorders, and therapy) was developed specifically to attend to
general psychopathology, not enough research the difficulties of depressed patients, with a focus
addresses the consequences of trauma and adver- on understanding and addressing interpersonal
sity in the lives of affected patients. Third, relationships. Such studies suggest that an
scientific study in this field appears oriented
approach to treatment-resistant depression should
toward addressing treatment response organized include awareness of psychological and syndro-
by diagnosis, not common themes in psychopa- mal complexity, as well as sensitivity to the prev-
thology or in treatment, despite growing aware- alence and experience of trauma.
ness of the overlapping psychopathology of Numerous studies have linked depression to
psychiatric disorders. psychological stress [56]. Bryant and co-authors
[57] found that the degree of depression experi-
enced after a disaster was related to the extent of
20.5 Treatment Resistance social connectedness of the affected individual,
and Mood Disorders suggesting that stress effects can be mitigated by
interpersonal connections. Caspi et al. [58] found
Treatment resistance has been most studied in evidence of a direct interaction between the pres-
depressive disorders. Numerous authors [14, 48– ence of a genetic polymorphism of the serotonin
50] have noted the cost to society of treatment- transporter promoter gene and stress in the etiol-
resistant depression. Definitions of ogy of depression. While there has been contro-
treatment-resistant depression vary, but a com- versy about this significant finding, it now has
monly used definition is the failure of the patient’s been replicated repeatedly and converges with
depressive illness to remit after two adequate tri- newer findings regarding effects of stress on the
als of different antidepressants [51]. Treatment amygdala that are linked to the serotonin trans-
recommendations for resistant depression rarely porter polymorphism [59]. Such data suggest a
include psychotherapy [52, 53]. In characterizing complex interplay between psychological stress,
current approaches to treatment-resistant depres- gene-environment interactions, and the presence
sion, Jenkins and Goldner [54] reviewed research or absence of social networks.
articles related to treatment-resistant depression Increasing evidence demonstrates effectiveness
in adults from 2005 to 2010. Eighty-one percent of short-term psychodynamic psychotherapy
of the papers studied fell within a biological para- (STPP) for depression. Town et al. [60] found
digm, with 3% judged to be within a psychologi- STPP to be superior to treatment as usual in a
cal paradigm. treatment-resistant sample. Driesen and co-authors
20 A Psychodynamic Approach to Treatment Resistance 301
[61] found that among patients recruited from a found to have a number of distinguishing charac-
Dutch outpatient clinic, a trial of STPP was non- teristics that included premorbid personality and
inferior to CBT. Gibbons et al. [62] also found social stress, factors likely to be useful targets for
non-inferiority for STPP as compared to CBT. It is psychotherapy [67].
possible that the effectiveness of psychotherapy in Mood disorders, although considered psychi-
the treatment of depression rests on “common fac- atric illnesses, also involve the same emotions
tors” of effective psychotherapy [63], such as the that are part of ordinary life. The neurovegetative
development of an alliance within the treatment symptoms of depression can be understood at
relationship and the experience of hope linked to least in part as physiologic reactions to intense,
shared goals, rather than to the name given to the sustained emotional distress. Evidence-based
psychotherapy. So far, research has not clarified therapies for mood disorders, including CBT,
the usefulness and effectiveness of specifically interpersonal therapy (IPT), and STPP, have
psychodynamic versus behavioral interventions. common goals of helping patients to recognize
Given the complex nature of treatment- and tolerate awareness of emotional and interper-
resistant depression, longer-term treatment may sonal problems. Each of these techniques has sig-
be indicated. This hypothesis was tested in the nificant advantages, and each is likely not to suit
Tavistock Adult Depression Study [14], which every patient. A full biopsychosocial assessment,
followed patients receiving weekly long-term including a psychodynamic formulation, can
psychodynamic psychotherapy (LTPP) for help the clinician to understand what feelings,
18 months, as compared to patients receiving conflicts, and needs contribute to the perpetua-
standard treatment according to British NHS rec- tion of unresolved sadness and emotional
ommendations. Both groups had access to medi- instability.
cation treatment, and the treatment-as-usual
group received more non-psychodynamic psy-
chotherapy interventions, such as CBT. Although 20.6 Treatment Resistance
both groups had similar rates of remission at the and Psychosis
end of the treatment phase, differences between
the groups widened significantly at 24, 30, and Since the introduction of antipsychotic medica-
42 months, with 30% of the psychodynamic tions in the 1950s, psychotic disorders have been
treatment group as opposed to 4% of the control reconceptualized as biomedical disorders. Even
group achieving partial remission. more than in the case of depression, published
Less is known about treatment resistance in criteria for treatment resistance in psychosis
bipolar disorder than in depression, especially exclusively rely on medication trials [68]. The
potential benefits of psychotherapy. Nevertheless, success of antipsychotic medications catalyzed a
Miklowitz [64] and Miklowitz and co-authors movement toward biological explanations for
[65] have noted superiority of intensive psycho- psychosis. Hallucinations, delusions, disorga-
therapeutic interventions compared to less inten- nized behavior, and paranoia are the most promi-
sive interventions, such as intermittent nent symptoms of psychosis. Medications have
“collaborative care” visits in the treatment of helped countless patients to contain these symp-
bipolar disorder. Bipolar disorder generally is toms well enough to avoid prolonged hospitaliza-
conceptualized as a “brain disorder,” yet trials of tion and limit the disruptive effects of illness on
aggressive medical intervention yield limited their lives.
results. In one comparison between ECT and Despite our growing understanding of the
algorithm-assisted treatment for patients with biology of psychotic disorders, psychosis remains
treatment-resistant bipolar disorder, results did difficult to treat. There is a growing literature
not distinguish the two groups and were modest at base on treatment-resistant psychotic disorders.
roughly 30% remission [66]. In one study, patients At the time of this writing, there are over 1900
with treatment-resistant bipolar depression were references for treatment-resistant schizophrenia
302 E. Weinberg et al.
on PubMed [69]. In seeking an explanation for cumvent negotiation of the therapeutic alliance.
treatment resistance, it is possible that at least While involuntary medication may have a place
part of the responsibility lies in currently pre- in treatment when there are acute safety concerns
dominant treatment approaches. Within the and other resources are limited or not adequate, it
United States, pharmacotherapy has been the pri- also has consequences for treatment effectiveness
mary mode of treatment for psychosis. Despite and the treatment alliance [28, 29]. In under-
the advances in medication development, not all standing “treatment resistance,” we may wish to
patients respond to medications, medications do consider the reasonable resistance of a patient
not treat all symptoms equally, and even for those who feels disrespected or whose concerns have
whom medications are effective, nonadherence is not been heard.
a common cause of relapse in psychotic illness Although in the last 60 years schizophrenia
[70]. Current studies indicate that for roughly and related psychoses have been seen through a
40% of patients, medications alone are partially biomedical lens, we have yet to identify specific
to minimally effective [71]. sets of genes that cause psychosis. Instead, stud-
Treatment that addresses psychosis as only a ies have demonstrated correlations between spe-
medical illness, disconnected from relationships cific chromosomal areas and single nucleotide
and meaning, both eclipses the patient’s experi- polymorphisms (SNPs) which confer vulnerabil-
ence of psychosis and contributes to the further ity to development of psychoses [73]. What we
isolation and stigmatization of the patient. To call schizophrenia is more likely a heterogeneous
understand problems with medication adherence, group of related disorders that each has their own
it is necessary to understand patients’ concerns. course and prognosis and responds differently to
Reasons for poor adherence can include side pharmacological and psychotherapeutic inter-
effects, reluctance to accept a diagnostic label, ventions [74]. In recent decades, there has
and even a need to protect the symptoms that the emerged a rich and provocative body of evidence
patient may value. The psychotic patient may be demonstrating links between psychosis and envi-
isolated by having perplexing symptoms but also ronmental stress. Increased risks of psychosis
may feel more powerful through being different have been related to life in urban environments,
and presenting mysterious difficulties. social fragmentation [75], and immigrant status,
Hallucinations can be a source of comfort and as well as to childhood trauma and early adver-
company and sometimes may actually be felt to sity [76]. Selten and Cantor-Graae [77] have pro-
provide useful information. Particularly follow- posed that social defeat is linked to schizophrenia,
ing trauma, paranoia may be experienced as a mediated by increased dopaminergic sensitivity.
helpful reminder to be vigilant. Delusions may This literature challenges a reductionist view by
confer otherwise elusive feelings of grandeur and demonstrating the complex interweaving between
power. In understanding the perceived value of biological and psychosocial development.
psychosis, we may consider Don Quixote, whose In 1998, the Agency for Healthcare Policy and
madness expressed nobility and revealed nuances the National Institute of Mental Health funded
of meaning. the Schizophrenia Patient Outcomes Research
The use of coercion further complicates treat- Team (PORT) report [78]. This report reviewed
ment of psychosis. Hospital systems institute available scientific literature in order to deter-
involuntary medication protocols for acute stabi- mine the most efficacious evidence-based treat-
lization of psychosis, and outpatient community ments for schizophrenia with the aim of unifying
psychiatry clinics can request court orders for standards of care. The initial report provided sub-
involuntary treatment. In 2017, the FDA approved stantial recommendations for pharmacotherapy
Abilify MyCite as the first psychiatric medica- but understated the value of psychosocial treat-
tion with an ingestible digital sensor to record ments. In particular, the report recommended
medication adherence [72]. Although ensuring against the use of psychodynamic individual or
adherence with treatment, such interventions cir- group psychotherapy. This recommendation was
20 A Psychodynamic Approach to Treatment Resistance 303
based on the limited evidence available and con- nized that lacking a full range of offerings
cerns about the potential for regression and deprives patients of optimal treatment [81].
development of psychotic transferences [78]. The Although the report recommended CBT, studies
report recommended therapies focused on behav- of actual CBT interventions effective in treat-
ioral and cognitive skills training as well as sup- ment of psychosis overlap with core psychody-
portive interventions, despite a similar lack of namic principles. They include emphasis on
scientific study and despite lack of evidence of collaborative understanding of the development
regression using contemporary models of PDT. and experience of symptoms, examining the
It is by now a truism that “absence of evidence antecedents of psychotic symptoms, and gener-
of effectiveness is not evidence of absence [of ating a shared case formulation [86].
effectiveness]” [79]. Research in psychodynamic In 2008, the National Institute of Mental
treatment of psychosis is a developing field, yet Health launched the Recovery After an Initial
the psychodynamic approach offers value to Schizophrenia Episode (RAISE) project with 17
patients and treaters. Taking a patient-centered sites and over 400 patients [83]. The RAISE proj-
approach, psychotic patients are people first, who ect examined the important components of treat-
have ordinary concerns such as navigating rela- ment for patients with first episode psychosis. As
tionships and finding meaning in work. The psy- recommended in the revised PORT report, the
chotic patient must adapt to having a disabling treatment integrated psychotherapy, medication
illness that can complicate meeting developmen- management, family education, case manage-
tal, emotional, and interpersonal goals. There is ment, and employment and education support,
increasing evidence that psychosocial interven- although still with emphasis on psychopharma-
tions are important to maximize treatment cology [83].
response and recovery from psychosis. In one The need-adapted (NA) approach to treatment
survey of patients with serious mental illness, [84, 87] and open dialogue (OD) [85, 86] inter-
three quarters felt psychotherapy had brought ventions developed in Scandinavia highlight
positive change to their lives. Most preferred a essential elements in addressing treatment resis-
combination of psychotherapy and medications, tance in psychotic conditions. NA was developed
but psychotherapy was valued more than medica- from studies of schizophrenic patients in Finland
tions [80]. with a goal of developing a comprehensive and
Rather than focusing on symptom reduction, therapeutically oriented approach to psychosis
some treatments have shifted toward a more that could be applied to community mental health
patient-centered approach with a framework of treatment [87]. NA emphasizes individualized
recovery and emphasis on individualized care and flexible treatment to meet “the real and
[81–85]. Several recent studies have found that changing needs” of patients and family members
intensive treatment with integration of many [84]. OD is a type of need-adapted approach
modalities, including psychotherapy, can reduce developed to focus on acute psychosis and crisis
morbidity associated with chronic psychosis. intervention [85]. The dialogue between patients,
The PORT report was further updated in 2003 staff, and family is “open,” with no treatment
and 2009 with greater emphasis on the impor- decisions made without the patient [85, 86].
tance of psychosocial treatments [81, 82]. Both NA and OD are community, family, and
Recommendations included assertive commu- team oriented, with all staff, including doctors,
nity treatment, supported employment, life skills psychologists, nurses, and social workers, given
training, family-based services, treatment of extensive training in family and individual thera-
comorbid substance use, and group or individual pies including PDT and CBT [87]. In one review
CBT [82]. In addition, the 2003 report recom- of the effectiveness of these approaches, patients
mended that psychotherapy should include the in the treatment group had fewer days in the hos-
development of a shared understanding of the ill- pital, were less likely to be living on a disability
ness between patient and therapist and recog- pension, were more likely to be free from psy-
304 E. Weinberg et al.
chotic symptoms on follow-up, and required less relationship to assist the patient in developing
psychiatric medication [85, 88]. NA and OD the ability to manage daily reality and to enhance
approaches empower patients to make their own interpersonal skills [89].
treatment decisions, attend to the meaning of
their experiences, individualize the use of medi-
cations, and strengthen networks of relationships. 20.6.1 Treatment Resistance
Psychotherapeutic interventions are primary with and Anxiety Disorders, Eating
medication use kept to a minimum, always in col- Disorders, and Trauma
laboration with the patient.
With growing evidence of the importance of While the bulk of research investigating treat-
psychosocial interventions in psychosis, ment resistance in specific disorders has
acknowledgement of the heterogeneity of psy- addressed mood and psychotic disorders, disor-
chotic illness, and the movement toward patient- ders discussed in this section are characterized by
centered care, there has been more interest in the being highly heterogeneous, subject to treatment
use of psychodynamic therapy. Supportive psy- resistance, and generally acknowledged to be
chodynamic psychotherapy (SPP) was developed best treated by psychotherapeutic interventions.
and manualized for use with psychotic patients CBT continues as the most recognized therapy,
[89]. SPP employs a modified psychodynamic despite evidence of effectiveness of other modali-
approach aimed at reducing regression and vul- ties. Given the complexity of these disorders,
nerability to overwhelming affect. As in NA and their comorbidity with histories of trauma and
OD approaches, SPP is grounded in a belief that personality disorders and limited treatment
psychotic experiences hold meaning and that response to medications and CBT, psychody-
treatment of psychosis is best approached through namic approaches are valuable both in offering
genuine respect for the patient’s experience [89]. frameworks for a patient-centered, biopsychoso-
The Danish Schizophrenia Project, a multi- cial formulation and also in providing treatment
site prospective longitudinal study of first-epi- alternatives. Although these disorders are diag-
sode psychosis, compared treatment as usual nostically distinct from mood disorders and psy-
(TAU) with SPP in addition to TAU [90]. TAU choses, as already discussed in this paper,
consisted of psychoeducational programs, treatment-resistant disorders are characterized by
groups, and individual meetings with nurses, diagnostic overlap and comorbidity [27, 44, 55].
psychologists, and social workers as well as Observations made in the preceding section
medication assessment. The study followed 269 regarding contributions of personality disorders,
patients over 2 years and found that the SPP trauma, and social adversity in most cases apply
group improved significantly with moderate to to these disorders as well.
strong effect sizes in social function, positive Although medications frequently are used in
and negative symptoms, as well as reduced gen- treatment of anxiety disorders, there is at present
eral psychopathology when compared to TAU no consensus regarding underlying neurobiologi-
[90]. In SPP, the therapist attends to issues of cal mechanisms. Moreover, psychological thera-
mistrust, difficulties in communication, and the pies have been highly successful and may be
patient’s degree of awareness of his or her ill- considered treatments of choice for anxiety dis-
ness. SPP not only builds trust and enhances orders. As in other disorders, CBT has been the
adherence but also can reduce pathological vigi- most studied. In particular, techniques of desensi-
lance and increase capacities for metacognition tization, exposure, and cognitive restructuring
[89]. In later sessions, the therapist addresses have been important tools in the treatment of
disavowed aspects of reality as well as defenses anxiety disorders. Nevertheless, as Bystritsky
such as denial, projection, projective identifica- notes [92] in a comprehensive review of interven-
tion, splitting, and attacks on linking [91]. tions for treatment-resistant anxiety disorders,
Finally, the therapist makes use of the treatment narrowly defined behavioral approaches may
20 A Psychodynamic Approach to Treatment Resistance 305
have limited benefit, particularly for more com- PTSD, and some sources emphasize the role of
plex, treatment-resistant patients. Anxiety disor- medications in treatment-resistant PTSD [98].
ders are often chronic and comorbid with mood Nevertheless, the United States Department of
and personality disorders, suggesting a need for Veterans’ Affairs in their most recent guidelines
complex treatment strategies that go beyond iso- [99] have recommended individual trauma-
lated symptom targets. focused psychotherapies as the treatments of
A psychodynamic approach includes attending choice. The Cochrane Review [100] of psycho-
to the developmental context, the meanings of logical interventions for PTSD described psycho-
anxiety to the patient, and the nature of interper- dynamic psychotherapies as insufficiently
sonal interactions and transactions relating to anx- studied but also noted that research in this area
iety. A useful concept drawn from psychoanalytic overall was affected by methodologic problems
theory is that of “signal anxiety,” which suggests and bias and that non-exposure-based therapies
that anxiety is a signal of potential psychological may have an advantage over exposure-based
danger. The task of encountering and mastering therapy in patient dropout. A randomized con-
this anxiety becomes a building block for psycho- trolled trial of prolonged exposure treatment ver-
logical structure in the developing child [93]. sus time-limited PDT found both treatments to be
Plakun notes, “In psychodynamic thinking, signal effective but prolonged exposure significantly
anxiety is seen as a symptom of a deeper problem more effective [101]. Notably, however, the PDT
rather than necessarily as a specific focus of clini- condition was used as an “active control,” and
cal attention, just as the dashboard “check engine” researchers are known experts in CBT. It is likely
warning light in a motor vehicle is a warning to the allegiance of the authors was not equally bal-
deal with some hidden but discoverable danger, anced for the two conditions. Moreover, the PDT
not a warning to turn off the light [94].” condition involved an unusual condition in that
Specific psychodynamic psychotherapies therapists explicitly did not ask about or explore
have been designed to target anxiety disorders. the subject of trauma with patients, a limitation
Leichsenring et al. [95] found short-term PDT that violates basic tenets of PDT.
and CBT to be similarly effective for treatment of Newer research suggests CBT-based therapies
generalized anxiety disorder, while Leichsenring are not the only effective therapies for PTSD.
et al. [30] found short-term PDT and CBT to be One study used nonrandom assignments to assign
equally effective in both short- and long-term patients either to CBT or PDT [102] based on
follow-up in treatment of social anxiety. Shear individual patient characteristics. Both treat-
et al. [96] have noted psychodynamic themes ments were equally effective. Noting that expo-
commonly identified in patients with panic disor- sure therapy has disadvantages in being
der, and Milrod and co-authors [97] studied a “grueling,” and often unacceptable to patients,
form of manualized psychodynamic psychother- Markowitz et al. [103] randomly assigned
apy for panic disorder based on core psychody- patients to IPT, prolonged exposure, or relaxation
namic concepts and found this therapy to be more training. Findings were that IPT was non-inferior
effective than a relaxation training treatment con- to prolonged exposure and both significantly
dition. Given these promising findings, a trial of more effective than relaxation training.
PDT could be considered in patients who have Response rates often are poor in treatment of
not benefited adequately from other modalities eating disorders [104]. Eating disorders often are
and may be a first-line approach for patients who ego-syntonic, and eating-disordered patients fre-
highly value psychological understanding. quently directly resist treatment [105]. While
PTSD stands alone among diagnoses associ- medications have been studied in the treatment of
ated with serious mental illness in that by defini- eating disorders, primary established treatments
tion its etiology involves the psychological are nutritional and psychotherapeutic. As in other
experience of traumatic stress. Numerous medi- disorders, CBT has been the most studied but
cations have been studied in the treatment of may have disadvantages for subgroups of
306 E. Weinberg et al.
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Cognitive Behavioral Therapy
and Behavioral Activation Therapy 21
for Treatment-Resistant
Depression: Traditional and Digital
Therapy Perspectives
Jennifer Apolinário-Hagen, Lara Fritsche,
Liesemarie Albers, and Christel Salewski
BA are effective and efficient stand-alone treat- ment and maintenance of psychological disorders
ment options for MDD in traditional face-to-face [17]. Beck’s cognitive model of depression [18]
health care [10, 11]. However, treatment gaps in constitutes a theoretical foundation for CBT. The
mental health care exist. More treatment spots model suggests three core mechanisms that are
are needed for large-scale provision of psycho- characteristic for depression: Typically, patients
logical treatment options [12]. To overcome bar- engage in negatively biased information process-
riers for face-to-face mental health services for ing. Additionally, they develop negative cogni-
depression, the Internet is proposed as a delivery tive schemas. Finally, the negative cognitive triad
mode for evidence-based digital interventions. describes patients’ negative cognitions about the
Internet-based CBT (ICBT) is suggested to be an self, the world, and the future. Generally, nega-
efficient format for self-help and treatment of tive cognitions, behavior, and emotions maintain
various mental health problems [13]. Internet each other [19]. The goal of CBT is to unlearn
interventions for depression can be delivered via these cognitive patterns and, thereby, to break the
computer, tablet, or smartphone. In recent years, cycle of cognitions, emotions, and behavior [20,
numerous mobile health applications (mHealth 21]. In CBT it is assumed that these thoughts are
apps), which could provide convenience and eas- automatic but not unconscious. This implies that
ily accessible support for persons suffering from patients can be made aware of these maladaptive
depression, are available through app stores [14]. cognitions and alter them. The task of the thera-
However, the evidence base for mHealth apps is pist is to actively guide the patient through ther-
still scarce, and progress is hard to evaluate for apy [22]. Techniques that are applied are both
patients and health-care providers [15]. Due to cognitive and behavioral with a stronger empha-
these innovations, health professionals need to sis placed on cognitive components. Behavioral
provide advice regarding the effectiveness and techniques, which are commonly implemented,
usefulness of Internet-based self-help programs, are activity planning, assessment of pleasure and
ICBT, and mHealth apps for depression. Thus, it mastery activities, gradual goal setting, cognitive
is important for health professionals to know rehearsal, and role playing [23]. Usually, these
about the latest advances in evidence-based psy- techniques are applied early in the therapeutic
chological treatments. process in order to restore minimum functioning
This chapter summarizes evidence for the and to subsequently change cognitions [24].
effectiveness of different delivery modes of CBT Common cognitive techniques are explaining the
and BA in order to derive recommendations for treatment rationale, cognitive reattribution,
the traditional and digital psychological therapy assessment of dysfunctional thoughts, and self-
of TRD, especially in light of persistent treatment monitoring. It is essential that the patient devel-
gaps in mental health care. ops a solid understanding of the relation between
cognitions and emotions as well as the nature of
maladaptive cognitions. This enables the patient
21.2 Cognitive Therapy to recognize and assess maladaptive automatic
and Behavioral Activation cognitions and to self-observe in what type of
for Depression: Theoretical situations these commonly occur. The key to cog-
Underpinnings, Approaches, nitive reattribution is the search for alternative
and Key Components explanations [23]. CBT can be delivered in indi-
of Therapy Programs vidual format, in group format, or in guided self-
help format. Duration of treatment can vary from
CBT is one of the most popular and most a single session up to 25 sessions [11].
researched psychological treatments for depres- BA originated from a component analysis of
sion [16]. It is a client-centered second-wave psy- CBT, which suggested that behavioral compo-
chological treatment which suggests that nents alone are as effective as cognitive and
cognitive factors play a major role in the develop- behavioral components combined to treat acute
21 Cognitive Behavioral Therapy and Behavioral Activation Therapy for Treatment-Resistant Depression 313
depression [25] as well as to prevent relapse [26]. laboration between the practitioner and the client.
The authors consequently suggested that it is not Higher emphasis is set on short-term goals in
a necessary condition to address cognitions order to maintain BA. Usually the goals that are
explicitly during treatment. They argued that addressed first are those that are concerned with
addressing maladaptive behavior suffices and avoidance behavior in order to enable reinforcing
serves as a mechanism to change cognitions as experiences. BA treatment usually consists of up
well [25]. Consequently, BA as a treatment based to 25 weekly sessions. Brief behavioral activation
on the behavioral components of Beck’s CBT treatment of depression (BATD), which is a
manual emerged [27]. BA gained attention as a shorter version of BA, usually constitutes 12
more parsimonious and more efficient way to weekly sessions [31].
treat depression that increases reinforcing experi- Commonly BA utilizes a variety of techniques.
ences by activating the client. Benefits of BA A review by Kanter and colleagues identified the
include that it is simpler to conduct than CBT and most common ones [32]. These include activity
that it does not require extensive training of men- monitoring, activity scheduling, assessment of
tal health staff. Therefore, widespread dissemina- goals and values, as well as contingency manage-
tion can be achieved more easily [28]. ment. Activity monitoring does not only serve to
Behavioral explanations for depression were identify behaviors that should be targeted; it also
already proposed 25 years before BA was intro- serves to demonstrate the association between
duced as a treatment. For example, Ferster [29] mood and behavior to the client. Activity schedul-
assumed that a lack of reinforcement plays a ing is a common feature among interventions.
major role in the maintenance of depression. Formerly, its purpose was to increase scheduling
Moreover, he emphasized a strong tendency of pleasant activities. However, focus nowadays
toward avoidance and escape behaviors to be has shifted toward scheduling functional activities
characteristic of depression. Additionally, even if they are not instantly rewarding. The pur-
Lewinsohn [30] introduced a behavioral treat- pose of contingency management is to balance the
ment for depression where he aimed to increase immediate reinforcement of previously engaged
reinforcing experiences by aiding the client to behavior with the long-term benefit of the goal
engage in pleasurable experiences. Comparable behavior. Contingency management typically has
to Ferster’s [29] explanation of depression, a key lower priority in treatment than activity schedul-
premise of BA is that avoidance behaviors are ing. Some BA interventions also include skills
typical for emotional disorders, such as depres- training, verbal training, and relaxation training.
sion. On the one hand, this avoidance pattern may Few interventions contain components explicitly
downregulate emotion intensity in the short term. directed at avoidance behavior.
On the other hand, it decreases opportunities for
the experience of positive emotions resulting
from pleasurable activities long term. In contrast 21.3 E
vidence Base for Face-
to these previous approaches, BA nowadays does to-Face CBT and BA
not only target classes of behaviors that are
assumed to be pleasurable. Rather any behavior Systematic reviews and meta-analyses yield
that is potentially beneficial for the client’s increasing support for the effectiveness of CBT
healthy functioning or mood is targeted [27]. and BA as stand-alone or complement psycho-
Jacobson and colleagues [27] provide a brief logical treatments for MDD in face-to-face care.
overview over the typical course of treatment in For instance, a review of 16 meta-analyses by
BA. First, they emphasize the importance of Butler and colleagues [33] showed that CBT is
establishing a good therapeutic relationship as effective for various mental disorders, including
well as explaining the treatment rationale. unipolar depression, achieving large effect sizes.
Secondly, treatment goals, usually several short- A recent meta-analysis by Cujpers and colleagues
term and fewer long-term goals, are set in col- [11] also confirmed the effectiveness of tradi-
314 J. Apolinário-Hagen et al.
tional CBT in reducing the symptoms of MDD had large effect sizes in the treatment of depres-
compared to a waiting-list control condition with sion. This meta-analysis [9] further revealed no
large effect sizes. However, effect sizes were significant difference between activity schedul-
small to moderate for CBT compared to TAU or ing and cognitive therapy in long-term effective-
placebo. Cujpers and colleagues [11] criticized ness at the follow-up assessments that ranged
the mostly low study quality and publication between few weeks up to 24 months. Mazzucchelli
bias. Another meta-analysis of 16 RCTs on the and colleagues [38] included 34 RCTs in their
effectiveness of CBT as monotherapy of chronic meta-analysis and review on BA for depressed
depression and dysthymia [34] demonstrated sig- adults. Most studies met the criteria for moderate
nificant but small effects of CBT compared to quality. Overall, BA was identified as effective in
control conditions and smaller effects compared the treatment of depression. They also found no
to antidepressant pharmacotherapy. A meta- differences in the effectiveness of BA and cogni-
analysis [35] on 32 RCTs targeting depressive tive therapy. Conversely, the authors [38] also
disorders that combined CBT and pharmacother- noted that more research is needed to determine
apy yielded enhanced therapeutic effects. whether simpler BA interventions are as effective
Several predictors and mediators for the as more complex BA therapy approaches.
effectiveness of CBT are discussed. For instance, Another meta-analysis by Ekers and colleagues
pretreatment patient predictors of negative out- [39] including 26 RCTs also confirmed the effec-
come or poor response to cognitive therapy for tiveness of BA for depression compared to con-
depression involve higher symptom severity trol conditions. However, the authors [39]
scores, number of previous episodes and chro- criticized the low study quality and brief follow-
nicity, younger age at onset of disease, as well up periods of the BA studies for depression.
as dysfunctional attitudes and beliefs about Overall, both CBT and BA appear to be
depression [36]. Moreover, some patients do not attractive alternatives or supplements for the
respond to pharmacotherapy; especially adoles- medication of TRD. If a patient is not respon-
cents are non-responders. According to a review sive to medication, health-care providers
by Hamill-Skoch and colleagues [37], adoles- should consider adding CBT to the treatment.
cents suffering from TRD benefit most from a Alternatively, they can consider BA as a sim-
switch in medication combined with appropri- pler approach. Nonetheless, several barriers for
ately dosed CBT, especially if CBT includes the using face-to-face mental health services exist,
components social skills training and problem- for example, treatment gaps in health care [12].
solving training. However, they also note that Apart from structural barriers, an individual
more large-scale research is needed to assess barrier to seek professional face-to-face help is
moderators of the effectiveness of CBT for ado- that many persons suffering from mild to mod-
lescents. Additionally, as a review of meta-anal- erate mental health problems prefer self-help
yses on CBT has demonstrated [17], there is a programs [40]. Another individual barrier for
lack of meta-analytic studies of CBT with other depressed persons to seek face-to-face help is
subgroups, such as ethnic minorities and low- stigmatization. Internet interventions have the
income populations. potential to reduce this burden as they grant
Like CBT, BA is an effective psychological more anonymity [41]. Thus, promoting early
approach for the treatment of MDD in face-to- utilization of professional help and increasing
face settings. For instance, a meta-analysis by access to evidence-based interventions could
Cujpers and colleagues [9] including 16 RCTs be achieved by the provision of Internet-based
showed that BA, activity scheduling in particular, and smartphone app-delivered mental health
and CBT have comparable effectiveness; both interventions for persons with TRD.
21 Cognitive Behavioral Therapy and Behavioral Activation Therapy for Treatment-Resistant Depression 315
n on-depressed activities. BATD, as it is delivered ues, and related activities; (3) daily monitoring
via the Moodivate app, includes four treatment and activity planning; and (4) contacts with
components: (1) psychoeducation regarding the respect to the identification of supportive indi-
BATD model; (2) identification of life areas, val- viduals [51].
100,000– Model explanation User control and (This app, other apps by
500,000 freedom the author, and
downloads homepage)
Depression rating Error prevention Type of information
collected
Monitoring Documentation Rationale for collection
cognitions and help
(recognize,
diagnose, and
recover from
errors)
Cognitive Flexibility and Sharing of information
techniques efficiency
Behavioral Visibility of User control
techniques system status
Monitoring Consistency and Safety
behaviors standards
Conceptualization Recognition
rather recall
BA (25%): Aesthetic and
Depression minimalist design
education
Depression rating
a
Data on the usability assessment was obtained from Huguet et al. [14]
21 Cognitive Behavioral Therapy and Behavioral Activation Therapy for Treatment-Resistant Depression 317
21.5 E
vidence Base for Internet- Furthermore, there is research evidence that
Based CBT and Mobile CBT/ therapeutic support in ICBT programs is associ-
BA Apps for Depression ated with improved outcomes in the treatment of
depression [53, 58]. For instance, a review by
Over the past two decades, a growing evidence Schröder and colleagues [45] concluded that
base clearly indicated the helpfulness of ICBT in stand-alone self-help Internet interventions
the treatment of mild to moderate forms of yielded small to medium effects in reducing the
depression [13, 52] For instance, a systematic symptoms of depression, whereas therapist-
review (40 studies) and meta-analysis (19 RCTs) guided Internet interventions resulted in medium
by Richards and Richardson [53] demonstrated to large effects. In line with this, a systematic
the effectiveness of ICBT for depression treat- review and meta-analysis by Andersson and col-
ment. Another systematic review by Arnberg and leagues [13] provided preliminary evidence that
colleagues [54] showed short-term efficacy of therapist-guided ICBT is effective comparable to
ICBT (versus waiting-list control condition) for face-to-face CBT. However, the evidence base
adults suffering from mild to moderate depres- regarding direct comparisons (two studies) is too
sion. As a meta-analysis [55] of 3876 depressed small to derive conclusions on the equivalence of
adults revealed, self-help ICBT was effective ICBT and face-to-face CBT. Different factors
compared to control condition, especially for could influence the effectiveness and acceptabil-
patients who did not want to have personal thera- ity of ICBT. For instance, data from a large cohort
peutic contact. Moreover, the online self-help study (N = 1738) of adult outpatients [59] identi-
interventions for depression MoodGYM and fied that the perceived credibility of an ICBT
Beating the Blues are shown to be effective when treatment for depression was a strong predictor
added to TAU (up to the 12-month follow-up) in for treatment response. The authors [59] con-
a pragmatic RCT with 239 patients, though the cluded that assessing patients’ expectations and
benefits of using both, self-help interventions and beliefs about the treatment could be a useful tool
TAU, including cost-effectiveness were marginal for clinicians to decide which patient might ben-
[47]. This is in line with a previous meta-review efit from ICBT for depression.
[56] that showed the effectiveness of ICBT for Like ICBT programs for the treatment of
depression but also questioned the cost- depression, mHealth apps improve the access to
effectiveness of such combined interventions evidence-based treatments for depression. BA
(blended treatment). A meta-analysis by Twomey apps potentially provide another way to ease the
and O’Reilly [57] identified support for the effec- implementation of behavior changes in daily life
tiveness of the freely available self-help ICBT by better matching the habits and preferences
program MoodGYM for depression in adults by especially of younger adults than traditional face-
comparing 11 studies. Several confounding fac- to- face interventions [14, 15]. A review by
tors restricted the conclusions, including publica- Donker and colleagues [15] on eight mental
tion bias. Furthermore, high attrition rates up to health apps, with three apps targeting depression
90% were found. Regarding different delivery (“Mobilyze,” “mobiletype,” and “Get Happy
modes, a systematic review [46] revealed that Program”) within four studies, demonstrated
VCP is also a feasible treatment option that has overall positive results. Whereas the apps
been used in various therapeutic settings and sev- Mobilyze using EMA [60] and the CBT Get
eral populations. In addition, results indicated Happy Program [61] yielded significant improve-
that VCP was generally associated with good ments in depressive symptoms, the app mobi-
participant satisfaction and similar clinical out- letype using EMA tested within two RCTs
comes to face-to-face psychotherapy. Despite an against active control groups with adolescents
increasing number of publications on VCP, it showed no improvements concerning depression
should be noted that large-scale clinical trials are [62, 63]. Another systematic review by Huguet
still necessary for assessing its effectiveness [46]. and colleagues [14] identified 12 evidence-based
318 J. Apolinário-Hagen et al.
CBT/BA apps for depression. Overall, the authors study examining all patients (N = 1203) who had
postulated lack of effective studies as well as received therapist-guided ICBT for the treatment
scarce usage of the core components of both CBT of depression between 2007 and 2013 in a routine
and BA models. Furthermore, utility and usabil- care setting (at an outpatient psychiatric clinic).
ity of these apps were found to be questionable or Results showed significant improvements at the
variable. Explicit privacy or safety policies were posttreatment that were maintained at 6-month
found to be rarely included in CBT/BA apps for follow-up. Conversely, the attrition rate was
depression [14]. This is in line with another assessed as high at 6-month follow-up [52].
review by Bakker and colleagues [64]. The Another important question regarding the
authors concluded that current evidence for the adherence to ICBT for depression is whether
effectiveness and application of user-centered face-to-face and digital therapies achieve compa-
design features of many mental health apps is rable adherence rates in routine care settings. A
still lacking [64]. For this purpose, qualitative systematic review [13], for instance, found no
research on user perspectives and experiences significant differences in terms of attrition rates
appears to be a necessary step. Concerning the between therapist-guided ICBT and face-to-face
user experience with BA, Ly and colleagues [65] CBT for different mental health problems (two
conducted in-depth interviews with 12 selected studies targeting depression). Generally, it should
participants that received guided smartphone- be considered that studies on direct comparisons
delivered BA treatment for depression that has between the attrition and non-completer rates of
been shown to be effective in previous research therapist-guided ICBT and traditional face-to-
[66]. Their analyses revealed three important face CBT in primary care are quite rare. A sys-
areas for individual experience: commitment, tematic review [68] identified 24 studies
expectations, and motivation. For instance, moti- published between 2000 and 2013 that described
vational factors varied, but most participants 26 treatment conditions (14 face-to-face CBT, 12
found the reminder function, mobility of the BA guided ICBT) targeting depressed adults. None
therapy app, and feedback from a therapist moti- of the studies compared guided ICBT and face-
vating [65]. to-face CBT in a single trial. Face-to-face CBT
interventions involved more sessions: while face-
to-face CBT therapies ranged from 12 to 28 ses-
21.6 Uptake of and Adherence sions, guided ICBT interventions contained 5 to
to Digital CBT/BA 9 sessions. On average, participants in face-to-
Interventions for Depression face CBT completed 83.9% of the treatment pro-
gram. This rate did not differ significantly from
Currently, the promotion of the uptake and imple- participants in guided ICBT (80.8%). However,
mentation of Internet interventions for depres- the percentage of completers was significantly
sion into routine care remain a challenge in higher in face-to-face CBT intervention studies
several countries, despite promising results on (84.7%) than in guided ICBT (65.1%). In addi-
the effectiveness and acceptability from clinical tion, this review showed that non-completers of
studies [41]. In clinical trials (n = 5), a systematic face-to-face CBT completed on average signifi-
review and meta-analysis by Andrews and col- cantly less (24.5%) of the treatment compared to
leagues [67] identified evidence for both the guided ICBT (42.1%) [68].
effectiveness and acceptability of ICBT, includ- Concerning the acceptability of ICBT for
ing good adherence and satisfaction ratings. depression, a systematic review by Rost and col-
According to a meta-analysis of individual par- leagues [69] including 29 studies demonstrated
ticipant data [55], adherence to self-help ICBT that most of the studies reported very high (8
program improved clinical outcomes. Regarding studies) or high (17 studies) level of acceptance.
the dissemination of ICBT in primary care, However, the operationalization of user accep-
Hedman and colleagues [52] performed a cohort tance was heterogeneous across included studies.
21 Cognitive Behavioral Therapy and Behavioral Activation Therapy for Treatment-Resistant Depression 319
Another review by Donker and colleagues [44] rably effective in reducing symptoms of depres-
has also demonstrated that mHealth apps were sion, BA interventions appear especially
associated with good ratings of acceptability, per- attractive for clinicians, because they are easy to
ceived usefulness, and utility. Nonetheless, the learn for professionals [28]. Also, BA interven-
number of included apps was very low (eight tions could reach more patients with TRD due to
papers investigating five evidence-based apps for their simplicity and lower demands for the cogni-
different mental health problems). In contrast to tive functioning of patients compared to CBT [8].
the high acceptability ratings reported in RCTs Nonetheless, more research is required to deter-
[44, 69], the uptake of ICBT in public health can mine whether simpler types or variants of BA are
be demanding. The slow dissemination and as effective as more complex interventions [38].
implementation of Internet interventions in pri- Furthermore, predictors of individual treatment
mary care in different countries worldwide could response to face-to-face therapies for depression
be due to the poor acceptability of digital treat- should be considered and investigated in more
ment services in the general population [70, 71] detail across different populations and settings
and among patients as well as health profession- within public health [17]. Digital delivery modes
als [72]. Various barriers and facilitators for the of CBT and BA represent an additional strategy
dissemination and implementation of Internet for the self-help or adjunctive treatment of
interventions in primary care are discussed, such TRD. Taken together, research suggests that digi-
as determinants of their acceptability [72], which tal mental health interventions hold great prom-
can be, in the case of low acceptance, the result of ise to improve the access to evidence-based
poor awareness or knowledge about digital inter- treatments and reduce treatment gaps in tradi-
ventions for common mental health problems tional health care in the future [45, 74]. Among
[70]. Acceptance-facilitating interventions (AFI) the digital treatment options for depression, the
represent a potential way to increase the accept- strongest evidence base exists for therapist-
ability of ICBT by providing appropriate infor- guided ICBT programs. Guided ICBT programs
mation for potential service users. Research on have demonstrated to be effective in the treat-
the effectiveness of AFI resulted in promising ment of mood disorders, achieving comparable
results regarding the improvement of the accept- effects to traditional face-to-face CBT [13]. To
ability of Internet interventions in clinical prac- make use of the best of both worlds, the advan-
tice. For instance, a RCT in primary care [73] tages of traditional and digital treatments in rou-
demonstrated that AFI using a brief psychoedu- tine care and blended treatments, a combination
cational video was effective in improving the of both traditional and digital interventions, could
acceptance of an Internet intervention among be a suitable, well-accepted strategy for the psy-
patients with depression. chological treatment of depression [75].
Apart from these positive findings indicating
the helpfulness of digital treatments for mild to
21.7 I mplications of Digital CBT/ moderate forms of depression, several uncertain-
BA Depression Interventions ties remained, especially with respect to the effi-
for Research and Practice cient dissemination of such interventions for
patients with TRD in clinical practice. This
Considering the overall positive research evi- includes, for instance, the questionable transfer-
dence on the effectiveness and acceptability of ability of interpersonal therapeutic principles
different delivery modes of CBT and BA, it can from traditional to digital treatments with respect
be concluded that patients and therapists can to clinical outcomes and adherence. While it can
choose between different but comparably helpful be concluded that at least some degree of profes-
adjunctive and stand-alone psychological treat- sional guidance in ICBT seems to be important to
ments of TRD. Since meta-analyses [9, 38] have achieve clinical outcomes comparable to face-to-
shown that face-to-face CBT and BA are compa- face CBT [13], other aspects regarding the quality
320 J. Apolinário-Hagen et al.
of therapeutic relationships and of perceived awareness and the acceptability of digital treat-
individual support are less clear for ICBT, for ment services for mental health problems, such
example, the role of the therapeutic relationship as TRD, educating the public and health profes-
between patient and therapist, respectively; the sionals via information campaigns [70, 71] and
therapeutic working alliance that is an important patients with depression in primary care via AFI
component of traditional face-to-face psycho- [73] appear to be suitable strategies. Further
therapy, in ICBT, can be classified as unclear due research and practice should therefore develop
to the limited amount of studies available target- and assess psychoeducational material provided
ing this outcome. However, there is also evidence using different media formats for different stake-
that the therapeutic relationship or working alli- holder groups.
ance can be evaluated as different as or less rele- To better understand the specific conditions
vant for the effectiveness of the therapy than in for an effective dissemination of ICBT pro-
face-to-face therapies, as a narrative review sug- grams and BA apps for the treatment of depres-
gested [76]. According to another systematic sion, future studies should explore differences
review [77] on the therapeutic working alliance regarding the delivery modes of psychological
in Internet therapies, the results of the 11 included treatments in real-world public health settings.
studies indicated that the therapeutic working For instance, there is an overall scarcity of RCTs
alliance was assessed positively, but the authors comparing face-to-face CBT and ICBT for
mentioned numerous limitations of the included depression that should be addressed in future
studies, such as the small number of eligible research [13]. Open questions further include,
studies, the heterogeneous operationalization of for instance, the clarification of the cost-
the measured constructs, and the highly selective effectiveness of ICBT programs in mental health
sample in terms of selection bias. For example, care [44, 54]. Furthermore, it should also be
most participants were recruited online via social considered that many evidence-based, Internet-
media websites and familiar with the Internet, based, or app-delivered psychological interven-
which could promote positive evaluations of ther- tions are presently inaccessible for the public
apeutic interactions in Internet interventions [77]. [42]. Therefore, it can be hard to decide for
Concerning the transferability of these findings help-seeking laypersons whether a freely acces-
to real-world primary care, a limitation for the sible digital service is useful. Despite the grow-
external validity is especially the use of such ing public demand, it should be noted that the
selective samples with persons that are well edu- helpfulness of most BA apps remains unclear at
cated and have access to and an affinity for new present [14, 15]. There is a deficiency of appro-
media. Keeping in mind that Internet interven- priate CBT and BA apps for depression from
tions are supposed to close treatment gaps, a both a clinical and legal perspective [14].
broader range of patient populations should be Generally, regarding the development of evi-
considered in view of social inequalities in terms dence-based mHealth apps for depression, more
of the so-called digital divide that can turn out as rigorous research is needed [15]. In addition, a
a significant drawback of the large-scale imple- limitation for clinical practice is that mobile
mentation of ICBT into primary care [78]. apps for depression appear to be only suitable
Additionally, data security concerns of users and for mild or moderate forms of depression [79].
clinicians are potential obstacles for developers Besides a lack of experimental validation,
and providers of digital mental health interven- Bakker and colleagues [64] identified a low
tions [74]. In countries where the implementation application of design principles for many of the
of electronic (e-)health services into health care available apps. Evidence-based guidelines that
is at an early stage, low knowledge about Internet have been developed for other self-help inter-
interventions for depression and rather skeptical ventions, like for mHealth apps to promote
opinions are other significant barriers for the uti- physical activity, can be rarely found among
lization of such services [75]. To improve the mental health apps [64]. Finally, because only
21 Cognitive Behavioral Therapy and Behavioral Activation Therapy for Treatment-Resistant Depression 321
very few evidence- based mHealth apps for 4. Hetrick SE, Cox GR, Merry SN. Treatment-resistant
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based CBT and BA programs are effective in therapeutic interventions for patients with depres-
reducing the symptoms of depression. ICBT sion: a network meta-analysis. PLoS Med. 2013;10:
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21 Cognitive Behavioral Therapy and Behavioral Activation Therapy for Treatment-Resistant Depression 323
R. J. Koek (*)
Mood Disorders Clinic, Sepulveda Amublatory Care
Center, VA Greater Los Angeles Healthcare System,
Los Angeles, CA, USA
Department of Psychiatry and Biobehavioral Department of Psychiatry, Olive View-UCLA
Sciences, David Geffen School of Medicine at Medical Center, Sylmar, CA, USA
UCLA, Los Angeles, CA, USA e-mail: JRoach@dhs.lacounty.gov
e-mail: rkoek@ucla.edu
N. Athanasiou · A. Korotinsky
J. Roach Mood Disorders Clinic, Sepulveda Amublatory Care
Mood Disorders Clinic, Sepulveda Amublatory Care Center, VA Greater Los Angeles Healthcare System,
Center, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
Los Angeles, CA, USA
Department of Psychiatry and Biobehavioral
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at
Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
UCLA, Los Angeles, CA, USA e-mail: nathanas@ucla.edu; Arkady.Korotinsky@va.gov
© Springer Nature Singapore Pte Ltd. 2019 325
Y.-K. Kim (ed.), Treatment Resistance in Psychiatry, https://doi.org/10.1007/978-981-10-4358-1_22
326 R. J. Koek et al.
of trains delivered. At the time of this publication, throughout a 20–30 min session, 5 days per week
rTMS has an indication by the US Food and Drug [13]. The most common side effects are redness,
Administration for treatment of MDD in patients itching and tingling at the electrode site, and
who have failed antidepressant treatment. Other headache [14].
uses remain experimental [10, 11].
22.1.3.1 Trigeminal Nerve
Stimulation (TNS)
22.1.3 Transcranial Direct Current Trigeminal nerve stimulation (TNS) (Fig. 22.4) is
Stimulation (TDCS) another noninvasive technique where electrodes are
placed on the forehead to stimulate the V1 branches
Transcranial direct current stimulation (tDCS) of the trigeminal nerve, most commonly at 120 Hz,
(Fig. 22.3) is a noninvasive neuromodulatory 250 μs pulse width for 30 s on/30 s off. Stimulation
technique, which places two electrodes against of the trigeminal nerve is thought to carry informa-
the scalp with a headband. A weak current is tion to structures in the brainstem which then con-
delivered through the skull; the anodal stimula- nect to forebrain structures. Side effects include
tion brings neuronal membranes toward depolar- mild discomfort at the electrode site as well as head-
ization, whereas the cathodal stimulation shifts ache [15]. TNS has received EU CE certification as
toward hyperpolarization [12]. Action potentials adjunctive treatment of MDD, though has not
are not reached because of subthreshold stimula- received FDA approval in the USA (http://www.
tion. Electrodes are placed to stimulate or inhibit medscape.com/viewarticle/770512).
areas implicated in the psychiatric disorder being
treated. TDCS is currently cleared by the FDA
for treatment-resistant depression, has received 22.1.4 Vagus Nerve Stimulation
CE mark approval in the EU for depression, and (VNS) and Transcutaneous
is used off-label for a number of other disorders. Vagus Nerve Stimulation
Most protocols involve a 1–2 mA current (tVNS)
Active Stimulation
a Ear electrode b
c Sham Stimulation
Fig. 22.6 Transcutaneous vagus nerve stimulation (tVNS). (Reprinted with permission from Elsevier)
22 Novel Neurostimulation Therapeutic Approaches for Treatment-Resistant Psychiatric Disorders 329
forms of neuromodulation is its fidelity in terms actual reduction in substance use in patients
of the brain target. This makes DBS a particularly unresponsive to standard intervention with neu-
valuable tool for better understanding the specif- romodulatory intervention, case reports describe
ics of brain-behavior relationships via integrating substantial, even long-term abstinence with DBS
DBS with functional neuroimaging and, in the targeting the nucleus accumbens—a key s tructure
future, with simultaneous micro-recording. A in the reward circuit—in alcohol [37, 38], opioid
third distinction of DBS is shared with VNS, i.e., [39–41], and cocaine [42] addiction. Based on
it can be a continuous, adjustable, “maintenance” the compulsivity inherent in addiction, the sub-
(once efficacy is established) intervention. This is thalamic nucleus (STN) is currently being tar-
valuable because our most treatment-refractory geted with DBS (NCT02892851).
patients are almost always long suffering, with
symptoms that vary in severity and quality over
time. 22.2.2 Bipolar Disorder
22.2.2.1 ECT
22.2 Clinical Application A randomized controlled trial (RTC) conducted
of Neuromodulation in Norway assigned a total of 73 bipolar depressed
in Treatment-Resistant patients to receive either ECT or algorithm-based
Psychiatric Disorders pharmacological treatment. A linear mixed-effect
modeling analysis found that ECT was signifi-
22.2.1 Addiction cantly more effective than algorithm-based phar-
macological treatment for both symptom
In addiction, the DLPFC plays an important role reduction and treatment response (73.9% versus
in craving, and inhibitory control [20] abnormali- 35%). [43] The remission rate did not differ
ties in reward circuitry are also prominent. (34.8% versus 30.0%), highlighting the degree of
Neuromodulation has targeted the DLPFC for treatment resistance in this population. Perugi
cravings [21], and high-frequency L DLPFC et al. (2017) published a meta-analysis of ECT in
rTMS has shown benefit for cravings in cigarette drug-resistant bipolar depression, mania, and
smokers, although results have been inconsistent mixed state and with catatonia [44]. The study
[22]. Similarly, five sham-controlled trials of L sample included 522 total patients with bipolar
DLPFC tDCS have shown reduced cravings in depression, evaluated prior to and after an index
cigarette smokers [23–27], although at least two ECT course. Responders and nonresponders
others have not [28, 29]. Hayashi et al. combined were compared in subsamples of depressed and
fMRI and low-frequency TMS (LF-rTMS) to mixed patients. Descriptive analyses were
inactivate the left DLPFC and were able to reported for patients with mania and with cata-
decrease cravings during cue-induced exposure tonic features. After the ECT course, 344 (68.8%)
to cigarettes but also, importantly, demonstrate patients were considered responders (final CGI-I
the role of the DLPFC in modulating the medial score ≤2) and 156 (31.2%) nonresponders.
OFC when assigning value to the anticipated Response rates were, respectively, 68.1% for BD
drug [30]. Notably, tDCS over the DLPFC has depression, 72.9% for mixed state, 75% for
been associated with reduction of drug craving in mania, and 80.8% for catatonic features. Length
alcohol [31, 32], cocaine [33], and cannabis [34] of current episode and global severity of the ill-
users. In addition, some investigations have ness were the only statistically significant predic-
found worsening of actual drug use [34, 35] tors of nonresponse, a finding consistently seen
despite acutely reduced craving, and one sham- in most treatment-resistant disorders. ECT was
controlled RCT of tDCS in methamphetamine found to be an effective and safe treatment for all
users found reduced craving at rest but increased phases of severe and drug-resistant BD. Positive
craving in association with cues [36]. In terms of response was observed in approximately two-
22 Novel Neurostimulation Therapeutic Approaches for Treatment-Resistant Psychiatric Disorders 331
thirds of the cases and in 80% of catatonic Further studies will be needed to better under-
patients. It is also worth noting that in this review stand a future role for TMS in the treatment of
the risk of ECT-induced mania was virtually both bipolar mania and depression [52].
absent and mood destabilization very unlikely,
often significant concerns with other available 22.2.2.3 tDCS
treatments. The ECT was well tolerated, with Most tDCS studies for depression include both
only 22 out of 522 patients excluded for adverse unipolar and bipolar depression, as criteria
effects of withdrawal of consent for ECT. In gen- include major depressive episode but do not spec-
eral, ECT treatment of bipolar mania has not ify primary diagnosis. A meta-analysis of tDCS
been rigorously evaluated, and thus most national/ in bipolar depression including 7 studies with 46
professional guidelines do not recommend or patients showed significant decrease in depres-
include mania as an indication for ECT sion, with 6 total affective switches [53]. In a
treatment. case report, tDCS was used in a patient who pre-
sented with acute mania while taking lithium,
22.2.2.2 rTMS olanzapine, and sertraline. The patient received a
As rTMS began showing positive outcomes for 5-day course of tDCS in combination with clo-
treatment-resistant depression, researchers have zapine and oxcarbazepine, and after the 3rd day,
been looking for new applications in bipolar there was a reduction in manic symptoms and
mania and bipolar depression. Grisaru et al. inappropriate behaviors. Seventy-two hours after
found benefit of right-sided in comparison to left- completing tDCS, symptoms reappeared and did
sided prefrontal HF-rTMS in reducing manic not improve until approximately 12 days later,
symptoms in patients who met criteria for mania presumably when medications took effect [54].
while on pharmacotherapy [45]. However, a
sham-controlled study of right-sided HF-rTMS 22.2.2.4 VNS
could not demonstrate benefit in a similar popu- Vagal nerve stimulation has not been studied as
lation [46]. Others have shown benefit of TMS as extensively in bipolar disorder as treatment-
an add-on to standard pharmacotherapy [47, 48]. resistant depression. In a 2-year open-label study,
Although there is notable efficacy for rTMS in the response rates of unipolar TRD and bipolar
TRD, the evidence is mixed in regard to bipolar TRD were 32% vs 34%, suggesting that the dif-
depression. Initially, Dolberg et al. found that ference in response rate to VNS in these two ill-
rTMS for 2 weeks was superior to sham in 20 nesses is not significant [55]. There is a case
patients with various symptom duration and report of a patient with bipolar disorder who had
treatments (including ECT) [49], while a subse- 9 years of remission after 20 months of adjunct
quent trial found that rTMS over the DLPFC was VNS whose battery in the device died, and there
no more efficacious than sham, but the study did was considerable time in getting replacement.
find the risk for inducing mania to be minimal The patient subsequently had recurrences of
[50]. More recently, a controlled trial of sequen- manic, depressed, and mixed episodes until
tial bilateral rTMS in patients with treatment- 17 months after reinitiation of VNS therapy [56].
resistant bipolar depression who received both Rapid cycling bipolar disorder is often treatment
HF-rTMS applied to the left DLPFC followed by resistant, and these patients tend to be excluded
LF-rTMS applied to the right did not show ben- from studies, though one study included nine out-
efit over sham [51]. However, a naturalistic study patients with rapid cycling bipolar disorder who
of 150 unipolar and 50 bipolar depressed patients were assessed after 40 weeks of open-label
who failed multiple antidepressants found similar adjunct VNS. Over 1 year there was a 38% reduc-
efficacy in response and remission rates between tion in total illness (combination of depression
the two groups when given bilateral sequential and mania symptoms) with significant reductions
rTMS or LF-rTMS to the right DLPFC. The in HDRS, MADRS, and CGI, though not mania
study lacked a sham group for comparison. scores [57].
332 R. J. Koek et al.
clinical intervention. Finally, some evidence provides a thorough review and recommenda-
supports the specific anti-suicidal effect of tions for clinical use [10].
ECT. Data from the first phase of an ongoing, It has been shown that there is likely a dose
collaborative, multicenter study suggested pro- effect with a higher total number of pulses
found short-term benefit in patients with sui- delivered resulting in a better antidepressant
cidal ideation who received ECT. One hundred effect [70]. Several studies have found that
thirty-one patients (representing 29.5% of the rTMS can have benefits past the initial treat-
entire study group) reported suicidal thoughts ment phase and with better durability in
and acts (either active suicidal thoughts or a sui- patients who show more robust response to
cidal event during current episode, a 3 or 4 on acute TMS. Mantovani et al. (2012) found that
the Hamilton depression scale) at baseline. 58% of acute rTMS responders maintained
Scores decreased to 0 after 1 week (three ECT benefits up to 3 months afterward with or with-
sessions) in 38.2% of the patients, after 2 weeks out medication; of those who did relapse, the
(six ECT sessions) in 61.1%, and in 80.9% at average time was 7 weeks [71]. Other studies
the end of the course of treatment. The resolu- have found relapse rates as low as 10% at
tion of suicidal thoughts further improved with 6 months with pharmacotherapy maintenance
increased number of ECT sessions [65]. Another only, and one-third at 1 year with pharmaco-
study [66] noted more rapid improvement in therapy or TMS reintroduction as needed [72].
depression and expressed suicidal intent in a These promising results suggest further con-
group of 30 patients receiving ECT compared sideration of TMS as a maintenance treatment
with a control group receiving pharmacother- for TRD. Fitzgerald et al. used clustered main-
apy. The ECT group received between five and tenance, consisting of five sessions over 2 days,
ten bilateral treatments administered at three monthly, to delay relapse until a mean of
times/week. Outcome was assessed with the 10 months [73], while Richieri et al. found
24-item Brief Psychiatric Rating Scale (BPRS) benefits of TMS maintenance using a tapering
before and after the ECT course. There were frequency of weekly, biweekly, and then
significant advantages for ECT on BPRS depres- monthly over 18 weeks [74]. However, a recent
sion and suicide item scores. Finally, an RCT study where patients who responded to acute
(N = 73) found that ECT reduced depressive TMS treatment were placed on monthly main-
symptoms and suicidal ideation scores on both tenance TMS for 1 year without medications
the HDRS and BDI more rapidly and effectively did not show a statistically significant benefit
than rTMS [67]. [75].
The left DLPFC is most often targeted in
22.2.3.2 rTMS depression, but it is worth noting that rTMS
TMS is an effective treatment for major depres- likely affects other regions that may help explain
sive disorder in patients who have not responded response to treatment. In the future, other targets
to pharmacotherapy [10]. In 2008, the US Food and possibly depression subgroups will likely
and Drug Administration approved TMS for guide treatment. Recently, Drysdale et al. pub-
treatment of MDD based on a double-blind mul- lished a study in which they calculated resting
tisite study of 301 patients who failed 1–4 antide- state-functional MRI connectivity in limbic and
pressants [68], and subsequently a study frontostriatal networks to develop four neuro-
sponsored by the National Institutes of Mental physiological subtypes (“biotypes”) of depres-
Health found fourfold greater remission rates sion [76]. They then evaluated response to
with active HF-rTMS targeting the left DLPFC HF-rTMS of the dorsomedial PFC and found that
when compared to sham [69]. Since those trials, a certain biotype (type 1) showed the highest
more than 15 meta-analyses and reviews have response rate (83%). Even more remarkably,
been published demonstrating the efficacy of their method distinguished responders from non-
TMS in depression, and the Clinical TMS Society responders with up to 90% accuracy. Such
334 R. J. Koek et al.
2/14 sham patients responded (p = 0.53)). unclear [105]. Initial experiments showed appli-
Notably in this study, the randomization phase cation of HF-rTMS to the DLFPC to be helpful
occurred after a few days of programming [106, 107], although some subsequent reviews
optimization. The second RCT involved 25 sub- suggested overall lack of benefit for HF-rTMS to
jects and was positive [98]. These investigators the DLPFC [108, 109]. Some research has found
targeted the nearby vALIC, but compared improvement with LF-rTMS to the supplemental
4 months active to sham stimulation in the 16/25 motor area (SMA) and OFC [109]. The most
subjects who had improved after up to 12 months recent meta-analysis found clear advantage for
of initial, open-label programming adjustment. active vs. sham rTMS that was not influenced by
The optimal site of stimulation is not yet clear. study heterogeneity [110]. In patients with OCD
Schlaepfer and colleagues in Germany have tar- who had failed multiple medication trials as well
geted the superolateral branch of the medial fore- as CBT, VNS showed statistically significant
brain bundle (slMFB) based on its involvement in improvement in symptoms in three of seven
the reward system and the potential benefit for patients over 4 years [111]. Multiple case reports
anhedonia [99]. Rapid benefit (within a week) and open-label studies suggest that tDCS target-
was seen in six out of seven initial patients, four ing the OFC, DLPFC, and SMA leads to reduc-
of whom were in remission at 3–8 months [99]. tion in OCD symptoms in some patients who
At 1 year, six out of eight patients were respond- have failed at least two SSRIs and CBT. [112–
ers and four out of eight were remitters, with sub- 116] The only RCT to date involving tDCS and
stantial improvements during most of 4 years of OCD showed significant reduction in symptoms
stimulation in seven out of eight subjects [100]. when electrodes were placed to decrease cortex
Results from additional subjects and a sham excitability and blood flow to the pre-SMA, an
phase are anticipated in this ongoing multiphase area thought to be hyperactive in patients with
study, which has been independently replicated OCD [117]. A meta-analysis of DBS studies tar-
in a ten-patient sham-controlled pilot study [101]. geting limbic structures including the VC/VS,
Epidural plate electrode stimulation of simulta- NAc, STN, ALIC, and inferior thalamic pedun-
neously the frontal pole and DLPFC was safe and cle (ITP) found a decrease in symptoms regard-
effective in five patients with TRD [102]. Both less of target in patients who have failed at least
RCTs [97, 98] in TRD found no neurocognitive three medication trials and CBT [118]. Other
differences between sham and active stimulation studies have shown improvement of quality of
[103, 104], although better cognitive outcomes life and long-term benefit in active vs. sham
were seen on some measures in responders, com- studies [119–122], leading the FDA to approve
pared with nonresponders in one study [104]. Medtronic’s Reclaim® device, targeting the
Ongoing trials include another sham-controlled vALIC, under a Humanitarian Device Exemption
SCG investigation (NCT00367003), R vs L SCG for severe, non-hoarding OCD patients who have
(NCT01898429), and a study with simultaneous failed ≥3 medication trials and intensive
recording of local field potentials—the “Brain CBT. Benefit has been shown with DBS target-
Radio” (NCT01984710) and bilateral habenula ing the BNST, MFB, and thalamus as well
DBS (NCT03254017). [123–125].
decrease in symptoms after ten sessions of TNS, tion learning. To date, one tDCS study based on
which was maintained for 1 month [126]. One this hypothesis in 28 veterans found greater effect
patient with panic disorder showed greater than on skin conductance reactivity during extinction
50% reduction in anxiety symptoms with VNS consolidation than during extinction learning, in
which was maintained over the 1-year study a 2-day Pavlovian fear conditioning paradigm
period [111]. Kuhn et al. (2007) found no effi- [133]. With DBS, only one case report has been
cacy in a single patient receiving NAc DBS for published, a 48-year-old man with extremely
treatment-refractory panic disorder [37], though severe combat PTSD (baseline CAPS, 119) who
studies of vALIC DBS for OCD have found obtained a 38% improvement after 8 months of
improvements in anxiety ratings [121]. bilateral DBS targeting the basolateral nucleus of
the amygdala (BLn) [134]. Clinical and electro-
physiologic safety was demonstrated at 1 year
22.2.6 PTSD [135].
groups in improving positive or negative symp- psychotics [150]; however, one double-blind
toms [145]. When using tDCS for the treatment sham-controlled trial showed a significant
of positive symptoms, the anode was placed on decrease in negative symptoms of schizophrenia
the left DLPFC (hypoactive area) and the cathode after ten sessions of dTCS [14], and another
on the L temporoparietal (hyperactive) area study showed a decrease in negative but not posi-
[146]. Of five sham-controlled RCTs exploring tive symptoms with left DLPFC stimulation
treatment of positive symptoms in patients who [159]. A case report of patient who had tried four
failed to respond to two or more antipsychotics, different antipsychotics including clozapine
three demonstrated a reduction in AH [147–149], underwent ten sessions of TNS and showed
and two did not [150, 151]. TNS was used for a improvement in negative symptoms [160].
patient with olfactory hallucinations refractory to
treatment with two antipsychotics; the patient
reported complete remission of olfactory halluci- 22.3 Adverse Effects
nations after ten sessions [152]. The earliest
efforts to use DBS for psychiatric illness were In neuromodulation, an important general consider-
carried out by Heath and colleagues, beginning in ation is discerning whether a given event is attribut-
the mid-1950s, for “schizophrenia” [153]. able to the device and its application/implantation,
Unfortunately, methodologic limitations made the stimulation from the device, or the psychiatric
the results of their trials in over 20 patients diffi- condition being treated [161]. Additional cost-bene-
cult to apply to today’s understanding of either fit analysis considerations affecting the clinical
DBS or schizophrenia [154]. A 2016 report applicability of neuromodulation in treatment-
described marked improvement in treatment- refractory conditions include (1) limited FDA
refractory positive symptoms over a 10-month approvals (as of December 2017, only rTMS and
period after NAc DBS [155] in a 27-year-old VNS for TRD and DBS for TR-OCD under HDE);
woman enrolled in an ongoing study comparing (2) device cost, availability, and standardization;
NAc to PFC DBS (NCT02377505). Additional and (3) availability of professionals qualified in uti-
ongoing trials include a comparison of NAc vs lization of the device, including long-term monitor-
SCG and DBS of the substantia nigra pars reticu- ing and management in the case of VNS and DBS.
lata (NCT02361554).
TMS does not require anesthesia or seizure induc- Vagal nerve stimulation is an invasive proce-
tion, as is the case with ECT, and it is a noninvasive dure, and it runs the risk of complications of
brain stimulation therapy that does not pose risks of surgery (e.g., infection, bleeding), as well as
surgical complications such as VNS or DBS. The cost estimated at approximately $25,000 USD,
risk of seizure induction from TMS is relatively and the common adverse effects of hoarseness,
small with less than 1% in the general population, dyspnea, nausea, and pain. Like with tDCS,
and these have been self-limited, occurring during heterogeneity in study design makes system-
treatment sessions [10]. More commonly, patients atic adverse effect risk difficult to estimate:
may complain of headache (28%) or localized pain lack of sham-controlled data beyond 10 weeks,
(38%), but these rarely cause patients to discon- limited sample size, variations in stimulus
tinue treatment and can oftentimes resolve within parameters, and widely varying durations of
the first few weeks [10, 165]. follow-up [167].
Transcranial direct current stimulation has some A very recent review found serious hardware
risks, the most significant being affective switches complications in 11.75% of 8983 patients in 96
at an incidence of 3.2% [166], as well as burning at studies of DBS for neurologic and psychiatric
site and tingling under the electrodes. The cost of indications combined [168]. In TRD studies,
the devices is relatively low, running at approxi- rates of attempted and completed suicide are
mately $100 USD, and they can be purchased high, although this can attributed to the condition
online without a prescription. Studies of tDCS show as much as to the treatment [61, 64].
considerable heterogeneity in study parameters Some psychiatric side effects may result
including concomitant medications, psychotherapy, directly from stimulation, since they are
session length (10–35 min), number of sessions quickly reversible upon change in stimulation
(1–20), and electrode size, placement, and current parameters, e.g., hypomania in depression or
strength [12]. A relatively low risk-benefit ratio is OCD, anxiety and panic with striatal DBS for
noted in tDCS studies, but these heterogeneities OCD, and impulsivity with NAc DBS in OCD
require further sham-controlled RCTs and long- [92, 161].
term data before firm conclusions can be drawn. Besides its invasiveness, DBS has other
important limitations. Patients eligible for
research protocols are severely ill despite multi-
22.3.4 TNS ple therapeutic interventions, and the relatively
high risk of suicide and other poor outcomes
Trigeminal nerve stimulation has few associated must be carefully considered. The risk of hope-
side effects, the most prominent are headache, lessness—which must be explicitly and carefully
irritation at the stimulation site, and mild discom- addressed before DBS—is significant. Thus, a
fort during stimulation. Thus far there have been healthy treatment alliance and carefully consid-
no documented treatment-related affective ered long-term therapeutic framework are criti-
switches [166]. The TNS studies have limited cal. Finally, DBS is expensive at outset, time
data for treatment-resistant psychiatric illnesses; intensive, and requires long-term commitment by
almost all data derive from case reports or small a multidisciplinary team of experts as well as
open-label studies. patients and their families.
22 Novel Neurostimulation Therapeutic Approaches for Treatment-Resistant Psychiatric Disorders 339
brain reward centers, may mediate anti-hedonic 13. Fregni F, Boggio P, Nitsche M, Marcolin M,
Rigonatti S, Pascual-Leone A. Treatment of major
effects of DBS [99]. Neuroimaging advances depression with transcranial direct current stimula-
will remain an ongoing complement to the intri- tion. Bipolar Disord. 2006;8:203–4.
cate merger of psychiatry, neurosurgery, neuro- 14. Palm U, Keeser D, Hasan A, Kupka MJ, Blautzik J,
psychology, and neurophysiology that allows Sarubin N, et al. Prefrontal transcranial direct cur-
rent stimulation for treatment of schizophrenia with
DBS to provide hope for some of our most predominant negative symptoms: a double-blind,
daunting sufferers. sham-controlled proof-of-concept study. Schizophr
Bull. 2016;42:1253–61.
15. Cook I, Schrader L, DeGiorgio C, Miller P,
Maremont E, Leuchter A. Trigeminal nerve stim-
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When Clozapine Fails:
Augmentation Strategies 23
in the Management of
Clozapine-Resistant Schizophrenia
A. Carano C. Tomasetti
NHS, Department of Mental Health, Psychiatric NHS, Department of Mental Health, Psychiatric
Service of Diagnosis and Treatment, Hospital Service of Diagnosis and Treatment, Hospital of
“Madonna Del Soccorso”, Giulianova, Teramo, Italy
San Benedetto del Tronto, Italy e-mail: carmine.tomasetti@aslteramo.it
M. Pompili G. Di Emidio
Department of Neurosciences, Mental Health and NHS, Department of Mental Health, Psychiatric
Sensory Organs, Suicide Prevention Center, Service of Diagnosis and Treatment, Mental Health
Sant’Andrea Hospital, Sapienza University of Rome, Center of Giulianova, Teramo, Italy
Rome, Italy e-mail: gabriella.diemidio@aslteramo.it
e-mail: maurizio.pompili@uniroma1.it
G. Martinotti
L. Orsolini Department of Neuroscience, Imaging and Clinical
Polyedra Research Group, Teramo, Italy Science, University “G. D’Annunzio”, Chieti, Italy
Psychopharmacology, Drug Misuse and Novel Psychopharmacology, Drug Misuse and Novel
Psychoactive Substances Research Unit, School of Psychoactive Substances Research Unit, School of
Life and Medical Sciences, College Lane Campus, Life and Medical Sciences, College Lane Campus,
University of Hertfordshire, Hatfield, Herts, UK University of Hertfordshire, Hatfield, Herts, UK
Table 23.1 Criteria for clozapine-resistant schizophrenia and, overall, the majority of them have shown
Clinical encouraging positive results [26, 27].
characteristics Clinical evaluation Assion et al. [28] showed that the augmentation
Clozapine- No less than 8-week clozapine with amisulpride improved the global outcome of
refractory treatment with serum levels
schizophrenia ≥350 μg/L patients suffering from chronic schizophrenia and
No improvement or failure to tended to be a helpful treatment option in cases
improve by at least 20% in total of partial or non- responsiveness to clozapine.
Brief Psychiatric Rating Scale Hotham et al. [29] found that amisulpride aug-
score
mentation of clozapine in patients with schizo-
Persistence of Item score ≥4 on at least two of
positive symptoms four positive symptom items on phrenia and a history of violence led to a clinical
the Brief Psychiatric Rating improvement and reduced aggression and vio-
Scale lence, thus showing anti-aggressive properties.
Actual presence of Total Brief Psychiatric Rating It has been also suggested that the augmenta-
at least moderately Scale score≥45
tion with amisulpride may reduce the sialorrhea
severe disorder Score of ≥4 on the Clinical
Global Impression Scale
often seen in patients treated with clozapine, thus
Persistence of Lack of a stable period of a improving their quality of life [30–32].
disorder and low satisfactory social and/or However, this combination is not void from
functioning occupational functioning within potential risks. It has been observed that often
the last 5 years regardless of
this combined treatment may lead to high rates
clozapine treatment
Global assessment of
of relevant side effects including bradykinesia,
functioning scale score ≥40 akathisia, tremor, and an increase of prolactin
Modified from Mouaffak et al. [19] serum levels, and therefore patients should be
accurately monitored [28].
To sum-up, the amisulpride add-on to clozap-
have been proposed to overcome this problem, ine may be a useful strategy especially in violent
yet, to date, it remains high-bar goal [22–24]. patients, but the development of adverse effects
The aim of this chapter was to provide an should be taken into account.
overview of the managing strategies of clozapine-
resistant schizophrenia with a particular focus on 23.2.1.2 Aripiprazole
augmentation strategies aimed to improve effi- One of the most used strategies in clozapine-
cacy on schizophrenia symptoms. resistant schizophrenia is to augment with aripip-
razole, a 5HT2 antagonist and dopamine D2
partial agonist featuring 5-HT1A partial agonist
23.2 Clozapine Augmentation [33, 34]. It has been suggested and is often seen
with Antipsychotics in clinical practice that aripiprazole add-on to
clozapine may improve metabolic adverse effects
23.2.1 Second-Generation that often may appear with clozapine treatment
Antipsychotics (SGAs) [35, 36]. However, relatively few studies have
investigated the effect of the aripiprazole aug-
23.2.1.1 Amisulpride mentation on disease symptoms, and results were
Amisulpride is a SGA promoting dopaminergic controversial.
neurotransmission blocking presynaptic dopa- Some earlier studies have demonstrated
mine D2/D3 autoreceptors when administered at that, despite its favorable effects on metabolic
low doses; the converse is true when amisulpride parameters, aripiprazole augmentation may only
is administered at higher doses when postsynap- slightly improve the symptoms of schizophrenia
tic D2/D3 blockade occurs [25]. Several studies on Brief Psychiatric Rating Scale (BPRS) and
have been conducted so far, aiming at investigat- Positive and Negative Syndrome Scale (PANSS)
ing whether amisulpride may be beneficial for [37–39]. In a multicenter, naturalistic, ran-
patients with clozapine-resistant schizophrenia, domized, superiority study, Cipriani et al. [40]
352 D. De Berardis et al.
Moreover, the possibility of adverse meta- monitoring or a clozapine dose reduction when
bolic effects should be considered due to the high coadministered with fluvoxamine. However,
propensity of both mirtazapine and clozapine to generally, the best rationale for a combined
cause weight gain [98, 99], and therefore caution clozapine-SSRIs therapy may be the presence
is recommended when mirtazapine is added to of moderate-to-severe depressive or obsessive
clozapine. symptoms that are not controlled or even wors-
ened by clozapine, but, even if in the clinical
practice this combination is relatively common
23.3.3 Other Antidepressants [23], more longitudinal tolerability studies are
definitely needed.
Concerning serotonin and norepinephrine reup- Some promising data are present for mirtazap-
take inhibitors (SNRIs), no data concerning ine which seems to have a limited but beneficial
clinical efficacy as add-on therapy are available effect on negative and cognitive symptoms, but
for venlafaxine, even if it seems to not influ- the risk of additive metabolic adverse effects
ence clozapine serum levels at least at low-to- should be taken into account.
moderate doses [100]. In a 16-week double-blind Too few data are available concerning other
RCT of duloxetine augmentation in a sample of antidepressants in combination with clozapine to
33 patients with TRS receiving clozapine, Mico allow a definite conclusion.
et al. [101] found that duloxetine augmentation
showed a beneficial effect on the negative and
general psychopathological symptomatology 23.4 Clozapine Augmentation
although without significant effects on executive with Mood Stabilizers or
cognitive functions and was well tolerated. Anticonvulsants
Only one study concerning the melatonergic
antidepressant agomelatine is, to date, available. 23.4.1 Lithium
Bruno et al. conducted a 16-week, open-label,
uncontrolled pilot trial evaluating the augmen- The lithium add-on to clozapine may have a ratio-
tation of partial responders to clozapine with nale when administered to severe and treatment-
agomelatine and found a promising effect of resistant patients with schizoaffective disorder
agomelatine on clinical and cognitive symptoms or bipolar disorder (wherein the latter clozapine
with a good tolerability. has an established clinical efficacy [105–107]) or
The add-on with older antidepressants such in the case of clozapine-treated patients with a
as tricyclics has been suggested [102, 103], but still high risk of suicide despite the known anti-
data are very limited and cardiac and cholinergic suicidal effect of clozapine [108, 109]. However,
adverse effects should be considered. The addi- surprisingly, only few studies have evaluated
tion of amitriptyline seems to be beneficial in this association in clozapine- resistant patients,
clozapine-induced sialorrhea [104]. whereas the majority has pointed out the benefi-
cial effects of lithium in clozapine-induced neu-
tropenia [110, 111].
23.3.4 Conclusions In a retrospective study, Kelly et al. [112] eval-
uated adjunctive divalproex or lithium in TRS
Adding the SSRI fluvoxamine to ongoing clo- patients taking clozapine compared to clozapine
zapine treatment may be useful in some clinical monotherapy and observed that the 6-month gen-
conditions, especially in patients with negative or eral symptomatology was similarly improved in
depressive symptoms or difficulty in achieving all treatment groups, but a significantly greater
sufficiently high plasma levels for an adequate improvement occurred in the first month for
response. However, critical raises in clozapine those on divalproex or lithium than clozapine
serum levels may happen and need a careful alone. However, in patients treated with lithium,
356 D. De Berardis et al.
several adverse effects were reported such as effective in reducing global symptoms (especially
weight gain and increased glycemia. Small et al. hostility and anxiety) in the first month of add-on
[113] in a mixed sample of patients with TRS and treatment when compared to clozapine mono-
treatment-resistant schizoaffective disorder (SD) therapy and to previous clozapine treatment.
showed that SD subjects improved with lithium However, it has been reported that the combi-
concerning the overall outcome, the Positive and nation of clozapine and valproate may be associ-
Negative Syndrome Scale (PANSS) total and ated to increased risk of several severe adverse
negative subscales, and the cognitive measures, effects such as neutropenia [122, 123], myocar-
whereas schizophrenic patients did not. Authors ditis, and pericarditis [16, 124, 125]. Therefore,
concluded that, for TRS patients, lithium add-on if not used for controlling the risk of clozapine-
did not improve but increased the risk of a pos- related seizures, this combination should be pos-
sible lithium toxicity. sibly avoided and used only when the clinical
In conclusion, the available evidences con- benefits overcome the risk of harmful effects.
cerning lithium add-on provide only support for
the utility of lithium in preventing or managing
clozapine-related neutropenia, but its effect on 23.4.3 Topiramate
symptoms is somewhat limited and further stud-
ies are needed. The topiramate does not affect the plasma lev-
els of clozapine [126] and has been proposed as
an effective add-on to clozapine especially in
23.4.2 Valproic Acid patients who experienced weight gain [127, 128]
and to prevent or treat seizures [129].
Valproic acid add-on to the ongoing clozapine Hahn et al. [130] carried out a 12-week natu-
therapy is mainly used to treat or avoid, in a pre- ralistic, open study to evaluate the potential ben-
ventive way in at risk subjects, clozapine-related efits of topiramate in clozapine-treated patients
seizures [114, 115]. with a suboptimal clinical response. They found
Besides the addition as anticonvulsant, val- that topiramate augmentation caused a 14%
proic acid also may play a significant role in improvement in total BPRS score together with
the treatment of some symptoms in TRS [116]. a reduction in body weight. Topiramate was well
Valproic acid is commonly used for individu- tolerated and the most common side effect was
als with schizophrenia with violent episodes, paraesthesia. In a 24-week RCT, Muscatello
because it is reported to decrease aggression and et al. [131] aimed to explore the efficacy and tol-
hostility [117, 118]. However, the addition of val- erability of topiramate add-on pharmacotherapy
proate has been reported to increase the plasma on clinical symptomatology and cognitive func-
or serum levels of clozapine [119, 120] through tioning in a sample of TRS patients receiving clo-
an inhibiting effect on the CYP1A2- or CYP3A4- zapine. They reported that topiramate appeared
mediated conversion of clozapine to norclozap- to be poor effective for reducing clinical symp-
ine, but this interaction is unlikely to be clinically tomatology in schizophrenic patients who have
significant [120]. had an incomplete clinical response to clozapine.
Concerning add-on therapy to clozapine, However, the patients included in the topiramate
Kando et al. [121] found that the combination of groups showed a slight worsening of perfor-
clozapine and valproate was efficacious and well mances on cognitive tasks.
tolerated in 55 patients with affective and psy- Therefore, on the basis of the current evidence,
chotic disorders without severe adverse effects. topiramate add-on cannot be recommended for
In the abovementioned (see Sect. 23.4.1) retro- controlling symptomatology of clozapine-resis-
spective study, Kelly et al. [112] showed that the tant schizophrenia, even if maybe cautiously
addition of divalproex was significantly more used to reduce weight and prevent seizures.
23 When Clozapine Fails: Augmentation Strategies in the Management of Clozapine-Resistant 357
a further improvement of negative, positive, and day. Moreover, Fenton et al. [157] found similar
overall symptoms in patients with clozapine- results confirming the negative results.
treated TRS was observed. The memantine was There are several evidences that minocycline, a
well tolerated without severe adverse effects. tetracycline antibiotic that has anti-inflammatory
In conclusion, the overall evaluation of published and neuroprotective properties, may play a role
data is very encouraging. The effect of memantine in schizophrenia as inflammation has been sug-
in clozapine-resistant patients seems to improve gested as one of the potential mechanisms leading
both cognitive and positive/negative symptoms to pharmacoresistance [151, 158–160]. Adjunctive
without evidence of severe adverse effect. Thus, minocycline has been successfully employed
this strategy may be recommended at least in some in patients with persistent schizophrenia symp-
clozapine-resistant patients, even if further studies toms despite clozapine treatment [150, 161]. In a
would be useful to confirm adjunctive memantine 10-week, double-blind RCT, Kelly et al. [162] ran-
as the first strategy of choice in such cases. domized 52 patients with persistent symptoms to
receive adjunct minocycline (100 mg twice daily)
or placebo to clozapine. They found that signifi-
23.6 Other Augmentation cant improvements with minocycline were seen in
Strategies working memory, avolition, and anxiety/depressive
symptoms in such patients. However, it is possible
Due to the “black hole” of clozapine-resistant that minocycline effects may be mediated by an
management strategies, several nonpsychiatric increase in clozapine levels [163].
drugs or other bioactive compounds were tried Further augmentation strategies have involved
to find a possible way to cope with this serious other glutamatergic agents than memantine (such
condition [148–151]. This trial aimed not only as glycine, D-cycloserine, D-serine, and ampa-
to overcome treatment refractoriness but also to kine). Several double-blind, placebo-controlled
improve the physical health of clozapine-treated trials have evaluated glycine add-on to clozapine
patients [24, 152]. alone or together with other antipsychotics, but
Some encouraging data come from the the results about its effectiveness on positive and
omega-3 fatty acid add-on that have demon- negative symptoms were inconsistent and gener-
strated to improve some anthropometric indices ally negative [164–166].
(such as weight, body mass index [BMI], wrist Recently, some preliminary data suggested
and waist circumference) in patients with schizo- that the extract of Ginkgo biloba was found
phrenia who were taking clozapine pharmaco- useful for enhancing the effect of clozapine on
therapy [153]. Peet and Horrobin [154] conducted negative symptoms in patients with treatment-
a 12-week placebo-controlled dose-ranging resistant schizophrenia [167].
exploratory study (1, 2, and 4 g/day of ethyl-
eicosapentaenoate [E-EPA]) on 115 patients with
persistent symptoms of schizophrenia, receiving 23.7 Adjunctive Electroconvulsive
either clozapine (31 patients), SGAs (48 patients), Therapy (ECT)
or FGAs (36 patients). In the clozapine group only,
a post hoc analysis showed a clinically important ECT is one of the oldest treatments in psychiatry,
and significant effect on all PANSS subscales, which has luckily survived till today and is con-
which was most pronounced at an E-EPA dos- sidered to be very useful in patients with several
age of 2 g/day. Moreover, omega-3 fatty acids severe psychiatric disorders including schizophre-
may be useful in patients taking clozapine who nia [168, 169]. Many studies have shown that ECT
have elevated serum triglyceride levels [155]. may be effective in patients with TRS [170, 171].
However, in a 12-week study, Emsley et al. [156] Moreover, there are several earlier reports that
found no significant changes in positive, negative, suggested an important positive effect of adjunc-
or overall symptoms of schizophrenia in patients tive ECT in patients with partial or non-response
taking clozapine after treatment with E-EPA 3 g/ to clozapine [172–175].
23 When Clozapine Fails: Augmentation Strategies in the Management of Clozapine-Resistant 359
More recently, a renewed interest has grown should be considered on a case-by-case basis
up from the results of several trials and reviews for those individuals who haven’t achieved a
that have further investigated the effect of adjunc- good response and/or experienced some clo-
tive ECT to clozapine [176–179]. Kho et al. [180] zapine-related adverse effects [20, 187]. It
observed a remission in eight patients with adjunc- should be noted that the majority of the stud-
tive ECT treatment. After remission of symptoms, ies that have evaluated augmentation strate-
five subjects experienced a relapse, and three of gies are mostly case report, case series, and
the five subjects who relapsed had a second effec- open trials with a relative few number of
tive ECT course and did not experience further patients and several biases [24, 188]. There
relapses with maintenance ECT and clozapine. No are too few available RCTs that may allow to
adverse effects were reported. Masoudzadeh et al. define a precise guideline on what to do in the
[181] assigned 18 TRS patients to three identical unluckily case of clozapine resistance [21,
groups: one group was given clozapine, another 188]. Nevertheless, given the devastating
group was treated with ECT, and the last group effect of the clozapine-refractory schizophre-
was treated with the clozapine-ECT combination. nia and the pervasive consequences on patients
They found that the clozapine-ECT combina- as well as caregivers quality of life and func-
tion was superior to single therapies with a fast tioning, even a modest response to a particular
response to combination treatment and a higher augmenting agent may be clinically signifi-
improvement in both positive and negative symp- cant for each subject [189].
toms. There were no significant adverse effects Some augmentations may be more useful
with clozapine-ECT combination. In a random- to manage clozapine adverse effects such as
ized single-blind 8-week study by Petrides et al. metabolic adverse effects and seizures (i.e.,
[182], patients with clozapine-resistant schizo- aripiprazole, valproate, and topiramate add-
phrenia were assigned to treatment as usual (clo- on), to address pharmacokinetics and pseudo-
zapine group) or a course of bilateral ECT plus resistant problems (i.e., fluvoxamine add-on),
clozapine (ECT plus clozapine group). Authors or to target specific symptoms (such as
found that the 50% of the ECT plus clozapine depressive symptoms with antidepressant
patients met the response criterion (≥40% reduc- add-on).
tion in symptoms based on BPRS scores, a CGI- However, some strategies seem more prom-
severity rating <3, and a CGI-improvement rating ising than others on some symptom domains
≤2), whereas none of the patients in the clozapine (i.e., memantine augmentation on cognitive
group met it. In the crossover phase, response was symptoms) or may be effective to improve
47%, and ECT combination was well tolerated. positive and negative symptoms (i.e., lamotrig-
Kim et al. [183] confirmed these positive obser- ine, mirtazapine, and ECT add-on), but further
vations in a sample of seven patients with a sig- larger studies are undoubtedly needed.
nificant reduction on PANSS total score. As well, As a concluding remark, we underline that,
other reports were positive [184–186]. while augmenting, the adverse effect profile of
In conclusion, combination treatment with each augmenting agent must be carefully consid-
clozapine and ECT was safe and effective in ered, and, in case of intolerability or inefficacy,
clozapine-resistant patients without severe the clozapine monotherapy should be promptly
adverse effects. It should be always considered, restored. We are absolutely aware that clozapine-
where available, for the treatment of clozapine- refractory schizophrenia is a great challenge and
resistant patients. a real troublesome condition, but we fully agree
with Jain et al. [19] when they wrote “…the pro-
Conclusions gressive nature of schizophrenia needs to be kept
When clozapine fails there are several strate- in mind while setting goals for functional recov-
gies that can be employed [152]. However, ery as unrealistic expectations may do more harm
such strategies are mostly empirical and than good….”
360 D. De Berardis et al.
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Fecal Microbiota Transplantation
in the Treatment-Resistant 24
Psychiatric Disorders
Alper Evrensel and Mehmet Emin Ceylan
cytokines can be prevented by antidepressant This situation that the baby is exposed on the
drugs [22, 23]. Antidepressants have anti-inflam- first day of life may have a lifelong impact on the
matory activity [24]. Probiotic bacteria, like anti- infant’s health and growth [8]. Intestinal micro-
depressants, also exhibit an anti-inflammatory biota of the children delivered by Caesarean
effect by increasing interleukin-10 (IL-10) levels section can be repaired by application of the
[25]. Injection of Lactobacillus GG (a probiotic mother’s vaginal flora into the baby’s mouth [35].
bacterium) to experimental animals increases Antibiotics are one of the most important fac-
plasma IL-10 levels [26]. The effects of changes tors that change the microbiota composition of
in the microbiota composition in the postnatal the body. Antibiotics use in the first year of life
period may last lifelong [27]. Dendritic cells, may carry the risk of developing depression in
which are a group of cells in the immune sys- adulthood [38]. In an experiment, it has been
tem of the intestinal tract, absorb the bacteria and observed that anxiety-like behaviors decreased
their metabolites in the intestinal lumen into its after 7 days of vancomycin application to rats.
cytoplasm by touching them. Bacterial metabo- However, this effect disappears 2 weeks after
lites and nucleic acids can thus reach the brain the intestinal bacterial composition returns to
via systemic circulation [28]. its original state [39]. Yet, the long-term use of
Intestinal epithelium constitutes the largest broad-spectrum antibiotics leads to a permanent
mucosa in the body. Its surface area is almost compositional change on the gut microbiota,
equal to the size of a tennis court (approximately which may continue for a long time [40].
260–300 m2) [29]. The intestinal mucosa pro- Depression-like behaviors are observed in
vides the absorption of nutrients as well as set- germ-free mice [39]. Still, germ-free mice have
ting a physical barrier between the bacteria and got lower scores in anxiety tests compared to
the host. This barrier is formed by tight junction conventional mice [41]. Microbiota has an effect
proteins and mucus layer [30]. The change in the on amygdala functions and fear response [42].
microbiota composition can cause micro damages The presence and absence of gut bacteria and its
in the intestinal epithelium wall. The leakage of bacterial composition play a significant role in
microorganism-derived endotoxins (lipopolysac- brain functions from the first day of life [43].
charides and peptidoglycans) into the systemic
circulation is called “leaky gut” [9, 31].
The leaky gut hypothesis was first expressed 24.3 FMT as a Restorer
by Jakop Fine in 1955, and it has been suspected of Microbiota Dysbiosis
for long time [32]. It has been later revealed in
animal experiments that bacterial-borne endotox- Dysbiosis, which occurs in the microbiota due to
ins are passed into the systemic bloodstream as a the causes such as nutrition, antibiotic use, stress,
result of deterioration in intestinal permeability and aging, can be restored through FMT [44, 45].
[33]. As a result, an immunological reaction may The main purpose of FMT is to restore the dys-
occur [34]. function in the intestines with a healthy bacterial
If the mother gives birth through vaginal route, flora transplantation [46].
the baby is colonized with the dominant bacte-
ria in the mother’s vaginal flora (Lactobacillus
and Prevotella species) [35]. If the baby is born 24.3.1 History of FMT
with Caesarean section, the bacteria living in
the mother’s skin flora (Staphylococcus and The first known FMT was applied in China
Corynebacterium species) move to the intestinal 1700 years ago [47]. The feces suspension called
microbiota of the newborn [36]. The incidence “yellow soup” has been orally ingested in cases
of allergic diseases is higher in the children born of diarrhea and food poisoning. We do not know
through Caesarean section than the children who with which knowledge Chinese physician Ge
are born by vaginal [37]. Hong applied this remedy. It may have been
24 Fecal Microbiota Transplantation in the Treatment-Resistant Psychiatric Disorders 371
used for emetic and purgative purposes in food be following a healthy diet, get no medication,
poisoning [48]. There is no record found in the and have a healthy lifestyle by paying attention
medical texts about the application of FMT in to their physical health [50].
the following centuries after Ge Hong. Another The transfer material should be between 150
traditional Chinese physician Li Shizhen applied and 250 g. Stool should be taken immediately
FMT for the treatment of gastrointestinal com- before FMT and should be fresh [50]. FMT may
plaints such as constipation, diarrhea, and vomit- induce defecation reflex by causing irritation in
ing in the sixteenth century [47]. Two centuries the intestines of the patient. However, for the pro-
after Li Shizhen, Italian anatomist Fabricius cess to be successful, the transplanted feces must
Aquapendente used the fecal suspension with remain in the intestines of the recipient for at
the name of “transfaunation” in the treatment of least 4 h. For this purpose, an antidiarrheal drug
animals [49]. We know that German soldiers had called lopermid is given before FMT [45, 57].
used camel stool in treatment of bacterial dysen- Before FMT, fecal suspension should be pre-
tery upon the suggestions of Bedouins during the pared. The stool can be diluted with water, physi-
Second World War in Africa [50]. ological saline, or milk. The fecal suspension
is cleaned from solid particles through filtering
and is transferred to 60 ml syringes [44, 50]. The
24.3.2 Main Application Area of FMT ideal method of preparing the stool suspension
has not yet been specified. When diluted with
FMT was first applied in modern medicine in physiological saline, feces were found to have a
1958. Four cases of pseudomembranous entero- lower success rate compared to the dilution with
colitis caused by Clostridium difficile have been water. It is argued that when the electrical mixer
successfully treated by fecal transplantation [51]. is used, the oxygen that was mixed into the sus-
Second series of Clostridium difficile infection pension decreases the number of anaerobic bac-
(CDI) cases treated with FMT has been reported teria, and thus the effectiveness of the treatment
in 1981 [52]. Following these publications, an is reduced [50].
in-depth investigation of FMT was carried out, The fecal suspension can be applied to the
and its effect mechanism was better understood. patient in two routes. It can be delivered to the
Today, we have strong evidence about the effec- upper gastrointestinal tract via esophagogastrodu-
tiveness of FMT in recurrent CDI cases. FMT odenoscopy or nasogastric tube. It can be delivered
is effective in treatment of recurrent CDI and to the lower gastrointestinal tract by colonoscopy
inflammatory bowel diseases [53]. There are no [45]. In 3/4 of the cases, colonoscopy was used,
randomized controlled studies about the use of and esophagogastroduodenoscopy was used in 1/4
FMT in treatment of psychiatric disorders. In this of the cases [58]. This proportion may be the result
respect, animal experiments are promising [54]. of patients’ demands because some of the patients
do not prefer FMT. Women are more reluctant
than men, and young people are more reluctant
24.3.3 Application of FMT than old people. Colonoscopy is rather preferred
by many patients. A third of the patients think that
FMT is applied according to the Amsterdam pro- this operation should be free [59].
tocol [50]. Ethical conditions must be fulfilled FMT may be rarely implemented because of
before its application [55]. In the past, stool sam- its unlikeable aspects for the patient. In cases
ple was used to be taken from a healthy person when the transfer needs to be urgently done, the
in the immediate circle of the patient. In the last donor’s health screenings may take time and FMT
5 years, it has been suggested to be taken from a may be delayed. For this reason, an a lternative
feces bank. Stool banks use fresh feces donated method to FMT has been tried [60]. The sample
by reliable and healthy donors who often have of stool was put in the swallowable capsules after
some medical screenings [56]. Donors should it has been centrifuged. Capsules were stored at
372 A. Evrensel and M. E. Ceylan
−80°. They were administered to the patients normal diet. Leaky gut syndrome, neuroinflam-
through per-oral route 15 times a day for 2 days. mation, and behavioral disorders were detected
In 70% of the cases, complete remission was in rats fed on a normal diet following FMT [69].
achieved after 3 days, and the same procedure In an animal experiment, autistic behavior of
was repeated once more to the rest of cases [61]. the rats has been reduced after given Bacteroides
Oral administration is a noninvasive and more fragilis (a probiotic bacteria). Bacteroides fragilis
comfortable method. It can be predicted that its has repaired the gut and reduced the leakage [70].
use will be spread and will be utilized to restore In one of the studies conducted on fecal speci-
intestinal microbiota after antibiotic treatments in mens, the stool of autistic children indicated more
the future [62]. Clostridium species [71, 72]. It has been reported
that autistic symptoms retrograded in two chil-
dren who were applied FMT and in five autistic
24.4 F
MT as a Treatment Method children who were given bacteroides [58].
in Treatment-Resistant In a study comparing the fecal microbiota
Psychiatric Disorders analysis of 28 cases of first episode psychosis and
16 healthy individuals, a significant difference
FMT has been searched mostly in CDI. The has been detected between two groups in terms
use of antibiotics can result in dysbiosis and of Lactobacillus levels. This difference also corre-
Clostridium difficile can become dominant in the lates with severity of the symptom and treatment
microbiota. FMT repairs the damaged bacterial [73]. In another study designed in a similar way,
flora [63]. FMT may be a promising method in Jiang and colleagues compared the fecal micro-
treatment-resistant psychiatric disorders. biota analysis of 46 depressed patients and 30
The relationship between depression and healthy individuals. Bacteroides, Proteobacteria,
microbiota has currently become quite visible and Actinobacteria levels were higher, and
[5]. Animal models of depression are obtained Firmicutes levels were lower in the depressed
through administration of bacterial lipopoly- patients. These results have been interpreted
saccharide [64]. Positive changes have been as the increase of harmful bacteria groups and
observed in immune parameters after intesti- the decrease of beneficial bacteria in depressed
nal microbiota repair in many animal experi- patients [74]. In a recently published meta-
ments. In one of the experiments, the level of analysis, it has been concluded that probiotic bac-
IL-10 increased after the supplementation of teria are effective in treatment of the depression
probiotic bacteria in germ-free mouse [65]. In [75]. The intestinal microbiota composition of
another experiment with a germ-free mouse, depressed patients may be modulated by FMT as
Bifidobacterium infantis reduced the anxiety and well as through probiotics. In the experiment of
depression scores [66]. Bifidobacterium infantis Zheng et al., FMT was applied to the germ-free
has been described as a “psychobiotic bacte- mice from depressed patients. Depression- like
rium” because of its antidepressant- like effect behaviors were observed in mice after FMT [54].
[16]. Probiotic bacteria such as Bifidobacterium If the depression can be transmitted through FMT,
longum and Lactobacillus helveticus have can the treatment be also transferred? We have
reduced anxiety scores in rats [67]. In a RCT hoped to give a positive answer to this question.
performed on healthy volunteers, experiment The microbiota composition changes with age,
subjects were given Lactobacillus helveticus and as a result, cognitive inefficiency may arise
and Bifidobacterium longum or placebo dur- [11]. The western diet may also disrupt the micro-
ing a month. Anxiety scores and the levels of biota composition. The resulting dysbiosis may
anxiety-related blood parameters reduced in the lead to hippocampal dysfunction and cognitive
subjects who had taken probiotic bacteria [68]. impairment [76]. Bifidobacterium longum 1714
In an experiment conducted by Bruce-Keller and has been found to reduce stress and to have a posi-
colleagues. FMT has been administered from tive effect on the memory in healthy individuals
the rats fed on a high fat diet to the rats fed on a [77]. However, in a RCT that the same researchers
24 Fecal Microbiota Transplantation in the Treatment-Resistant Psychiatric Disorders 373
performed on healthy individuals in the follow- whether the feces obtained from the stool bank
ing year, the application of Lactobacillus rham- is different from the fresh stool in terms of activ-
nosus (a probiotic bacterium) was not superior to ity. The use of water, saline, or milk in dilution
the placebo with regard to its effects on anxiety, of feces may have different consequences on the
stress-related measures, HPA response, and cog- efficacy of treatment. It may be appropriate to use
nitive performance [78]. Nevertheless, the num- different diluter for each indication. There is no
ber of publications has been increasing, which consensus about how many grams the ideal stool
suggests that leaky gut and bacterial LPS-induced should be. It is necessary to determine whether
neuroinflammation are the etiopathogenesis of the transplantation is more effective by oral route
Alzheimer’s disease [79]. or anal route. The changes in the immune and
Another factor that disrupts the intestinal per- metabolic system in short and long term after
meability and cause dysbiosis is the chronic alco- FMT should be revealed in detail. No serious risk
hol use. Probiotics may be useful in treatment of has been reported in patients with poor physical
alcohol addiction by restoring the intestinal tract health. However, possible risks of FMT that may
[80]. It is also possible to make the same predic- be encountered when it is applied with psychiatric
tion for FMT. indications are not yet known. Large-scale case
In the light of these studies, the potential use series and RCTs are required in order to determine
of FMT in treatment resistant psychiatric disor- these risks and illuminate the unknown points.
ders emerges through the restoration of impaired
gut microbiota. Conclusion
The composition of healthy gut microbiota
may change due to nutrition, medications
24.5 Reliability and Side Effects (antibiotics, antidepressants), and stress.
Change in the composition of microbiota can
Basic indications for the use of FMT are CDI and lead to various metabolic and immunological
inflammatory bowel diseases such as Crohn’s dis- problems. The microbiota composition can be
ease and ulcerative colitis. Although the overall restored using FMT and probiotic bacteria.
medical condition of the patients who had stool FMT is a life-saving, easily applicable and
transplantation is quite bad, FMT is a reliable reliable treatment method for recurrent CDI
practice. Diarrhea, constipation, gas, and abdomi- and inflammatory bowel diseases. Positive
nal pain can be observed in the day of FMT appli- results have been reported in the treatment of
cation even though it is rare [50]. In a series of metabolic, immunologic, and neuropsychiat-
317 cases, enteritis, bleeding, and peritonitis ric disorders that are accompanied by intesti-
were reported only in 3 cases [81]. Exacerbation nal permeability. In this respect, preclinical
of colitis has been reported in one case [82]. studies are promising. It carries the potential
Posttransplant peritonitis has caused the death of to be effective in treatment-resistant disorders
a case [83]. Brandt et al. have not reported any that do not respond to the classical psychiatric
side effect in long-term follow-up study [53]. treatment methods. It seems that this potential
Although the history of the FMT goes seven- will be clearly understood in the next decade.
teen centuries back, its use has increased in the
last 30–40 years. For this reason, there are many
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Neurosurgical Intervention
for Treatment-Resistant Psychiatric 25
Disorders
Daniel E. Nijensohn and Teodoro Forcht Dagi
that inspired the careful and limited reintroduc- From a historical perspective, contagious exu-
tion of psychosurgery in the USA. The guiding berance appeared unwisely, but not uncommonly
principles were based on guarding against the after initial improvements in a small number of
errors of the past, careful reporting and monitor- cases. A large series may not lead to the same
ing, and on highly restricted limited indications. conclusions. St. Jude Medical, now Abbott, aban-
Regarding DBS, many psychiatrists have doned the recent Broden trial (BROdmann Area
agreed with Insel, former director of the National 25 DEep brain Neuromodulation (DBS) of the
Institute of Mental Health, who wrote “if men- subgenual cingulate gyrus for the treatment of
tal disorders are brain circuit disorders, then major depression) [120] because under careful
successful treatments need to tune circuits with monitoring, it proved beneficial in no more than
precision. Chemicals may be less precise than 20% of cases – no better than the 17% of the con-
electrical interventions that target specific cir- trol group (Holtzheimer et al., Lancet Psychiatry,
cuits” and have proved increasingly willing to October 2017) [173].
reconsider their objections to psychosurgery in
general and DBS in particular [72].
Although outcome studies began to reemerge 25.1.1 The Proper Ambit
in the mid-1990s and the FDA approved a of Psychosurgery
humanitarian device exemption for DBS for
severe OCD in 2009 based on a review of data The original indications for prefrontal leucotomy
from 26 patients with severe and treatment- were agitation and violence, indications for
resistant disease, long-term data remained which the alternatives in the late 1930s ranged
elusive. A 2014 consensus statement on ethi- from restraints to ice baths to insulin-induced sei-
cal and scientific guidelines for stereotactic zures, to electroshock therapy, and to barbiturates
neurosurgery for psychiatric disorders spon- [179]. It could be argued that the induction of sei-
sored by the World Society for Stereotactic zures and perhaps the use of barbiturates were
and Functional Neurosurgery Committee on intended to be therapeutic, but the other treat-
Neurosurgery for Psychiatric Disorders and ments were simply ways in which difficult
authored by a multidisciplinary international patients were managed by the understaffed insti-
consortium of neurosurgeons, neurologists, tution to which they were relegated. The side
psychiatrists, neuropsychologists, bioethicists, effects of leucotomy, which included passivity,
philosophers, regulatory experts, and legal flattened affect, and blunted cognition, were not
scholars highlighted, for example, the lack of necessarily considered objectionable given the
Level I evidence, even around established pro- objectives, not unlike facial anesthesia after tri-
cedures such as cingulotomy and capsulotomy geminal rhizotomy for trigeminal neuralgia. Over
for depression and obsessive-compulsive disor- time, however, as the indications for psychosur-
der. It emphasized unreservedly the categorical gery were uncritically expanded to include far
importance of comprehensively collecting cred- more normal individuals, these side effects were
ible data around investigational procedures such re-adjudicated and judged to be unwanted com-
as DBS [89, 137]. “Credible data” is a difficult plications. Until psychosurgery was first effec-
but necessary target. Trial design must be care- tively abandoned, the goal was more carefully
fully thought through. The classical randomized targeted procedures, more carefully performed,
controlled trial approach may not be applicable using more advanced techniques.
in this field. Recent developments in trial meth- The current ambit of psychosurgery can be
odology and statistics suggest that alternative divided into two parts. On the one hand, there
designs may be more applicable and, ultimately, are strong signals of efficacy in obsessive-
more productive [15, 35, 41, 57, 64, 69, 70, compulsive disorder (OCD) and in major
101, 103, 118, 134, 142, 150, 151, 159, 164, affective disorders including major depressive
170, 174, 188]. disorder (MDD), bipolarity, and severe anxiety.
380 D. E. Nijensohn and T. F. Dagi
On the other hand, there is interest in develop- making process, and patients must not be aban-
ing models and exploring indications for other doned once the psychosurgical procedure is
disabling, treatment-resistant conditions includ- completed. The postoperative psychiatric treat-
ing anorexia nervosa (AN) and morbid obesity, ment and management program must be in place
post-traumatic stress disorder (PTSD), and before any procedure is contemplated. In general,
substance abuse (SA). Some include treatment only patients older than 18 years who are able
for certain residual aspects of traumatic brain to render voluntary informed consent and par-
injury (TBI), memory and sleep disorders (i.e., ticipate in the decision-making process should be
Alzheimer’s and cognitive disorders), aggres- considered for surgery [27].
siveness, and Tourette’s syndrome (TS). Whether Finally, it should be self-evident that the only
the objectives of surgery for TBI, TS, and mem- acceptable goal of psychosurgery is the treatment
ory and sleep disorders should be classified as of illness. It must never be deployed for social or
psychosurgery remains disputed. Indeed, the political purposes [117–119, 189].
entirety of this second category is highly fraught For social and historical reasons, one should
with controversy. not be surprised to see a higher level of evidence
In any case, psychosurgery is reserved for required for psychosurgical interventions than
severely incapacitated patients with treatment- for other indications. The answer to the ques-
refractory illnesses and low quality of life. A his- tion “what is evidence enough?” cannot be eas-
tory of personality disorder, substance abuse, or ily answered, nor answered across the board.
other Axis II symptomatology serves as a relative The elevation of psychosurgery to a standard
contraindication. In rare instances only, patients of care will require both professional and social
with severe violent outbursts and potential for consensus and a great deal of discussion around
serious injury or self-mutilation or severe aggres- criteria for defining costs and for assigning ben-
sive disorders – typically on the basis of certain efits [28].
recognized genetic abnormalities – might be
considered for amygdalotomy, thalamotomy, and
hypothalamotomy. 25.1.2 Identity, the Mind, the Brain
Schizophrenia has proven to be much more
difficult to treat than depression and OCD and is Diffusion MRI is becoming an indispensable
not currently a surgical indication. Some patients tool to investigate a variety of psychiatric disor-
with mixed disorders, combining symptoms of ders such as schizophrenia, major depressive
anxiety, depression, and OCD, remain candidates disorder, eating disorders, attention deficit dis-
for surgery [96]. order, addictions, and so on. It has shed insight-
Certain principles should govern the practice ful light on our understanding of neural
of psychosurgery. All patients must be referred connectivity and how abnormalities in connec-
for surgical intervention by the treating psychia- tivity may contribute to the pathogenesis of psy-
trist, who must be committed to continue caring chiatric illnesses [174].
for the patient, to the evaluation process and to While the notion that brain function might
postoperative management. Detailed documen- be successfully modulated through the ablation
tation of the extent, severity, and diagnostic and or stimulation of specific anatomical targets is
therapeutic history must be provided. The specif- rooted in ideas around cerebral localization, the
ics of pharmacologic trials should include agents biological basis of most psychiatric illnesses
used, dose, duration, response, and reason for remains poorly understood, and the direct associ-
discontinuation [27]. ation of targets, symptoms, and diseases remains
Although this point should be obvious, it elusive. Nevertheless, there is strong support
requires frequent restatement. The family must for the idea that signaling within the central
participate in the evaluation and the decision- nervous system involves two parallel systems,
25 Neurosurgical Intervention for Treatment-Resistant Psychiatric Disorders 381
one neuronal and synaptic, and the other neuro- It is helpful to think of outcomes in this domain
chemical. In addition, experimental and clinical in the same way one would approach clinical tri-
evidence suggests that a number of psychiatric als: the key is to correlate primary clinical indi-
conditions are open to chemical (pharmacologi- cations and endpoints. Currently, data supporting
cal) modulation; the stimulation or ablation of the overall clinical superiority of any one proce-
certain anatomical targets in the brain and else- dure is not persuasive [147].
where (procedures like vagal nerve stimulation
will not be discussed here) modulates neuronal
and neurochemical signaling and that such mod- 25.1.3 Prevalence of Various
ulation may benefit some forms of psychiatric Procedures
illness [72, 148].
All things being equal and without reference to
25.1.2.1 Outcome Measures specific indications, cingulotomy is the most prev-
It is important to develop uniform, standardized, alent functional operation carried out for psychi-
and clinically meaningful outcome measures. atric illness in general in the USA, whereas in
Many obstacles will have to be overcome including Europe, capsulotomy and limbic leucotomy are
diagnostic ambiguities, existing non-standardized more prevalent. They all appear roughly equiva-
presurgical evaluation tools, center bias, and varied lent therapeutically but in terms of unwanted side
outcome assessment scales [26, 27, 130]. effects, cingulotomy appears to be the safest of all
Some existing tools include: procedures currently performed. Regardless of
procedures, surgical failures should be investi-
1. The Yale-Brown Obsessive-Compulsive Scale gated, and if the lesion size or location is subopti-
(YBOCS) to assess the severity of OCD: a mal, then consideration should be given to a
score >20 is enough for candidacy for a psy- repeat procedure. At least 45% of patients under-
chosurgical procedure. going cingulotomy require repeat operation with
2. The Beck Depression Inventory (BDI): a score good results being salvaged in half. Repeat sur-
>30 confirms the severity of depression. gery in capsulotomy patients has been reported as
3. The Global Assessment of Function (GAF) to 20%. The exact size or volume of tissue required
assess disability: a score <50 justifies for an effective outcome at each of the target sites
psychosurgery. has yet to be determined. As already noted, sur-
4. The Pippard Postoperative Rating Scale gery should be considered as only one aspect in
(PPRS) assesses outcomes according to five the overall management of these patients [26, 27].
categories: symptom free (A), much improved There is increasing interest in neuromodu-
(B), slightly improved (C), unchanged (D), lation over a number of functional indications
and worse (E). Although comparisons are including memory enhancement in age-related
imperfect, the PPRS appears to have some dementia, as well as in psychosurgery for
clinical validity. For example, if categories A major depression, PTSD, substance abuse, and
and B are considered satisfactory, then cingu- others [95].
lotomy is effective in 56%, subcaudate trac-
totomy in 50%, limbic leucotomy in 61%, and
capsulotomy in 67% of patients with OCD 25.2 Neuroanatomy, Targets,
[125]. In patients with major affective disor- Techniques
der, in contrast, cingulotomy is slightly more
effective [27]. Capsulotomy patients did bet- While the neuroanatomical correlate of psychi-
ter than cingulotomy patients, but transient atric illness has been associated with the limbic
deterioration in mental status was much more system (LS), described by Broca [19], Jakob
marked [27]. [78], Papez [29, 141], McLean [122], and others,
382 D. E. Nijensohn and T. F. Dagi
there is no specific site or set of sites in which Berlin meeting) offer a useful sample of the ques-
psychiatric illness can be rooted. Nevertheless, a tions that continue to be asked in the field:
large number of sites have been targeted for
stimulation or ablation. Indeed, some have pro- • Is surgery for psychiatric disorders really
posed the term limbic system surgery as an alter- needed?
native to psychosurgery. Neurosurgical • DBS for OCD: Why it is not flying like DBS
interventions for psychiatric disorders have been for Parkinson’s?
directed at various targets within this system and • Two failed trials of DBS for depression: what
its interconnections with the cortico-striato-tha- went wrong?
lamic-cortical circuits (CSTCC) which appear • What happened to DBS of the subthalamic
to play a central role in the pathophysiology of nucleus (STN) for OCD?
major affective illness, OCD, and other anxiety • How to proceed? Why is the field stagnating?
disorders. Electrical stimulation of specific areas • Are psychiatrists averse to psychiatric
within the LS (e.g., the anterior cingulum (AC)) surgery?
has been shown to alter both autonomic responses • Why is psychosurgery still “experimental”?
and anxiety levels in humans. • What are the “ideal requirements” for neuro-
Additional interventions have been directed surgery to become an accepted credible treat-
at the anatomical circuit of Papez [141], which ment of refractory patients?
consists of the hippocampus-fornix-septum- • When is a patient with OCD
mammillary bodies-anterior thalamic nuclei- treatment-refractory?
cingulate gyrus-hippocampus. The term • When is a patient with major depression
“anatomical” is used because these anatomi- treatment-refractory?
cal connections can be clearly identified, even • How can we image the brain circuitry involved
though their physiological relationships are less with psychiatric disease?
convincing. In some reported cases, the inter- • Are there good animal models for psychiatric
nal capsule, the basal ganglia, and the nucleus disorders? [41, 159, 185]
accumbens have also been targeted. Stimulation
of the hypothalamus produces autonomic, endo-
crine, and complex motor effects which suggest 25.2.1 Stimulation and Ablation
that it may integrate and coordinate the behav-
ioral expression of emotional states [100, 115]. Early psychosurgery was predicated on the idea
Neurochemical models suggest that affective and that certain circuits should be interrupted and/or
anxiety disorders may be mediated via monoami- nuclei ablated. Superficial and deep stimulating
nergic systems. Because of the diffuse nature of electrodes were used experimentally to stimulate
the monoaminergic projections and their role as and to study brain tissue in humans since the late
neuromodulators, these models are not particu- 1940s, but it took another half century before
larly instructive in terms of functional neuroanat- they were applied to psychosurgery, even though
omy and target identification. The serotonergic the technology was well known and stimulation
system has received emphasis when relating to had been used for experimental studies in ani-
OCD. Although the exact neuroanatomical and mals since the nineteenth century.
neurochemical mechanisms underlying OCD, The introduction of stereotactic techniques
depression, and other anxiety states remain to create well-localized and discrete cere-
unclear, it is believed that the basal ganglia, lim- bral lesions in specific target sites in the 1950s
bic system, and frontal cortex play a principal represented a major advance in neurosurgery
role in the pathophysiology of these diseases. (Fig. 25.2). Stereotactic methods were particu-
Presentations included in the recent scientific larly attractive in psychosurgery and functional
program of the World Society for Stereotactic and neurosurgery because it was thought they would
Functional Neurosurgery (WSSFN) (June 2017, improve the risk-benefit ratio [71, 85, 171, 176,
25 Neurosurgical Intervention for Treatment-Resistant Psychiatric Disorders 383
Continuous electrical
signal sent to brain at
specified amplitude,
pulse width and
frequency
Pulse generator
term DBS for clinical and investigative purposes. lant about transparency, and the use of scientific
The DBS electrodes are connected via Medtronic and ethical rigor when treating disorders of the
lead extenders to their battery- powered IPG mood and mind [12, 13].
(implantable pulse generator). Trials of DBS in treatment-resistant psychi-
Medtronic Activa™ series of open-loop atric disorders began in the late 1990s, initially
neurostimulation devices (Activa SC™, Activa focusing on OCD, MDD, and TS. Despite serious
PC™, and Activa RC™) are FDA-approved issues – small participant numbers and a lack of
and differ on the basis of dimensions, weight, consensus over brain targets – DBS is now trialed
and battery type. These IPG devices are capable in a wide range of psychiatric conditions [2, 3,
of delivering single- or dual-channel electrical 6, 34, 35, 41, 48, 50, 57, 60, 61, 66, 69, 78–80,
stimulation with a frequency of 2–250 Hz, a 87, 94–97, 99, 101, 102, 105, 110, 113, 116, 120,
pulse width of 60–450 ms, and an amplitude of 122, 124, 129, 133, 137, 146, 147, 154, 157–160,
0.0–10.5 V [40, 173]. 162, 164].
The precise mechanism of action of DBS The number of ablative procedures has also
remains controversial. Nevertheless, high-increased. In both stimulation and ablation pro-
frequency stimulation was noted to act clinically cedures, a stereotactic cage-frame is attached to
very much like a lesion, appearing to block or the head as a means of directing electrodes or
override the abnormal activity in the network. energy beams to deep brain locations mapped
As already noted, DBS was initially developed by MRI, although frameless computer-assisted
by Benabid in France as a less abrasive approach neuro- navigation is emerging. All but three
than lesioning for treatment of tremor. It even- of the psychosurgical procedures in current
tually earned a second chance for psychosur- use involve the insertion of electrodes into the
gery. Although DBS does not work better than brain. The exceptions are vagal nerve stimula-
pallidotomy to alleviate the symptoms of PD, it tion (VNS) [165], made minimally invasive by
became preferred because it was reversible and Ventureyra in Ottawa, as per personal commu-
adjustable. In 2006 Benabid wrote “beware, psy- nication, gamma knife capsulotomy (through
chosurgery is back,” recommending being vigi- gamma knife surgery, where multiple nar-
25 Neurosurgical Intervention for Treatment-Resistant Psychiatric Disorders 385
Table 25.1 2017 psychosurgical cerebral targets tional MRI approaches have emerged for DBS
Target Psychiatric disorder implantation, eliminating the need for awake
Deep brain surgery. In addition, a number of tools for pre-
Anterior limb of the OCD, major depressive cise lesioning, e.g., implanted lasers and focused
internal capsule disorder (MDD) depression,
(ALIC) anorexia nervosa (AN)
ultrasound, have also emerged.
Nucleus accumbens OCD, MDD, AN, addictions With respect to psychosurgery specifically,
(NAcc) several DBS targets have been adopted for cer-
Subgenual cortex MDD tain specific conditions. These targets, which
(SG)/area 25 were found to produce the most benefit with the
Globus pallidus (GPi) Tourette’s syndrome (TS) fewest adverse effects, were initially chosen in
Habenula (Hb) MDD
four ways:
Posterior Aggressive behavior (AB)
hypothalamus (PH)
Thalamus, TS 1. The subthalamic nucleus (STN) became the
centromedian nucleus favored target in Parkinson’s (PD). Following
(CM) DBS for Parkinson’s, some patients with
Subthalamic nucleus OCD comorbid OCD experienced a reduction in the
(STN)
severity of those symptoms, hence its selec-
Inferior thalamic MDD
peduncle (iThP) tion for trials in OCD.
Nucleus basalis of Alzheimer’s disease (AD) 2. The first DBS trial, in 1999, targeted the ante-
Meynert (NBM) rior limb of the internal capsule (ALIC),
Basolateral amygdala Post-traumatic stress disorder because lesion surgery to that area had been
complex (BLAc) (PTSD) found in some cases to reduce the symptoms
Cortical
of severe OCD. The anterior cingulate and
Dorsolateral frontal MDD
Orbitofrontal MDD
subcaudate areas, and the combination of the
two, were chosen for similar reasons, in rela-
Targets and original authors
Gabriels, OCD, anterior limb of the internal capsule tion to MDD.
(ALIC), 2003 [53, 58] 3. fMRI revealed increased metabolic activity in
Sturm, OCD, nucleus accumbens (NAcc), 2003 [93, 175] the subgenual cortex and habenula in some
Jiménez, MDD/OCD, inferior thalamic peduncle (iThP)
patients with MDD. Hence, those areas were
2005/2009 [81]
Mayberg, MDD, subgenual cortex (SG)/area 25, 2005 targeted based on the hypothesis that such
[94, 120] hyperactivity may be causal, rather than sim-
Visser-Vandewalle, Tourette’s, Inferior thalamic peduncle ply a manifestation of depression.
(InThP), 2006 [1, 138, 180]
4. Tourette’s occupies a boundary zone between
Mallet, OCD, subthalamic nucleus (STN), 2008 [112]
Kuhn, Addiction to alcohol/tobacco, nucleus accumbens movement and compulsive disorder, contrib-
(NAcc), 2007/2009 [109, 129] uting to the wide range of brain targets avail-
Wu, Anorexia, nucleus accumbens (NAcc), 2013 [121, 186] able: thalamus, STN, globus pallidus,
Nuttin, OCD, Bed nucleus of the stria terminalis (BNST),
nucleus accumbens, and internal capsule
2017 [110]
[93, 111, 138].
row beams of gamma radiation intersect at a Several authors have sought to explain the ben-
pre-mapped point in the brain, hence the skull eficial effects of stimulation-based procedures and
is not opened) [102], and the relatively new lesion surgery on depressed mood and anxiety
and increasingly utilized MR image-guided by referencing to two cortico-striato-thalamo-
high-intensity focused ultrasound (MR-HIFU, cortical (CSTC) loops. Similar loops were
MRgFUS) lesioning [9, 89, 118]. previously identified in relation to movement dis-
With the explosion in putative targets for the orders – prior to the introduction of DBS – includ-
alteration of functional neural states (Table 25.1), ing inhibitory (−) (GABA-based) and excitatory
the roster of potential tools for intervention has (+) (glutamate-based) pathways. The CSTC-
also expanded. On the engineering side, interven- affective loops, by contrast, involve a wider range
386 D. E. Nijensohn and T. F. Dagi
of neurotransmitters and complex interactions that Four main lesioning procedures evolved as
are yet to be defined. Such circuits may explain the safest and most effective; these all performed
the variety of targets that seem to produce at least bilaterally and under stereotactic conditions to
some benefit in psychiatric DBS studies. It seems allow for precise lesioning of target structures
reasonable to speculate that tapping into and stim- (see Table 25.3):
ulating the loop at many points could influence
and modify the whole network. 1. Anterior cingulotomy
Currently, DBS therapy is FDA approved 2. Subcaudate tractotomy
for medically refractory PD, essential tremor, 3. Limbic leucotomy
dystonia, and OCD; in addition, other disor- 4. Anterior capsulotomy
ders under investigation include Tourette’s syn-
drome, treatment-resistant depression, chronic Anterior Cingulotomy
pain, alcohol and drug addiction, cluster head- Fulton [51] was the first to suggest that the ante-
ache, and Alzheimer’s disease [92, 106, 109, rior cingulum would be an appropriate target for
138, 162]. psychosurgical intervention, initially carried out
as an open procedure. Foltz and White [46]
25.2.1.1 Targets reported their experience with stereotactic cingu-
For some of the main targets and their indications lotomy for intractable pain and noted the best
for some psychiatric disorders, see Table 25.1. results were in those patients with concurrent
anxiety-depression. Ballantine [8] in the 1960s
25.2.1.2 Techniques subsequently demonstrated the safety and effec-
Each procedure has different indications, tech- tiveness of cingulotomy, which became the psy-
niques, results, and complications (see Tables chosurgical procedure of choice in North America
25.2 and 25.3). for many decades [26, 153]. Results of bilateral
cingulotomy on patients suffering from a variety
Table 25.2 Psychosurgical techniques of psychiatric disorders were reported retrospec-
tively by Ballantine et al. (MGH, Boston, MA) in
a. Stimulation Cerebral cortical stimulation
Deep brain stimulation (DBS),
1987: 62% of patients with severe affective disor-
neuromodulation der had worthwhile improvement. Cingulotomy
Vagal nerve stimulation (VNS) was less effective for OCD (25–30%) [5, 8, 26,
b. 27, 39, 45, 70, 80, 86, 96].
Ablation-lesioning Surgical indications: treatment-refractory
“Open” Leucotomy-lobotomy, MDD, chronic anxiety, or OCD, and occasion-
“modified” lobotomy,
topectomy [145] ally for severe chronic pain [26, 53, 97].
“Closed” Initially these procedures were performed
Stereotactic with ventriculography, but over the past several
Framed or years, this has been replaced by MRI-guided ste-
frameless reotactic techniques [170]. Target coordinates:
Through a burr Thermocoagulation, cryo- a point in the cingulum 7 mm from the midline
hole, cortical or coagulation, radiofrequency,
subcortical LASER and 20–25 mm posterior to the tip of the frontal
(electrode- horns. Lesions are done by thermocoagulation.
mediated) Intraoperative stimulation: not performed rou-
Through an intact MRI image-guided high- tinely. On the day after surgery, a postoperative
skull intensity focused ultrasound
MRI scan is obtained to document the place-
(MR-HIFU)
Gamma radiosurgery, like ment and extent of the lesions and R/O compli-
capsulotomy for OCD, and cations [27].
nucleotomy, nucleus accumbens In over 800 cingulotomies performed at the
for addiction MGH since 1962, there have been no deaths, few
25 Neurosurgical Intervention for Treatment-Resistant Psychiatric Disorders 387
complications, and no infections. An independent rior part of the sella turcica. Lesions were ini-
analysis demonstrated no significant behavioral tially done using radioactive implantable Yttrium
or intellectual deficits as a result of the lesions 90 seeds [27].
themselves with significant IQ gains postopera- Patients with schizophrenia, personality disor-
tively. This improvement was greatest in patients der, and drug or alcohol abuse did poorly. Some
with chronic pain and depression but negligible patients who had only temporary benefit from the
in those with the diagnosis of schizophrenia [27]. initial lesion had second lesions lateral to the first
with good results seen in about half [27].
Subcaudate Tractotomy The incidence of complications was small but
Subcaudate tractotomy was introduced by Knight has included postoperative seizures in 2.2% and
[90] in Great Britain in 1964 as an attempt to undesirable personality traits in 6.7%. Transient
restrict the size of the surgical lesion and there- disinhibition was common. Of the 25 patients that
fore minimize the side effects seen with standard had died at the time of a review, 3 patients had
prefrontal lobotomy. The aim was to interrupt committed suicide. One patient died from inad-
white matter tracts between orbital cortex and vertent destruction of the hypothalamus when an
subcortical structures by placing a lesion in the yttrium seed migrated off target [27, 100].
region of the substantia innominata just below
the head of the caudate nucleus [10, 27, 55, 74, Limbic Leucotomy
107, 147]. Limbic leucotomy was introduced by Kelley [85]
In patients with MDD and OCD, improvement in 1973, which combines subcaudate tractotomy
with minimal symptoms was clinically observed and anterior cingulotomy.
in two thirds of the patients. The best review of This procedure was designed to disconnect
the surgical results for subcaudate tractotomy orbital-frontal-thalamic pathways with the first
was presented by Gotekpe in 1975 [55, 107]. lesion and interrupt an important portion of
Good results were seen in 68% of patients suf- Papez’s circuit with the latter, reasoning that
fering from depression, 62.5% of patients with these two lesions might lead to a better result
anxiety states, and 50% of patients with OCD. for the symptoms of OCD than either lesion
Surgical indications included MDD, OCD, and alone.
anxiety states as well as a variety of other psychi- Indications for surgical intervention included
atric diagnoses [27]. OCD, anxiety states, depression, and a variety of
The surgical procedure was performed with other psychiatric diagnoses [27, 30, 35, 125, 127,
stereotactic techniques using boney landmarks 129, 148, 154].
and ventricular outline. The target coordinates Gotekpe found 89% of patients with OCD clin-
were 15 mm from the midline and 10–11 mm ically improved; chronic anxiety, 66%; depres-
above the planum sphenoidale at the most ante- sion, 78%; and a small number of s chizophrenics.
388 D. E. Nijensohn and T. F. Dagi
Overall, 80% were improved. It was noted that with the gamma knife and with ultrasound [75,
postoperative symptom improvement was not 83, 85, 88, 102, 152].
immediate, with a fluctuating but progressive In a review of all cases of capsulotomy pre-
reduction of symptoms over the first postopera- viously reported in the literature, Mindus [123,
tive year [55]. 124] found sufficient data to categorize 64% to
This procedure is carried out stereotactically, have a satisfactory result. In the first patients
and three small (6 mm diameter) lesions are operated by Leksell [16, 99], 50% of patients
placed in the lower medial quadrant of each fron- with OCD and 48% of depressed patients had
tal lobe and two lesions in each cingulate gyrus. a satisfactory response. Only 20% of patients
Lesions are done with a cryoprobe or thermoco- with anxiety neurosis and only 14% of patients
agulation [27]. with schizophrenia were improved. In this clas-
Intraoperative stimulation is performed, and sification system, only patients who were free of
if pronounced autonomic responses are observed, symptoms or markedly improved were judged as
it is felt it provides physiologic proof of correct having a satisfactory response. In another series
location [27]. with OCD who underwent capsulotomy and were
Although many patients suffer of lethargy, followed prospectively by independent psychia-
confusion, and lack of sphincter control in the trists, there was an overall satisfactory result of
early postoperative period, persistent complica- 70% [27, 102].
tions are rare. No patients developed seizures Complications of the surgery included tran-
postoperatively, one patient suffered severe sient episodes of confusion with occasional noc-
memory loss due to improper lesion placement, turnal incontinence. One patient was noted to
and 12% of patients complained of persistent have an intracranial hemorrhage without neuro-
lethargy. Measurements of IQ showed slight logical sequelae, and another suffered seizures.
improvement postoperatively [27]. One patient committed suicide in the postopera-
tive phase, and eight suffered from depression
Anterior Capsulotomy requiring treatment. Excessive fatigue, poor
Although Talairach (France) was the first to memory, slovenliness, and weight gain are com-
describe it in 1973 [176, 178], Leksell (Sweden) mon after capsulotomy. No evidence of cognitive
popularized the procedure for patients with a dysfunction has been reported in 200 capsulot-
variety of psychiatric disorders [85, 99]. The aim omy patients studied using a variety of psycho-
is to interrupt presumed fronto-thalamic connec- metric tests. Reoperation was required in two
tions in the anterior limb of the internal capsule patients who did not achieve a satisfactory result
as they pass between the head of the caudate with only one improving after the second opera-
nucleus and the putamen. tion [27, 139, 156].
Clinical indications of capsulotomy initially
include MDD, chronic anxiety states, and OCD
[27, 70, 89, 123, 139, 156]. 25.2.2 Other Less Frequent Ablation
The target coordinates are in the anterior one Procedures:
third of the anterior branch of the internal cap- Hypothalamotomy,
sule, 5 mm behind the tip of the frontal horns, Amygdalotomy, Thalamotomy
and 20 mm lateral to the midline at the level of
the intercommissural plane [27]. Lateral hypothalamotomy has been performed
Intraoperative electrical stimulation has not for morbid obesity (MO) [101].
been helpful in terms of determining optimal Posteromedial hypothalamotomy has been
placement of lesions within the capsule [27]. tried for aggressive violent behavioral disorders
Lesions: through thermocoagulation, using (Sano) [161]. The stereotactic target coordinates
a bipolar electrode system, and also performed are 3 mm inferior to the middle point between
25 Neurosurgical Intervention for Treatment-Resistant Psychiatric Disorders 389
Table 25.5 Neurosurgery for OCD divided into two regions: core and shell. The
Ablation core is located in the lateral part of the nucleus
Thermo-capsulotomy and connects with the extrapyramidal system.
Gamma knife anterior capsulotomy The shell is located in the ventromedial part of
Cingulotomy the nucleus as well as two thirds caudal, sur-
Limbic leucotomy
rounding the core and connecting with the lim-
DBS
bic system. The nucleus accumbens receives the
Subthalamic nucleus (STN)
Anterior limb of the internal capsule (ALIC) afferent glutamatergic pathway from the hippo-
Electrodes in four different targets produce similar campus, amygdala, thalamus and prefrontal cere-
results: nucleus accumbens (NAcc), anterior limb of bral cortex, and the dopaminergic inflow from
the internal capsule (ALIC), ventral striatum (VS), the substantia nigra. The principal efferent flow
subthalamic nucleus (STN)
is GABAergic toward the ventral pallidum with
Stimulation of the inferior thalamic peduncle (InThP)
achieve even better results
projections toward the substantia nigra compacta
Bed nucleus of the stria terminalis (BNST) and to the limbic portions of the subthalamic
nucleus. Only the shell of the nucleus accumbens
has efferent connections toward the lateral hypo-
(InThP) (see Table 25.5). Among early out- thalamus and the amygdala. This portion of the
come reports, Nuttin and colleagues found that nucleus accumbens is the possible surgical target
three of four patients with OCD benefited from for DBS in patients with OCD [5, 16, 17, 21, 30,
DBS. A study by Greenberg et al. found positive 35, 37, 47, 48, 50, 53, 69, 75, 76, 80, 93, 100,
outcomes in 16 of 26 [58]. Interestingly, several 101, 105, 108, 120, 123, 129, 139, 140, 151, 152,
studies found that DBS in the region of the ven- 155, 169, 170, 174, 175].
tral capsule/ventral striatum (VC/VS) resulted in
smiling and laughter during surgery, indicating 25.2.2.2 Tourette’s Syndrome (TS)
that this circuitry may be related to mood altera- TS is a neuropsychiatric disorder which becomes
tion. Because of these positive results, a humani- symptomatic in childhood or adolescence and
tarian device exception (HDE) from the US FDA that involves uncontrollable repetitive move-
was obtained in 2009 for DBS for OCD. ments or unwanted sounds, repeatedly blinking
Bilateral DBS appears to be more effective of the eyes, shrugging shoulders (tics), or blurt-
than unilateral. ing out offensive words.
Parkinson’s patients also suffering OCD show World prevalence: 5 cases every 10,000 peo-
OCD improvement with DBS of the STN; PET ple. It is associated with OCD, attention deficit
shows decreased metabolism in the left cingulum disorder, and hyperactivity. Tourette’s is consid-
(areas 24 and 32) and in the left medial fron- ered malignant when the symptoms become dis-
tal gyrus (area 6). At the same time, those with abling and associated with self-aggression [96,
decrease of Y-BOCS with DBS show decreased 148].
orbitofrontal cortex and ventromedial prefrontal TS is felt to be a disorder of cortico-striato-
region metabolism, close to the tract that con- thalamic-cortical loops.
nects the thalamic nuclei with the cortical orbito- Cappabianca et al. [23] reported four patients
frontal region. This is precisely the tract included with Tourette’s treated with thalamotomy (dorso-
in the subcaudate tractotomy. medial and interlaminar nuclei). Treatment was
Due to its anatomical location, it is probable unilateral in three and bilateral in the 4th. There
that an electrode placed for DBS or for ablation was great improvement in one patient with total
in the ALIC will also affect the NAcc. It is still resolution of the tics, but in two cases only a tran-
not known with exactitude which one of these sient improvement ensued. Babel et al. published
two targets is responsible for improvement. The a series of 16 patients with Tourette’s treated with
nucleus accumbens is involved with the process- a ventrolateral/medial thalamotomy together
ing of reward, motivation, and addiction and is with a thermoablation of the zona incerta, with
25 Neurosurgical Intervention for Treatment-Resistant Psychiatric Disorders 391
significant improvement of the tics [4, 62, 138, epines, at least for 12 weeks at an adequate
162, 163, 181]. therapeutic dose
DBS of CM/PF and PVS interrupts the retro- 4. Failure to respond to no less than ten sessions
excitatory feed between the thalamus and the of behavioral modification
striatum. Voi projects to the region of the face in
the premotor area; hence, it is used as target for The pathophysiology of TS is related to an
TS. Since TS is also close to OCD, NAcc is also excessive dopaminergic activity of the striatum,
used as a surgical target [82, 93, 116, 138]. with direct stimulation of the internal part of the
DBS of GPi is not effective. The reason is globus pallidum (GPI), inhibiting the indirect
unclear since GPi is known to be inhibited by route [22]. The hypoactivity of the GPI leads to
the same physiopathology. Some researchers a disinhibition of the thalamocortical pathway,
tried DBS on the postero-ventrolateral part of retro-feeding in a positive way the centromedian-
GPi because of TS tics being considered hyper- parafascicular complex (CM-Pf) of the thalamus,
kinesias similar of the dyskinesias of patients and the medial nucleus of the thalamus substan-
with Parkinson’s. One thing to take into account tia paraventricularis (PVS) toward the striatum
is that the limbic region of GPi is located antero- where there is also increase activity [111]. All
medially and is not reached by DBS if the elec- this contributes to maintain the circuit in hyper-
trode is in the postero-ventrolateral region of activity and the thalamocortical projections dis-
the nucleus, since it is rather large. So, DBS of inhibited. CM projects to the motor region of the
GPi for TS requires precise placement of the putamen, while PF does it to the associate regions
electrode for the modulation of the circuitry of both the putamen and the caudate. PVS proj-
[101, 116, 160]. DBS of globus pallidus exter- ects toward the VS (ventral striatum). It is prob-
nal (GPe) is based on the hypothesis that this able that in TS, there is an alteration of the D2
nucleus is hyperactive in TS. inhibitory dopaminergic receptor in the indirect
For ablation and/or DBS targets for TS, see pathway. In summary, both the motor and limbic
Table 25.6. circuits seem involved in Tourette’s with hyper-
Surgical candidates for DBS for TS: activity of the thalamus leading to prefrontal
cerebral hyperactivity.
1 . Older than 18 (or even 25) years of age Electrical activity recordings of neurons of
2. Yale Global Tic Severity Scale (YGTSS)
the medial thalamus in patients undergoing
>35/50, for at least 12 months DBS show that those that received DBS at low
3. Failure of conventional medical treatment: at frequency (2–15 Hz) show increased electrical
least three different α-adrenergic agonists, activity, while DBS at high frequency (25–45 Hz)
two dopaminergic antagonists and benzodiaz- seems to exert a calming effect and is associated
with clinical improvement. DBS does not seem
to produce permanent and persistent neuroplastic
Table 25.6 Neurosurgery for Tourette’s changes [1, 4, 6, 9, 22, 82, 88, 92, 97, 98, 105,
Ablation and/or DBS targets for Tourette’s (TS) 106, 117, 122, 138, 154, 162].
Thalamus
Intralaminar thalamic nuclei (ILN) 25.2.2.3 M ajor Depressive Disorder
Centromedian-parafascicular thalamic complex (MDD)
(CM-Pf)
Prevalence: 5–10% of the world’s population;
Ventral oral internal thalamic nuclei (Voi)
20–40%, refractory to pharmacological treat-
Medial thalamic nuclei – substantia
paraventricularis (PVS) ment. Suicide rate (in refractory depression):
Globus pallidus, internal segment-GPi 15%. Treatment-resistant/refractory depression
Anterior limb of the internal capsule/nucleus definition: when patients fail with at least four
accumbens (ALIC/NAcc) antidepressants and psychotherapy. To be consid-
Other: GPe, STN, zona incerta (ZI) ered for surgery, depression must be severe: a
392 D. E. Nijensohn and T. F. Dagi
score bigger than 20 in the Hamilton Rating Scale Table 25.7 Neurosurgery for depression (MDD)
for Depression (HAMD) or equal or bigger than Ablative surgery
30 in the Beck Depression Inventory (BDI). Cingulotomy
Electroconvulsive therapy (ECT) is no longer a Anterior capsulotomy
precondition for surgery, since some patients Subcaudate tractotomy
Limbic leucotomy
refuse ECT and are afraid of memory loss and
Cerebral stimulation
general adverse public opinion [69]. Depression
a-Cortical Dorsolateral cerebral cortex
occurs when there is a loss of emotional homeo- b-Deep-DBS Targets
stasis at stressful situations of life. The physiopa- Subgenual cortex cingulum
thology is multidimensional, involving more than Nucleus accumbens (NAcc)
one cerebral region and several neurotransmitter Ventral striatum (VS)
systems. The structures that originate this pathol- Ventral/Anterior limb of the
ogy are still elusive. The metabolic findings internal capsule (ALIC)
observed in functional studies could be just a con- Inferior thalamic peduncle (InThP)
Lateral habenula (LHb)
sequence rather than a cause and perhaps only
Medial forebrain bundle (MFB)
adaptive changes of the circuitry to a certain Limbic-Internal globus pallidus
lesion. There is involvement of the cortico- (GPi)
striatal-thalamic-cortical circuit with cognitive, Vagal N. STIM Cervical vagal nerve (VN)
motor, neuroendocrine, and affective involvement (VNS)
and manifestations. At the cortical level, there is a
hypoactive “dorsal compartment,” explaining the
“negative” motor and cognitive symptoms. This [108]. The subgenual cingulum shows increased
compartment would be comprised by the anterior, metabolism in depression. PET and fMRI show
dorsal, and lateral prefrontal cortex, the dorsal decreased blood flow in the prefrontal (areas 46
anterior cingulum, and the parietal and premotor and 9) and premotor cerebral cortex (area 6),
cortex connecting with the dorsal striatum. The anterior dorsal cingulum (area 24), and anterior
“positive” affective symptoms can be explained insula. These findings can be reversed with the
by the hyperactivity of a “ventral compartment” use of SSRIs and other antidepressants, ECT
including the subgenual cingulum, the orbitofron- and transcranial magnetic stimulation (TMS).
tal cortex, and the anterior insular region. This For these reasons, the SC was suggested as a
compartment connects with the limbic region, and possible target to treat depression with high-
both compartments inhibit each other in a recipro- frequency DBS. After treatment, imaging shows
cal fashion. In addition, there are three structures decrease of cerebral blood flow in the SC and
that intervene in the balance of the activity of an increase in the prefrontal cortex, concomitant
those two compartments: the amygdala (that with clinical improvement, but as mentioned,
directs this balance towards the stimulation of the the Broden trial by St. Jude’s failed [173]. To
ventral compartment), the pregenual cingulum avoid confusion: the subgenual cingulum is a
(that inhibits both compartments), and the hippo- different target than that used for anterior cin-
campus (HC). The hippocampus has connections gulotomy ablation [2, 3, 31, 62, 64, 72, 75, 89,
with the amygdala and projects toward the hypo- 108, 113, 114, 120, 148, 149, 158, 164]. Another
thalamus influencing sleep, appetite, and the target used for DBS in depression is the nucleus
hypothalamic pituitary adrenal axis. One hypoth- accumbens (NAcc). The most optimal location
esis regarding the neuroanatomy of depression to place the electrode is in its ventral, caudal,
involves hyperactivity of the amygdala caused by and medial regions. This is where the reward
dysfunction of the hippocampus [72, 100]. system is located, clinically manifested as anhe-
The most commonly used DBS target for donia [14, 147].
depression is the subgenual cingulum (SC) For neurosurgery for depression (MDD), see
(area 25 of Brodmann) (Mayberg and Lozano) Table 25.7.
25 Neurosurgical Intervention for Treatment-Resistant Psychiatric Disorders 393
Table 25.8 Neurosurgery for aggressive behavior (AB) ment of disruptive behavior [20, 33, 36, 37, 42,
disorders
43, 47, 73, 80, 86, 119, 161, 166].
Ablation
Anterior capsulotomy (AC) 25.2.2.5 “Reward-Based” Psychiatric
Cingulotomy (C)
Disorders: Drug
Subcaudate tractotomy (SCT)
Limbic leucotomy (LL)
Addiction/Substance
Posterior hypothalamotomy (PH) Dependence (SD)
Amygdalotomy (A) Although DBS is FDA-approved to treat move-
DBS ment disorders and, through a humanitarian
Internal globus pallidus (GPi) device exception (HDE), also OCD, it is not
Posterior hypothalamus (PH), thalamus (T) approved for addiction. Intermittent bilateral
DBS of the nucleus accumbens (NAcc) shell
reduces intravenous methamphetamine intake
Surgical indications are limited to those and seeking in Wistar rats. In humans, there have
with chronic and/or progressive AB, treatment- been case reports of DBS having a beneficial
resistant, usually associated with mental retar- effect on reducing the consumption of alcohol,
dation and other social/occupational disability. nicotine, cocaine, and heroin, although these
Patients who fall in this category also constitute were patients receiving DBS for disorders other
classical examples of vulnerable individuals. than addiction (such as depression). A recent
They are generally under special legal protec- small case series of five severely alcohol-
tion, and their management is generally subject dependent patients from Lübeck, Germany, in
to special ethical oversight. It is mandatory that whom bilateral electrodes implanted in the
family, an ethics committee, and sometimes the nucleus-accumbens, showed a reduction in crav-
court participate fully and actively. ing. In two patients, there was complete absti-
The appropriate modern surgical technique nence from alcohol. In heroin dependence, a case
for AB involves high-frequency DBS of the pos- report of two subjects who received bilateral
teromedial hypothalamus [100, 115, 119, 128]. It DBS to the NAcc reported an improvement in
has been effective in patients with both violence depressive symptoms and anxiety and a reduc-
against others and against themselves. DBS has tion, though not cessation, in their drug use [102,
similar results to radiofrequency posteromedial 109, 129].
hypothalamotomy with the advantage of revers-
ibility [36]. Surgery of this area bears a significant 25.2.2.6 Eating Disorders (ED)
risk, since this region is eloquent and vascularized, These are severe psychiatric disorders associated
and a deep cerebral hemorrhage can be fatal. DBS with self-driven food refusal and emaciation,
of the posterior hypothalamic region was origi- altered body perception, and preoccupations with
nally introduced to treat trigeminal autonomic weight. They include anorexia nervosa (AN),
cephalalgias, thought to result from hyperactiva- bulimia nervosa (BN), and eating disorder not
tion of the posterior hypothalamic region (pHr) otherwise specified (EDNOS) [63, 121, 169].
during the painful episodes. Patients experienc- AN has high rates of morbidity, comorbidity,
ing chronic cluster headaches were often found and mortality and a chronic course in a consid-
to exhibit aggressive bouts during such episodes. erable percentage of patients. Evidence-based
The pHr was used as a lesional target in patients treatment options based on underlying neuro-
with aggressive behavior and disruptive behavior biological mechanisms of the disease are scarce.
that could be induced by acute electrical stimula- The fronto-striatal circuitry, in particular the
tion of the so-called triangle of Sano [161]. The insula, the ventral striatum (VS) and the prefron-
known interconnections between the pHr, the tal, orbitofrontal, temporal, parietal, and anterior
amygdala, and the overall so-called Papez circuit cingulate cortices appear to be implicated in the
may explain the role of the pHr in the develop- etiopathogenesis of AN. Thus, the areas com-
25 Neurosurgical Intervention for Treatment-Resistant Psychiatric Disorders 395
municating between the limbic and the cortical tions remain the first choice. However, some 20%
systems, such as the NAcc and the cingulate and of patients with schizophrenia exhibit refractory
insular cortices, may be of investigational inter- schizophrenia that does not respond well to phar-
est as target areas for future neurosurgical inter- maceutical intervention. This is a persistent prob-
ventions [142]. lem that has prevailed for decades. Alternatives
The reversibility of DBS is a major advantage have long been sought. Psychosurgery has long
over ablative surgery. The overlap in symptomatol- been tried as an alternative treatment. Nevertheless,
ogy and the common neural circuitry associated and despite many refinements and innovations,
with reward-related disorders like OCD and AN, the procedures are ineffective [27].
as well as the established efficacy of accumbal-
DBS in OCD, has been intriguing. It suggests 25.2.2.8 Memory: Alzheimer’s
that DBS of the NAcc and other areas associated Memory is the ability to recall information,
with reward might offer an effective treatment encoded and stored in the brain and retrieved by
for patients with chronic, treatment- refractory the brain. There are three types of memory:
AN. The goal is not only to provide weight resto- immediate or “working” memory (based in the
ration but also significant and sustained improve- superior frontal cerebral cortex); short-term or
ment in AN core symptoms and other associated “episodic” memory, associated with the circuit of
comorbidities and complications [105]. Papez; and long-term or “semantic-procedural”
Targets for DBS in anorexia nervosa (AN) memory, which is more complex. There are also
[63, 101] include the ventral caudate nucleus, three types of amnesia: transient global amnesia
the anterior limb of the internal capsule, and the (TGA), anterograde amnesia, and retrograde
NAcc. Patient BMIs have recovered to normal amnesia. The hippocampus, fornix, entorhinal
after 3–6 months of DBS. Comorbid psychiatric cortex, and nucleus basalis of Meynert have been
conditions such as OCD and anxiety have also targeted in animal models and patients [92].
been shown to improve. The time course for Memory loss is the salient symptom and sign of
recovery is slow, but no severe side effects or dementia-related disorders, including the increas-
complications have been reported. Nevertheless, ingly prevalent and socially pressing Alzheimer’s
bilateral DBS implantation-stimulation of the disease (AD). To date, pharmacological treat-
NAcc failed to show clinical efficacy in patients ments for AD have had limited and only short-
with bulimia nervosa (BN) 66 and in those with lasting effects. For this reason, other approaches,
severe coexisting psychological conditions such including DBS, have been suggested, i.e., DBS of
as substance misuse, compulsive hair-tugging or the fornix [24, 65]. Additional translational work
twisting (trichotillomania), or self-harm. There is has focused on the ability of implantable brain
some evidence to indicate that bilateral anterior or neuromorphic chips to improve brain func-
capsulotomy may be a better target approach for tion, to be tolerated by the cerebral environment,
these conditions [105]. The same group, led by to establish functional connections with neurons,
Lozano in Toronto has tried subcallosal cingulate and to improve neurological performance. The
DBS for treatment refractory anorexia nervosa. mechanisms underlying memory enhancement
Lateral and dorsomedial ablative hypothala- may include the release of specific neurotrans-
motomy and DBS of the lateral and dorsomedial mitters and neuroplasticity. DBS might even be
hypothalamus have been used for morbid obesity disease-modifying. Nevertheless, it is still pre-
(MO) [101]. mature to conclude that DBS can be used in the
treatment of AD, and this will need to wait for
25.2.2.7 Schizophrenia the results of ongoing clinical trials (Lipsman
Schizophrenia is a chronic, severe, and disabling and Lozano) [90].
psychiatric disease characterized by perturbations Kahana (University of Pennsylvania), under
in cognition, affect, and behavior. Of the many a contract from the Defense Advanced Research
available treatments, pharmaceutical interven- Projects Agency (DARPA), studies the hippocam-
396 D. E. Nijensohn and T. F. Dagi
pus, the very seat of memory formation [84]. The trochemical feedback system for DBS developed
importance of the hippocampus emerged from the in 2014. It is optically and wirelessly linked to
study of a patient, Henry Molaison, known world- WINCS and implantable for closed-loop dynamic
wide as H.M., who had severe seizures until Scoville neurochemical control of psychotherapeutic inter-
removed the hippocampus from both hemispheres ventions [2, 68, 177].
[167]. In 1953, Milner of the MNI-McGill showed Lee’s closed “smart” loop system is the WINCS
that without them, H.M. could form no new memo- Harmoni (WINCS plus MINCS) [2, 177].
ries for facts, figures, or faces. This finding, one of
the most important in modern brain science, opened 25.2.2.12 Optogenetics:
the way for direct-recording experiments [38]. Nanotechnology
Fried (UCLA), also with DARPA, found The future of psychosurgery likely includes sono-
improved spatial memory by electrically stimu- genetics, brain augmentation, neuromorphic
lating the entorhinal cortex. The subjects played chips, cyborgs, trans-humanity technologies, the
a virtual taxi driver game in which the goal is to field of brain-machine technologies (carbon nano-
drop off passengers as quickly as possible in an tubes, nanowires, nanoscale coating), labs-on-a-
unfamiliar city [50]. chip, and other fusion technologies. If the problem
of plasticity is solved, the brain-machine interface
25.2.2.9 Post-traumatic Stress may result in a humans’ analogue to Moore’s law.
Disorder (PSTD) Indeed, were that to be the case, the application of
Deep brain stimulation (DBS) of the basolateral implants will surpass simple memory augmenta-
amygdala is tested for management of treatment- tion. Human cyborgs, linguists may say, will be
refractory combat post-traumatic stress disorder directly connected to a vast database of informa-
(PTSD) by Koek et al. (UCLA) [88]. tion. Progress on this scale will doubtlessly result
in tremendous and far reach ethical dilemmas.
25.2.2.10 Coma Endovascular nanotechnology may also advance
DBS of the thalamus has been attempted in the promise of the brain-computer interface
patients with severe traumatic brain injury (TBI), (BCI), by leveraging a human’s innate capacity to
with the goal of improving arousal and attention adjust the activity of fields of cortical neurons as
in patients relegated to a vegetative or minimally new motor tasks are learned or recreated after
conscious state [168, 187]. injury. Emerging techniques may also allow for a
new means of target selection, modulation, and
25.2.2.11 Closed Loop, WINCS, control, offering specificity of effect and other
and MINCS advantages over current ablation and DBS tech-
A number of tools to explore the mechanisms of niques. In optogenetics, genes encoding photore-
DBS have been developed. The Wireless ceptor membrane proteins (channel rhodopsins)
Instantaneous Neurotransmitter Concentration are delivered to specifically targeting neurons.
System (WINCS) (Lee, Mayo Clinic (2010)) Because expression is controlled by cell-specific
treats refractory psychiatric illness disrupted- promoters, only particular cells will bear the pho-
disordered neurocircuitry using neuromodula- toreceptor. These cells can be activated by specific
tion. WINCS measures levels of serotonin – a wavelengths of light, allowing for differential
neurotransmitter with a key role in depression – control of neuronal subpopulations in a given tar-
in real time. It uses fast-scan cyclic voltammetry, get by expressing different channel rhodopsins
an electrochemical method. WINCS is miniatur- under the control of various promoters. Control
ized, wireless, and computer controlled, tried in requires an implanted light source, which still car-
both animal studies and human patients undergo- ries, however, many of the disadvantages of
ing DBS [2, 142, 177]. implanted DBS, including infection and device
Mayo Investigational Neuromodulation failure. Chemogenetics, like optogenetics, utilizes
Control System (MINCS) is a closed-loop elec- the delivery of the gene for repair of a defective
25 Neurosurgical Intervention for Treatment-Resistant Psychiatric Disorders 397
receptor, sensitive to novel ligands. As such, neu- “Psychosurgery and Mind Control”: ethical
ronal subpopulations expressing the relevant issues in psychosurgery are many, and they are
channel/receptors could be activated by the inseparable from the political order. Psychosurgery
administration of a drug. This scenario avoids the can be used for good or evil: as a treatment or a
need for an implanted device. The pursuit and tool for political control. Surgery on the brain for
realization of these technologies and approaches psychiatric indications is aggressive and hazard-
will inevitably invoke pressing and profound ethi- ous. To counter the risk of psychosurgical abuses,
cal issues [35, 44, 118, 134, 142]. societies must be kept informed of the advances,
opportunities, and risks in this field with utmost
Neuroethics transparency [27, 32, 33, 134–136, 189]. It is nec-
Ethics is the study of moral behavior. It pertains essary to guarantee appropriate professional safe-
to right and wrong, and how to live well. guard based on guidelines that emerged after the
Neuroethics is the field focused specifically on Nuremberg Trial and are embodied in the Helsinki
research in and treatment of neurological and Accord, the Belmont Report (Ethical Principles
psychiatric conditions. There are a number of and Guidelines for the Protection of Human
models of ethical behavior and a number of Subjects of Research, issued by the National
approaches to ethical decision-making. One of Commission for the Protection of Human Subjects
the best-known approaches is based on the prin- of Biomedical and Behavioral Research, HEW,
ciples of beneficence, non-maleficence, respect 1974), and similar documents [132].
for persons and autonomy. Only democracies are
capable of guaranteeing independence of ethical
oversight entities [28, 54, 91, 104, 105, 140, 150,
163, 184]. References
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Index
A noradrenaline deficiency, 83
Aberrant Behavior Checklist–Irritability (ABC-I) olfactory bulbectomy, 81
scores, 34 oxotremorine, 81
Ablative procedures, 384 pharmacological interactions, 81
Absolute risk reduction (ARR), 6 physiological mechanisms, 82
Acceptance and commitment therapy (ACT), 171 Porsolt forced swimming test, 82
Acceptance-facilitating interventions (AFI), 319 preclinical research, 79
Addiction, DLPFC, 330 psychomotor stimulants, 79
Adult-onset tics, 237 reserpine, 81
Aggressive behavior (AB) disorders, 393, 394 tail suspension test, 81
Aggressive personality traits, 393 telomeres, 82
Aggressive violent behavioral disorders, 388 yohimbine, 81
Alcoholism, 39, 40 Anorexia nervosa (AN), 253–255, 306
Alliance-based approach of psychodynamic repetitive transcranial magnetic stimulation, 258
psychiatry, 296 treatment-resistant model, 254, 255
Allostatic load model, 155, 156 Anterior capsulotomy, 386, 388
Alzheimer’s disease (AD), 395, 396 Anterior cingulotomy, 386
Amsterdam protocol, 371 Antidepressant-induced synaptic plasticity
Amygdala reactivity, 156 enhancement, 92
Amygdalotomy, 380 Antidepressants, 6
Animal models of binge eating, 255 Antidepressant trials, 15
Animal models of depression Antipsychotics, 5, 6
abnormal behavior simulations, 82 Anxiety disorders, 304
amphetamine, 81 evidence-based treatments, 207
apomorphine, 81 machine learning and prediction of treatment
behavioral alterations and serotonergic response/resistance, 73
dysfunction, 82 prevalence, 207
behavioral models, 81 selective serotonin reuptake inhibitors, 207
behavioral strategy, 80 Apnea-hypopnea index (AHI) in children, 264
biochemical tests, 80 Asp40-allele carriers, 39
biological hypothesis, 81, 83 Attention-deficit/hyperactivity disorder (ADHD), 9, 264
chronic mild stress, 81 academic and social functioning and parenting
directed reproduction of mice, 82 styles, 218
dopaminergic receptors, 79 alpha-2 agonists, 229
drug co-administration, 83 behavioral therapy, 223
forced swimming test, 81 behavioral treatments, 219
genetic model, 83 catechol-O-methyltransferase, 36
glutamatergic activity, 84 cell adhesion, 216
glutamatergic modulators, 84 in childhood, 215
glutamatergic receptor transcripts, 84 combined behavioral and medication treatment, 219
ketamine, 84 core symptom presentation, 218
muricide model, 80, 81 dopamine beta-hydroxylase genes, 36
NMDA receptor antagonist, 84 dietary treatments, 225
E G
Eating disorders (ED), 253, 305, 394, 395 Gene-childhood trauma interaction
behavior, 306 bipolar disorder, 89
CRT, 257, 258 depression, 90
oxytocin, 258 PTSD, 90, 91
recovery approach, 256 schizophrenia, 89
Index 409
O pharmacotherapies, 180
Observer effect, 8 prognosis and treatment adherence, 179
Obsessive–compulsive and related disorders psychological and behavioural symptoms, 179
(OCRDs), 38 psychosocial therapies, 179
Obsessive−compulsive disorder (OCD), 9, 335 retention and treatment adherence, 183
ablative procedures, 170 Opioid-induced QT prolongation or arrhythmias (torsade
in adolescence, 165 des pointes), 181
anterior limbs of internal capsules, 170 Optimism, 275
baseline EEG measurement markers, 71 Optogenetics, 396
biological predictors, 171 Outcome measures, 14
in childhood, 165
clinical trials, 166
cognitive-behavioral therapy, 165 P
compulsions, 165 Paediatric autoimmune neuropsychiatric disorders
DBS target, 389 associated with streptococcal infections
developmental trajectories, 165 (PANDAS), 246
direct and indirect pathways, 389 Pallidotomy, 383
electroencephalography, 69 Panic disorders, 9
endophenotype, 239 and anxiety disorders, 335
ERP brain MRI measurements, 67
distress-provoking stimuli, 169 clinical guidelines, 189
patient adherence, 168, 169 cognitive domain, 189
predictors of, 168 prevalence, 189
psychotherapy, 169 somatic/physical domain, 189
residential treatment, 169 TRPD (see Treatment-resistant panic disorder
treatment response, 169 (TRPD))
first-line pharmacotherapy, 165 World Health Organization survey, 189
gamma knife capsulotomy, 170 Panic Disorder Severity Scale (PDSS) score, 190
glutamatergic agents, 172 Panic disorder with agoraphobia (PDA), 37
neurosurgical interventions, 170, 390 Patient adherence, 298
neurosurgical lesions, 170 Patient-centered medicine in primary care, 296
noninvasive neuromodulation, 172 Patient management, 275
obsessions, 165 Periodic limb movement disorder (PLMD), 264
pharmacotherapy Periodic limb movements during sleep (PLMS), 264, 265
antipsychotic medication, 168 Personalized medicine, 18, 159, 160
aripiprazole, 167 Person-centered narratives of therapeutic benefit,
clomipramine, 167 286, 287
haloperidol, 167, 168 Person-centered psychopharmacology, 276
medication adherence, 167 Person-centered psychopharmacotherapy, 289, 290
mirtazapine, 168 P-glycoprotein, 17
monotherapy with clomipramine, 167 Pharmacogenetics, 33
olanzapine, 167 cocaine dependence, 41
quetiapine, 167 genetic biomarkers identification, 33
risperidone, 167, 168 on nicotine dependence, 40, 41
serotonergic medication, 167 opioid dependence, 41
SRI response, 166 therapeutic response, 33
switching SSRIs, 167 treatment algorithms, 33
venlafaxine, 168 Pharmacogenomics, 34
prevalence rates, 165 Pharmacokinetic factors, 12
randomized controlled trials, 165 Pharmacotherapy to medical interventions, 9
repetitive TMS, 170 Pharmacotherapy treatment outcomes, 4
serotonin reuptake inhibitors, 165 Physician-patient relationship, 285
stereotactic target, 389 Pippard Postoperative Rating Scale (PPRS), 381
transcranial magnetic stimulation, 170 Placebo and nocebo phenomena, 7, 287, 288
OCD, see Obsessive−compulsive disorder (OCD) Plasma drug concentrations, 12
Opioid dependence Plasticity-augmented psychotherapy, 88
buprenorphine, 179 Polymorphic alleles for cytochrome P (CYP) 450, 13
long-acting depot formulation, 183 Polymorphisms, 13
oral methadone, 179 Polypharmacy, 280
oxycodone, 179 of mental health medicines, 284
412 Index
W Y
Wireless Instantaneous Neurotransmitter Concentration Yale-Brown Obsessive Compulsive Scale (YBOCS),
System (WINCS), 396 165, 381
Working memory deficits, 224