Treating Depression Effectively Applying Clinical Guidelines, 2nd Edition

Treating
Depression
Effectively
Applying Clinical Guidelines
second Edition
Sidney H Kennedy
Raymond W Lam
David J Nutt
Michael E Thase
Treating Depression Effectively
Treating Depression
Effectively
Applying Clinical Guidelines
Second Edition
Sidney H Kennedy MD FRCPC

Professor of Psychiatry
University of Toronto
Psychiatrist-in-Chief
University Health Network
Toronto, Canada
Raymond W Lam MD FRCPC

Professor and Head
Division of Clinical Neuroscience
University of British Columbia
Vancouver, Canada
David J Nutt DM FRCP FRCPsych FMedSci

Professor of Psychopharmacology
University of Bristol
Bristol, UK
Michael E Thase MD
Professor
Department of Psychiatry
University of Pennsylvania
School of Medicine
Philadelphia, PA, USA
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Contents
About the authors vi

Preface vii
1 Prevalence, burden and diagnosis 1
2 Principles of management 9
3 Psychotherapies, alone and in combination 29
4 Evolution of antidepressant agents 49
5 Evidence based antidepressant selection across depressive

disorders 61
6 Practical issues in using antidepressants 75
7 Sequential pharmacotherapies and treatment-resistant 93

depression
8 Neuromodulation and other physical treatments 105
9 Complementary, light, sleep deprivation and exercise therapies 119
10 Depression in women 129
11 Depression in children and adolescents 145
12 Depression in late life 155
13 Psychiatric and physical comorbidities in depression 167
Index 177
About the authors
Sidney H Kennedy MD FRCPC David J Nutt DM FRCP FRCPsych

Professor of Psychiatry FMedSci
University of Toronto Professor of Psychopharmacology
Psychiatrist-in-Chief Dean of Clinical Medicine and
University Health Network Dentistry
200 Elizabeth Street Head of the Department of Clinical
Eaton North, 8th Floor, Room 222 Medicine
Toronto, ON, M5G 2C4 University of Bristol
Canada Psychopharmacology Unit
School of Medical Sciences
Raymond W Lam MD FRCPC University Walk
Professor and Head Bristol BS8 1TD
Division of Clinical Neuroscience United Kingdom
University of British Columbia
2255 Wesbrook Mall Michael E Thase MD
Vancouver, BC, V6T 2A1 Professor
Canada Department of Psychiatry
University of Pennsylvania
School of Medicine
3535 Market St, Room 689
Philadelphia Veterans Association
Medical Center
University of Pittsburgh
School of Medicine
Philadelphia, PA 19102
USA
Preface
This is the second edition of Treating Depression Effectively. The first edition
was inspired by the Canadian Network for Mood and Anxiety Treatments
(CANMAT, www.canmat.org) ‘Clinical guidelines for the treatment of
depressive disorders’1 published by the Canadian Psychiatric Association in
2001. Members of this CANMAT Depression Work Group were Murray Enns,
Stanley Kutcher, Sagar Parikh, Arun Ravindran, Robin Reesal, Zindel Segal,
Lillian Thorpe, Pierre Vincent and Diane Whitney, with Sidney Kennedy and
Raymond Lam as co-chairs.
Since publication of the first edition in 2004, there have been significant
advances in the triad of pharmcotherapies, psychotherapies and somatic
therapies. In this edition we have attempted to present these advances using
the same reader-friendly format.
We are very grateful to all our colleagues for their contributions and
acknowledge the importance of their work as the foundation for this
volume, and to our families for their patience and support. We also appreci-
ate the role of Beata Eisfeld who provided editorial assistance for the first
edition and Sakina Rizvi for this edition.
Sidney H Kennedy
Raymond W Lam
David J Nutt
Michael E Thase
1. CANMAT Depression Work Group. Clinical guidelines for the treatment of depressive disorders.
Can J Psychiatry 2001; 46 (Suppl 1): 1S–92S.
Chapter 1
Prevalence, burden and

diagnosis
Prevalence, course and burden of illness

Major depressive disorder (MDD) is among the most prevalent of medical ill-
nesses. Recent epidemiological studies have highlighted the similarity in preva-
lence rates of depression in different countries (Figure 1.1). For many patients,
depression is a chronic and recurrent illness. In follow-up studies, up to
30% of patients with MDD are still depressed after one year, 18% are ill after
two years and 12% remain ill after five years. Many patients treated for MDD
still have residual and subsyndromal symptoms that result in poor outcomes,
including higher risk for relapse and suicide, poor psychosocial function and
higher mortality from other medical diseases. Among patients who recover
from a depressive episode, over 50% will have a recurrence.
Given the high prevalence of depression, it is not surprising that the
socioeconomic costs are also high. The World Health Organization (WHO), in
an updated 2000 study comparing all medical illnesses, reported that depres-
sion remains the fourth leading cause of disability adjusted life years (DALYs)
and accounts for 4.4% of total worldwide DALYs. This ranges from 8% of the
total burden in the Americas to 1.2% in Africa (Table 1.1). The economic
costs associated with premature mortality (e.g. from suicide), and the indirect
costs such as reduced productivity and days off work are staggering. People
with depression are four times more likely to have days off work than people
without depression (Figure 1.2). In the USA, the annual direct costs (hospitals,
medications, doctor fees) of treating depression are estimated at US$12.4
billion. In the UK, excess mortality is estimated to cost over £4.7 million per
year, while in Canada, the indirect cost of depression (lost productivity) is
estimated at C$2.53 billion. Many nations now recognize that the diagnosis
and treatment of depression are priorities for the medical system.
2 Treating Depression Effectively
Belgium 5
France 9.1
Germany 3.8
Netherlands 6.9
Spain 6.2
UK 9.9
Canada 6
USA 10.3
0 2 4 6 8 10 12
% of general population with MDD
Figure 1.1 Six-month prevalence of MDD across different countries.
Table 1.1 Worldwide Disability Adjusted Life Years attributed to

depression (estimates for 2000)
WHO regions % of total DALYs Ranking in region
Americas 8 1
Europe 6.1 3
Western Pacific 6.0 2
South East Asia 4.7 4
Eastern Mediterranean 3.5 5
Africa 1.2 13
WHO – World Health Organization epidemiological subregions.

DALYs – Disability Adjusted Life Years. Adapted from Ustun et al. 2004.
Diagnosis of depression
The diagnostic criteria for an episode of MDD are similar in both the
Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revi-
sion (DSM-IV-TR) (Table 1.2) and the International Classification of Diseases,
Prevalence, burden and diagnosis 3
14
12
10
Lost work days
0
France Germany Spain UK USA
Figure 1.2 Lost work days in the last 6 months in depressed and non-
depressed workers: , depressed; , non-depressed.
10th revision (ICD-10). Table 1.3 shows the differentiating features between
MDD and normal bereavement. Despite the wide acceptance of these crite-
ria, MDD is not well recognized or diagnosed in primary care settings
because the presenting complaints are often physical in nature, such as
insomnia, fatigue and pain.
Moreover, one of the most prominent and disturbing features for patients
suffering from major depressive disorder is disturbed sleep. The association
between sleep disturbance and clinical depression has long been recognized.
Almost all patients with MDD report some form of sleep difficulty including
insomnia, oversleeping and poor quality sleep. The most reliable and pre-
dictable sleep abnormalities of depression include a sleep continuity distur-
bance, diminished slow wave sleep (SWS) (delta), a shortened rapid eye
movement (REM) latency and an alteration in the temporal distribution of
REM sleep.
Patients seen in primary care who present with unexplained physical
symptoms should be screened for the presence of MDD (Table 1.4).
While screening questionnaires can be used, a quick two-question screen-
ing for depression is helpful in these presentations:
Table 1.2 DSM-IV-TR criteria for the diagnosis of major

depressive episode
A. Five (or more) of the following symptoms have been present during the same two-
week period and represent a change from previous functioning; at least one of
the symptoms is either (1) depressed mood or (2) loss of interest or pleasure:
1. Depressed mood most of the day or nearly every day, as indicated by either
subjective report (e.g. feels sad or empty) or observation made by others (e.g.
appears tearful). Note: in children and adolescents, can be irritable mood.
2. Markedly diminished interest or pleasure in all, or almost all, activities most of
the day or nearly every day (as indicated by either subjective account or
observation made by others).
3. Significant weight loss when not dieting or weight gain (e.g. a change of more
than 5% of body weight in a month), or decrease or increase in appetite nearly
every day. Note: in children, consider failure to make expected weight gains.
4. Insomnia or hypersomnia nearly every day.
5. Psychomotor agitation or retardation nearly every day (observable by others;
not merely subjective feelings of restlessness or being slowed down).
6. Fatigue or loss of energy nearly every day.
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be
delusional) nearly every day (not merely self-reproach or guilt about being sick).
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day
(either by subjective account or as observed by others).
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation
without a specific plan or a suicide attempt or a specific plan for committing
suicide.
B. The symptoms do not meet criteria for a mixed episode.

C. The symptoms cause clinically significant distress or impairment in social,
occupational or other important areas of functioning.
1. In the last month, have you been bothered by little interest or pleasure in
doing things?
2. In the last month, have you been feeling down, depressed or hopeless?
An answer of ‘Yes’ to either question should trigger a more detailed assessment.
Diagnostic instruments for clinical use

Semistructured clinical interviews can also help to confirm or validate a clin-
ical diagnosis. For primary care physicians, the PRIME-MD interview
Table 1.3 Features that help distinguish between

bereavement and a major depressive episode
Feature Bereavement Major depressive episode
Time course Less than two months More than two months
Feelings of worthlessness Absent Present
Suicidal ideas Absent Common
Delusions of guilt, etc. Absent Possible
Psychomotor changes Mild agitation Marked slowing
Functional impairment Mild Marked to severe
Table 1.4 Patients with the following factors are at high risk for
MDD and should be screened for depressive illness (level 2)
• Sleep disturbances
• Chronic pain
• Chronic physical illness (diabetes, heart disease, etc.)
• Unexplained somatic symptoms
• Frequent visits
• Postpartum state
• Psychosocial stressor
(Primary Care Evaluation of Mental Disorders) takes approximately nine

minutes to administer and has good predictive power for depression. For spe-
cialists, the Structured Clinical Interview for DSM-IV-TR (SCID) is the most
widely used instrument, but it requires training, is difficult to use and takes
an hour or more to administer. The Mini International Neuropsychiatric
Interview (MINI) is a more practical and convenient instrument and is avail-
able in a number of languages (free download available at www.medical-
outcomes.com). The MINI takes 15–20 minutes to administer and aids in the
diagnosis of 15 major psychiatric conditions in DSM-IV-TR and ICD-10.
A major diagnostic issue is differentiating between bipolar and unipolar
depression. Hypomanic episodes, in particular, are difficult to identify in
routine clinical practice. A scale such as the Mood Disorders Questionnaire
may be a helpful tool to screen for bipolarity.
Table 1.5 Specifiers of MDD according to DSM-IV-TR
Specifier Key features
With melancholic features Non-reactive mood, anhedonia, weight loss, guilt,

psychomotor retardation or agitation, morning worsening
of mood, early morning awakening
With atypical features Reactive mood, oversleeping, overeating, leaden

paralysis, interpersonal rejection sensitivity
With psychotic features Hallucinations or delusions
With catatonic features Catalepsy (waxy flexibility), catatonic excitement,

negativism or mutism, mannerisms or stereotypies,
echolalia or echopraxia. This subtype is not commonly
seen in clinical practice
With chronic pattern Two years or more with full criteria for major depressive
episode
With seasonal pattern Regular onset and remission of depressive episodes

during a particular season (usually fall/winter onset)
With postpartum onset Onset of depressive episode within four weeks postpartum
Subtypes of MDD
DSM-IV-TR includes a number of subtype specifiers for MDD based on cross-
sectional clinical features or patterns of depressive episodes (Table 1.5). These
various subtypes of MDD may have important implications for the selection
of treatment and, ultimately, prognosis (see Chapter 5). ‘Anxious depression’
is not listed as a subtype within DSM-IV-TR, but the term is often used to
describe depressed patients who experience a preponderance of worry,
tension and somatic symptoms related to anxiety. Symptoms of anxiety
occur in 60–90% of patients with MDD, and up to 50% of MDD patients
may have a comorbid anxiety disorder (see Chapter 13).
Conclusions
Major depressive disorder is among the most common and debilitating of
medical illnesses. The burden of depression is being increasingly recognized
as a major public health concern in part because of the severe economic con-
sequences of absenteeism and reduced productivity due to depression in the
work force. The diagnosis and differential diagnosis of depression require
careful attention to emotional, physical and cognitive signs and symptoms,
as well as the course and context of episodes. Diagnostic instruments can be
useful for busy clinicians to help identify and characterize symptoms of
depression. Distinguishing the various subtypes of depression (or episode
specifiers in DSM-IV) is also important because of different options for treat-
ment selection.
Bibliography
Buysse DJ, Germain A, Nofzinger EA, Kupfer DJ. Sleep and mood disorders. In: Stein
DJ, Kupfer DJ, Schatzberg AF, eds. The American Psychiatric Publishing Textbook of
Mood Disorders. Arlington, VI: American Psychiatric Publishing, 2006: 717–37.
Hirschfeld RM, Williams JB, Spitzer RL et al. Development and validation of a screen-
ing instrument for bipolar spectrum disorder: The Mood Disorder Questionnaire. Am J
Psychiatry 2000; 157: 1873–5.
Lepine JP, Gastpar M, Mendlewicz J, Tylee A. Depression in the community: the first
pan-European study DEPRES (Depression Research in European Society). Int Clin
Psychopharmacol 1997; 12: 19–29.
Ohayon MM, Schatzberg AF. Using chronic pain to predict depressive morbidity in the
general population. Arch Gen Psychiatry 2003; 60: 39–47.
Parikh SV, Lam RW, CANMAT Depression Work Group. Clinical guidelines for the
treatment of depressive disorders: I. Definitions, prevalence and health burden. Can J
Psychiatry 2001; 46 (Suppl 1): 13S–20S.
Spitzer RL, Williams JB, Kroenke K et al. Utility of a new procedure for diagnosing
mental disorders in primary care. The PRIME-MD 1000 study. JAMA 1994; 272:
1749–56.
Ustun TB, Ayuso-Mateos JL, Chatterji S et al. Global burden of depressive disorders in
the year 2000. Br J Psychiatry 2004; 184: 386–92.
Weissman MM, Bland RC, Canino GJ et al. Cross-national epidemiology of major

depression and bipolar disorder. JAMA 1996; 276: 293–9.
Wilson S, Argyropoulos S. Antidepressants and sleep; a qualitative review of the litera-

ture. Drugs 2005; 65: 927–47.
Chapter 2
Principles of management
The management of major depressive disorder (MDD) involves establishing a

correct diagnosis and applying evidence based and goal directed principles of
treatment. These treatment principles include recognizing and treating any
coexisting medical conditions, building a therapeutic alliance with patients
and choosing an appropriate treatment, as well as monitoring and maintain-
ing response (Table 2.1).
Set goals of treatment

The overall goals of treatment are to achieve remission of symptoms, restore
quality of life and prevent relapse or recurrence. The treatment of depression
consists of two phases – acute and maintenance – each with specific goals,
Table 2.1 Nine principles of management for a major depressive

episode
• Set clear goals for treatment

• Assess and treat comorbid medical conditions
• Assess suicide risk
• Establish a therapeutic alliance
• Consider psychotherapy
• Choose an appropriate antidepressant
• Enhance adherence (compliance) to treatment regimen
• Monitor treatment outcome
• Maintain response to treatment
Table 2.2 The phases of treatment of depression
Phase Duration Objectives Activities
Acute 6–12 weeks Remission of symptoms Establish therapeutic alliance

or longer Return to previous full Provide education
function Choose treatment
Monitor response
Maintenance Six months Prevention of relapse Provide education

following and recurrence Manage side-effects
remission, Rehabilitation
or longer Monitor for recurrence
objectives and activities (Table 2.2). There is increasing recognition of the

importance of achieving full remission of symptoms and a return to baseline
psychosocial function.
Treat comorbid medical conditions

Many medical conditions and medications are associated with symptoms of
depression. It is important to recognize, investigate and treat comorbid con-
ditions. Tables 2.3 and 2.4 show some general medical conditions and med-
ications that are frequently associated with depression. However, depression
can also coexist with these conditions, and requires independent treatment
(see Chapter 13).
Assess suicide risk

Suicide risk should be regularly assessed throughout the course of treatment;
when appropriate, family or friends should also be consulted. Paradoxically,
suicide risk may increase when patients begin to show response, partly
because improvement in energy level may precede improvement in mood.
Table 2.5 shows risk factors that are statistically correlated with suicide.
One of the strongest clinical predictors is hopelessness, and hence the assess-
ment of suicide risk should include inquiries into the patient’s plans or
hopes. Table 2.6 shows the questions from the Mini International
Neuropsychiatric Interview (MINI) that help assess suicide risk.
The management of suicidal thoughts can include distraction techniques
(e.g. taking a walk or calling a friend), keeping a list of reasons for living and
access to telephone crisis lines. Involving the patient and significant others
Principles of management 11
Table 2.3 General medical conditions frequently associated with

depression
Neurological disorders Endocrine disorders

Alzheimer’s disease Adrenal
Cerebrovascular disease Cushing’s
Cerebral neoplasms Addison’s
Cerebral trauma hyperaldosteronism
Central nervous system (CNS) infections Menses-related
Dementia Parathyroid disorders
Epilepsy Thyroid disorders
Extrapyramidal diseases Vitamin deficiencies
Huntington’s disease B12/folate
Hydrocephalus vitamin C
Migraine niacin
Multiple sclerosis thiamine
Narcolepsy Other disorders
Parkinson’s disease Acquired immune deficiency
Progressive supranuclear palsy syndrome (AIDS)
Sleep apnea Cancer
Wilson’s disease Cardiopulmonary disease
Systemic disorders Klinefelter’s syndrome
Viral and bacterial infections Myocardial infarction
Porphyrias
Inflammatory disorders
Postoperative states
Rheumatoid arthritis
Renal disease and uremia
Sjögren’s syndrome
Systemic neoplasms
Systemic lupus erythematosus
Temporal arteritis
in the treatment plan is useful, as is documenting treatment plans. Patients

who are at high suicide risk require urgent referral or hospitalization, which
may include involuntary admission under local mental health laws.
Establish a therapeutic alliance

As with any treatment plan, informed consent should be obtained from the
patient and/or the family. This provides an opportunity for education, which
includes a brief discussion of the causes of depression, its symptoms, options
for treatments, risks and benefits of such treatments, possible side-effects and
expectation of remission (Table 2.7). Primary care physicians are in a good
position to establish a strong alliance as they already have a therapeutic
Table 2.4 Medications frequently associated with depression
Antibacterials and antifungal agents Analgesics and anti-inflammatory agents

Ampicillin Fenoprofen
Clotrimazole Ibuprofen
Cycloserine Indomethacin
Dapsone Opiates
Griseofulvin Phenacetin
Metronidazole Phenylbutazone
Nitrofurantoin Pentazocine
Sulfonamides Stimulants and appetite suppressants
Streptomycin Amphetamine
Tetracycline Diethylpropion
Thiocarbanilide
Phenmetrazine
Cancer drugs Sedatives and hypnotics
Beiomycin Barbiturates
C-asparaginase Benzodiazepines
Mithramycin Chloral hydrate
Trimethoprim Ethanol
Vincristine
Psychotropic medications
Zidovudine
Antipsychotics
Cardiac and antihypertensive drugs
Neurological agents
Beta-blockers
Amatadine
Clonidine
Baclofen
Digitalis
Bromocriptine
Guanethidine
Carbamazepine
Hydralazine
Levodopa
Lidocaine
Methosuximide
Methyldopa
Phenytoin
Prazosin
Tetrabenazine
Reserpine
Procainamide
relationship with the patient from continuity of care. Through better under-
standing of the illness and its expected course, patients may have more trust
in the proposed treatment plans. Patients may also feel more in control as
they are actively involved in the decision-making process.
Consider psychotherapy
Psychotherapy is an effective treatment for depression in motivated
patients. The evidence for efficacy is greatest for structured, time-limited
Table 2.4 continued
Steroids and hormones Miscellaneous drugs

Corticosteroids Acetazolamide
Danazol Anticholinesterases
Oral contraceptives Choline
Norethisterone Cimetidine
Triamcinalone Cyproheptadine
Disulfiram
Isotretinoin
Meclizine
Metaclopramide
Methysergide
Pizotifen
Salbutamol
Table 2.5 Risk factors associated with suicide
Demographic Clinical
Male History and severity of prior attempts

Adolescent or geriatric age Family history of depression and suicide
Unemployed Hopelessness
Socially isolated Impulsive and agitated state
Single/separated/divorced Psychotic features
Poor support network Alcohol and substance abuse
Borderline/antisocial personality traits
Chronic medical or psychiatric illnesses
Recently discharged from hospital
psychotherapies, particularly cognitive behavior therapy (CBT), inter-

personal psychotherapy (IPT) and problem-solving therapy (PST, developed
specifically for primary care) (Table 2.8). For MDD of mild to moderate
severity, these psychotherapies are as efficacious as antidepressants and can
be used as monotherapy (see Chapter 3). The Cognitive Behavioral Analysis
System of Psychotherapy (CBASP) has been developed for use in chronic
depression, with validation in a large clinical trial. Unfortunately, access to
therapists who are trained in these evidence based psychological treatments
is limited in most countries.
Table 2.6 Suicidality assessment from the MINI*
In the past month did you: YES points
C1. Think that you would be better off dead NO YES 1

or wish you were dead?
C2. Want to harm yourself? NO YES 2
C3. Think about suicide? NO YES 6
C4. Have a suicide plan? NO YES 10
C5. Attempt suicide? NO YES 10
In your lifetime:
C6. Did you ever make a suicide attempt? NO YES 4
Add the total number of points for the answers (C1–C6) checked
YES and specify the level of suicide risk as follows TOTAL ________
SUICIDE RISK – CURRENT

Low 0–5 points
Moderate 6–9 points
High 10 or more points
*Adapted with permission from Sheehan et al. 1998.
Table 2.7 Suggested topics to be discussed before initiating treatment
• Depression is a medical disorder with serious consequences

• The cause of depression is multifactorial, including biological/genetic factors
(‘chemical imbalance in the brain’; changes in neurotransmitters that are corrected
by medications), psychological experiences and social and economic stressors
• Effective treatment is available with medications and/or psychotherapies
• Adherence to treatment is important because the treatments take time
Whether or not formal psychotherapy is offered, physicians should also

provide supportive interventions that may improve patient outcomes
(Tables 2.9 and 2.10).
Choose an appropriate antidepressant

Antidepressants are often the treatment of choice for depression in primary
care settings. A number are now available with different neurochemical actions
and side-effect profiles. Most systematic reviews have not shown any clinically
significant differences in standard response rates among antidepressants, but
Table 2.8 Evidence based psychotherapies for treatment of

depression (Level 1)
Psychotherapy General principles Length of therapy
Cognitive Identify automatic, maladaptive thoughts and 12–16 sessions

behavior distorted beliefs that lead to depressive moods
therapy (CBT) Learn strategies to modify these beliefs and
practice adaptive thinking patterns
Use a systematic approach to reinforce positive
coping behaviors
Interpersonal Identify significant interpersonal/relationship issues 12–16 sessions

psychotherapy that led to, or arose from, depression (unresolved
(IPT) grief; role disputes; role transitions; social isolation)
Focus on one or two of these issues, using
problem-solving, dispute resolution and social
skills training
Problem-solving Use a structured approach to identify and actively 6–8 sessions

therapy (PST) solve problems that contribute to depression
Cognitive Use a combination of techniques from cognitive 16–20 sessions

behavioral and interpersonal therapies to motivate patients
analysis system with chronic depression to change their
of psychotherapy behaviors
(CBASP)
Table 2.9 Simple and supportive interventions to manage depression

(Level 3)
• Arrange regular follow-up visits

• Use the power of the prescription pad to ‘prescribe’ one brief walk per day and
one pleasurable activity per day
• Keep a daily mood chart
• Recommend ‘bibliotherapy’ for depression, e.g. self-help workbooks: The Feeling
Good Handbook by David D Burns (Plume Books, 1999); Mind Over Mood by
Dennis Greenberger and Christine A Padesky (Guilford Press, 1995); the Self-Care
Depression Patient Guide (available for free download at www.mheccu.ubc.ca)
Table 2.10 Helpful web resources for depression (Level 3)
• The Blue Pages (Australia) www.bluepages.anu.edu.au

• Canadian Network for Mood and Anxiety Treatment www.canmat.org
• MacArthur Foundation Initiative (Primary Care; USA) www.primary-care.org
• Mental Health on the Internet (Canada) www.mentalhealth.com
• National Institute of Mental Health (USA) www.nimh.nih.gov
• PsychDirect (Canada) www.psychdirect.com
• STAND (Stress, Anxiety and Depression; UK) www.depression.org.uk
Table 2.11 Five simple messages to promote medication

adherence (Level 2)
• Antidepressants are not addictive

• Take your medication every day as prescribed
• It may take two to four weeks to start noticing improvement
• Do not stop medication without talking to your doctor, even if you are feeling better
• Mild side-effects are common but are usually temporary. If you have more side-
effects than you think reasonable, call your doctor
there are some clinical factors that are important to consider when choosing a
medication (see Chapters 4, 5 and 6).
Enhance treatment adherence

Adherence or compliance is crucial in the successful treatment of depression.
Some simple messages to patients from their physicians have been shown to
greatly enhance adherence to medication (Table 2.11).
Monitor treatment outcome

Patients should initially be followed on a weekly or bi-weekly basis until
they achieve remission. Follow-up frequency can then be reduced to
monthly or less often, depending on individual circumstances.
Most patients begin to respond to treatment within two to four weeks,
show a good clinical response within six to eight weeks, and achieve full
remission of symptoms by 8–12 weeks. Recovery of full baseline function to
pre-depressed levels may take longer. If there is no response at all after four
weeks of treatment, a change in the treatment plan is indicated (e.g. increas-

ing the dose).
Response can be tracked using validated symptom rating scales.
Traditionally, response is defined as a 50% or greater reduction in score from
baseline, while remission is defined as a score within the normal (not
depressed) range. Decisions about strategies for non-response or inadequate
response (see Chapter 7) are often based on degree of response as measured by
severity scores. Termed ‘measurement-based care’, this approach has been
found to increase response to treatment.
There are many validated rating scales to assess severity of depression. The
most widely used interviewer-rated scales include the Hamilton Depression
Rating Scale (HDRS/HAM-D, various versions; most commonly used in its
version with 17 items, HAM-D17) and the Montgomery Asberg Depression
Rating Scale (MADRS). One version of the HDRS includes items for so-called
atypical symptoms of depression, such as overeating and oversleeping; other
abbreviated versions (e.g. the HAM-D7, see Table 2.12) were developed for
ease of administration by family physicians, psychiatrists and other health-
care specialists.
Patient-rated scales include the Beck Depression Inventory II (which
includes items for atypical symptoms), the Hospital Anxiety and Depression
Scale (HADS) and the Patient Health Questionnaire (PHQ), an easy-to-use,
self-rated version of the PRIME-MD that is validated in primary care set-
tings. Some of these measures are included in the Appendix to this chapter.
Maintenance response to treatment

For patients with a single episode of depression, the risk of relapse is two
times higher in the first year following remission of symptoms than in the
next year. Hence, once patients are in full remission from MDD, maintenance
issues (e.g. how long a patient should continue to take their medication)
become important. Remission is an important target for both acute and main-
tenance phases, as residual symptoms increase the relapse/recurrence rate, the
degree of chronicity and suicide rate, and are associated with poor quality of
life and greater health services utilization. Psychoeducation in the main-
tenance phase focuses on recognizing early signs of relapse or recurrence, and
on adherence to medications. Practical aspects of maintenance therapy are
summarized in Table 2.13.
Table 2.12 Seven-item Hamilton Rating Scale for Depression (HAM-D7)
Please enter the appropriate score for each item

Item Legend Score
1. Depressed mood 0. Absent

1. These feelings indicated only on questioning
2. These feelings spontaneously reported verbally
3. Communicates feeling states non-verbally,
i.e. through facial expression
4. Patient reports virtually only these feeling states in
his or her spontaneous verbal and non-verbal
communication
2. Feelings of guilt 0. Absent

1. Self-reproach, feels he or she has let people down
2. Ideas of guilt or rumination over past errors or
sinful deeds
3. Present illness is a punishment; delusions of guilt
4. Hears accusatory or denunciatory voices and/or
experiences threatening visual hallucinations
3. Work and 0. No difficulty

activities 1. Thoughts and feelings of incapacity, fatigue or
weakness related to activities, work or hobbies
2. Loss of interest in activities, hobbies or work, either
directly reported by subject or indirect in listlessness,
indecision and vacillation
3. Decrease in actual time spent in activities or
decrease in productivity. In hospital rate 3 if subject
does not spend at least three hours a day in activities
(hospital job or hobbies) exclusive of ward chores
4. Stopped working because of present illness. In
hospital, rate if subject engages in no activities
except ward chores, or if subject fails to perform
ward chores unassisted
4. Anxiety psychic 0. No difficulty

1. Subjective tension and irritability
2. Worrying about minor matters
3. Apprehensive attitude apparent in face or speech
4. Fears expressed without questioning
Table 2.12 continued
Please enter the appropriate score for each item

Item Legend Score
5. Anxiety somatic 0. Absent

1. Mild
2. Moderate
3. Severe
4. Incapacitating
6. Somatic 0. None
symptoms (general) 1. Heaviness in limbs, back or head. Backaches,
headache, muscle aches. Loss of energy and
‘fatigability’
2. Any clear-cut symptoms rate 2
7. Suicide 0. Absent
1. Feels life is not worth living
2. Wishes he or she were dead or any thoughts of
possible death to self
3. Suicide ideas or gestures
4. Attempts at suicide (any serious attempt rates 4)
Total Score
Score Interpretation
0–3 Normal range; remission

4–7 Mild severity
8–15 Moderate severity
15 or higher Marked/severe severity
Table 2.13 Recommendations for maintenance treatment of major

depressive disorder
Recommendations Evidence
All patients should continue on antidepressants for at least six months after Level 1
a full remission of symptoms
Patients with the following risk factors require longer maintenance treatment – Level 2
at least two years, and for some, lifetime:
• Chronic episodes (> 2 years’ duration)
• Severe episodes (suicidality; psychotic depression)
• Resistant or hard-to-treat episodes
• Frequent episodes (two episodes in past two years)
• Recurrent episodes (three or more lifetime episodes)
• Older age (>65 years)
The antidepressant dosage in the maintenance phase should be the same Level 2
dosage as in the acute phase
If the decision is made to discontinue an antidepressant, the antidepressant Level 3

should be tapered slowly to avoid discontinuation symptoms
Psychoeducation about early signs of relapse should continue (e.g. recurrence Level 3
of sleep disturbances) and patients should have regular follow-up every two to
three months
Psychotherapy, e.g. cognitive behavior therapy (CBT), may be helpful to Level 2

prevent relapses
Comorbid medical conditions and psychiatric disorders should be treated and Level 3
rehabilitation programs (e.g. vocational counseing) may be helpful
Appendix
Montgomery Asberg Depression Rating Scale (MADRS)
Note: Each item is scored on a 0–6 scale. Although the anchors list only even
scores, odd numbers can be used if the rating is between scores.
Response Score
1. Apparent sadness No sadness 0

Despondency, gloom and despair Looks dispirited but does brighten 2
that is more than just ordinary up without difficulty
transient low spirits Appears sad and unhappy most 4
of the time
Looks miserable all the time; 6
extremely despondent
2. Reported sadness Occasional sadness in keeping 0

Reports of depressed mood regardless with the circumstances
of whether it is reflected in appearance Sad or low but brightens up without 2
or not. This includes low spirits, difficulty
despondency or the feeling of being Pervasive feelings of sadness or 4
beyond help and without hope. Rate gloominess. The mood is still
according to intensity duration and the influenced by external circumstances
extent to which the mood is reported Continuous or unvarying sadness, 6
to be influenced by events misery or despondency
3. Inner tension Placid with only fleeting inner tension 0

Feelings of ill-defined discomfort, Occasional feelings of edginess and 2
edginess, inner turmoil, mental tension ill-defined discomfort
mounting to panic, dread or anguish. Continuous feelings of inner tension or 4
Rate according to intensity, frequency, intermittent panic which the patient
duration and the extent of reassurance can only master with some difficulty
called for Unrelenting dread or anguish; 6
overwhelming panic
4. Reduced sleep Sleeps as usual 0

Reduced duration or depth of sleep Slight difficulty dropping off to sleep; 2
compared to the subject’s own normal slightly reduced light or fitful sleep
pattern when well Sleep reduced or broken by at least 4
two hours
Less than 2–3 hours of sleep 6
5. Reduced appetite Normal or increased appetite 0

Loss of appetite compared with when Slightly reduced appetite 2
well. There may be a loss of desire for No appetite and food is tasteless 4
food or the need to force oneself to eat Needs persuasion to eat at all 6
6. Concentration difficulties No difficulties with concentrating 0

Difficulties in collecting one’s thoughts Occasional difficulties in collecting 2
mounting to an incapacitating lack of one’s thoughts
concentration. This is rated according Difficulties in concentrating and 4
to the intensity, frequency and degree sustaining thought which reduces the
of incapacity produced ability to read or hold a conversation
Unable to read or converse without 6
great difficulty
7. Lassitude Hardly any difficulty in getting 0

Difficulty in getting started; slowness in started; no sluggishness
initiating and performing everyday Difficulties in starting activities 2
activities Difficulties in starting simple routine 4
activities which are carried out with
effort
Complete lassitude; unable to do 6
anything without help
8. Inability to feel Normal interest in the surroundings 0

Reduced interest in the surroundings or and in other people
in activities that normally give pleasure. Reduced ability to enjoy usual interests 2
The ability to react with adequate Loss of interest in the surroundings; 4
emotion to circumstances is reduced loss of feelings for friends and
acquaintances
Emotionally paralyzed; unable to feel 6
anger, grief or pleasure; complete or
even painful failure to feel for close
relatives and friends
9. Pessimistic thoughts None 0

Feelings of guilt, inferiority, Fluctuating ideas of failure, 2
self-reproach, sinfulness, remorse or ruin self-reproach or self-depreciation
Persistent self-accusation or definite 4
but still rational ideas of guilt or sin;
increasingly pessimistic about the
future
Delusions of ruin, remorse or 6
unredeemable sin; self-accusations
which are absurd and unshakeable
10. Suicidal thoughts Enjoys life or takes it as it comes 0

Feeling that life is not worth living Weary of life; only fleeting suicidal 2
and/or that a natural death would be thoughts
welcome; presence of suicidal thoughts Probably better off dead; suicidal 4
and the making of preparations for thoughts common and suicide is
suicide considered as a possible solution but
without specific plans or intentions
Explicit plans for suicide when there 6
is an opportunity; active preparations
for suicide
Total score
Score Interpretation
0–11 Normal range; remission

12–19 Mild severity
20–29 Moderate severity
30 or higher Marked/severe severity
Hospital Anxiety and Depression Scale (HADS)

Doctors are aware that emotions play an important part in most illnesses. If
your doctor knows about these feelings he or she will be able to help you
more. This questionnaire is designed to help your doctor know how you feel.
Read each item and place a firm tick in the box opposite the reply that
comes closest to how you have been feeling in the past week. Do not take
too long over your replies: your immediate reaction to each item will proba-
bly be more accurate than a long thought-out response.
Tick only one box in each section
1. I feel tense or wound up: 2. I still enjoy the things I used to enjoy:
➂ Most of the time 0 Definitely as much
➁ A lot of the time ➀ Not quite so much

➀ Time to time ➁ Only a little
0 Not at all ➂ Hardly at all
3. I get a sort of frightened feeling as if 4. I can laugh and see the funny side of
something awful is about to happen: things:
➂ Very definitely and quite badly 0 As much as I always could
➁ Yes but not too badly ➀ Not quite as much now

➀ A little, but it doesn’t worry me ➁ Definitely not so much now
0 Not at all ➂ Not at all
5. Worrying thoughts go through my mind: 6. I feel cheerful:

➂ A great deal of the time ➂ Not at all
➁ A lot of the time ➁ Not often
➀ From time to time but not too often ➀ Sometimes
0 Only occasionally 0 Most of the time
7. I can sit at ease and feel relaxed: 8. I feel as if I am slowed down:

0 Definitely ➂ Nearly all the time
➀ Usually ➁ Very often
➁ Not often ➀ Sometimes
➂ Not at all 0 Not at all
9. I get a sort of frightened feeling like 10. I have lost interest in my appearance:
butterflies in the stomach: ➂ Definitely
0 Not at all ➁ I don’t take so much care as
➀ Occasionally I should
➁ Quite often ➀ I may not take quite as much
➂ Very often care
0 I take just as much care as ever
11. I feel restless as if I have to be on the 12. I look forward with enjoyment to
move: things:
➂ Very much indeed 0 As much as ever I did
➁ Quite a lot ➀ Rather less than I used to

➀ Not very much ➁ Definitely less than I used to
0 Not at all ➂ Hardly at all
13. I get sudden feelings of panic: 14. I can enjoy a good book or radio or
➂ Very often indeed TV program:
➁ Quite often 0 Often
➀ Not very often ➀ Sometimes

0 Not at all ➁ Not often
➂ Very seldom
Total for odd-numbered questions Total for even-numbered questions

Anxiety score: Depression score:
Scoring:
On either subscale a score of 8 or more is significant; a score of 11 or more is highly
significant
Patient Health Questionnaire – PHQ-9

(www.primary-care.org)
1. Over the last 2 weeks, how often have you been bothered by any of the
following problems?
More
Several than half Nearly
Not at all days the days every day
(0) (1) (2) (3)
a. Little interest or pleasure in doing things

b. Feeling down, depressed or hopeless
c. Trouble falling/staying asleep; sleeping
too much
d. Feeling tired or having little energy
e. Poor appetite or overeating
f. Feeling bad about yourself, or that you are
a failure, or have let yourself or your
family down
g. Trouble concentrating on things, such as
reading the newspaper or watching TV
h. Moving or speaking so slowly that other
people could have noticed.
Or the opposite: being so fidgety or restless
that you have been moving around more
than usual
i. Thoughts that you would be better off dead
or of hurting yourself in some way
2. If you checked off any problem on this questionnaire so far, how difficult
have these problems made it for you to do your work, take care of things
at home or get along with other people?
Not difficult Somewhat Very Extremely

at all difficult difficult difficult
Total score __________
Instructions: how to score the PHQ-9

Major depressive disorder is suggested if:
1. Of the nine items, five or more are checked as at least ‘more than half the
days’;
2. Either item a. or item b. is positive, that is, at least ‘more than half the days’.
Other depressive syndrome is suggested if:
1. Of the nine items, a, b. or c. is checked as at least ‘more than half the

days’;
2. Either item a. or item b. is positive, that is, at least ‘more than half the days’.
Also, PHQ-9 scores can be used to plan and monitor treatment. To score
the instrument, tally each response by the number value under the answer
headings, (not at all = 0, several days = 1, more than half the days = 2 and
nearly every day = 3). Add the numbers together to total the score on the
bottom of the questionnaire. Interpret the score by using the guide below.
Guide for interpreting PHQ-9 scores
Score Action
0–4 The score suggests the patient may not need depression treatment
5–14 Mild major depressive disorder. Physician uses clinical judgment about
treatment, based on patient’s duration of symptoms and functional
impairment
15–19 Moderate–major depressive disorder. Warrants treatment for depression,

using antidepressant, psychotherapy or a combination of treatment
20 or higher Severe major depressive disorder. Warrants treatment with antidepressant,

with or without psychotherapy, follow frequently
Functional health assessment

The instrument also includes a functional health assessment. This asks the
patient how emotional difficulties or problems impact work, things at home
or relationships with other people. Patient responses can be one of four: not
difficult at all; somewhat difficult; very difficult; extremely difficult. The last
two responses suggest that the patient’s functionality is impaired. After
treatment begins, functional status and number score can be measured to
assess patient improvement.
Conclusions
Treating depression effectively requires a long-term focus, since it is impor-
tant not only to get patients well, but also to keep them well. Attending to
the principles of management for patients with depression: careful diagnos-

tic assessment; recognition of the various tasks and goals for acute and
maintenance phases of treatment; selection of evidence-based treatments;
appropriate monitoring and follow-up will provide the best chance for
optimal outcome and restoring full psychosocial function.
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IV (SCID-IV). Washington, DC: American Psychiatric Press, 1995.
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Chapter 3
Psychotherapies, alone
and in combination
Introduction
Psychotherapy is the oldest form of treatment for depression still in wide
use, yet historically it has been the least well established in terms of evi-
dence from controlled clinical trials. Once relegated to the sidelines of
research on the differential therapeutics of mood disorders, several forms of
depression-focused psychotherapy have now been identified as being
efficacious treatments of major depressive disorder (MDD). These contempo-
rary, depression-focused forms of therapy are characterized by a number of
elements that have permitted investigation in controlled clinical trials:
(1) they are intended to be shorter-term, time-limited interventions (which
approximate the length of the acute phase of pharmacotherapy); (2) they
are conducted according to procedurally specified protocols; and (3) they are
targeted to relieve the core symptoms of the depressive disorder.
The empirically verified forms of psychotherapy for depression have
evolved from the disparate traditions of radical behaviorism, psychoanalysis
and social work. Although each of these depression-focused psychotherapies
emphasizes the importance of different aspects of the patient’s phenomeno-
logical world, e.g. cognitive, behavioral or interpersonal factors that may be
related to the onset or persistence of the depressive state, there are neverthe-
less a number of common or pan-theoretical elements. All emphasize prag-
matic approaches to ‘here and now’ problems and a high level of activity on
the part of the therapist. Monitoring of symptom outcomes is an integral
part of treatment, and measures such as the Beck Depression Inventory are
used routinely to document progress. The depression-focused psychothera-
pies also make ample use of psychoeducation, including both information
about the nature of depression and how the methods of therapy will be used
to address these problems. Many patients perceive these therapies to be
directly relevant to their problems and experience an immediate morale-
boosting effect, which serves to amplify expectations for success. Of course,
the depression-focused psychotherapies also build upon a foundation of
basic psychotherapeutic skills. These skills include the abilities to form an
effective working alliance with the patient, maintain professional boundaries
and promote a safe therapeutic milieu.
Treatment overview and limitations

The recommendations included in this chapter are based on the results of
studies using specific forms of cognitive, behavioral and interpersonal psy-
chotherapy. While evidence from randomized controlled trials (RCTs) is
central to establishing treatment efficacy, it is noted that not all treatments
have been evaluated in this manner. Moreover, the number of studies avail-
able to evaluate a particular treatment is not a reliable indicator of the inter-
vention’s inherent worth. Thus, the statement: ‘There is no evidence that
Treatment X is effective’ should not be viewed as synonymous with the
statement that: ‘Treatment X is not effective’. Psychoanalytic psychotherapy,
which has seldom been studied in controlled trials, represents a case in
point. That said, an evidence-based approach to therapeutics gives higher
rankings to interventions that have been evaluated in multiple RCTs and
have been shown to have effects that surpass those of credible control
groups (i.e. pill placebo or pseudotherapy conditions).
Depression-focused psychotherapy can be provided by clinical psycholo-
gists, psychiatrists and experienced masters degree prepared clinicians (e.g.
social workers, nurses and counselors). In our experience, virtually all capable
therapists can learn to conduct at least one type of depression-focused psy-
chotherapy. At least six months of supervised practice, augmented by read-
ings and watching videotapes, is usually needed to achieve the minimum
level of competence used to qualify therapists for participation in research
studies. Some forms of therapy, such as Beck’s model of cognitive therapy,
may require an even longer period of training and supervision.
Although all forms of depression-focused psychotherapy have been
adapted for use in group and couples formats, most research studies mirror
practice patterns by continuing to emphasize individual models of treat-
ment. Sessions typically last 45–60 minutes and are conducted either twice
Psychotherapies, alone and in combination 31
weekly or once a week. The latter is assuredly more common; the former
may convey some advantage early in the course of treatment when working
with more severely or chronically depressed patients. A standard course of
therapy thus consists of 12–20 sessions provided across three to four months.
Extended models of continuation (up to nine months) and maintenance (up
to three years) phase psychotherapy have been developed for the treatment
of patients at high risk for relapse or recurrence.
It is noted that relatively few practitioners have received extensive training
in one or more of these forms of therapy. Moreover, even fewer practicing
clinicians actually employ ‘pure’ models of psychotherapy; most prefer to
use an eclectic mix of interventions. If the specific techniques used in the
different models of depression-focused psychotherapy actually contribute to
treatment efficacy, eclecticism may run the risk of diluting the utility of
therapy. In cognitive therapy, for example, several groups have found that
routinely using an agenda to begin sessions and carefully attending to home-
work assignments correlate with better outcomes. As neither of these rela-
tively basic strategies are particular favorites of a traditionally trained
therapist, it is plausible that deviations from the ‘pure’ model of therapy
may reduce efficacy. Therefore, the guidelines outlined below may not be
applicable to the more widely practiced, eclectic forms of psychotherapy.
Indications for psychotherapy alone

Several factors may be used to guide case selection for treatment with a
depression-focused psychotherapy alone, instead of pharmacotherapy. First
and foremost, the depression-focused psychotherapies have not been evalu-
ated for treatment of the most severe depressive states, such as psychotic
depression. Some evidence suggests that patients presenting with more
severe forms of recurrent depression may be less likely to respond to psy-
chotherapy alone (as compared with the combination of psychotherapy and
pharmacotherapy). Similarly, psychotherapy alone should not be used to
treat bipolar depression without appropriate concomitant pharmacotherapy.
Case selection should therefore focus on ambulatory patients with mild-to-
moderately severe non-psychotic, non-bipolar depressive disorders. As is the
case for other interventions, better outcomes are usually observed among
people with more acute, circumscribed problems.
A second important factor is patient preference. Some people have decidedly
non-medical treatment preferences and feel more comfortable approaching
their problems from a psychosocial perspective. Yet others have comparably

strong negative biases against psychotherapy. When all other factors are equal,
patients should be able to receive their treatment of first choice.
Availability of therapists is sometimes a rate-limiting step, particularly in
rural areas. If a therapist is not trained in one of the newer, empirically vali-
dated therapies, factors such as communication with the referring physician,
assessing syndromal outcome, and willingness to refer back for pharma-
cotherapy when the patient is not responding to treatment can serve as
proxies for quality control.
General principles of cognitive, behavioral and

interpersonal therapies
Many practitioners blend cognitive and behavioral therapies, the result
being referred to as cognitive behavior therapy (CBT). In the following brief
descriptions, however, these models will be described separately for heuristic
reasons.
Cognitive therapy
Beck’s model of cognitive therapy (CT) is based on the proposition that
changes in depressed patients’ maladaptive ways of thinking are the most
direct means to achieve durable symptomatic relief. CT is aimed at modify-
ing three levels of cognition. At the most fundamental level are schemas,
which are the core beliefs or unspoken principles that organize perception
and guide behavior. The knowledge of how to tie a shoe lace is an example
of a simple schema used in everyday life. Of greatest relevance to depression
are schemas about lovability, self-worth, fairness and the trustworthiness of
significant others.
At a second, more accessible level are dysfunctional attitudes, which are
the more specific rules that translate or operationalize schemas. For example,
someone with a schema of low self-worth may approach life with the follow-
ing operational attitude: ‘I must succeed at everything I do’. A depressogenic
attributional style (i.e. the predisposition to view a negative event to have
large, irreversible effects) is another example of this level of cognitive
dysfunction.
At the most superficial level are the thoughts, images, memories and day-
dreams that constitute the depressed person’s waking mental life. These
various types of ‘surface’ cognition can be recorded as a way of objectifying a
depressed individual’s running negative commentary about self, the world

and the future (which was referred to by Beck as the ‘cognitive triad’). When
such spontaneous cognitions are associated with dysphoric effects, they are
referred to as automatic negative thoughts. Turning one of Freud’s dictums
on its head, Beck asserted that affect is the ‘royal road to cognition’.
Cognitive therapists help patients to recognize the link between depressive
feelings and habitual ways of thinking and begin to organize automatic neg-
ative thoughts into themes, which in turn can guide case formulations about
schematic vulnerability.
The cognitive model of psychopathology also emphasizes the importance
of information processing biases that tend to increase states of affective dis-
tress. These biases include processes such as selective abstraction, overgener-
alization, emotional reasoning, all-or-none thinking, personalization and
‘mind-reading’. During depressive states memory retrieval is biased, with rel-
atively decreased access to positive or disconfirmatory memories and greater
access to mood-congruent, negatively themed memories.
Effective cognitive therapists employ a high degree of structure to help
patients focus on learning more active and effective ways of coping. Each
session is organized around an agenda that almost always includes three
activities: symptom evaluation; review of homework; and selection of new
homework activities. These tasks are sandwiched around two or three other
segments of in-session work.
Therapists use a style of interaction referred to as collaborative empiricism,
which emphasizes guided discovery (also known as Socratic questioning).
The therapist’s role as a guide or teacher is thus emphasized, although it
should not be at the expense of maintaining an empathic rapport. Therapists
seek explicit feedback at each transition point in a session to help ensure
that patients are in ‘synch’ with the material being discussed, and feel under-
stood by (and connected to) the therapist.
In a typical course of CT (Table 3.1), the early phase (e.g. sessions 1–6)
emphasizes establishing a therapeutic relationship, enculturating patients to
the style of the therapy, educating them about the cognitive model of
treatment, identifying target symptoms and setting shorter-term goals and
establishing the relationship between depressive feelings and automatic
negative thoughts. In practice, it is usually helpful to also use behavioral
activation strategies (described below) to help patients begin to engage in
more productive activities.
The middle phase of therapy (e.g. sessions 7–12) centers around extensive
use of a systematized approach to addressing automatic negative thoughts.
Table 3.1 Phases of treatment with CT
Early phase (sessions 1–6)

• Establishes therapeutic relationship
• Identifies target symptoms and short-term goals
• Educates about model and clarifies links between depressive feelings and
automatic negative thoughts
Middle phase (sessions 7–12)

• Systematized approach to addressing automatic negative thoughts – Daily
Record of Dysfunctional Thoughts
Later phase (session 13 to end)

• Identification of risk factors for relapse
• Implementation of balanced view of self, the world and the future
• Preparation for termination
Using a form called the Daily Record of Dysfunctional Thoughts, patients

learn to focus on periods of low mood by recording the following sequence:
the event; mood state (pre-intervention); automatic negative thoughts; ratio-
nal alternatives; and mood state (post-intervention). Asking patients to write
down their automatic negative thoughts as well as rational alternatives helps
the individual to examine the basis for these and to consider different (less
biased) interpretations.
The later phases of CT (e.g. sessions 13 through termination) address
preparing the patient for termination, including the identification of high-
risk situations relevant to relapse risk and facilitating self-directed learning
via more independent homework tasks. Longer-term goals are set and a life
plan is developed to help guide goal attainment. Ideally, a successfully
treated patient will have recognized their schematic vulnerability, practiced
living with more functional attitudes and have begun to implement a life
plan that will support a more balanced way of thinking about oneself, the
world around and the future.
In some countries it may be difficult to find a capable, well-trained cognitive
therapist. Where available, local professional societies may be helpful.
Alternatively, the shortage of trained therapists may be offset by the use of
computer-assisted models of CT, such as the one developed for CD-ROM by
Wright, Wright and Beck. A number of useful self-help manuals are also avail-
able, including Mind Over Mood (Greenberger and Padesky, 1995) and The
Feeling Good Handbook (Burns, 1999).
Behavior therapy
Behavior therapies (BTs) are based on the fact that depression is associated
with decreased levels of operant (goal-directed) behavior and a resulting deficit
in positive reinforcement. The anhedonia of depression may actually reduce
the reinforcing ‘power’ of pleasurable activities, underpinning cognitions such
as ‘Why bother – it won’t make a difference’. Most depressed people also man-
ifest behavioral excesses (i.e. crying, complaining and other signs of hyper-
arousal including anxiety and insomnia). A third set of targets for behavioral
interventions results from recognition that some people prone to depression
have longstanding difficulties in assertiveness, conflict resolution and problem
solving. These social skill deficits increase the likelihood of difficulties in both
intimate relationships and vocational pursuits.
In the early stages of behavior therapy, patients learn to monitor their moods
and activities and to rate the associated degree of mastery and pleasure.
Typically, a patient would be asked to keep an hour-by-hour or day-by-day log
of their activities and mood states. If this functional analysis reveals deficits in
mastery or pleasure, homework assignments are used to increase the level of
behavioral activation. Large, potentially overwhelming tasks are tackled by
homework assignments that break down a complex chain of behaviors into
more manageable units; this technique is referred to as graded task assign-
ment. Specific behavioral strategies, including progressive deep muscle relax-
ation, diaphragmatic breathing and thought stopping, are utilized when
indicated to help patients cope with symptoms of anxiety and insomnia.
Social skills training (including behavioral rehearsal and role playing) might be
used later in the course of therapy to help increase self-confidence and address
the patient’s difficulties in relationships. Similarly, a step-wise approach to
problem solving may be used to help patients incorporate a more systematic
method into their repertoire to help lessen the impact of future stressors. The
book Coping with Depression (Beck and Greenberg, 1974) outlines a 12-session
course of behavior therapy developed for individual or group interventions.
Cognitive Behavioral Analysis System of Psychotherapy

A hybrid model of treatment, referred to as the Cognitive Behavioral Analysis
System of Psychotherapy (CBASP), was developed by McCullough (2000) to
address the more pervasive and longstanding problems of patients with chronic
forms of depression. CBASP is distinguished from CT by the use of a standard-
ized, relationship-based approach to problem solving. This method builds upon
a situational analysis of behavior by incorporating the patient’s desired
outcomes and an appraisal of what prevented obtaining that desired outcome.

In short, CBASP takes a very ‘molecular’, situation-by-situation approach to help
patients learn to become more effective in their interpersonal relations. CBASP
was initially developed and tested as a 12-week (16–20 session) intervention. As
clinical experience with more complex and dysfunctional populations has
accrued, therapists have often added an additional continuation phase, which
permits four to six additional months of less frequent sessions to work on gener-
alization and mastery of the skills learned during the acute phase of therapy.
Interpersonal psychotherapy
By contrast, interpersonal psychotherapy (IPT) uses more conventional ‘talk
therapy’ strategies to address the problems that patients face in relation to
the onset or persistence of the depressive disorder. There is a basic assump-
tion in IPT that depression is a biopsychosocial phenomenon, and that
addressing interpersonal difficulties, whether they are contributing factors
or consequences of the disorder, will facilitate symptomatic improvement.
Paradoxically, IPT is the form of depression-focused psychotherapy that
most explicitly embraces a medical or illness model, yet takes the most
decidedly traditional approach to foster symptom resolution.
The work of IPT revolves around addressing problems in one or more of the
following themes: unresolved grief; role transitions; role disputes; and inter-
personal deficits (i.e. loneliness and social isolation). This therapy is less struc-
tured than CT or CBASP, although therapists may actively assist the patient to
clarify, resolve and/or better cope with their interpersonal problems. Strategies
include eliciting emotional expression to facilitate grief work, brainstorming to
identify novel methods to resolve impasses in communication with significant
Table 3.2 Phases of treatment with IPT
Early phase (sessions 1–6)

• Establish a working alliance
• Provide education about depression and the IPT model
• Develop interpersonal industry
Middle phase (sessions 7–12)

• Work on resolution of problem areas defined in early phase, e.g. facilitate grief
work, resolve impasses in communication with significant others, etc.
Later phase (sessions 13–16)

• Review course of treatment and suggest techniques to deal with anticipated
future problems
others, acceptance of problems that cannot be changed and encouragement to

try out different types of social activities to reduce social isolation.
IPT is typically conducted with 12–16 weekly sessions (Table 3.2), which can
be viewed as divisible into three phases. Therapists use the earlier sessions to
develop the interpersonal inventory, as well as to establish a working alliance,
provide education about depression and acclimatize patients to the workings of
psychotherapy. The middle phase of IPT is intended for work on resolution of
one or more of the problem areas noted on the interpersonal inventory.
Although IPT does not prescribe the use of specific cognitive or behavioral
strategies or make regular use of formal homework assignments, there is a
degree of technical eclecticism permitted that results in overlap with
CT and BT. A final or termination phase (e.g. sessions 13–16) is devoted
to reviewing the course of treatment and discussing anticipated future
problems. One resource for learning more about IPT is the textbook
A Comprehensive Guide to Interpersonal Psychotherapy (Weissman et al., 2000).
Effectiveness of depression-focused psychotherapies

As of March 2007, there are more than 100 published studies that have eval-
uated the efficacy of one or more forms of depression-focused psychother-
apy. The most clear-cut evidence comes from studies that have used waiting
lists or pseudotherapy control conditions. A number of meta-analyses docu-
ment that cognitive and behavioral therapies have definite efficacy when
compared with these relatively weak standards. Although only a few IPT
studies used such a low contact control condition, these studies consistently
documented significant antidepressant effects.
For psychiatrists, RCTs that compare a depression-focused psychotherapy
with antidepressant pharmacotherapy provide a more meaningful index of
therapeutic benefit. This design also permits the efficacy of the active compara-
tor – pharmacotherapy – to be established in relation to a pill placebo. Again,
meta-analyses document efficacy: all three forms of depression-focused psy-
chotherapy have effects that are comparable (definitely not inferior) to those
documented for antidepressants as administered in these trials. Unfortunately,
as only a few of these RCTs have employed a pill placebo control group, one
could still assert that the studies do not unequivocally confirm the efficacy of
psychotherapy (i.e. it is possible that the RCTs systematically sampled from
patient groups that are less responsive to pharmacotherapy).
Although the weight of evidence from published RCTs favors CT, there is
little evidence that one model of depression-focused therapy is more effective
than any other. This is particularly true after the impact of the allegiance of
the studies’ principal investigators is taken into account. It is not clear if the
allegiance effect reflects a higher level of expertise with the particular model
of therapy or, more likely, a greater expectation that the ‘chosen’ therapy will
be more effective. The only way to neutralize an allegiance effect is to ensure
that each therapy in a comparative study is administered with a comparable
level of expertise, enthusiasm and expectation.
Only two published trials have directly compared CT and IPT. Results from
the first of these studies, the Treatment of Depression Collaborative Research
Project (TDCRP), have had the most impact. This trial was relatively large (i.e.
250 patients), had the imprimatur of the US Government’s National Institute of
Mental Health and exemplified the state of the art in psychotherapy outcome
research at the time the study was conducted (1981–84). Moreover, in addition
to using an active control group, treatment with the antidepressant
imipramine, the study included a fourth group that received double-blind
placebo. Overall, the TDCRP found some advantage for each of the active treat-
ments when compared to the placebo control group, but the differences were
modest and inconsistent. Among the less severely depressed subgroup of
patients (~60% of the sample), the patients treated with placebo generally did
as well as those who received the active treatments. In the more severely symp-
tomatic subgroup, imipramine therapy was definitely superior to placebo, with
IPT and CT showing intermediate effects. Comparing the two psychotherapies,
non-significant trends favored IPT over CT, and there was some evidence of
differential predictors of psychotherapy response. Within the IPT cell, therapy
was more effective among patients with endogenous features, less pathologic
personality profiles and less social impairment. Among those treated with CT,
outcomes were better for married patients, as well as those with atypical depres-
sion or relatively low levels of cognitive distortions. A strong therapeutic
alliance was predictive of improvement in all four treatment modalities,
whereas chronicity of illness predicted poorer across-the-board outcomes.
The second trial compared response to IPT and CBT among a predomi-
nantly male, human immunodeficiency virus (HIV)-positive patient group
with either dysthymia or MDD. In this 16-week trial, IPT (n = 24) and sup-
portive therapy plus imipramine (n = 26) were comparably effective and both
interventions were significantly more effective than both CT (n = 27) and
supportive therapy alone. Comparing the two psychotherapies, the outcome
of the IPT group was strikingly superior to that of the CT group (e.g. a mean
difference in final Hamilton Rating Scale for Depression (HAM-D) scores of
nearly 0.8 standard deviation units).
Table 3.3 Recommendations for individual, group and marital therapies
Therapeutic choice Recommendations Evidence
First Individual CBT or IPT for non-psychotic non-bipolar Level 1

MDD
Second Group formats of CBT: Level 2
there is less evidence for efficacy of group as
compared to individual forms of psychotherapy and
the latter is recommended for treatment of more
severe depressive episodes
Third Marital or couples therapy, in patients with significant Level 2

marital distress
Although a number of studies have compared CT and BT, most studies

were inconclusive because of low statistical power and, frankly, flawed by
strong investigator allegiance effects. One large (n = 150) study found CT, BT
and their combination to be comparably effective treatments for outpatients
with mild-to-moderately severe depressive episodes. In a subsequent report,
this group of investigators both confirmed and extended these findings, with
the more severely depressed subset of the BT group improving as much as
patients randomly assigned to paroxetine and significantly more so than
those treated with double-blind pill placebo.
Several randomized studies have contrasted group and individual forms
of CT or BT. Results of meta-analyses of comparative studies documented
that group therapies were effective (compared to waiting list controls), with
antidepressant effects that approached the magnitude of individual therapy.
Likewise, both BT and CT have been modified for the treatment of depres-
sion within couples therapy formats. Among depressed patients with dis-
tressed marriages, the couples approach had antidepressant effects
comparable to individual CT, with broader, mode-specific effects on dyadic
adjustment. This information is summarized in Table 3.3.
Other psychosocial treatments for depression

The simplest, least expensive approach to treatment is bibliotherapy (Table 3.4),
which relies upon books such as The Feeling Good Handbook (Burns, 1999) to
convey the therapeutic intervention. A number of studies have compared biblio-
therapy to a waiting list control condition in patients with milder depressive states.
Table 3.4 Recommendations for other psychosocial treatments
First None are recommended in lieu of standard treatments Level 1

Exercise is an effective adjunct to standard treatments
Second Bibliotherapy – this should be considered an adjunct Level 2

treatment to other first line treatments
Third Yoga – this should be considered an adjunct treatment Level 3

to other first line treatments
A meta-analysis of the first six studies concluded that bibliotherapy has a definite
therapeutic effect, which may be especially useful for depressed people who are
unable to see a psychotherapist. In the 21st century it is likely that bibliotherapy
will be replaced by various forms of internet- and computer-administered therapy.
A number of studies have found that internet applications of CT likewise have
antidepressant effects that surpass the improvements observed in waiting list
control conditions. In one recent randomized controlled study, a hybrid model of
therapy utilizing DVD-ROM modules and brief ‘in person’ sessions was at least as
effective as a full course of conventional CT. Computerized CT has also proved
effective when evaluated in depressed patients in primary care.
Yoga and meditation may facilitate self-awareness, acceptance and tolerance
of affective experience, which are useful skills for dealing with some aspects of
depression, such as anxious hyperarousal and ruminative negative thinking.
However, there are no well-controlled RCTs of these approaches. Mindfulness
based stress reduction combines mindfulness meditation and yoga, while mind-
fulness based cognitive therapy (MBCT) provides information about depression
as well as cognitive therapy based exercises. Positive results with MBCT for
relapse prevention have been reported. By contrast, aerobic exercise has been
studied and found to have antidepressant effects of sufficient magnitude to
warrant use as a routine adjunct to all standard therapies (see Chapter 9).
Preventive effects of depression-focused

psychotherapies
The relatively higher shorter-term costs of the depression-focused psy-
chotherapies could be offset if it was shown that treatment had enduring
effects on subsyndromal, residual symptoms or relapse rates. This is particu-

larly important because the well-established preventive effects of pharma-
cotherapy are essentially lost within six months of stopping antidepressants.
Some evidence of durability of antidepressant effects following acute
phase CT has been reported. Follow-up studies of a number of the early RCTs
contrasting CT and pharmacotherapy have yielded fairly consistent findings
that suggest some enduring benefit over one or two years. In these studies,
patients who had responded to pharmacotherapy had a higher probability of
relapse after withdrawal of medication than patients who had responded to
CT (e.g. 50–66% relapse risk following medication discontinuation versus
20% following termination of CT). The major exception to this pattern of
results came from the follow-up of the TDCRP, in which patients treated
with CT were about as likely to relapse as were patients who had been
treated with other modalities (i.e. interpersonal psychotherapy, imipramine
and clinical management, or placebo and clinical management). Although
these results are not indicative of a more durable benefit, it should be
recalled that CT was not a particularly effective treatment in that study and
the absence of a significant difference between the groups treated with
imipramine and placebo calls into question the power/assay sensitivity of
the design. In addition a lack of evidence of enduring antidepressant effects
was observed for IPT in either the TDCRP or the initial RCT conducted by
the treatment’s developers.
Work by Thase, Jarrett and their colleagues suggests that an enduring
benefit following a time-limited course of CT is contingent upon achieving a
full and stable remission within the first eight weeks of therapy. When
response was so classified in two independent studies, fewer than 10% of
this remitted group relapsed across one year after treatment termination, as
compared to 50–60% of those who responded in a slower or less complete
manner.
Continuation phase psychotherapy

Based on the association between residual symptoms and/or slower remis-
sion and relapse following termination of acute phase CT, Jarrett and col-
leagues developed a ten-session, eight-month model continuation phase CT.
The efficacy of this strategy was suggested in a case control study and
confirmed (relative to an assessment-only control condition) in a prospective
RCT. Of note, patients who had remitted rapidly during acute phase CT
Table 3.5 Recommendations for psychotherapy as maintenance

treatment
• There is limited evidence to recommend psychotherapy as maintenance Level 2

treatment
• Acute phase treatment with CT may have sustained benefits that provide Level 2
modest protection against relapse
• Longer-term models of CT and IPT may reduce relapse rates, although

there is insufficient evidence about the optimal frequency and duration of Level 2
maintenance sessions
obtained no further objective benefit from the additional therapy sessions

included in the continuation phase. In other words, their low risk of relapse
could not be reduced further. For the patients whose response to CT was
slower or less complete, by contrast, continuation phase therapy conveyed a
three-fold reduction in relapse risk.
Maintenance phase models of psychotherapy have been developed as an
analog to prophylactic pharmacotherapy (Table 3.5). Three studies have
investigated the impact of monthly sessions of IPT after successful acute
phase treatment in combination with antidepressants. In the first study of
adults with a history of highly recurrent depressive episodes, monthly ses-
sions of IPT resulted in a modest reduction in recurrence risk after withdrawal
of pharmacotherapy. However, maintenance IPT did not significantly extend
survival time for patients who continued to take imipramine, and the effect
of IPT alone paled in comparison with the preventive effect of the antide-
pressant. In the other two studies, which focused on recurrent depression in
late life, the effects of IPT and antidepressants alone (study 1: nortriptyline;
study 2: paroxetine) were modest when compared with maintenance therapy
with the combination. In fact, in the second study, maintenance IPT alone
did not significantly reduce the relapse of recurrence compared to placebo.
Combining antidepressants and psychotherapy

For many years, combined treatment was one of the cornerstones of the prac-
tice of psychiatry. However, in an era of limited resources, the additional costs
of combined treatment (not only economic costs but also costs associated with
side-effects and time for treatment) may not be justified if results are not
Table 3.6 Recommendations for concurrent combined treatment
Acute phase treatment – concurrent combined treatment is recommended in the

following circumstances:
First Severe depression – IPT + pharmacotherapy are more Level 1

effective than either treatment alone
Chronic depression – although the combination of Level 2
Cognitive Behavioral Analysis System of Psychotherapy
(CBASP) and nefazodone was more effective than
either treatment alone, nefazodone is no longer
available and replication is required with an available
antidepressant
Maintenance phase treatment – concurrent combined treatment is recommended in the

following circumstances:
First Elderly patients – IPT + nortriptyline reduces recurrence Level 2
rates compared to either treatment alone in patients
treated with the combination in the acute phase
clearly superior to monotherapies. Despite the public health importance of

this issue, there are very few adequately powered studies evaluating combined
treatment. There are three key reasons to consider combining psychotherapy
and pharmacotherapy (Table 3.6): (1) increasing acute phase efficacy; (2)
broadening the scope of response; and (3) reducing the subsequent risk of
relapse/recurrence. Nevertheless, most of the earlier studies of combined treat-
ment failed to detect additive effects on any of these indices. In fairness,
however, it is likely that this lack of effect was probably the result of a type 2
error, because none of these studies had adequate statistical power to detect
moderately sized additive effects. Alternatively, it is plausible that it is not nec-
essary to combine treatment modalities for the relatively easier-to-treat depres-
sions, i.e. milder, more acute first or second episode cases without significant
comorbidity, and that the modest ‘average’ advantage of combined treatment
in smaller controlled studies reflected the heterogeneity of the patient groups
studied (i.e. an admixture of easier and more difficult-to-treat cases).
Evidence in support of both propositions is found in a pooled analysis of
595 depressed outpatients who had received 16 weeks of CT, IPT alone or IPT
plus antidepressants. There was a modest difference in remission rates
among the less severely depressed patients (psychotherapy alone, 37%; com-
bined treatment, 48%). The magnitude of this difference is comparable to
the ‘not statistically significant’ differences observed in the early controlled

trials of combined treatment. By contrast, combined treatment conveyed a
marked advantage (over psychotherapy alone) for patients with more severe
depressive episodes (remission rates: 49% versus 25%).
Further evidence that combined treatment conveys a large advantage for a
more difficult-to-treat subset of patients was revealed in a large RCT delim-
ited to patients with chronic forms of depression. In this multicenter trial,
the combination of nefazodone and CBASP was significantly more effective
than either treatment alone (response rates for CBASP, nefazodone and the
combination were 48%, 48% and 73%, respectively). The advantage of
adding CBASP to nefazodone was particularly evident among the subset of
patients with a history of physical, emotional or sexual trauma.
Unfortunately, nefazodone is no longer available and these results require
replication with other antidepressant medications.
Curiously, although anxiety disorder and personality disorder comorbidi-
ties are also widely thought to increase treatment difficulty, there have been
no prospective studies to date to systematically evaluate the additive effects
of psychotherapy and pharmacotherapy in such complicated patients.
With a few exceptions, combined treatment is provided by either a psychi-
atrist or a primary care physician and a non-medical therapist working
together. When two clinicians are involved, ongoing communication to
lessen the impact of splitting, provision of coherent education about both
modalities and explicit respect for the other member of the treatment team
are important ingredients. We are not aware of any studies formally compar-
ing single- and two-provider forms of combined treatment.
Sequential combined treatment

Combined treatment can also be provided in sequence (Table 3.7). Results of
one case control study suggested that it may be more efficient to provide IPT
and pharmacotherapy in sequence rather than routinely start the therapies
in combination. Specifically, 79% of the group treated with IPT followed, if
indicated, by pharmacotherapy achieved remission, as compared with 66%
in a historical comparison group that was treated with both IPT and
imipramine from the outset of treatment. Conversely, the benefit of adding
CT to antidepressant medications was demonstrated in three studies: two
focusing on patients who obtained partial remission on antidepressants and
one studying patients with highly recurrent depression who were being
Table 3.7 Recommendations for sequential combined treatment.

Sequential application of therapies (i.e. adding psychotherapy following
partial response to pharmacotherapy) may be an effective strategy
First Adding CT to treat residual depressive symptoms after Level 2

acute treatment with pharmacotherapy improves
remission rates and reduces relapse/recurrence rates
Adding pharmacotherapy for women with partial or Level 3
no response after acute treatment with IPT improves
remission rates
withdrawn from medication. In all three trials CT reduced the risk of relapse,
and, in two of the studies, patients who received CT were significantly more
likely to discontinue antidepressants without relapsing.
In a large sequencing trial that mainly involved switch and augmentation
pharmacotherapy (STAR*D – see Chapter 7 page 93 for review) CT was sur-
prisingly unacceptable as an option for two-thirds of eligible candidates.
Response and remission rates among those who accepted this option was
comparable to the pharmacotherapy groups, although the time to
response/remission was approximately 3 weeks in the group that had added
to ongoing citalon therapy as compared to those in the medication regim-
men group.
Two studies have evaluated the preventive effects of a modified form of
group CBT emphasizing the use of mindfulness based cognitive therapy
strategies (MBCT); both studies compared MBCT with treatment as usual
(TAU) for relapse prevention in patients who had both recovered from a
recent episode of recurrent depression and elected to stop antidepressant
medication. Both studies found that MBCT significantly reduced the risk of
recurrence, particularly among patients who had experienced three or more
lifetime depressive episodes.
Conclusions
There is sufficient evidence to consider three forms of depression-focused
psychotherapy (CT, BT and IPT) to be effective treatments for mild-to-
moderately severe, non-bipolar depressive disorders. When available and
preferred by the patient, these therapies may be first choice interventions.

Concurrent depression-focused psychotherapies also increase the effective-
ness of pharmacotherapy for patients with severe, recurrent or chronic
depression. Sequential application of treatments is a possible alternative.
Although long-term enduring benefits have not been definitively estab-
lished, some evidence does support preventive effects following termination
of CT or with continuation of CT or IPT.
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Chapter 4
Evolution of
antidepressant agents
In the beginning …
All currently available antidepressants fit into one of three pharmacological
classes (Figure 4.1). In each class the first or prototypical drug was discovered
empirically. For the first two classes, this was as a result of astute clinical
observation of patients who were receiving the drugs for other disorders:
tuberculosis (TB) in the case of the monoamine oxidase inhibitors (MAOIs)
and schizophrenia in the case of the tricyclic antidepressants (TCAs). In the
third class, the discovery was made on the basis of animal studies with
Enzyme inhibitors Uptake blockers Receptor-

acting drugs
MAOI TCA
1950s
1960s
NE+DA NE 5-HT2C
Subtype- selective selective Mianserin
selective MAOI
1970s Trazodone
1980s NRI SNRI SSRI
Bupropion Nefazodone
1990s RIMA
Mirtazapine
2000s Agomelatine
Figure 4.1 Evolution of antidepressants. MAOI, monoamine oxidase inhibitor; RIMA,

reversible inhibitor of monoamine oxidase A; NE, norepinephrine; 5-HT2C, serotonin; TCA,
tricyclic antidepressant; DA, dopamine; SSRI, selective serotonin reuptake inhibitor; NRI,
norepinephrine reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor.
agents that showed similar behavioral properties to established drugs, despite

different pharmacological mechanisms. This last class of antidepressants has
been somewhat refined over the past couple of decades as scientific advances
continue to identify the most relevant receptors for antidepressants to act
upon.
Since these empirical and serendipitous beginnings, each class of antide-
pressant drug therapy has undergone major growth and refinement. The
biggest gains have been in the areas of increased tolerability and safety; in
terms of efficacy the gains have been less apparent.
Enzyme inhibitors
The irreversible monoamine oxidase inhibitors (MAOIs)
This was the first class of antidepressants to be identified. In the late 1940s
isoniazid and related compounds were used to treat TB patients, many of
whom experienced a sense of elation even though they were experiencing
little or no improvement in their physical health. This led to early clinical
trials and the use of these drugs in depressed patients, with considerable
success.
At the same time it became known that the link between all these drugs
was the property of inhibiting the enzyme MAO, hence the name MAO
inhibitors. This enzyme blockade prevents the degradation of amines, espe-
cially serotonin (5-HT2C) and norepinephrine (NE). By the 1960s it was rec-
ognized that there were two forms of MAO, type A and type B, both of
which were irreversibly blocked by the MAOIs.
Because the type A enzyme is responsible for the metabolism of NE and
5-HT2C, this became the main target for antidepressant drug development.
Selective but irreversible MAO-A antagonists such as pargyline were tested,
but they were disappointing as antidepressants, so were not licensed. Later,
the selective and irreversible MAO-B antagonist selegiline was synthesized
and shown to be of use in Parkinson’s disease, probably because dopamine is
mostly metabolized by the B form of the enzyme. In 2006, a transdermal
selegiline patch became available in the United States as a treatment for
depression. This delivery system avoids first-pass hepatic metabolism and
yields plasma drug levels that are high enough to achieve central inhibition
of both MAO-A and MAO-B without inhibiting MAO-A in the intestine and
liver. This allows a normal diet without restrictions on tyramine-containing
foods at the lower dosages of the treatment.
Evolution of antidepressant agents 51
Reversible MAOIs
An earlier step in the evolution of the MAOIs came with the development of
the RIMA agents such as moclobemide and befloxatone. The acronym is
derived from ‘reversible inhibitor of monoamine oxidase A’. Conventional
MAOIs destroy the MAO enzyme by binding to it irreversibly. As a conse-
quence, little enzyme is left to metabolize other amines, such as tyramine,
found in many foods and medicines. High concentrations of tyramine are
found in fermented meat, yeast preparations and mature dairy products.
Tyramine is usually metabolized by MAO in the gut wall and liver, so little
enters the body. However, MAOIs stop this local breakdown, allowing tyra-
mine to enter the central nervous system where it is taken up into amine
neurons, displacing neurotransmitter monoamines from their storage vesi-
cles. When large amounts of tyramine are ingested, a massive release of
amines can occur, with potentially disastrous consequences due to increased
blood pressure and hyperthermia – ‘the cheese reaction’.
By contrast, RIMAs do not permanently inactivate the MAO enzyme. They
simply compete with amines at the active site of the enzyme. This means
that, in the presence of rising tyramine levels, the RIMA agent will be dis-
placed, freeing the enzyme to break down potentially harmful tyramine.
Moreover, as RIMAs only block the A form of the enzyme and tyramine is a
substrate for both A and B enzyme, there is plenty of spare MAO to complete
the metabolism.
The RIMAs are fairly safe drugs, although a mild cheese reaction can be
observed, particularly at higher than recommended doses (in the case of
moclobemide, this means a daily dose of 900 mg or more). There are also
risks of interactions with sympathomimetic drugs such as cold cures, and
the serotonin syndrome has been observed when moclobemide is combined
with a selective serotonin reuptake inhibitor (SSRI) antidepressant or with
the serotonin precursor, tryptophan.
Amine uptake blocking agents

The tricyclic antidepressants (TCAs)
Imipramine is a derivative of the first antipsychotic chlorpromazine. In the
late 1950s it was tested in schizophrenia: it had little effect on the psychotic
symptoms but was observed to elevate mood. Soon, imipramine and its close
relative amitriptyline were tested in depressed patients and found to have
good efficacy.
In 1964 Iversen and colleagues showed that imipramine prevented the

uptake of tritiated NE into brain tissue. This heralded the beginning of the
‘neurotransmitter/transporter’ era in pharmacology, with the subsequent dis-
covery of different families of transporters that regulate neurotransmitter
concentrations in the synaptic cleft. These transporters are targets for a
variety of psychotropic drugs. It also contributed to the emerging NE theory
of depression and antidepressant drug action, as several TCAs such as nor-
triptyline and protriptyline were NE selective uptake blockers. In recent
years, several NE reuptake inhibitors (NRIs) of non-tricyclic structure have
been developed. These include maprotiline and reboxetine as well as the
NE/dopamine uptake blockers bupropion and nomifensine. Nomifensine
was withdrawn worldwide in the mid-1990s due to an unacceptably high
incidence of hematological adverse effects, but these other agents will be dis-
cussed in later chapters (see Chapters 5 and 6).
The selective serotonin reuptake inhibitors (SSRIs)

The next advance occurred when Carlsson and Ross observed that the TCAs
also blocked the uptake of 5HT into synaptosomes. This provided support for
the 5-HT2C theory of depression, and suggested that selective 5-HT2C uptake
blockers might also be antidepressant. The effectiveness of clomipramine, a
relatively 5-HT2C-selective TCA, supported this view, but the real break-
through came with the synthesis and testing of the first SSRI, zimelidine.
Even though it had a totally different profile of side-effects compared with
the TCAs and was safe in overdose, zimelidine’s useful life was cut short by
reports of rare but severe cases of hepatitis and Guillain–Barré syndrome.
The company that developed it thought that these adverse effects were a
consequence of blocking 5-HT2C reuptake and discontinued their SSRI devel-
opment program. However, other companies took a different view and were
later confirmed as correct with the development of a series of SSRIs that have
proved to be exceptionally safe and effective antidepressant and anxiolytic
agents.
Although efficacy and side-effects across drugs in the SSRI class are gener-
ally similar, there are some pharmacological distinctions. Citalopram selec-
tively blocks the 5-HT2C transporter (SERT), paroxetine blocks SERT and to a
lesser extent the NE transporter, while sertraline mainly blocks SERT and has
a minor blocking effect on the dopamine (DA) transporter. The discovery
that escitalopram – the active S enantiomer of citalopram – has unexpectedly
greater efficacy than the parent compound citalopram (which is an equal
mixture of both S and R enantiomers) has revitalized research in the area of

5-HT2C uptake blockade. It is now clear that the added efficacy seen with esc-
italopram is due to the fact that the R enantiomer attenuates the neuro-
chemical actions of the S, so reducing its efficacy. Additionally it has been
discovered that escitalopram, as well as blocking the 5-HT2C uptake tran-
porter, also binds to another (allosteric) site on the complex. This may give it
greater ability to prolong the inhibition of 5-HT2C uptake and and has led to
the descriptor ‘allosteric serotonin reuptake inhibitor’ (ASRI).
Dual-action antidepressants
In recent years, the potential advantages of dual 5-HT2C and NE reuptake
blockade compared with either alone have been reported. First, the Danish
University Antidepressant Group conducted three studies that compared the
TCA clomipramine at high doses with paroxetine, citalopram and moclobe-
mide in severely depressed hospitalized patients. In each study
clomipramine showed superior efficacy, which they attributed to the NE
uptake blocking properties of a metabolite of clomipramine as well as the
5-HT2C-blocking properties of the parent compound. Second, Nelson et al.
(1991) showed that an SSRI (fluoxetine) combined with an NRI
(desipramine) produced a more rapid outcome than fluoxetine alone.
These findings have supported the development of the dual-action non-
TCA uptake blockers venlafaxine, milnacipran and duloxetine. In a series of
meta-analyses, venlafaxine has been shown to have superior response and
remission rates compared with the SSRIs in depressed patients. It should be
noted, however, that remission rates for SSRIs in these comparison studies
are generally lower than those reported in other SSRI trials, and more often
involve fluoxetine as the SSRI competitor. Hence, the issue remains contro-
versial, and requires adequately powered trials to compare remission rates
between SSRI and serotonin and norepinephrine reuptake inhibitor (SNRI)
agents. Interestingly, among the SSRI class, paroxetine has been suggested to
have dual 5-HT2C and NE effects ‘in vitro’ (a finding that distinguishes it
from other SSRIs, though the main metabolite of fluoxetine, norfluoxetine, is
also somewhat of an NE uptake blocker). In one study, paroxetine was
shown to have comparable efficacy to TCAs in hospitalized patients. There is
also evidence that mirtazapine, which promotes 5-HT2C and NE transmis-
sion, has superior efficacy to SSRIs in severely depressed patients.
Milnacipran is available in France, Japan and some other countries. It dis-
plays greater NE- than 5-HT2C-blocking effects – the opposite of venlafaxine.
NE
Attention
Mood 5-HT2C
Sleep
Obsessions
Drive
Anxiety
Appetite
Loss of pleasure Negative cognitions
DA
Figure 4.2 Neurotransmitters and depressive symptoms.
This dual-uptake blocking drug has been shown to be effective in a number

of clinical trials in depression. Early data suggest that it may show increased
efficacy compared with SSRIs such as fluoxetine.
Duloxetine is the newest member of this class. It is a more potent dual
reuptake inhibitor than venlafaxine. At a standard dose of 60 mg daily,
blockade of both 5-HT2C and NE transporters has been reported. In contrast,
venlafaxine requires a dose increase from 75 to 150 mg for comparable NE
blockade to occur.
There are interesting theoretical reasons why an antidepressant that acts
on more than one transmitter system might have superior efficacy. Although
increasing the actions of either 5-HT2C or NE is an effective way to treat
depression, there is some evidence that these two transmitter systems have
rather different effects on the various physical and emotional functions that
are disrupted in depression (Figure 4.2).
Although there is considerable overlap between transmitters and symptoms,
some symptoms are more relevant to either 5-HT2C or NE. The implication of
this differentiation of transmitter functions is that certain antidepressants
might preferentially treat some depressive symptoms and not others. So, an
NE-enhancing antidepressant might be preferred in individuals who are
lacking in energy, drive or attention, whereas a more 5-HT2C-targeting drug
would be preferred in patients with prominent obsessional or anxiety symp-

toms. Dual-action or triple-action agents would be effective across more than
one symptom cluster; however, the development of triple-acting agents has
been hampered by their substantial adverse effect profile, presumably related
to additive adverse effects from the elevations of each neurotransmitter.
Receptor-acting drugs
These are the third class of antidepressants, and again they were discovered
before a theory of action was developed. The first two drugs in this class
(mianserin and trazodone) were both found to have antidepressant activity
in animal and other preclinical models of antidepressant action. On this
basis they were taken into human trials, where they proved effective.
Subsequent animal studies helped to unravel their mode of action, although
it should be said that this issue is still debated.
The first theory to explain the therapeutic actions of mianserin was that of
α2-adrenoceptor antagonism. This fitted with emerging ideas about antide-
pressant mechanisms for other treatments, such as TCAs and electroconvul-
sive therapy (ECT). A decrease in α2-adrenoceptor function would remove
autoinhibition of NE neurons, so increasing NE concentration in the synap-
tic cleft. Based on this theory, mirtazapine and other α2-adrenoceptor antag-
onists (e.g. fluparoxan and idazoxan) were evaluated in clinical trials. Only
mirtazapine proved to be both effective and well tolerated, possibly because
it is also a 5HT2 and 5HT3 receptor antagonist.
Mianserin (available in many European countries but not in the USA or
Canada) and trazodone also interact with 5HT receptors. Mianserin antag-
onizes 5HT1A and 5HT2C receptors, whereas trazodone acts through its own
5HT2-blocking effects and through its metabolite mCPP (metachlorophenyl-
piperazine), which has 5HT1 and 5HT2C agonist properties. Both are proto-
types for antidepressants in this class. Mirtazapine is a refinement of
mianserin with 5HT2 and 5HT3 receptor-blocking activity, which likely
explains the virtual absence of 5HT-mediated side-effects such as headache,
sexual dysfunction, insomnia and nausea. Mirtazapine also has less α1-
adrenoceptor blocking affinity than mianserin, but is a potent histamine H1
receptor blocker, so both agents promote sleep and can cause daytime seda-
tion, especially early in treatment. Nefazodone is a follow-up compound of
trazodone that is a weak 5HT uptake blocker and a potent 5HT2 receptor
antagonist. Its side-effect profile is distinct from the SSRIs based on less
sexual dysfunction and sleep disturbance. However, its use has recently been
restricted to named patients in some countries due to reported cases of hepa-
totoxicity and it is withdrawn from the European market.
A completely new approach to the treatment of depression involves mela-
tonergic and serotonergic receptors. Agomelatine is a novel agent that is
both a melatonergic receptor agonist (MT1 and MT2 receptors) and a 5-HT2C
antagonist. Agomelatine has been shown to correct circadian and sleep
abnormalities found in depression. In addition, rat microdialysis studies
have shown that the 5HT2C receptor antagonist actions lead to elevations in
dopamine and norepinephrine in the frontal cortex. It seems likely that
these receptor actions contribute to its antidepressant profile, which is char-
acterized by an at least equivalent antidepressant efficacy to that of other
currently used antidepressants, an improvement of disturbed sleep in depres-
sive patients and a low incidence of sexual adverse effects.
Delayed onset of antidepressant action

One of the goals of antidepressant discovery has been the development of
compounds with a faster onset of action. The prevailing view of the typical
three to four week therapeutic delay with most antidepressants is that it takes
Raphe
Forebrain
SSRIs
5HT1A
5HT1B
5HT1D
5HT neuron 5HT 5HT
5HT2C
–ve –ve
5HT2A
5HT1A 5HT1B/D 5HT3
Figure 4.3 Serotonergic synapse: effect of uptake blockade.

this long to disable compensatory receptor-based mechanisms that initially

offset the uptake blockade or amine oxidase inhibition. To some extent the
receptor-blocking drugs should be free of this problem, although clinical data
have been equivocal. For example, mirtazapine does seem to produce
significantly greater improvements in mood and anxiety symptoms as well as
sleep, compared with SSRIs during the first two weeks of treatment, although
these differences are not sustained after six to eight weeks of treatment.
Improvements in anxiety symptoms and depression associated sleep distur-
bances were also observed under agomelatine treatment.
A targeted approach to this issue came from animal studies in which
blockade of the presynaptic 5HT1A autoreceptor by antagonists such as pin-
dolol produced a rapid rise in 5HT in the cortex. However, a clinical trial
programs to test combined SSRI/pindolol therapy (with both fluoxetine
and paroxetine) failed to produce support for the approach. This may have
been because pindolol also blocks the post-synaptic 5HT1A receptor, which
likely needs to be stimulated to mediate the antidepressant cascade (Figures
4.3 and 4.4), or alternatively because the clinically tolerated doses of pin-
dolol were too low to block enough of the autoreceptors to release the
inhibition.
Firing rate
of raphe
Therapeutic level
5HT concentration
in cortex
SSRI treatment
0 4
Weeks
Figure 4.4 Time lag of SSRIs.

Conclusions
Many antidepressants have been discovered through serendipity. However,
intense research efforts over the past 50 years have led to a better understand-
ing of their pharmacology and modes of action in the brain, with a focus on
the adaptive brain changes that alleviate depression. All three classes of anti-
depressants have been subject to significant refinements in drug action,
resulting in improved adverse effect and safety profiles. Current evidence sup-
ports the recruitment of more than one neurotransmitter system to address
the range of symptoms associated with major depressive disorder, and the
targeted interference with certain post-synaptic receptor systems especially
5HT2 receptor antagonism, to minimize adverse effects and improve disturbed
sleep in depressive patients. New approaches to the treatment of depression
and an understanding of the pharmacology of antidepressants can improve
their use both as single agents and when combined with other antidepres-
sants in cases of treatment resistance, partial response and unwelcome
adverse effects.
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Chapter 5
Evidence based
antidepressant selection
across depressive disorders
Evidence based criteria for choosing an

antidepressant
Major depressive disorder (MDD) exists in many clinical forms, which may
reflect different biological and environmental disturbances. Clinicians recog-
nize distinct subtypes of MDD, which are described in the Diagnostic and
Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-
TR), but not in the International Classification of Diseases, 10th revision
(ICD-10) (see Chapter 1). The following guidelines are offered for the phar-
macological treatment of MDD, and, where evidence is available, its sub-
types dysthymic disorder, minor depressive disorder and recurrent brief
depression are also considered.
The reader is reminded that the lack of evidence for a particular antide-
pressant treatment should not be equated with evidence for lack of efficacy.
The process for developing evidence based therapeutic choices uses standard
methods. Criteria from the periodic health examination guidelines were used
to establish levels of evidence for specific treatments (see Table 5.1), and rec-
ommendations for therapeutic choices incorporate clinical evidence on tol-
erability and safety as well as effectiveness and efficacy (Table 5.2).
Major depressive disorder

Selective serotonin reuptake inhibitors (SSRIs) and various dual-action agents
have superior side-effect and safety profiles and generally comparable efficacy
Table 5.1 Criteria for levels of evidence
Level of evidence Criteria
1 Meta-analysis or replicated randomized controlled trial (RCT) that

includes a placebo condition
2 At least one RCT with placebo or active comparison condition
3 Uncontrolled trial with ten or more subjects
4 Anecdotal case reports
Table 5.2 Criteria for therapeutic choices
Therapeutic choice Criteria for levels of evidence
First Level 1 or Level 2 evidence + clinical support
Second Level 1, Level 2 or Level 3 evidence + clinical support
Third Level 1, Level 2, Level 3 or Level 4 evidence + clinical support
Not recommended Level 1 or Level 2 evidence for lack of efficacy, or insufficient

information to evaluate efficacy
Table 5.3 Recommendations for treatment of MDD
First SSRIs, serotonin and norepinephrine reuptake inhibitors Level 1

(SNRIs), agomelatine, bupropion and mirtazapine
Higher rates of remission have been reported with Level 1
venlafaxine and particularly in severe depression
with escitalopram
Second Among TCAs amitriptyline and clomipramine have Level 2

greater efficacy than SSRIs in hospitalized depressed
patients (safety and tolerability issues need to be
considered)
Third Other TCAs and MAOIs (lower recommendation Level 2

because of safety and tolerability issues)
Evidence based antidepressant selection across depressive disorders 63
to tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors

(MAOIs). This has resulted in their adoption as first-choice antidepressants
for the treatment of MDD. Recent evidence has been presented to support
higher rates of remission for some dual-action agents compared with SSRIs
(Table 5.3). Definitions of response and remission are reviewed in Chapter 2.
Treatment options for subtypes of MDD

Current diagnostic criteria for MDD (DSM-IV and ICD-10) focus on a unitary
concept of depression, although the following subtype specifiers: atypical fea-
tures; melancholic features; chronic pattern; psychotic features post partum
onset (see Chapter 10); and seasonal pattern, as well as severity, have been eval-
uated in a limited number of studies.
MDD with atypical features – atypical depression

This disorder is characterized by preservation of mood reactivity, often with
reversed diurnal mood change (better in the morning) accompanied by at
least two of the following symptoms: excessive appetite or weight gain,
increased sleeping, heaviness of limbs (leaden paralysis) or extreme sensitiv-
ity to perceived rejection. The evidence to support one antidepressant or
class of antidepressants over another is limited, mainly because there have
been very few studies that have focused exclusively on ‘atypical depression’.
In one study, fluoxetine and imipramine were equally effective, although
fluoxetine was better tolerated. Sertraline and moclobemide were also
equally effective for atypical depression, with some quality of life advantages
for sertraline. While phenelzine was superior to imipramine and is histori-
cally associated with the treatment of atypical depression, it is considered a
second line agent due to safety and tolerability issues (Table 5.4).
Table 5.4 Recommendations for treatment of MDD with atypical

features
First Fluoxetine; sertraline (and probably other SSRIs); Level 2

moclobemide
Second Phenelzine (choice reduced due to poor tolerability) Level 2
Third Imipramine Level 2

Melancholia Severity
Treatment
resistance
Figure 5.1 Melancholia, severity and treatment resistance.
Melancholia, severity and treatment resistance

There is considerable overlap between the terms ‘melancholia’, ‘severity’ and
‘treatment resistance’ in relation to an episode of major depression (Figure
5.1). However, these terms are not synonymous, and the same treatment rec-
ommendations do not apply across groups. The implications of ‘melancho-
lia’ and ‘severity’ for treatment outcomes will be discussed in this chapter,
while the broader issue of treament resistance will be considered in Chapters
7 and 8.
MDD with melancholic features – melancholia

The specifier ‘with melancholic features’ requires complete or almost com-
plete loss of pleasure (anhedonia) and loss of mood reactivity, accompanied
by several other symptoms. As well as the distinct symptom profile, there is
evidence to suggest that physiological disturbances, particularly in the hypo-
thalamic–pituitary–adrenal axis, distinguish patients with melancholic
versus non-melancholic features, and that differences in response rates to
various treatments also exist. For example, TCAs and several dual-action
agents have been investigated in melancholia and found to be superior to
SSRIs. Clomipramine was associated with higher remission rates than sertra-
line, paroxetine and moclobemide in individual trials, and in a meta-analy-
sis, other TCAs were superior to SSRIs but produced worse side-effects.
Table 5.5 Recommendations for treatment of MDD with

melancholic features
First Mirtazapine; paroxetine; venlafaxine Level 1

Second Clomipramine; duloxetine; nortriptyline Level 1
Third Citalopram; fluoxetine; moclobemide Level 2
Venlafaxine produced higher remission rates than fluoxetine, and nortripty-

line was also more effective than fluoxetine in elderly melancholic patients.
These findings were not supported by a separate meta-analysis, in which
paroxetine, moclobemide and venlafaxine were as effective as TCAs. Also, in
an analysis of pooled data, duloxetine had equivalent efficacy in patients
with melancholic features compared to those without melancholic features
(Table 5.5). Preliminary evidence suggests that agomelatine also is effective
in patients with melancholic features.
Severity
The DSM-IV-TR categorizes major depressive episodes as mild, moderate or
severe according to the intensity of symptoms. Other indices of severity
include suicide risk, hospitalization status and diagnostic subtype. Although
the presence of melancholia is often viewed as a proxy for severity, this need
not be the case, as melancholic patients manifest a range of severities. In
practical terms, most evaluations of severity are based on a minimum thresh-
old on a rating instrument such as the Hamilton Depression Rating Scale
(HDRS) or the Montgomery Asberg Depression Rating Scale (MADRS).
Examples include a score of 24 or greater on the 17-item HDRS and 30 or
more on the MADRS.
Evaluating efficacy in severe populations is a valuable secondary analysis
for antidepressants, as not all SSRIs have shown equal effects in this group.
For example, escitalopram was superior to other SSRIs and comparable to
venlafaxine, especially in ‘severe depression’. Preliminary evidence suggests
that this may also be true for agomelatine.
MDD with psychotic features – psychotic major depression

The presence of distinct phenomenology, particularly mood-congruent delu-
sions or hallucinations, particularly together with evidence of dopamine–
corticosteroid abnormalities in psychotic major depression (PMD), suggest
that specific treatment approaches are required. Unfortunately, there are too
few adequately powered trials to provide definitive recommendations. In
many instances, psychotic and non-psychotic depressed patients have been
compared ‘post hoc’ from trials that were completed under controlled and
uncontrolled conditions.
Although there are isolated reports that SSRI monotherapy is effective as a
treatment for PMD (sertraline and paroxetine), this approach does not have
widespread clinical acceptance. The most commonly investigated treatments
involve a combination of antidepressant–antipsychotic medications or elec-
troconvulsive therapy (ECT). In one study, the combination of amitriptyline
and perphenazine was significantly better than either alone. In a meta-analy-
sis, ECT was superior to TCA alone, but was not significantly better than the
combination of TCA and antipsychotic therapy. Bilateral ECT was also more
effective than unilateral ECT. However, the recurrent nature of PMD and the
high relapse rate associated with ECT support the use of pharmacotherapy
for acute treatment and prophylaxis.
Although atypical antipsychotics (particularly olanzapine, risperidone and
quetiapine) may be effective antidepressant monotherapies, they have also
been evaluated in combination with an SSRI and are recommended in the
acute treatment of PMD (Table 5.6; see also Chapter 7).
While still investigational, preliminary results suggest that mifepristone, a
potent antagonist of type II glucocorticoid and progesterone receptors and
also known as RU486, has antipsychotic but not antidepressant effects in
PMD.
Table 5.6 Recommendations for treatment of psychotic major

depression
First Electroconvulsive therapy (ECT) Level 1

Antipsychotic + antidepressant (olanzapine Level 2
or risperidone with SSRI or SNRI)
Second Typical antipsychotic + amitriptyline Level 2

Mifepristone + antidepressants Level 2
Not recommended Monotherapy with SSRIs Level 2 but limited

clinical support
Table 5.7 Recommendations for treatment of winter depression
First Bright light therapy; fluoxetine; Level 1

bupropion XL (for prevention)
Second Moclobemide; sertraline Level 2
Third Agomelatine; citalopram; Level 3
escitalopram; tranylcypromine
MDD with seasonal pattern – winter depression

Winter depression refers to the most prevalent form of MDD with a seasonal
pattern. Clinical guidelines for winter depression support light therapy as a
first-choice therapy (see Chapter 9). In a double-blind study of light with
placebo pills versus fluoxetine with placebo light, there was no difference in
response rates between fluoxetine and light treatment groups, although
there was an early but unsustained advantage for light therapy. Among other
antidepressants that have been evaluated, sertraline and moclobemide were
effective, while agomelatine, bupropion, citalopram, escitalopram and
tranylcypromine were beneficial in open trials (Table 5.7). Placebo controlled
trials have found bupropion XL to have a prophylactic effect if taken
through fall and winter, and it is now licensed for this indication in the
United States.
MDD with anxiety – anxious depression

Although ‘anxious depression’ is not specified as a subtype of MDD within
DSM-IV-TR, most patients (60–90%) with a primary diagnosis of depression
also experience symptoms of anxiety, and up to 50% of MDD patients meet
criteria for at least one comorbid anxiety disorder. Individuals who suffer
from anxious depression tend to have higher severity scores on depression
rating scales; greater functional and psychosocial impairment; higher suicide
risk; and a poorer prognosis following treatment, when compared to
depressed individuals with low levels of anxiety. Most SSRIs, venlafaxine and
agomelatine have proven efficacy in the treatment of generalized anxiety
disorder and other anxiety disorders, which supports their use in anxious
depression. A widely held clinical perception that bupropion SR is less effec-
tive in depressed patients with high levels of anxiety is not substantiated in
various comparisons with SSRIs.
Table 5.8 Recommendations for treatment of ‘anxious depression’
First Citalopram; escitalopram; mirtazapine; moclobemide; Level 1

paroxetine; sertraline; venlafaxine; agomelatine
Second Amitriptyline; fluvoxamine; imipramine; trazodone Level 1
Not recommended Lorazepam or other benzodiazepines Level 2
In three meta-analyses, moclobemide, mirtazapine and venlafaxine respec-

tively were as effective as active comparators and superior to placebo.
Paroxetine and sertraline were as effective as clomipramine, while fluvoxam-
ine and lorazepam were comparable in efficacy. Other studies also support
the efficacy of paroxetine and agomelatine in reducing symptoms of anxiety
associated with depression. Clonazepam augmentation of fluoxetine was
superior to fluoxetine alone in the first three weeks of a double-blind trial,
although dependency concerns restrict recommendations for ongoing ben-
zodiazepine prescription (Table 5.8).
MDD with chronic pattern – chronic depression

Chronic depression, dysthymic disorder and double depression (a major
depressive episode superimposed on dysthymia) are often indistinguishable.
For some patients, the duration of symptoms may be as long as 30 years
prior to treatment. Despite the limited number of trials, there is evidence
that several antidepressants are more effective than placebo in the acute
treatment of dysthymia. In a meta-analysis, fluoxetine, sertraline, MAOIs
(including moclobemide) and TCAs all had equivalent efficacy, although
TCAs were associated with more side-effects and higher dropout rates. There
were no significant differences in rates of response between patients with
pure dysthymia and those with double depression. For this reason, the term
‘chronic depression’ is preferred.
Sertraline is the most investigated SSRI as a treatment for chronic depres-
sion, and had advantages over imipramine in a large trial. Also, in patients
over the age of 60, who were treated in primary care settings, paroxetine was
superior to placebo. Venlafaxine and mirtazapine were effective in open trials
(Table 5.9), while combined pharmacotherapy with nefazodone and a
Table 5.9 Recommendations for treatment of chronic

depression/dysthymic disorder
First Fluoxetine; fluvoxamine; moclobemide; paroxetine; Level 2

sertraline
Second Desipramine; imipramine Level 2
Third Mirtazapine; venlafaxine Level 3
modified form of cognitive behavior therapy (CBT) – Cognitive Behavioral

Analysis System of Psychotherapy (CBASP) – produced superior results com-
pared to either treatment alone (see also Chapter 3). Since, nefazodone has
been withdrawn, these results require replication with another antidepres-
sant.
Minor depressive disorder

Minor depression (mDD) is characterized by depressed mood or anhedonia,
accompanied by 1–3 additional depressive symptoms that are present for at
least two weeks. Particularly in older adults, this is the most prevalent form
of depression, although the majority of these patients remain in primary
care settings and are rarely seen by psychiatrists. While SSRIs such as sertra-
line have been effective in the treatment of late-life mDD, several trials in
primary care settings support a combined pharmacotherapy–psychotherapy
approach: paroxetine and problem-solving treatment were both superior to
placebo in a primary care trial in patients over 60 years of age, and else-
where, paroxetine was superior to maprotiline in a middle-life population.
There were also some trends to support exercise combined with sertraline
over usual care in older mDD adults. Fluvoxamine was associated with a
significant decrease in depressive symptomatology and an improvement in
psychosocial functioning in an open-label trial (Table 5.10).
Recurrent brief depression

In recurrent brief depression (RBD), the number and severity of symptoms
are comparable to MDD but the duration is shorter: at least two days but less
than two weeks. Despite case reports describing the effectiveness of fluoxe-
tine, mirtazapine, reboxetine and tranylcypromine, neither fluoxetine nor
Table 5.10 Recommendations for treatment of mDD and RBD
Therapeutic choice Recommendations* Evidence
mDD
First Paroxetine (based on individuals aged 60 years and older) Level 2
Second Fluvoxamine Level 3

Maprotiline Level 2
RBD
Not recommended No available support for antidepressant treatment Level 2
*Combining pharmacotherapy with exercise or focused psychotherapy has advantages.
paroxetine was superior to placebo under controlled conditions. The fre-

quency and design of assessments in these trials may account for the nega-
tive results (Table 5.10).
Conclusions
While most antidepressants have demonstrated efficacy across a spectrum of
depressed subpopulations, there is evidence to support specific interventions
in certain populations, including PMD and winter depression. Progress in
defining subgroups of depressed patients based on unique psychobiology,
while promising, has not yet led to unique targeted treatments for distinct
subpopulations.
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Chapter 6
Practical issues in using

antidepressants
Factors influencing antidepressant choice

Selective serotonin reuptake inhibitors (SSRIs) and dual-action antidepres-
sants are the predominant first choice treatments for major depressive disor-
der, although the evidence in favor of superior efficacy compared to classical
antidepressants is limited. Their superior safety and tolerability profiles
account for their widespread use, yet side-effects are not insubstantial and
vary across drug classes and within each drug class.
Some of the antidepressants described in Figure 6.1 (bupropion, duloxe-
tine, milnacipran, moclobemide, reboxetine and selegiline) may not be avail-
able in certain countries; agomelatine, a melatonergic agonist and
serotonergic antagonist agent, is currently under review.
This chapter will address dosing, side-effects, drug interactions, overdose
toxicity and discontinuation-emergent symptoms. Because comparisons of
side-effects across drugs and drug classes are limited by the absence of direct
‘head-to-head’ trials, those side-effects that occurred with a frequency ≥10%
and ≥30% compared to placebo are reported. Clinicians should be aware of
the benefits and prototypic side-effects associated with each antidepressant
class, and develop expertise in using one or two drugs from each class.
First generation antidepressants

The monoamine oxidase inhibitors (MAOIs)
Although no longer first line agents, the monoamine oxidase inhibitors
(MAOIs) continue to serve as a valuable third line alternative when other
First generation Second generation Third generation
MAOI RIMA SSRI SNRI Melatonergic
Phenelzine Citalopram Venlafaxine XR Agomelatine

Tranylcypromine Fluoxetine Milnacipran
Selegiline patch Fluvoxamine Duloxetine
Moclobemide Paroxetine CR
Sertraline
TCA ASRI NDM
Amitriptyline Escitalopram Bupropion SR/XL

Clomipramine
Nortriptyline
and others
NRI NaSSA
Reboxetine Mirtazapine
Figure 6.1 Antidepressant classification by mechanism of action. MAOI,

monoamine oxidase inhibitor; RIMA, reversible inhibitor of MAO-A; TCA, tricyclic
antidepressant; SSRI, selective serotonin reuptake inhibitor; ASRI, allosteric
serotonin reuptake inhibitor; NRI, norepinephrine reuptake inhibitor; SNRI,
serotonin and norepinephrine reuptake inhibitor; NaSSA, noradrenergic and
specific serotonergic antidepressant; NDM, norepinephrine and dopamine
modulator; Melatonergic, melatonergic (MT1 and MT2) agonist and 5-HT2C
antagonist.
Table 6.1 Dosing of MAOIs
Drug Dosage adjustment (mg)

Starting* Usual High†
Irreversible
Isocarboxazid 10–20 30–40 60
Phenelzine 15–30 45–75 90–120
Tranylcypromine 10–20 30–60 70–90
Selegiline transdermal 6/24 hours 6/24 hours 12/24 hours
Reversible
Moclobemide 200–300 450–600 900
*Lower starting dose indicated with previous sensitivity to side-effects or with polypharmacy; often
applies to elderly patients.
†Higher doses often exceed recommended upper limits in formularies; these doses should be used with
caution.
Practical issues in using antidepressants 77
Table 6.2 Frequently reported side-effects across MAOIs
Antidepressant Incidence of side-effects

≥ 30% ≥ 10%
Moclobemide None Insomnia Blurred vision

Excitement; hypomania Hypotension/dizziness
Headache GI distress
Dry mouth
Isocarboxazid None Headache Hypotension/dizziness

Dry mouth GI distress
Tremor
Phenelzine Dry mouth Drowsiness; sedation Tremor

Sexual Insomnia Hypotension/dizziness
dysfunction Excitement; hypomania Tachycardia; palpitations
Blurred vision GI distress
Constipation
Selegiline None Local skin reactions Hypotension; insomnia

transdermal
Tranylcypromine None Drowsiness; sedation Hypotension/dizziness

Insomnia Tachycardia; palpitations
Excitement; hypomania
GI, gastrointestinal.
Table 6.3 Dosing of TCAs*

Starting† Usual High‡
Tertiary amines
Amitriptyline 25–50 75–200 250–300
Clomipramine 50–75 100–250 300–450
Imipramine 50–75 100–250 300–450
Secondary amines
Desipramine 25–50 75–150 200–300
Nortriptyline 25–50 75–150 200
*These are five examples of TCAs; other TCAs include doxepin, dosulepin, maprotiline, protriptyline and
trimipramine. Maprotiline is a heterocyclic antidepressant.
†Lower starting dose indicated with previous sensitivity to side-effects or with polypharmacy; often
‡Higher doses often exceed recommended upper limits in formularies; these doses should be used with
caution.
classes of agents are ineffective or intolerable (Table 6.1). Phenelzine is effec-

tive in the treatment of ‘atypical depression’, while tranylcypromine is often
reserved for previously treatment-resistant depression. Selegeline (L-deprenyl)
has recently become available in the United States as a transdermal prepara-
tion. By avoiding first-pass hepatic metabolism, dietary precautions are not
required within the recommended dose range.
It is necessary to carry out an antidepressant ‘washout’ before starting
MAOIs. In most cases, 10–14 days is adequate, but fluoxetine requires a four-
to five-week washout because of the long half-life of its metabolites. In
general it is important to initiate treatment at a low dose with gradual dose
increments. A two-week washout period is also necessary following discon-
tinuation of any irreversible MAOI, before starting another antidepressant.
The two main limitations of MAOIs are the high side-effect burden (Table
6.2) and concerns about food and drug interactions. Dizziness and orthostatic
hypotension are common to all MAOIs, are often dose related and frequently
result in drug discontinuation. Insomnia and sexual dysfunction are also fre-
quently encountered adverse events. However, the collection of data on side-
effects for these antidepressants was less rigorous than would occur today, so
accurate prevalences are difficult to establish. In clinical practice, side-effects
can sometimes be minimized by altering the timing of dosing. For example,
in some patients, switching from morning to night-time dosing may reduce
insomnia. Foods with high tyramine content, including red wines, tap beer,
aged cheeses, smoked meats, yeast extracts and pickled fish should be avoided
because of the risk of a hypertensive crisis. Decongestants and over-the-
counter cough medicines containing pseudoephedrine or ephedrine may also
produce a hypertensive reaction and should also be avoided.
Moclobemide, as a reversible and selective inhibitor of the MAO-A
enzyme, is available in most countries, and when used within usual dose
ranges does not require dietary restrictions. It is an alternative to SSRIs, par-
ticularly when tolerability is a significant issue. A washout of two to three
days is required following moclobemide discontinuation. Although other
reversible and selective MAO-A inhibitors were evaluated in clinical trials,
none is available by prescription.
Selegiline, an irreversible, but selective inhibitor of MAO-B, has been approved
as an adjunctive treatment for Parkinson’s disease for many years. To overcome
concerns about tyramine-mediated food and drug interactions, a selegiline trans-
dermal system has been developed, and was approved for the treatment of
depression by the US Food and Drug Administration (FDA) in 2006.
The tricyclic antidepressants (TCAs)

TCAs continue to be prescribed worldwide (Table 6.3), although in most
countries they are considered second line agents due to their limited safety
and tolerability. Among the tertiary amines, amitriptyline, clomipramine
and imipramine are the main mixed-uptake blocking agents (see Chapter 4)
and have been most extensively investigated. In meta-analyses of TCAs com-
pared to SSRIs, amitriptyline was more effective in hospitalized depressed
patients compared to SSRIs, although discontinuation rates were also higher.
Amitriptyline, usually at a sub-antidepressant dose, continues to be pre-
scribed for the management of chronic pain, but this may decrease in
response to recent reports that several dual-action antidepressants (duloxe-
tine, milnacipran and venlafaxine) effectively treat painful physical symp-
toms, including diabetic neuropathic pain. While clomipramine is often
used to treat hospitalized depressed patients in Europe, it is only indicated
for the treatment of obsessive compulsive disorder in the United States.
Desipramine and nortriptyline are secondary amines that preferentially
block norepinephrine (NE) reuptake. They respectively display linear and
curvilinear dose–response pharmacokinetics. Monitoring of TCA plasma
levels is recommended for therapeutic and safety reasons.
A major limitation of TCAs is their actions beyond inhibition of NE or
serotonin (5HT) transporters, including effects on cholinergic muscarinic,
Psychomotor activation
Sedation/ Psychosis Sexual dysfunction
drowsiness Activating
Weight gain side-effects
DA reuptake
5HT2
Blurred vision H1 antagonism inhibition agonism
Dry mouth Nausea
5HT 3
Constipation agonism
Ach Traditional
Sinus
antagonism antidepressants 5HT reuptake
tachycardia
inhibition GI disturbances
Urinary Activating effects
retention α1 NE reuptake
Memory inhibition
antagonism inaryg
dysfunction α 2 antagonism – Ur
y m outh ActivatinV
Postural hypotension Dr tion – mor-C
n
Priapism rete ts – Tre s
Dizziness effec trouble
Reflex tachycardia
Figure 6.2 Antidepressant side-effects. Ach, acetylcholine; DA, dopamine.

Adapted with permission from Richelson, 1993.
Table 6.4 Frequently reported side-effects across TCAs

≥ 30% ≥ 10%
Amitriptyline Dry mouth; sedation Disorientation/confusion Tremor

Weight gain Asthenia; fatigue Orthostatic
Blurred vision hypotension/dizziness
Constipation Tachycardia; palpitations
Sweating ECG changes
Clomipramine Dry mouth Insomnia Orthostatic

Sexual Blurred vision hypotension/dizziness
dysfunction Constipation Tachycardia; palpitations
Sweating ECG changes
Tremor GI distress
Weight gain (over 6 kg)
Imipramine Dry mouth Drowsiness; sedation Sweating

Orthostatic Insomnia Delayed micturition
hypotension/dizziness Excitement; hypomania Tremor
Desipramine None Blurred vision Delayed micturition

Dry mouth Tachycardia; palpitations
Constipation
Nortriptyline None Disorientation/confusion Constipation

Asthenia; fatigue Tremor
Dry mouth
ECG, electrocardiogram.
α-adrenergic and histamine H1 receptors (Figure 6.2). Antagonism of these

receptors may result in various side-effects: anticholinergic and cardiovascu-
lar effects are the most prevalent, especially in elderly patients. Side-effects
for the most frequently prescribed TCAs are reviewed in Table 6.4.
Second and third generation antidepressants

The selective serotonin reuptake inhibitors (SSRIs)
Greater tolerability and once-daily dosing have contributed to the wide-
spread adoption of SSRIs as first line antidepressants. For many patients
the starting dose is the effective dose in both acute and maintenance
phases of treatment. When required, dose increments can be made
Table 6.5 Dosing of SSRIs

Citalopram 10–20 20–40 60

Escitalopram 10 10–20 30
Fluoxetine 10–20 20–40 60–80
Fluvoxamine 50–100 150–200 400
Paroxetine 10–20 20–40 60
Sertraline 25–50 50–100 150–200
caution.
without altering the once-daily dosing schedule (Table 6.5). Recent evi-
dence supports differences in mechanisms and outcomes with escitalo-
pram, the only member of the allosteric serotonin reuptake inhibitor
(ASRI) subclass. At a dose of 10 mg, escitalopram appears to be a more
potent inhibitor of the 5HT transporter and a more efficacious antidepres-
sant than the equivalent dose of citalopram (the racemic mixture of S-
citalopram and R-citalopram). This has been linked to the existence of
secondary allosteric binding sites on the 5HT transporter, to which the S
isomer (escitalopram) binds in a manner more favorable to antidepressant
action than the combined R and S isomers contained in citalopram.
Gastrointestinal (GI) side-effects, especially nausea, are common, particularly
during the first one to two weeks of SSRI treatment (Table 6.6). High rates of
sexual dysfunction are reported on direct questioning, but these rates are proba-
bly comparable to those encountered with classical TCA and MAOI therapies.
Serotonin and norepinephrine reuptake inhibitor (SNRI) and

other antidepressants
Venlafaxine, milnacipran and duloxetine all inhibit both 5HT and NE reup-
take, albeit in different ratios. Venlafaxine more potently inhibits the 5HT
transporter, milnacaprin has more NE inhibiting effects and duloxetine
appears to provide a more balanced dual inhibition. Desvenlafaxine succi-
nate (DVS), an active metabolite of venlafaxine, received FDA approval for
the treatment of major depressive disorder (MDD) in 2007.
Table 6.6 Frequently reported side-effects across SSRIs*

≥ 30% ≥ 10%
Citalopram None Drowsiness; sedation Sweating

Escitalopram† Insomnia Tremor
Headache GI distress
Asthenia; fatigue Sexual dysfunction
Dry mouth
Fluoxetine Sexual dysfunction Drowsiness; sedation Dry mouth

Insomnia Tremor
Disorientation/confusion Orthostatic
Headache hypotension/dizziness
Asthenia; fatigue GI distress
Fluvoxamine GI distress Drowsiness; sedation Dry mouth

Sexual dysfunction Insomnia Constipation
Excitement; hypomania Sweating
Headache Tremor
Asthenia; fatigue
Paroxetine Sexual dysfunction Drowsiness; sedation Sweating

Insomnia Tremor
Headache Orthostatic
Asthenia; fatigue hypotension/dizziness
Sertraline GI distress Drowsiness; sedation Dry mouth

Sexual dysfunction Insomnia Tremor
Excitement; hypomania Orthostatic
Headache hypotension/dizziness
*Adapted from Kennedy et al., 2001.

†Escitalopram is the stereoisomer of citalopram – comparable side-effects to citalopram have been
reported.
Mirtazapine acts on both systems by blocking inhibitory receptors, so

indirectly increasing NE and 5HT release, while bupropion has dual-uptake
blocking actions on the dopaminergic and noradrenergic systems.
Agomelatine is a novel antidepressant which acts as a melatonergic (MT1
and MT2) agonist and a 5HT2C antagonist (Table 6.7).
Because of these diverse mechanisms of action, agents in this class have
different side-effect profiles. Bupropion, with dopaminergic effects, tends
to be alerting, and if taken at night would be likely to increase insomnia.
Table 6.7 Dosing of SNRI and other antidepressants

Agomelatine 25 25–50 50
Bupropion (bupropion SR) 75 150–300 375–450
Desvenlafaxine succinate (DVS) 50 100 200
Duloxetine 60 60–120 120
Milnacipran 100 200
Mirtazapine 30 30–45 60
Tianeptine 37.5 37.5 37.5
Trazodone 150–200 300–400 600
Venlafaxine (venlafaxine XR) 37.5–75 112.5–225 300–375
caution.
On the other hand, trazodone and mirtazapine, because of their 5HT 2

receptor-blocking properties, usually improve sleep. As a melatonergic
agonist and a 5HT 2C antagonist agomelatine is not associated with the
various receptor-mediated side-effects described in Figure 6.2 (see also
Chapter 4). Preliminary evidence suggests that it is particularly effective in
restoring restful sleep without causing daytime sleepiness, and is unlikely
to cause sexual dysfunction (Table 6.8).
Other antidepressants with transporter actions

Reboxetine is a NE reuptake inhibiting antidepressant that is prescribed in a
dose range of 4–12 mg. Noradrenergic side-effects include dry mouth, con-
stipation, insomnia and sweating. Tianeptine, a glutamate modulator, is
prescribed at a dose of 37.5 mg and has been associated with rare cases of
insomnia, dry mouth, paresthesia and chest pain. Tianeptine has an effec-
tive clinical profile and preclinically is a potent regulator of neuroplasticity.
Comparing side-effects across SSRIs and SNRIs and

other antidepressants
Early side-effects of SSRIs typically involve central nervous system (CNS) and GI
system disturbances that are usually self-limiting. Delayed side-effects such as
Table 6.8 Frequently reported side-effects across SNRI and other

antidepressants

≥ 30% ≥ 10%
Agomelatine None None

Bupropion None Insomnia Constipation
Headache Tremor
Dry mouth GI distress
Blurred vision
DVS Nausea Abdominal pain Dry mouth
Insomnia Asthemia Constipation
Anorexia Sexual dysfunction
Dizziness; vertigo Nervousness
Sweating
Duloxetine GI distress Drowsiness; sedation Constipation

Insomnia Orthostatic
Dry mouth hypotension/dizziness
Milnacipran Dizziness Constipation;
insomnia
Mirtazapine Drowsiness; sedation Asthenia; fatigue Constipation

Dry mouth Blurred vision
Weight gain (over 6 kg)
Trazodone Drowsiness; sedation Asthenia; fatigue Orthostatic

Dry mouth hypotension/dizziness
GI distress
Venlafaxine GI distress Drowsiness; sedation Dry mouth

Sexual disturbances Insomnia Constipation
Headache Orthostatic
Asthenia; fatigue hypotension/dizziness
GI, gastrointestinal.
sexual dysfunction, weight gain and apathy may occur during ongoing treat-
ment, and in many cases do not remit until after treatment is discontinued.
Sleep, alertness and neurocognition

CNS side-effects associated with the SSRIs and serotonin and norepinephrine
reuptake inhibitors (SNRIs) lie midway between more alerting agents such as
bupropion, and more sedating agents such as mirtazapine. SSRIs and SNRIs
may also cause initial drowsiness and sedation but at a lower rate and level of
intensity. Fluvoxamine and fluoxetine have been associated with apathy and
indifference, although it is often difficult to distinguish between drug-
induced apathy and residual symptoms of depression. The anticholinergic
actions of TCAs and paroxetine affect cognitive function and have been
shown to delay word recall. Ironically, most antidepressants have a pro-
nounced inhibitory effect on rapid eye movement (REM) sleep, which further
disrupts circadian rhythm, in a disorder characterized by circadian rhythm
disturbance: the majority of antidepressants prolong REM latency, disrupt
sleep continuity and decrease total REM sleep. Agomelatine does not appear
to have any adverse effects on sleep, alertness or neurocognition and may
improve the sleep disruption found in depression.
Metabolism and weight change

Antidepressant-related weight gain is one of the main reasons for poor treat-
ment adherence and drug discontinuation, and it is more likely to occur in
patients who are overweight or obese prior to treatment. Rapid weight gain
with TCAs and mirtazapine has been linked to blockade of histamine H1
receptors, resulting in increased carbohydrate craving and food intake.
Weight gain during MAOI therapy is more likely to be caused by fluid reten-
tion.
Table 6.9 Conclusions about weight gain during antidepressant

treatment
Conclusions Evidence
Acute phase
Weight neutral
SSRIs; agomelatine; bupropion; duloxetine; moclobemide; venlafaxine Level 2
Weight gain
Mirtazapine results in weight gain of 7% or more in up to 14% of patients Level 2
TCAs cause weight gain in a significant proportion of patients Level 2
Maintenance phase
Data on weight change with maintenance treatment are inconclusive
Low rates of weight gain (< 10%) are reported with bupropion and Level 2
moclobemide
Minimal weight loss may occur during the first few weeks of SSRI or SNRI
treatment because of nausea, although weight gain during long-term SSRI
treatment has been reported, especially with paroxetine. Agomelatine and
bupropion SR/XL do not appear to cause weight gain. Short-term trials
suggest that venlafaxine, milnacipran and duloxetine are also weight-neutral
(Table 6.9).
Sexual dysfunction
Agomelatine, bupropion and mirtazapine are associated with low levels of
sexual dysfunction, while fluoxetine, paroxetine, sertraline, venlafaxine and
other SSRIs are associated with diminished arousal and orgasmic dysfunc-
tion in up to 50% of patients. Men are more likely to report sexual dysfunc-
tion with SSRIs than are women (Table 6.10).
Potential for drug–drug interactions

Most antidepressants are metabolized by one or more of the cytochrome
P450 (CYP) hepatic isoenzymes. Pharmacokinetic interactions occur when a
co-prescribed medication acts as an inhibitor or inducer of one or more of
these isoenzymes (Table 6.11). Among SSRIs, fluvoxamine is a potent
inhibitor of CYP1A2 and CYP2C19, fluoxetine and fluvoxamine are potent
CYP2C9 inhibitors and fluoxetine and paroxetine potently inhibit CYP2D6.
Among the other antidepressants, including SNRIs, none is a potent
inhibitor of CYP isoenzymes, although duloxetine is a moderate inhibitor of
CYP2D6.
Table 6.10 Frequency of sexual dysfunction during antidepressant

treatment (Level 2)
Incidence of sexual dysfunction
<10% 10–30% >30%
Agomelatine Citalopram Fluoxetine

Bupropion Duloxetine Fluvoxamine
Mirtazapine Escitalopram Paroxetine
Moclobemide Venlafaxine Sertraline
Protein binding may also influence the potential for drug interactions.
When a highly protein-bound drug is displaced, there is a greater increase in
the amount of unbound drug in plasma compared with a drug that has low
protein binding. This is particularly a problem with the anticoagulant war-
farin, because dangerous alterations in clotting time can occur. Among cur-
rently available antidepressants, venlafaxine has the lowest degree of protein
binding and would be least affected by competitive displacement.
Table 6.11 Pharmacokinetics of second and third generation

antidepressants
Medication Biotransformation pathways Half-life Protein

(hours) binding (%)
Second generation
Bupropion SR Hydroxylation involves 21 84
CYP2B6 (parent)
Citalopram and Demethylation in two steps involves 37 (citalopram) 80

escitalopram CYP2C19, 2D6 and 3A4 30 (escitalopram)
Duloxetine Oxidation (involves CYP2D6 and 9–19 >95

1A2), methylation and no active (parent)
conjugation (sulfate and metabolite
glucuronide)
Fluoxetine Demethylation involves CYP2D6 96–144 95
Fluvoxamine Demethylation and deamination 17–22 80

involve CYP2D6 and 1A2
Mirtazapine Demethylation and 20–40 85

hydroxylation involve (parent) (parent)
CYP2D6, 1A2 and 3A4
Paroxetine Oxidation and demethylation 24 95

involve CYP2D6
Sertraline Demethylation involves CYP3A4 25–26 98
Venlafaxine O-demethylation involves 5–7 (parent) 27 (parent)

IR/XR CYP2D6 and others 11–13 (ODV) 30 (ODV)
Third generation
Agomelatine Metabolism involves CYP1A2 1–2 95
and CYP2C9
ODV, O-desmethylvenlafaxine.
Safety in overdose
In countries where TCA prescriptions remain high, death following overdose
continues to be an important concern. Among TCAs and MAOIs,
desipramine and tranylcypromine have been the most lethal. Venlafaxine
has also been linked to higher rates of death by suicide. However, these
uncontrolled retrospective reports do not take into account prior psychiatric
history, including suicidality, severity of depression and previous treatment
resistance.
Discontinuation and discontinuation-emergent symptoms

Discontinuation rates in the 15–30% range are typical during acute treat-
ment, and are significantly higher in patients who receive TCAs compared
with SSRIs. Discontinuation rates are also likely to be higher in actual prac-
tice than in clinical trials. Unfortunately, there are no consistent evidence-
based biological markers to predict recurrence of depression, although some
demographic and clinical parameters have been identified as risk factors (see
Chapter 2). At the end of two years, patient and physician should confer
about stopping medication. The decision reflects a balance between the
benefits (preventing recurrence) and the risks (side-effects, cost and inconve-
nience) of staying on medication versus discontinuation. Patients who
decide to discontinue an antidepressant should be educated about prodro-
mal symptoms that might signal impending recurrence. These are often
specific for a given individual, and may include alterations in sleep and
appetite, lowering of mood or other idiosyncratic changes such as increased
sensitivity to emotional films or literature. Relapse may be preceded by
periods of life stress, and patients should be warned to be more vigilant
about their mood when under stress.
Although discontinuation-emergent effects were observed with TCAs, the
experience of many patients who rapidly discontinued SSRIs or venlafaxine
highlighted the importance of tapered discontinuation. Tapering, and in
some cases substituting one or two doses of fluoxetine, may prevent or allevi-
ate these symptoms. However, tapering does not guarantee the prevention of
at least some discontinuation symptoms. Agents with a short half-life are the
most likely to be associated with discontinuation-emergent symptoms such as
nausea, insomnia, sweating, headache and delirium. These agents include
venlafaxine, paroxetine and fluvoxamine. However, discontinuation of newer
agents, such as agomelatine, does not appear to result in these symptoms.
Conclusions
Despite advances in treatment options, many patients do not achieve remis-
sion, and frequently experience recurrence. This limitation in effectiveness
across antidepressant classes, and the side-effect burden associated with
current antidepressants, in particular CNS side-effects, weight gain and
sexual dysfunction, argue for exploration of alternative therapeutic targets in
the treatment of depression. Clinicians are advised to have a working knowl-
edge of standard dosing, side-effect and safety profiles as well as drug interac-
tions and discontinuation effects for antidepressants from established and
emerging classes.
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Chapter 7
Sequential
pharmacotherapies and
treatment-resistant
depression
There is no generally accepted evidence-based sequence for antidepressant

interventions. However, there is agreement that several strategies should be
considered. These include optimization, switching, augmentation and combi-
nation strategies (Figure 7.1). Until recently, no single large trial had been
carried out to compare many of these options. This chapter will review results
from the first such trial published in 2006 on sequential treatments and
extend the discussion to other treatment options, including the role of atypi-
cal antipsychotics. Neuromodulatory therapies including electroconvulsive
therapy (ECT) and other somatic treatments also have an important role to
play in treatment-resistant depression (TRD) and are discussed in Chapter 8.
Overview of STAR*D results

A large effectiveness trial sponsored by the US National Institute of Mental
Health, involving over 40 psychiatric and primary care sites and more than
3000 ‘real world’ patients, was published in 2006. This Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) trial was designed to include
generalizable samples and to ensure the delivery of adequate treatments in a
sequenced design. Citalopram was selected as the first-level antidepressant,
and approximately 30% of depressed patients achieved remission after treat-
ment for up to 14 weeks. Patients who did not achieve remission were
encouraged to proceed to each of the next treatment levels until they did
achieve symptom remission.
Optimization
(up to 12 weeks)
Failure to achieve remission
Switch Combine
Failure to achieve remission
Switch Combine
ECT Novel therapies
Figure 7.1 Sequential approach to treatment-resistant depression.
Level 2 and 3 interventions involved either switching or augmentation/

combination strategies. Although assignment to Level 2 and Level 3 treat-
ments was random, patients were allowed to exercise choices about the
acceptability of each option. The switching options at Level 2 were: another
selective serotonin reuptake inhibitor (SSRI) (sertraline) or one of two dual-
action drugs (bupropion SR or venlafaxine XR). Approximately one in four
patients achieved remission at this level, irrespective of the substitution.
Level 2 augmentations to citalopram involved either bupropion SR or bus-
pirone, and approximately 30% achieved remission in each of these groups.
Cognitive therapy was also an option for switching and for augmentation at
Level 2. At Level 3, switching to mirtazapine or nortriptyline were the
options, and remission rates of 12% for mirtazapine and 20% for nortripty-
line were reported. These were not significantly different, because of the
small sample size. The augmentation options at this level were lithium and
triiodothyronine (T3). Again, modest remission rates were reported: 16% for
lithium and 25% for T3, and these differences were not statistically different.
Sequential pharmacotherapies and treatment-resistant depression 95
Finally, at Level 4, approximately 100 of the original 4000 enrolled patients

were randomly assigned to receive open-label treatment with either tranyl-
cypromine or venlafaxine XR plus mirtazapine. Remission rates were not sig-
nificantly different (7% for the tranylcypromine group and 14% for the
venlafaxine XR plus mirtazapine group).
This large sequenced trial will likely provide valuable additional informa-
tion about patient characteristics associated with favorable outcomes for
each level of treatment. More importantly, it may also contribute to the lit-
erature on predictive factors for poor outcome. The STAR*D study also high-
lights the high attrition rate in long-term studies, paricularly where multiple
consents and randomizations are required. It is extremely unfortunate that
adequate samples within the subtrials were not available to detect statisti-
cally significant and clinically meaningful differences among the various
switching and combination strategies. The adoption of a ‘self selection’
option within the design of STAR*D did add to the ‘real world’ generalizabil-
ity of the trial, but it also prevented a comparison between these combina-
tion and switching therapies.
Treatment-resistant depression
Treatment-resistant depression (TRD) is a relative concept. Several definitions
have been proposed, ranging from non-specific (inadequate response follow-
ing adequate antidepressant therapy) to more operationally defined (failure
to respond to two adequate trials of different classes of antidepressants).
Others have suggested staging levels of resistance, with a recommendation
that treatment with first line antidepressants from SSRI and serotonin and
norepinephrine reuptake inhibitor (SNRI) classes should precede trials of
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

Failure of one Stage 1 resistance Stage 2 resistance Stage 3 resistance Stage 4 resistance
adequate AD plus failure in a plus failure of plus failure of plus failure of
trial distinctly different adequate TCA adequate MAOI course of bilateral
pharma class trial trial ECT
Figure 7.2 Proposed switching sequence for treatment-resistant depression.

Treatment resistance can be conceptualized as a continuum, beginning with
the first failure to respond to an adequate trial of an antidepressant (AD).
Adapted with permission from Thase and Rush, 1997.
tricyclic antidepressant (TCA) and monoamine oxidase inhibitor (MAOI)

antidepressants before moving to ECT (see Figure 7.2). While most studies of
TRD have used this definition for eligibility, it poses several disadvantages: it
does not include augmentation or combination strategies and does not dis-
tinguish between full and partial clinical response. The remainder of this
chapter will focus on the evidence to support various switching and combi-
nation strategies, including the data from STAR*D.
Optimization
Practically speaking, optimization usually means increasing to the maximum
approved dose or until limited by side-effects. Particularly for TCAs, plasma
monitoring is an important aspect of clinical care. Most TCAs have a linear
dose–response relationship with the exception of nortriptyline, which has a
limited ‘window’ of therapeutic efficacy, above which antidepressant effects
are reduced. In contrast, SSRIs do not show a dose–response pattern, which
limits the value of obtaining plasma levels. Among the dual-action agents,
venlafaxine shows most evidence of a dose–response relationship, with supe-
rior response rates at the higher dose ranges; this has been linked to the
engagement of norepinephrine (NE) transporter blockade at doses of 125 mg
or more. Duloxetine has yet to be evaluated at higher than recommended
dose levels, while mirtazapine does not appear to offer increased effective-
ness above 60 mg daily. Safety concerns about increased risk of seizure limit
the use of bupropion beyond 450 mg daily. Agomelatine has only been eval-
uated at 25 mg and 50 mg doses in clinical trials, so there is no evidence to
support its use at other doses.
Patient differences also need to be considered. Genetically determined dif-
ferences in drug metabolism include cytochrome P450 polymorphisms, and
variations in monoamine transporters such as the serotonin transporter.
These individual differences influence the experience of thereapeutic and
adverse effects and may result in some patients requiring higher than usual
doses, while others may require very low doses. Brain imaging studies of
receptor or transporter occupancy may offer a clinically useful measure of
maximum dosing, although these techniques are not available routinely.
Switching
Switching medications is typically the first recommended strategy, but even
after STAR*D there is no evidence to guide the clinician in deciding whether
to switch from or augment the index antidepressant. In two studies, these

strategies yielded different results. In the first, there were no differences
between optimization (higher-dose fluoxetine), augmentation (lithium
added to standard-dose fluoxetine) and combination (desipramine added to
fluoxetine), although lower than usual doses were prescribed in the combi-
nation and augmentation groups. In the second study, optimization (higher-
dose sertraline) was less effective than the combination of mianserin and
sertraline.
In the absence of evidence-based results, practical considerations, includ-
ing the side-effect burden of a particular medication, whether there is a
partial response and previous medication history, should all be taken into
account to guide the sequence of treatment selection.
Practical aspects of switching

Antidepressants can be switched either within a medication class or to a dif-
ferent class. There is no evidence to support switching within the TCA class,
but switching among SSRIs may be an option, particularly when the reason
for switching is lack of tolerability. However, most clinicians switch from
one class of antidepressant to another when there has been no response to
the first drug (e.g. from SSRI to dual-action or TCA). The judicious use of
MAOIs remains an option for TRD, provided that appropriate dietary and
drug precautions are followed.
Generally, there is no need for a washout period between stopping one
antidepressant and starting another. As the first antidepressant is being
tapered, the new agent is added (‘cross-over’), but some patients may experi-
ence additive side-effects in the overlap period. For a patient who has not
tolerated the first antidepressant, it may be wise to provide a washout period,
allowing the side-effects to dissipate before starting a second antidepressant.
An important exception involves starting or stopping MAOIs. When starting,
it is necessary to implement a two-week washout (four to five weeks for
fluoxetine). When stopping an MAOI there is also a need to wait two weeks
before starting another antidepressant (including the switch from phenelzine
to tranylcypromine). As a reversible MAOI, moclobemide only requires a
two- to four-day washout after it is discontinued.
Drug–drug interactions related to the cytochrome P450 system must also
be considered during a cross-over switch. For example, when switching from
fluoxetine (a long half-life SSRI that significantly inhibits CYP2D6) to
desipramine (a TCA that requires this isoenzyme for metabolism), the start-
ing dose of desipramine should be lower than usual. If problems emerge, an
electrocardiogram and plasma levels of desipramine should be obtained as
there is significant risk for cardiotoxicity.
Augmentation and combination therapies

Technically, ‘augmentation’ describes adding a medication that by itself is
not an antidepressant to a recognized antidepressant. The addition of a
second antidepressant at subtherapeutic doses is also considered to be an
augmentation strategy, while ‘combination’ therapy involves the prescrip-
tion of two antidepressants at therapeutic doses. However, these terms are
often used interchangeably, as in STAR*D.
There have been relatively few controlled trials to evaluate augmentation
strategies for TRD. There is most evidence to support antidepressant aug-
mentation with lithium and olanzapine, athough the comparable outcomes
with lithium and T3 augmentation as Level 3 interventions in STAR*D
support renewed interest in thyroid augmentations (Table 7.1). Lithium-
induced side-effects are dose related, and in STAR*D were more burdensome
than side-effects with T3.
Atypicals as augmentation therapies

There is emerging evidence that novel antipsychotic agents are effective aug-
mentation agents for non-psychotic major depressive disorder (MDD) and
TRD. Compared to typical or first generation antipsychotic agents (e.g.
haloperidol), these agents produce lower rates of extrapyramidal symptoms or
tardive dyskinesia. On the other hand, concerns about weight gain and dysreg-
ulation of glucose metabolism have been raised. Among these ‘atypicals’ there
is most evidence to support olanzapine as an augmentation therapy with
SSRIs. Olanzapine (5–15 mg daily) in combination with fluoxetine (20–60 mg
daily) was significantly more effective than either agent alone for TRD in
several trials. Risperidone was also more effective than placebo when com-
bined with SSRI and non-SSRI antidepressants. This was replicated in a second
study, where risperidone augmentation of citalopram under unblinded condi-
tions enhanced response in TRD, but this combination was not superior to
placebo augmentation of citalopram in preventing relapse. In 2007 only open-
label trials have been published to support the role of other atypicals (quetiap-
ine, ziprasidone and aripiprazole) as augmentors, often in TRD.
Table 7.1 Recommendations for augmentation strategies in

treatment-resistant depression
Therapeutic choice Recommendations Dose Evidence
First Lithium 600–900 mg Level 1

or to therapeutic
serum levels
Olanzapine 5–15 mg Level 1
Triiodothyronine (T3) 25–50 µg Level 2
Second Risperidone 0.5–2 mg Level 2

Buspirone 30–60 mg Level 2
Psychostimulants* Usual doses Level 2
Third Lamotrigine 100–200 mg Level 3

Trazodone 100–200 mg Level 3
Tryptophan† 2–4 g Level 3
Not recommended Pindolol 7.5–1.5 mg Level 1
*Enhances motivation and energy.

†Limited availability.
Other augmentation strategies

Buspirone, a partial post-synaptic 5HT1A agonist with a metabolite that pro-
motes NE neuron-firing, was beneficial in a number of open-label studies,
but a placebo-controlled trial was negative. Subsequently, in STAR*D, the
effect of adding buspirone to citalopram was comparable to adding bupro-
pion at the Level 2 stage.
Pindolol, a beta-blocking drug that, in low doses, also acts as a specific
antagonist of the 5HT1A presynaptic autoreceptor, was also investigated to
see whether it accelerated onset of action and increased response rates.
However, in a large randomized study, pindolol failed to augment either an
SSRI or clomipramine in TRD. Tryptophan is a natural amino acid and a pre-
cursor of serotonin. Limited evidence exists to support the use of tryptophan
as an augmentation agent (see Chapter 9 for further discussion).
Although there is a long tradition of using psychostimulants to augment
antidepressants, the evidence from randomized controlled trials (RCTs) for
both methylphenidate and modafinil, a non-dopaminergic stimulant,
confirms enhanced effects on energy and alertness but not mood, as a
consequence of augmentation therapy. There is also anecdotal evidence to

support the use of trazodone in low doses as an augmentation strategy,
although trazodone is mainly prescribed as a hypnotic, at doses that are con-
siderably below the antidepressant dose range.
Combination strategies
One of the first combination antidepressant strategies to be evaluated
involved adding an MAOI to a TCA. However, in the only controlled trial,
this combination was not superior to treatment with either agent alone, and
given the safety concerns it is rarely used. Since then numerous combina-
tions have been advocated, but surprisingly few have been studied in a con-
trolled design.
Two antidepressants with different monoaminergic actions are often pre-
scribed in TRD (Table 7.2). Theoretically this should enhance antidepressant
effects. For example, combining desipramine and an SSRI provides both NE
and serotonin (5HT) transporter inhibition. Unfortunately, the combination
of fluoxetine and desipramine has potentially dangerous kinetic interactions
that may result in high plasma desipramine levels and cardiac death. If this
combination is used it requires careful monitoring.
In other cases the combination may allow one agent to offset the adverse
effects of the other in addition to enhancing antidepressant outcomes. This
has been the rationale for bupropion combinations with an SSRI or venlafax-
ine to increase remission rates and improve sexual dysfunction. Similarly,
adding mirtazapine to an SSRI or venlafaxine provides potential additional
antidepressant action and may also improve sleep, nausea or sexual dysfunc-
tion. Mianserin, like mirtazapine, has presynaptic α2-blocking properties that
indirectly enhance both noradrenergic and serotonergic transmission. This
drug has been effective in combination with TCAs as well as sertraline and
fluoxetine.
Generally, adding two antidepressants in combination is well tolerated, but
drug–drug interactions must be considered. Several combination strategies
were evaluated in the STAR*D protocol: at Level 2 adding bupropion to citalo-
pram; and at Level 4 combining venlafaxine XR and mirtazapine. The citalo-
pram–bupropion combination was one of the few to achieve a statistical
advantage, while the mitazapine–venlafaxine XR combination was only eval-
uated under open conditions in a relatively small population of depressed
patients who had failed three previous trials within the STAR*D protocol.
Table 7.2 Recommendations for combination strategies in

treatment-resistant depression
First SSRI + mirtazapine/mianserin Level 2

Second SSRI/SNRI + bupropion SR Level 3
Third SSRI + TCA (caution for increased serum Level 2
TCA levels with some SSRIs)
SSRI + RIMA* Level 3
*Caution for serotonin syndrome. RIMA, reversible inhibitor of monoamine oxidase A.
Conclusions
Advantages of switching from one to another antidepressant, compared to
augmentation or combination strategies, include the simplicity of monother-
apy and the lack of potential drug–drug interactions. Monotherapy may also,
but not necessarily, lead to fewer side-effects and better adherence. On the
other hand, augmentation and combination strategies have the potential
advantage of building on a partial response, avoiding potential discontinua-
tion symptoms, and the possibility of achieving a rapid response. Adding
another agent also buys more time for a latent therapeutic effect from the
index medication. The drawbacks to combination antidepressant use include
the possibility that a patient might simply have responded to monotherapy
with the second agent, yet he or she is exposed to additional side-effects and
the extra cost of a second medication. Finally, the differences between
sequential build combinations and immediate combination strategies have
generally not been evaluated.
While the field of sequenced antidepressant strategies, including the role
of single versus combination treatments, has received considerably more
attention in the new millenium, it is still not possible to provide evidence
based guidelines to support or abandon many suggested options.
Nevertheless the burgeoning use of atypical antipsychotic agents in the treat-
ment of depression, as well as the provocative but frequently unanswered
questions raised by STAR*D has highlighted the need for further large ran-
domized controlled trials in TRD.
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842–8.
Barbee JG, Jamhour NJ. Lamotrigine as an augmentation agent in treatment-resistant

depression. J Clin Psychiatry 2002; 63: 737–41.
Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-

analysis of placebo-controlled studies. J Clin Psychopharmacol 1999; 19: 427–34.
Baumann P, Nil R, Souche A et al. A double-blind, placebo-controlled study of citalo-

pram with and without lithium in the treatment of therapy-resistant depressive
patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin
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tation of partial and non-responders to serotonergic antidepressants. J Clin
Farvolden P, Kennedy SH, Lam RW. Recent developments in the psychobiology and
pharmacotherapy of depression: optimising existing treatments and novel approaches
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Fava M. Diagnosis and definition of treatment resistant depression. Biol Psychiatry

2003; 53: 649–59.
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lithium or desipramine augmentation of fluoxetine in partial responders and nonre-
sponders to fluoxetine. J Clin Psychopharmacol 2002; 22: 379–87.
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following two consecutive failed medication treatments for depressed outpatients: a
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Kennedy SH, Eisfeld BS, Meyer JH, Bagby RM. Antidepressants in clinical practice: lim-
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of depressive disorders. IV. Medications and other biological treatments. Can J
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and sexual dysfunction effects. J Clin Psychiatry 2002; 63: 181–6.
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sequential combination treatment strategies in partial responders to antidepressant
medication: an exploratory trial. J Clin Psychiatry 2003; 64: 439–44.
Lam RW, Wan DD, Cohen NL, Kennedy SH. Combining antidepressants for treat-
ment-resistant depression: a review. J Clin Psychiatry 2002; 63: 685–93.
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Chapter 8
Neuromodulation and
other physical treatments
Approximately 50% of patients fail to achieve an adequate response to a first

antidepressant treatment, and over half of those fail to respond to a second
pharmacotherapy approach. However, with the increase in evidence sup-
porting neuromodulatory therapies, these treatments provide a viable alter-
native for the treatment of depression, although many are investigational
options. This chapter will evaluate the evidence to support electroconvul-
sive therapy, repetitive transcranial magnetic stimulation, vagus nerve stim-
ulation and deep brain stimulation.
Electroconvulsive therapy
Among currently available physical treatments for depression, electrocon-
vulsive therapy (ECT) is the most established and most effective. It appears
to have faster and more marked effects than antidepressant drugs as well as a
plausible rationale for activity. ECT has been shown to stimulate amine func-
tion in a progressive fashion, starting with dopamine (DA), then norepi-
nephrine (NE) and finally serotonin (5HT). These neurochemical changes
and sequential alterations in second messengers and growth factors probably
underlie the mechanism of action of ECT to ameliorate the many symptoms
of depression (Figure 8.1).
Efficacy and indications

A sustained response rate of 80% and a remission rate of 75% were achieved
in a prospective acute trial of bilateral ECT (and these rates were higher in
the psychotic major depression group compared to the non-psychotic
group). However, many of the trials involving ECT have methodological
limitations. In particular, many are uncontrolled, and there are very few
Seizure number
1–2 Enhance dopamine receptor function
3–5 Enhance synaptic norepinephrine
6–8 Enhance 5HT function
Figure 8.1 Proposed sequential neurotransmitter mechanisms following ECT.
direct comparisons between ECT and selective serotonin reuptake inhibitor

(SSRI) or dual-action antidepressants.
There is evidence to suggest that response rates to ECT are higher in
elderly patients compared with middle-life patients. This means that it is
often used as a first choice in elderly depressed patients, particularly those
experiencing psychotic or melancholic symptoms. Polarity of mood disorder
does not appear to influence outcome, although chronicity of episode and
comorbid personality disorders are predictors of a poor response. It has also
been suggested that patients who are resistant to antidepressants have both a
lower response rate to ECT and a higher relapse rate within six months,
although naturalistic studies do not show a relationship between antidepres-
sant refractoriness and clinical outcome.
Careful pre-anesthetic examination is essential, particularly for patients
who have additional risk factors, including myocardial ischemia, cardiac
arrhythmias, a pacemaker or an abdominal aneurysm. Indications for ECT
are presented in Table 8.1. Apart from raised intracranial pressure, there are
no absolute contraindications.
Treatment parameters
With fewer hospital beds available for psychiatric admissions and shorter
lengths of stay in inpatient units, ECT is increasingly provided on an ambu-
latory or outpatient basis. During the acute-treatment phase, ECT should be
administered two or three times weekly for up to six weeks, and a typical
Neuromodulation and other physical treatments 107
Table 8.1 Indications for ECT
• Acute suicidal ideation

• Psychotic major depression
• Catatonia
• Treatment-resistant depression
• Repeated medication intolerance
• Rapidly deteriorating physical status (food/fluid refusal)
• Prior favorable response
course is between six and 20 treatments. A less frequent schedule may mini-
mize some of the immediate cognitive side-effects of ECT, but response is
slower.
Electrode placement may be unilateral (UL) to the non-dominant hemi-
sphere, or bilateral (BL). Patients who receive UL-ECT (Figure 8.2) usually
experience less short-term impairment of memory or language. However, it
can be harder to achieve an adequate duration of seizure, making it espe-
cially important to optimize the electrical dose relative to the seizure thresh-
old at the first treatment. Individual assessment of seizure threshold is
critical because there is at least a 12-fold range in seizure threshold among
patients.
The effectiveness of ECT depends on both duration and intensity of
seizures. Seizures should last at least 25 seconds and should be monitored
visually, and if possible by electroencephalogram (EEG). Accurate visual
Figure 8.2 Patient about to receive ECT.

Table 8.2 Strategies to promote seizure activity
• Increase the electrical charge

• Discontinue any drugs that raise seizure threshold, e.g. benzodiazepines; valproic acid;
carbamazepine
• Use a seizure threshold-lowering agent such as caffeine or doxapram
• Switch from UL to BL placements
monitoring is best done using a blood pressure cuff to exclude muscle relax-
ant from one arm, so that muscle contractions can be seen. Recom-
mendations to manage inadequate seizure activity are provided in Table 8.2.
Adverse effects
ECT is a safe procedure. Mortality and morbidity rates are extremely low in the
modern era, approximating to the risk of general anesthesia. Mortality associ-
ated with ECT is estimated to be 0.2 per 100 000 treatments, and is most often
related to cardiovascular anesthetic complications. The adverse event rate asso-
ciated with ECT is around 0.4%. Adverse events can include musculoskeletal or
dental injuries, superficial skin burns, oral lacerations and persistent myalgia
(secondary to the muscle relaxant). Nausea, headaches and muscle aches are
common post-treatment events, which can be treated with antiemetics or
analgesics.
Cognitive side-effects associated with ECT have limited its level of recom-
mendation in the treatment of depression. These effects are well documented,
and include an acute confusional state lasting minutes to hours, as well as
anterograde and retrograde amnesia. Subjective complaints of immediate and
often persistent (at least two months) deficits in some aspects of autobiograph-
ical memory (mostly impersonal memories such as public events) occur fre-
quently. In some studies, objective memory testing six months after treatment
showed a marked improvement compared to the depression-associated pre-
treatment memory, although persistent lacunae of memory deficits for events
occurring around the time of the ECT are common. In a prospective study, the
administration of BL-ECT and sine wave stimulation were associated with
more severe and persistent cognitive deficits. In addition, electrical dosages
above threshold levels, more frequent administration (three times rather than
twice a week) and persistence of depressed mood have been associated with
cognitive impairment.
Table 8.3 Indications for maintenance ECT
• History of previous response to ECT

• Failure to remit with pharmacotherapy – non-response or intolerance
• Frequent recurrence of depressive episodes
• Recurrent delusional (psychotic) major depression
• Patient preference
Maintenance ECT
ECT may also be used as a maintenance treatment, with titration schedules
ranging from once weekly to once monthly. In one randomized study with a
six-month follow-up after a successful acute course of bilateral ECT, there were
no differences between continuation ECT and a combination of nortriptyline
and lithium. Continuation or maintenance ECT (Table 8.3) is less likely to
cause cognitive side-effects, possibly due to the longer time interval between
treatments. There is no credible evidence that ECT causes any form of struc-
tural brain damage; in fact electroshock in animals has been shown to
promote neurogenesis, and prospective neuroimaging studies using computed
tomography (CT) or magnetic resonance imaging (MRI) techniques show no
structural changes in the brain after ECT.
ECT in combination with antidepressant medication

There is very little evidence to suggest that combining antidepressants with
ECT improves the response. When patients are receiving ECT, they have
usually failed antidepressant treatment, so it does not make much sense to
continue the same medication. Starting a new medication during ECT causes
clinical confusion about both efficacy and side-effects. Also, there is no good
evidence that starting an antidepressant concurrently with ECT improves
outcome, and it has also been reported that in some cases antidepressant
drugs, including SSRIs, may prolong seizure duration. The usual practice is
therefore to start medication after the last ECT session.
There are claims that concurrent lithium therapy is responsible for delir-
ium or prolonged confusion after ECT. For this reason most ECT protocols
require discontinuation of lithium before initiating ECT. The use of seda-
tives including benzodiazepines and anticonvulsants, such as carbamazepine
or valproic acid, may inhibit seizures or shorten seizure duration, and there-
fore their use with ECT is not recommended.
Table 8.4 Summary of evidence regarding ECT
• ECT is an effective treatment for major depressive disorder (MDD) Level 1
• Indications for ECT include acute suicidal risk, severe physical deterioration, Level 2
• depression with psychotic features, treatment resistance to medications
and patient preference
• Unilateral electrode placement requires suprathreshold current for optimal Level 2

• results
• Side-effects of ECT are greater with BL electrode placement and frequently Level 2
• include retrograde memory disturbance
• Maintenance ECT should be considered when pharmacotherapies have Level 3

• been ineffective or intolerable
Prevention of relapse following ECT

Without some form of maintenance treatment, the rate of relapse following
ECT is high: between 50% and 95% within six months. Predictors of relapse
include medication resistance prior to ECT and greater severity of depres-
sion. Maintenance pharmacotherapy for at least one or two years is nearly
always indicated to prevent relapse, yet there are very few studies to inform
clinicians about treatment selection. The combination of nortriptyline and
lithium was significantly more effective in reducing relapse rates following
ECT compared to nortriptyline alone. Continuation ECT was also as effective
as the combination of nortriptyline and lithium in reducing relapse.
Medications that were ineffective when used in an optimal fashion prior to
ECT should not be used for post-ECT maintenance.
Recommendations for ECT are summarized in Table 8.4.
High frequency repetitive transcranial magnetic

stimulation
Efficacy and indications
The non-invasive nature of this treatment increases its potential application
compared to other more invasive neuromodulatory therapies. Repetitive
transcranial magnetic stimulation (rTMS) involves repeated subconvulsive
magnetic stimulation delivered with a wand positioned over the left dorso-
lateral prefrontal cortex (Figure 8.3).
Figure 8.3 Patient about to receive rTMS, sitting relaxed and awake before
application of high frequency stimulation. (Courtesy of Dr Jeff Daskalakis.)
Positive results in a number of small randomized trials are supported by

meta-analyses, comparing high frequency rTMS to sham conditions, antide-
pressant medications and ECT. Although ECT was superior to rTMS in major
depressive disorder (MDD) patients with psychotic symptoms, non-psychotic
patients responded equally well to both treatments. The authors of a recent
review concluded that while it is premature to recommend rTMS in the treat-
ment of depression, this method deserves further investigation. Prefrontal
atrophy, non-response to pharmacotherapy and the presence of psychotic
or melancholic symptoms are predictive of non-response. This treatment,
and those that follow, are summarized in Table 8.5.
rTMS involves the stimulation of cortical neurons by magnetic induction,
using a brief, high-intensity magnetic field. The electrical current is rapidly
turned on and off to produce a time-varying magnetic field lasting 100 to
200 microseconds. Repetitive stimulation with frequencies in the range of 1
to 20 Hz is applied over the course of about 30 minutes during a treatment
session. The magnetic pulse crosses the scalp almost painlessly, causing neu-
ronal stimulation and depolarization to a depth of about 2 cm below the
surface of the brain. The strength of the magnetic field is insufficient to
reach deeper subcortical cingulate or limbic structures. Mild headache and
discomfort at the site of stimulation are the main side-effects.
Table 8.5 Recommendations for investigational neuromodulation

therapies
• rTMS: preliminary evidence supports the efficacy of rTMS in non-psychotic Level 2

• and non-TRD populations
• VNS received FDA approval as an adjunctive long-term treatment of TRD Level 2
• DBS: preliminary results for TRD await replication under RCT conditions Level 3
• Neurosurgical procedures including subcaudate tractotomy and anterior Level 4

• cingulotomy have support in TRD from case series only
rTMS, repetitive transcranial magnetic stimulation; TRD, treatment-resistant depression; VNS, vagus nerve
stimulation; FDA, Food and Drug Administration; DBS, deep brain stimulation; RCT, randomized
controlled trial.
Combination with antidepressants

Potential clinical uses include the treatment of medication-refractory
patients, perhaps in place of ECT. Because of its rapid onset of effect, it may
also hasten clinical response in conjunction with antidepressants. As yet,
however, there is no consensus about the optimal treatment parameters,
including frequency and anatomic location of stimulation. Most of the posi-
tive results have yet to be replicated, the follow-up periods are brief (two to
four weeks) and there are no long-term or maintenance studies.
In summary, rTMS is an attractive alternative to ECT because it is non-
invasive, can be conducted in outpatient settings, does not require anesthe-
sia or sedation and has no effects on cognition and virtually no other
side-effects.
Vagus nerve stimulation: efficacy and treatment

parameters
Vagus nerve stimulation (VNS) is approved for the treatment of drug-refrac-
tory epilepsy and in the United States received approval in 2005 for treat-
ment-resistant depression (TRD), although there is as yet no acute
double-blind evidence for the effectiveness of VNS in TRD.
Figure 8.4 Schematic to illustrate lead and stimulator positions for vagus
nerve stimulation.
Treatment with VNS requires the surgical insertion of an electrical wire

around the left vagus nerve in the neck (Figure 8.4). This is connected to a
stimulator located in the chest wall, which delivers continuous but intermit-
tent (30 seconds on, 5 minutes off) pulsed electrical signals to the vagus
nerve. The stimulation parameters, including intensity, frequency and dura-
tion of stimulation, can be programmed. In an open trial, intermittent stim-
ulation of the vagus nerve resulted in a 40% response rate in patients with
TRD. In a subsequent randomized trial with a sham condition (the stimula-
tor was turned off), there were no differences in response or remission rates
between the active and sham conditions at the end of eight weeks. However,
with prospective open-label follow-up there was continued improvement in
VNS-treated patients after one and two years, a similar time course of
response to that seen in epilepsy patients treated with VNS. The VNS-treated
patients also had better outcomes than a comparison group of patients with
TRD who received usual care. These positive results led to the Food and Drug
Administration (FDA) approval of VNS for TRD. Besides the surgical and
postoperative risks, the most common side-effect is voice alteration or
hoarseness.
Figure 8.5 Deep brain stimulation electrodes inserted and connected to

subclavicular pacemaker. The stimulator remains on all the time and batteries
last 3–5 years.
Deep brain stimulation

Deep brain stimulation (DBS) represents a unique targeted intervention for
TRD in which electrodes are neurosurgically implanted in bilateral areas of
the brain and electrical stimulation is applied (Figure 8.5). Safety and efficacy
data were first acquired in Parkinson’s disease, where stimulation of the sub-
thalamic nucleus markedly improved tremor and rigidity. Advances in func-
tional and structural neuroimaging techniques and the emergence of a
hypothesis of ‘depression neurocircuitry’ created favorable conditions for an
investigational protocol to be conducted in highly treatment-resistant
depressed patients.
Although there is no clear consensus on the optimal target, evidence from
functional imaging studies supports the selection of subgenual cingulate
Brodmann area 25 (BA25) as the target for bilateral stimulation. Increased
activity in BA25 has been demonstrated using positron emission tomogra-

phy in healthy volunteers during sadness and in depressed patients before
treatment. This overactivity decreased following effective antidepressant
treatment. By continuously providing electrical stimulation to this overac-
tive region, depolarization reduces the hyperactivity, and in a preliminary
report was associated with a clinically and statistically significant response in
a small clinical sample of patients with TRD. Other investigators have pro-
posed stimulation in the anterior limb of the internal capsule or in the
nucleus accumbens. Controlled trials are now required; randomized, double-
blind studies are possible because there is no sensation with stimulation, so
the stimulator can be switched on and off without either the evaluator or the
patient being aware of its status.
Lesion based neurosurgery

Additional neurosurgery techniques use precise computer guided stereotactic
techniques to position small lesions in different limbic areas of the brain.
The lesion locations currently targeted are anterior cingulotomy or capsulo-
tomy and subcaudate tractotomy. While there are no controlled studies of
modern limbic surgery yet reported, several case series with long-term
follow-up show benefits with minimal side-effects in highly refractory
patients. Also, a multinational study using a non-invasive gamma knife
approach is ongoing.
Conclusion
These developments in neuromodulation techniques reflect advances in the-
oretical models for depression, paired with emerging technologies to deliver
continuous or intermittent electrical stimulation and years of experience
with applying the procedures in other disease conditions. While results
beyond ECT are preliminary, each of these neuromodulation treatments has
the potential to improve outcome for selected patient groups.
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Chapter 9
Complementary, light,
sleep deprivation and
exercise therapies
Introduction
There has been a growing demand for ‘natural therapies’, including herbal
preparations, light therapy, sleep deprivation and exercise, in recent years.
While some of these treatments have been evaluated under controlled condi-
tions, many, particularly herbal remedies, have only anecdotal and historical
evidence to support their effectiveness. There is also limited knowledge
about dose regimens and concerns about internal consistency in the manu-
facturing processes.
This chapter will consider each of these approaches. Only studies that
describe diagnostic criteria for the inclusion of depressed patients and
include accepted outcome measures are considered.
St John’s Wort
Extracts of the plant St John’s Wort (Hypericum perforatum) have been
reported to elevate mood and have been a popular form of herbal therapy,
especially in central Europe, for many years. Since the publication of a meta-
analysis in 2001 supporting the efficacy of H. perforatum in depression of
mild-to-moderate severity, there have been at least three large trials, two in
the USA and one in France, that met standards for good clinical trial design.
Table 9.1 Side-effects and drug interactions of Hypericum perforatum
Side-effects Drug interactions
Gastrointestinal discomfort Serotonin syndrome with SSRI

Photosensitivity Decreased effect of warfarin and protease inhibitors due to
Fatigue enzyme induction
Hypomania
In both US studies, H. perforatum was no more efficacious than placebo,

although in one of these trials the active comparator agent, sertraline, was
also no more effective than placebo. In contrast, results of the European
placebo-controlled trial in mild-to-moderate depression were positive.
Up to nine potentially active ingredients have been identified, with evidence
to suggest that hyperforin has mild inhibitory effects on the serotonin trans-
porter and monoamine oxidase as well as weak effects on γ-aminobutyric acid
(GABA) receptors. It is likely that different preparations contain different
amounts of hyperforin and other ingredients such as hypericin.
The dosages of H. perforatum used in trials ranged from 300 to 900 mg daily.
Side-effects appear to be milder and less frequent than those reported with stan-
dard antidepressants. There are, however, reports of interactions between H.
perforatum and several prescription medications, including selective serotonin
reuptake inhibitors (SSRIs) (Table 9.1).
Omega-3 fatty acids and inositol

Phospholipids are the main structural elements of all internal and external
neuronal membranes, and contain both highly unsaturated fatty acids from
the omega-3 or omega-6 series as well as inositol. Dietary sources of omega-3
essential fatty acids include cold-water fish such as salmon and halibut, as
well as canola and soybean oils. These fatty acids may have therapeutic ben-
efits in atherosclerotic heart disease as well as depression. Three types of
omega-3 fatty acids are particularly important to humans: α-linolenic acid,
eicosapentaenoate (EPA) and docosahexanoic acid (DHA).
Building on previous reports of phospholipid abnormalities in depressed
patients, several investigators have added EPA to standard antidepressants
in unresponsive patients and reported antidepressant benefits. In contrast,
Complementary, light, sleep deprivation and exercise therapies 121
no significant differences were found between placebo and DHA in a US

study. There is also evidence that omega-3 fatty acids may help to protect
against relapse when added to traditional mood stabilizers in bipolar
patients. Side-effects include gastrointestinal discomfort, flatulence and a
malodorous ‘fishy’ breath. Overall, the heterogeneity of populations and
trial methodologies including dosing of fish oils does not provide suffi-
cient evidence to recommend these supplements as primary antidepressant
therapies, although they may have a potential benefit as augmentation
therapies.
Inositol is thought to act as a second messenger for 5HT2 receptors.
Several small clinical trials suggest that inositol may be helpful in depres-
sion and anxiety disorders, although it has not been effective as an adjunc-
tive agent with SSRIs. It requires large oral doses (12 g) and may cause
gastrointestinal distress and fish-like odors.
S-adenosyl methione
S-adenosyl methione (SAMe) is a naturally occurring amino acid derivative
that is found in all cells. It plays a role in methylation, and as a dietary sup-
plement may increase the availability of neurotransmitters including the
monoamines: serotonin (5HT), dopamine (DA) and norepinephrine (NE).
In a meta-analysis of studies comparing SAMe mainly to low-dose tricyclic
antidepressants (TCAs) there was comparable antidepressant effectiveness,
and in several cases patients on SAMe developed mania. There are no com-
parisons with SSRI or dual-action antidepressants. Although SAMe has been
of interest to practitioners of complementary medicine for over a decade, it
has only recently emerged in the USA as a popular self-administered treat-
ment for depression. Nausea is a relatively common side-effect.
Tryptophan
Tryptophan was withdrawn in the USA and several European countries in
1990 following the outbreak of eosinophilia myalgia syndrome, which was
traced to the presence of a bacterial contaminant in a single manufacturing
batch of the product. It has continued to be available by prescription only in
Canada, where it is subject to higher levels of quality control than non-pre-
scription health supplements.
Although there is limited evidence that tryptophan has antidepressant

effects on its own, there is more evidence to support its use as an augmenta-
tion therapy in depressed patients, including evidence that it improves sleep
when combined with fluoxetine. It is generally well tolerated, but may cause
serotonergic syndrome when used in high doses with high-dose SSRI
therapy. Tryptophan in doses of 2–6 g daily is also used as a hypnotic.
Dehydroepiandrosterone
Dehydroepiandrosterone (DHEA) is a precursor of androstenodione, which is
converted to estrogens and androgens. Although there are some preliminary
reports of its antidepressant properties, potential adverse effects, including
increased risk of prostate cancer and liver toxicity, should limit its use in
depressed patients.
The above complementary preparations are summarized in Table 9.2.
Table 9.2 Conclusions about complementary therapies
Preparation Evidence
St John’s Wort
Contradictory findings in major depressive disorder (MDD) Level 1
Limited support for use in mild depression
Drug interactions have been reported
Omega-3 fatty acids

Potential augmentation strategy Level 2
Inositol
Some evidence of antidepressant effects; use limited by large dosing Level 3
requirements
SAMe
Limited antidepressant benefit with low-dose TCAs Level 2
Tryptophan
Limited antidepressant augmentation and hypnotic effects Level 2
DHEA
Potential hazards may outweigh antidepressant benefits Level 2
Light therapy
Efficacy
The efficacy of light therapy (LT) for winter depression – major depressive
disorder (MDD) with seasonal pattern (see Chapter 5) – has been established
with response rates of 60% and higher. LT was comparable in outcome to flu-
oxetine in one of the few randomized controlled trials (RCTs) to directly
compare antidepressants and LT. In contrast, the efficacy of light therapy
alone in the treatment of non-seasonal depressive disorders has yet to be
established. While a Cochrane systematic review found evidence for benefi-
cial effects of light in non-seasonal depression, this was based on small studies
with many methodological limitations, so there is currently insufficient evi-
dence to recommend LT alone for non-seasonal depression. However, its use
in combination with antidepressant medications may speed response and be
more effective than antidepressant monotherapy for some patients.
The fluorescent light box is the ‘gold standard’ light device, although a
recent meta-analysis supported the role of dawn-simulating alarm clocks but
not rechargeable light visors. The recommended treatment regimen requires
exposure to light at an intensity of 10 000 lux for 30 minutes daily, in the
early morning, as soon as possible after awakening (Table 9.3). The light box
should have an ultraviolet (UV) filter to screen out harmful UV rays.
Improvement in symptoms may be apparent during the first week, but full
response usually takes two to four weeks.
Table 9.3 Summary of evidence regarding light therapy
• Demonstrated efficacy for winter depression of mild-to-moderate Level 1

severity
• An adequate trial requires two to four weeks of fluorescent light at an Level 2

intensity of 10 000 lux for 30 minutes each day in the early morning
• Patients usually need to continue daily light therapy throughout the Level 3
winter and can discontinue treatment in the summer
• There is insufficient evidence to recommend light therapy for None

long-term or maintenance use
Table 9.4 Adverse effects of light therapy
• Eyestrain
• Headache
• Nausea
• Sedation
• Visual disturbances
• Agitation or feeling ‘wired’
• Sweating
• Hypomania or mania
Side-effects are usually minimal and transient (see Table 9.4). They may be
alleviated by a reduced dose of light; there is no evidence of ocular damage
with proper use of LT. Nevertheless, ophthalmological assessment and moni-
toring are recommended if patients have ocular risk factors for potential
light toxicity, such as pre-existing retinal disease, or are being treated with
photosensitizing medications including phenothiazine antipsychotics,
lithium, melatonin or St John’s Wort.
Maintenance and prevention

Since most patients experience rapid recurrence of symptoms after discon-
tinuation of LT, it should be continued throughout the period of risk for
winter depression and discontinued during the summer months. There are
few data on long-term or maintenance use of light therapy for seasonal
(winter) or non-seasonal depression. Other conditions where LT may be ben-
eficial are premenstrual dysphoric disorder, bulimia nervosa, depression
during pregnancy and delayed sleep phase disorder.
Sleep deprivation
Efficacy
Total sleep deprivation (TSD) can improve depressive symptoms, sometimes
dramatically. On occasion, manic switches have been triggered in bipolar
patients. Unfortunately, the antidepressant effect of TSD is usually transient,
and most patients relapse after even a brief recovery of sleep, leaving a
minority (up to 15%) in sustained remission.
In an effort to prevent this rapid relapse after TSD, modified partial sleep
deprivation (i.e. sleep deprivation in the second half of the night) has been
evaluated with some success. Unfortunately, even partial sleep deprivation is
difficult for patients to continue for more than a week, and when carried out
in hospital is quite demanding of nursing staff.
Given the rather simple procedure, sleep deprivation may be considered as
an alternative approach, particularly when a rapid response is required (e.g.
in acutely suicidal inpatients). One protocol supported in the literature
includes three TSD periods within one week. During each 48-hour period,
the patient is awake from 7am on day 1 to 7pm on day 2 (36 hours of sleep
deprivation) followed by recovery sleep from 7pm to 7am on day 3 (12 hours
of sleep). The sleep deprivation period is then repeated.
Combination and maintenance

Strategies to sustain the antidepressant effect include combining sleep depri-
vation with antidepressant medications, lithium, pindolol, light therapy
and, paradoxically, tryptophan depletion. Placebo-controlled studies are
obviously difficult to conduct for such a treatment, but several controlled
studies of sleep deprivation support these combined treatments. Sleep depri-
vation has no evidence base to recommend it as a maintenance therapy.
Exercise
Intuitively, exercise makes sense as an adjunct to virtually all forms of anti-
depressant treatment. Unfortunately there are very few studies involving
exercise that meet methodological standards. In one controlled trial involv-
ing elderly people with depression, exercise alone was as effective as sertra-
line alone or the combination of both, although sertraline produced a faster
onset of response. In a six-month follow-up to this study, the exercise group
had a lower relapse rate than did the medication group. A subsequent ran-
domized controlled trial supported aerobic exercise over non-aerobic exercise
as an effective treatment for mild to moderate MDD. Including exercise in a
treatment program may also help to address concerns about medication-
related weight gain.
The above therapies are summarized in Table 9.5.
Table 9.5 Recommendations for light, sleep and exercise therapies
Light therapy
Efficacy in winter depression Level 1
Sleep deprivation
Effective transient treatment for MDD Level 2
May augment other treatments
Response may be maintained using medications or bright light
Exercise
May be effective in patients with minor depressive disorder (mDD) Level 1
Useful to augment first-line treatments
Conclusions
Complementary or nutriceutical therapies have produced uneven results.
The evidence to support St John’s Wort as a primary antidepressant is
limited. On the other hand, preliminary evidence suggests at least that some
omega-3 fish oils may augment standard antidepressant agents. Light
therapy has comparable efficacy to SSRIs for winter depression. While sleep
deprivation may provide a transient response even in severe major depres-
sion, it is difficult to implement and impractical as a sustained intervention.
Finally, there is growing evidence to support exercise, particularly aerobic, as
a treatment or adjunct to other therapies for depression.
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Chapter 10
Depression in women
Introduction
This chapter addresses the treatment of depressive disorders during different
reproductive events in the life cycle of women (Figure 10.1).
Gender differences in depression

Women are almost twice as likely to suffer from major depressive disorder
(MDD) as men, beginning in early adolescence and continuing through to
menopause. Atypical depression and seasonal (winter) depression occur even
more frequently in women than in men. Women are likely to have an earlier
age of onset, and experience longer episodes and more recurrences than
Menarche Pregnancy Menopause
Perimenopausal Postmenopausal
PMDD depression depression
Miscarriage-
Depression in PPD Infertility
related
pregnancy PPP depression
depression
Figure 10.1 Depression and the reproductive cycle in women. PMDD, premenstrual dysphoric
disorder; PPD, postpartum depression; PPP, postpartum psychosis.
men. Episodes in women tend to be more functionally disabling, and are

more expensive to treat when employment costs are included.
Rates of comorbid psychiatric disorders also differ between men and women.
Comorbid anxiety disorders are three times more prevalent in women; comor-
bid eating disorders and somatization disorders occur more commonly in
women, whereas alcohol/substance abuse and dependence are more prevalent
in men. Although borderline, histrionic and dependent personality disorders
are diagnosed more frequently in women, the traditional assumption that per-
sonality disorders are more prevalent in women than men has been challenged.
Rates of attempted suicide are also more prevalent in women, while completed
suicide is approximately three times more prevalent in men.
The reasons for this gender difference in so many depression-related phe-
nomena are not well understood, but probably relate to a combination of
physical, psychological and social factors. Women have faster rates of sero-
tonin (5HT) metabolism than men, and so may be more vulnerable to reduc-
tions in the availability of the precursor amino acid L-tryptophan.
Neurosteroid levels alter markedly during the menstrual cycle and in preg-
nancy, and these can induce alterations in other neurochemicals. Social
roles, especially those limiting self-effectiveness and financial autonomy,
may evoke a sense of helplessness. Violence to women is an additional risk
factor.
Gender differences in treatment response

Psychotherapy
Several studies indicate that both men and women have similar outcomes
with cognitive behavior therapy (CBT), although one study indicated that
women with greater symptom severity were less likely to achieve remission
than were men. On the other hand, women have been reported to benefit
more than men from group therapy and interpersonal psychotherapy (IPT).
Pharmacotherapy
Gender differences in pharmacokinetic and pharmacodynamic effects of psy-
chotropic medications may be related to the effects of female hormones on
the absorption and bioavailability of medications, to differing distributions
of lean/adipose body tissue, to differences in hepatic blood flow and possibly
to the effects of the menstrual cycle. With comparable oral dosing, women
are likely to have higher plasma levels of antidepressant medications and
experience more frequent side-effects than men. They may also be more
Depression in women 131
concerned about antidepressant-induced weight gain than men, and this

should be taken into account when prescribing an antidepressant, especially
when weight gain has been one of the features of the depression.
Electroconvulsive therapy (ECT)

Seventy percent of patients who receive ECT are women, which reflects the
greater prevalence of depression among women. Evidence indicates that
women may have lower seizure thresholds than men, and that gender differ-
ences in lateralization of brain function may produce differences in cognitive
side-effects of ECT (see Chapter 8 for a full discussion of ECT).
Premenstrual dysphoric disorder

Prevalence
The diagnosis of premenstrual dysphoric disorder (PMDD) according to
DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, fourth
edition, text revision) requires five or more symptoms, for most of a 12-
month time span, which start after ovulation and disappear shortly after
the onset of menses (Table 10.1). They should be confirmed by at least
two months of prospective ratings and cause functional impairment.
Although not singled out as a core symptom, irritability is considered by
many to be of particular importance. The prevalence of PMDD among
women in their reproductive years is between 2% and 10%.
Psychotherapy for PMDD

In a randomized controlled trial (RCT), 10 sessions of CBT delivered over six
months were as effective as fluoxetine for PMDD, with better maintenance of
treatment effects one year later. Other approaches, including lifestyle
therapy, stress management and attention to diet, have been recommended
but not evaluated.
Pharmacotherapy for PMDD

There is strong evidence that selective serotonin reuptake inhibitors (SSRIs)
are effective in the treatment of PMDD. Citalopram, escitalopram, fluoxe-
tine, paroxetine and sertraline have all been shown to be superior to
placebo, and in several cases more effective than noradrenergic antidepres-
sants (desipramine, bupropion and maprotiline). Fluoxetine has been evalu-
ated more frequently than the other SSRIs. The non-selective SRI
clomipramine has also been shown to be effective (Table 10.2).
Table 10.1 Symptoms of PMDD
Five or more symptoms must be present, with at least one being 1, 2, 3 or 4:

1. Sad, hopeless or self-deprecating feelings
2. Tense, anxious or ‘on edge’ state
3. Marked lability of mood with frequent tearfulness
4. Persistent irritability, anger and increased interpersonal conflicts
5. Decreased interest in usual activities
6. Difficulty concentrating
7. Fatigue, lethargy or lack of energy
8. Changes in appetite often associated with binge eating or craving
9. Hypersomnia or insomnia
10. Subjective feeling or being overwhelmed or being out of control
11. Physical symptoms such as breast tenderness or swelling, headaches, or sensations of
‘bloating’ or weight gain
Table 10.2 Recommendations for the treatment of PMDD
First Citalopram; escitalopram; fluoxetine; Level 1

paroxetine; sertraline
Second Clomipramine Level 2
There is evidence to support intermittent dosing during the luteal phase

only for various SSRIs including citalopram, escitalopram, paroxetine and
sertraline, and these brief treatments did not result in significant discontinu-
ation symptoms.
Gonadotropin-releasing hormone therapies may be used to suppress ovu-
lation, but are associated with substantial side-effects. There is insufficient
evidence to recommend alternative therapies, including St John’s Wort and
evening oil of primrose.
Depression during pregnancy

Prevalence
During pregnancy, approximately 20% of women have some depressive
symptomatology, and about 10% develop a major depressive episode (MDE).
These rates are comparable to those in non-pregnant women. Risk factors
include prior history of depression, younger maternal age, limited social

support, living alone, greater number of children, ambivalence about preg-
nancy, negative life events and low socioeconomic status.
Treating depression during pregnancy

Psychotherapy
There is evidence to support the efficacy of psychotherapy for depression
during pregnancy. IPT was significantly more effective than a parenting edu-
cation control program in rates of maternal improvement and mother–infant
interactions. Although cognitive behavior therapy (CBT) has demonstrated
efficacy in postpartum depression, its role in treating depression during preg-
nancy has not been reported.
Pharmacotherapy
Concerns about potential adverse effects of antidepressants on fetal devel-
opment have restricted the opportunity to carry out randomized trials.
Nevertheless, data on efficacy and safety for SSRIs in almost 3000
depressed pregnant women have been published. Over 2000 of these cases
involved the use of fluoxetine, where third trimester use has been linked
to jitteriness. In a meta-analysis, the relative risk of major malformation
with SSRI, norepinephrine reuptake inhibitor (NRI) and dual-action anti-
depressants (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxe-
tine, sertraline, reboxetine, venlafaxine, nefazodone, trazodone,
mirtazapine and bupropion) was 1.01. The authors concluded that these
antidepressants were not associated with an increased risk of malforma-
tions above the population level of 1–3%. However, concerns have been
expressed about third trimester use of SSRIs – particularly paroxetine – and
an increased incidence of cardiac malformations.
Two large prospective surveys from the European Network of Teratology
Information Services (ENTIS) and the Swedish Medical Birth Registry indi-
cated no causal relationship between in utero exposure to antidepressants
and adverse pregnancy outcome. In a subsequent matched comparison of
infants born to mothers receiving tricyclic antidepressants (TCAs) and SSRIs
compared to an unexposed comparison group, there was a decrease in gesta-
tion, birth weight and Apgar score in the infants of SSRI-treated mothers.
There were no differences in the infants exposed to TCAs. Neither class was
associated with congenital malformations or developmental delay. However,
in a small study of infants born to women who received monoamine oxidase
inhibitor (MAOI) therapy, there was an increased risk of congenital malfor-

mations. Therefore, it is best to avoid MAOIs in pregnant women.
In another study, there was no effect on global intelligence quotient (IQ),
language development or behavioral development in preschool children
exposed to TCAs or fluoxetine in the first trimester or throughout preg-
nancy. There were also no significant differences in mood, temperament,
arousal or activity levels, distractibility or behavioral problems in these
groups of children.
Because pregnancy is a hypermetabolic state, it is not surprising that
higher doses of antidepressants are often required, particularly in the later
stages of pregnancy, to maintain adequate plasma levels and prevent recur-
rence of symptoms. In a retrospective review of dosing for fluoxetine, parox-
etine and sertraline during pregnancy, the dose at delivery was
approximately 1.8 times higher than the initial dosage, and the mean time
for dose increase was 27 weeks into the pregnancy. There were no significant
differences in dosage changes across SSRIs. It should be noted, however, that
all SSRIs cross the placental barrier, and caution is advised. Similar findings
have also been reported with TCAs.
Pregnancy is not protective with respect to risk of relapse into a major
depressive episode. Over 60% of women who discontinued antidepressant
therapy during pregnancy experienced a relapse, compared to 26% in
women who maintained medication throughout pregnancy. The conse-
quences of antidepressant discontinuation during pregnancy are substantial.
As of 2006, five prospective controlled trials identified significant withdrawal
symptoms in neonates. These were generally similar to those encountered in
adults following abrupt SSRI discontinuation, and included neurobehavioral,
motor, gastrointestinal and respiratory effects – respiratory distress was par-
ticularly prevalent. The majority of cases involved paroxetine, and included
several reports of neonatal seizures. Up to 75% of pregnant women who dis-
continue antidepressant treatment experience a relapse of major depression
by the end of pregnancy, with most relapses occurring in the first trimester.
Inadequate antenatal care, poor nutrition, obstetric complications and post-
partum depression (PPD), as well as the increased risk of exposure to tobacco,
alcohol or drugs, are all potential consequences of relapse. Untreated depres-
sion during pregnancy has been associated with low birth weight, neonatal
distress, prematurity and a threefold increase in the risk of PPD.
The Motherisk Program is a Canadian resource center that deals specifi-
cally with the effects of medication on fetal development and other
Table 10.3 Recommendations for the treatment of depression

during pregnancy
First Fluoxetine Level 1
Second Citalopram; escitalopram; fluvoxamine; paroxetine; Level 2

sertraline; venlafaxine
Third Tricyclic antidepressants (TCAs) Level 2

Electroconvulsive therapy (ECT) Level 3
Interpersonal psychotherapy (IPT) Level 3
pregnancy-related concerns (www.motherisk.org). The National Women’s

Health Information Center at www.4woman.gov is a US website that may
provide additional information.

There are no prospective, controlled studies of ECT during pregnancy,
although it is known that pregnancy may alter the seizure threshold, and
that fetal arrhythmias may occur as a consequence of ECT. Most of these
effects can be minimized by modifying the standard ECT technique when
treating pregnant patients; however, the patient’s ability to understand and
evaluate the risks to both herself and her fetus should be considered in the
decision to use ECT.
For a summary of the recommendations for the treatment of depression
during pregnancy, see Table 10.3.
Postnatal mood disorders

Prevalence
Postnatal mood disturbance occurs frequently, and may be considered along
a continuum of severity from ‘maternity blues’, a mild self-limiting disorder
occurring in over 50% of new mothers in the first two weeks after delivery,
to ‘PPD’ and ‘postpartum psychosis’ (PPP).
PPD, termed MDD with postpartum onset in DSM-IV-TR, requires onset
within the first four weeks after delivery. However, depression occurring
within three months of delivery is considered to be PPD by many clinicians.
Table 10.4 Risk factors associated with postpartum depression
1. Previous episode of postpartum depression

2. Previous history of a mood disorder or other psychiatric disorder
3. Depressive symptoms during pregnancy
4. Family history of depression
5. Inadequate social support
6. Chronic stressors
7. Lower socioeconomic status
8. Depression and high levels of expressed emotion in one’s partner
It affects 10% to 15% of new mothers. Screening for known risk factors
should be part of antenatal care (Table 10.4). The Postpartum Depression
Checklist and the Edinburgh Postnatal Depression Scale have been devel-
oped as diagnostic aids (Table 10.5).
Psychotherapy for PPD

Women who are at risk for PPD may benefit from counseling, enhanced
social support and education prior to delivery. CBT for six sessions was as
effective as fluoxetine in one small comparative trial, and equivalent to
paroxetine in another. IPT with specific modifications to help resolve marital
disputes and major role transition issues after childbirth was also effective.
There was also a significant benefit to involving both parents in psychoedu-
cation, compared with psychoeducation only for mothers.
Pharmacotherapy for PPD

There are some indications that antidepressant medication decreases recurrence
rates for PPD. Fluoxetine, nortriptyline, paroxetine, sertraline and venlafaxine
have all shown efficacy. Women with a history of PPD who began antidepres-
sant treatment within 24 hours of delivery had a relapse rate of 6.7%, com-
pared with a rate of 62% in women who deferred prophylaxis in one study,
although nortriptyline was not superior to placebo in the prevention of recur-
rent PPD in another study.
Estrogen was also significantly more effective than placebo in improving
symptoms in women with severe depression, although the effect was only
significant after one month of treatment (onset within three months postpar-
tum). High-dose estrogen therapy has been evaluated as a prophylactic treat-
ment, but its efficacy is mitigated by a number of considerations, such as
Table 10.5 Edinburgh Postnatal Depression Scale (EPDS)
Instructions
How are you feeling? Because you have recently had a baby, we would like to know how
you are feeling now. Please circle the answer that comes closest to how you have felt in
the past 7 days, not just how you feel today.
Never/ Sometimes Often Most of

not often the time
1. I have been able to laugh and see the 3 2 1 0

funny side of things
2. I have looked forward with enjoyment 3 2 1 0

to things
3. I have blamed myself unnecessarily when 0 1 2 3

things went wrong
4. I have been worried and anxious for no 0 1 2 3

good reason
5. I have felt scared or panicky for no very 0 1 2 3

good reason
6. Things have been getting on top of me 0 1 2 3
7. I have been so unhappy that I have had 0 1 2 3

difficulty sleeping
8. I have felt sad or miserable 0 1 2 3
9. I have been so unhappy that I have been 0 1 2 3

crying
10. The thought of harming myself has 0 1 2 3

occurred to me
A score of 12 or more is indicative of probable major or minor depression.
interference with breast milk production and coadministration of anticoagu-

lants. In a large, naturalistic follow-up of women with PPD, some of whom
requested progesterone, it was found that the relapse rate in the progesterone-
treated group was 7%, compared with 67% in the non-progesterone group.
Further controlled studies are needed to confirm these impressive findings.
It should also be noted that women who suffer from bipolar disorder have a
high risk of relapse (35% to 50%) in the postpartum period. Lithium, given in
the third trimester or 48 hours postpartum, has been shown to be prophylactic.
Recommendations for the treatment of PPD are summarized in Table 10.6.
Table 10.6 Recommendations for the treatment of postpartum

depression
Women with risk factors for postpartum depression (PPD) should be monitored Level 3
closely during and following pregnancy
If there is a history of previous PPD, antidepressant prophylaxis should be Level 3

considered
First choice Fluoxetine; paroxetine; sertraline Level 2

Interpersonal therapy (IPT) Level 2
Second choice CBT-focused counseling Level 2

Patient and partner psychoeducation as adjunctive treatment Level 3
Third choice Estrogen or progesterone Level 2

Progesterone Level 3
Postpartum psychosis
Prevalence
Postpartum psychosis (PPP) is a rare disorder, occurring in two out of 1000
deliveries within the first four weeks postpartum.
Treatment
This is a psychiatric emergency that invariably requires hospitalization (on a
voluntary or involuntary basis). In the majority of cases (70%), PPP is associated
with bipolar disorder, and should be managed accordingly using antipsychotic,
mood-stabilizing and, if warranted, antidepressant medications. ECT is also
effective, and can be first choice for speed of response. The risk of recurrence of
psychotic episodes following a subsequent pregnancy or at other times is
greater than 50%. Transdermal estrogen started 48 hours after delivery was not
effective in reducing relapse in a high-risk group of women.
Pharmacotherapy and breast-feeding

The desire to breast-feed, and the increased risk of recurrence in the post-
partum period, present an added clinical dilemma, as all antidepressants are
excreted in breast milk. There are limited data on the safety of antidepres-
sants during breast-feeding. However, it does appear that some TCAs, MAOIs
and SSRIs have no adverse effects on breast-fed infants.
Table 10.7 Recommendations for the treatment of depression

during breast-feeding
Data regarding antidepressants during breast-feeding are limited; long-term Level 2

developmental effects are unknown
Current safety data do not contraindicate the use of several TCAs Level 2
(amitriptyline, desipramine and nortriptyline) as well as citalopram, fluoxetine,
fluvoxamine, paroxetine, sertraline and venlafaxine
Most studies of SSRIs report very low (fluoxetine) to nearly undetectable

(sertraline and paroxetine) levels of the antidepressant in the nursing infant,
but the levels of the drug and its metabolite vary with maternal dosing.
Some studies report that there is a gradient effect, with greater concentra-
tions occurring in the later portions of breast milk (hind milk) than in the
early portions (fore milk); this has been reported for paroxetine and sertra-
line. The use of sertraline, paroxetine, fluvoxamine and citalopram as well as
venlafaxine in nursing mothers has not been associated with infant harm,
although side-effects in infants have been reported. In the case of fluoxe-
tine, at a standard dose of 20 mg daily, plasma levels were approximately
10% of maternal levels. Long-term studies, however, are not available and
more studies are required to investigate possible long-term developmental
effects (Table 10.7).
Depression and menopause

Prevalence
Controversy over the existence of ‘involutional melancholia’ has spanned
several centuries. More recently, the influence of estrogen on serotonin
(5HT) receptors has been a topic of growing interest. There is also evidence
that depressive symptoms increase around the perimenopause.
Approximately 30% of women in this age group endorse symptoms associ-
ated with major depression or a primary anxiety disorder, and the associa-
tion between physical symptoms and mood disorder is doubled in those
women with artificial or surgically induced menopause, compared with
other menstrual status groups. Given the increased likelihood of depression
during the perimenopausal period it is advisable to screen women aged 45 to
Table 10.8 Risk factors for depression in menopause
• History of postpartum depression

• History of major depressive episodes
• History of premenstrual dysphoric disorder
• Prolonged perimenopause (>27 months)
• Surgically induced menopause
• Thyroid dysfunction
55 years for depressive symptoms, particularly those who carry identified risk
factors (Table 10.8).
Problems inherent in defining a menopause-related disorder include lack
of adequately standardized diagnostic tools, variability in age and definitions
of menopause and variability in psychosocial and biological factors among
women. Careful monitoring of symptomatology and endocrinological status
may, however, assist in diagnosis and treatment. Considerations for treat-
ment include whether the menopause is naturally or surgically induced, the
role of hormone replacement therapy (HRT) and the nature and severity of
symptoms. It is also important to determine whether a patient with a previ-
ous history of depression is having a recurrence or is suffering from
menopause-related depression.
Treatment
There is considerable controversy about the influence of menopausal
status on antidepressant response, although the consensus is that pre-
menopausal women respond better than postmenopausal women to SSRIs,
while men and postmenopausal women respond equally well to TCAs. In a
pooled dataset from eight controlled trials, venlafaxine was superior to
SSRIs in women 50 years of age and older, but comparable to SSRI plus
hormone replacement therapy in this older age group. The availability of
desvenlafaxine succinate (DVS) as a treatment for vasomotor symptoms
and as a dual-action 5HT and norepinephrine (NE) reuptake inhibitor anti-
depressant will provide an additional therapeutic option in this popula-
tion. There is also evidence that women have a better response than men
to augmentation with triiodothyronine (T3). Studies of estrogen augmenta-
tion in women with postmenopausal depression are inconclusive.
Estrogen replacement therapy may provide some relief of vasomotor,
minor cognitive and mood symptoms. In a small placebo-controlled trial
Table 10.9 Recommendations for the treatment of postmenopausal

depression
First Standard pharmacological or psychological treatments Level 3

(in the absence of specific trials in this population)
Second Estrogen supplementation alone or estrogen Level 2

augmentation of antidepressant
involving perimenopausal women with minor and major depression, trans-

dermal estrogen was significantly more effective than placebo. There are,
however, case reports of mania occurring during estrogen treatment. This
association may indicate that estrogen has a destabilizing effect in vulnerable
patients. In a preliminary report, estradiol effectively treated perimenopausal
depression. The use of estrogen replacement must be considered in the
context of other data on long-term safety for such interventions (Table 10.9).
Most estrogen augmentation studies involved TCAs, although recent
studies examined estrogen augmentation of fluoxetine or sertraline, with
contradictory conclusions. Treatment of women suffering from affective
changes in the menopausal period is comparable to that of MDD: SSRIs can
be of benefit for women on HRT, and some observations suggest that TCAs
may be better tolerated and more effective than SSRI monotherapy.
Mirtazapine has also proved to be an effective monotherapy. Interestingly,
the decline in HRT prescription has been correlated with increases in pre-
scriptions of SSRI antidepressants in women over 50 years old. This suggests
that antidepressants are being prescribed for physiological symptoms for-
merly controlled by HRT, and possibly that HRT contributed antidepressant
effects that were previously underrecognized.
Conclusions
It is important to recognize the influence of the reproductive system on
depression in women. There is substantial evidence to support the role of
various SSRIs in PMDD, including the use of intermittent-dosing regimens.
Clinicians should pay attention to various ‘at risk’ stages in women’s lives,
diagnose depression and provide evidence-based treatments. During preg-
nancy and breast-feeding this often requires discussion of the risks of
untreated depression on mother and infant compared to any medication-

related concerns, so that optimally informed decisions can be made. The evi-
dence concerning antidepressant response in postmenopausal women is
inconsistent, with some suggestion that SSRIs are less effective than in pre-
menopausal women.
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Chapter 11
Depression in children and

adolescents
Introduction
Clinicians have very little evidence-based information to guide their choice of
treatments for depression in children and adolescents. Until recently, they
were often forced to rely on adult-based evidence in selecting antidepressant
treatments. Emerging results from pharmacotherapy trials conducted in young
populations provide information on the relative advantages and hazards of
antidepressant medications.
Risk factors for depression in children and

adolescents
Prepubertal boys and girls are equally affected by depression, but the preva-
lence changes in teens and young adults, with depression affecting girls
twice as frequently as boys. There is some evidence to suggest that girls who
experience puberty much earlier than their peers are biologically and psy-
chologically predisposed to developing depression. Other risk factors are
summarized in Table 11.1. Prepubertal children who rapidly experience a
major depressive episode (MDE) are also at considerable risk of developing
bipolar disorder in their teens or in adulthood. Early-onset major depressive
disorder (MDD) is often associated with high rates of comorbid anxiety dis-
orders, including obsessive compulsive disorder (OCD).
Psychotherapies in children and adolescents

There is good evidence to support the benefits of cognitive behavior therapy
(CBT) in 8- to 11-year-old children, although diagnostic criteria for MDD may
Table 11.1 Risk factors for developing depression early in life*
• Learning and developmental disorders

• Attention deficit/hyperactivity disorder (ADHD)
• Anxiety disorders
• Parental separation and divorce
• History of head injury
• Abuse, neglect, trauma or bereavement
• Early-onset puberty
• First-degree relative with depression
• Chronic medical illness
• Drug misuse
*Adapted with permission from Garland and Solomons, 2002.
not have been met in some studies. Similarly, adolescents (12–19 years old)
have benefited significantly from individual and group CBT; also, there are
trials to support interpersonal psychotherapy (IPT) in this age group. In
general, these studies support the use of CBT or IPT in mild-to-moderate
forms of childhood or adolescent depression. However, the efficacy of psy-
chotherapies in severe depression has yet to be established, since at least one
trial (Treatment for Adolescents with Depression Study, TADS) found that flu-
oxetine was superior to pill placebo while CBT alone was not; however, the
combination treatment appeared to be most effective in this severely ill
sample (Table 11.2).
Although there is strong evidence linking the development of depression
in children to family relationships, it is surprising that the role of family
therapy in reducing symptoms of depression has not been rigorously investi-
gated. It is also recognized that many children with depression grow up in
healthy families.
Table 11.2 Recommendations for psychotherapy in children and

adolescents
First CBT for mild-to-moderate but not severe depression Level 1

IPT for mild-to-moderate but not severe depression Level 2
Depression in children and adolescents 147
Pharmacotherapy in children and adolescents

There have been relatively few pharmacokinetic and pharmacodynamic
studies of antidepressants in children and adolescents, although metabolism
usually takes place at similar or faster rates than in adults. While the ‘start
low, go slow’ axiom is particularly appropriate here, children may ultimately
require doses that are higher than usual adult doses on a mg/kg basis. Time
to response or remission may also take longer (six to eight weeks) in younger
age groups compared with adults; therefore, a longer than usual trial may be
warranted.
Most standard antidepressant drugs have not received the approval of gov-
ernmental regulatory bodies, such as the Food and Drug Administration
(FDA) in the USA, for use in children because efficacy studies have not been
carried out. In an attempt to correct this, the FDA requested manufacturers
to carry out such trials, and results of several controlled trials evaluating
antidepressant efficacy and safety in these age groups have become avail-
able.
There is enough evidence to state that tricyclic antidepressants (TCAs)
should not be prescribed for the treatment of depression in children or ado-
lescents. This is based on consistently negative results and concerns about
side-effects, particularly cardiac arrhythmias. Monoamine oxidase inhibitors
(MAOIs) are rarely prescribed in these age groups, although case series
support their effectiveness in otherwise treatment-resistant patients.
SSRIs and dual-action antidepressants

Several published studies have shown evidence of efficacy for selective sero-
tonin reuptake inhibitors (SSRIs) (including fluoxetine, sertraline, citalo-
pram) in the treatment of childhood depression, albeit with low effect sizes.
However, emerging data in 2003 regarding reports on increased suicidal
ideation in children and adolescents during treatment with paroxetine and
venlafaxine led to a reevaluation of recommendations for SSRI or serotonin
and norepinephrine reuptake inhibitor (SNRI) therapy in the treatment of
childhood depression (see Table 11.3).
In 2003, advisory letters naming paroxetine and venlafaxine were sent to
physicians warning against the use of these agents in the treatment of child-
hood depression. The FDA commissioned a reanalysis of the pediatric trials
which found a small but statistically significant excess of suicidal behaviors
(including ideation and attempts) during antidepressant treatment compared
Table 11.3 Dosing of SSRIs in adolescents*
Medication Initial dose (mg) Target dose (mg) Dose range (mg)†
Citalopram 10 20 10–40
Escitalopram 5 10 5–20
Fluoxetine 5 20 10–60
Fluvoxamine 50 200 100–300
Sertraline 50 50 50–200
*Adapted with permission from Kutcher, 1997.

† High ends of range may exceed recommended upper limits in formularies and should be used with
caution.
to placebo; however, there was not a single completed suicide in the entire
database. This small effect translated to about 1–3 patients with increased
risk of suicidal ideation/behaviors for every 100 patients treated with antide-
pressants, compared to placebo. Although the pattern was similar for all anti-
depressants, only venlafaxine was statistically associated with increased risk,
while paroxetine showed a trend to statistical significance.
Complicating this safety concern was the fact that the overall meta-analysis
of published and unpublished trials with the newer antidepressants (which
included patients with mild–moderate severity) showed no convincing evi-
dence of efficacy compared to placebo, with the exception of fluoxetine.
Consequently, only fluoxetine was approved by the FDA for use in youths
with depression. In addition, recommendations were given for patient and
family education and close monitoring of clinical status (both depressive
symptoms and potential side-effects of medication) to optimize safety.
Atomoxetine is an inhibitor of the norepinephrine (NE) transporter that
has recently become available to treat attention deficit/hyperactivity disorder
(ADHD) in some countries, including the USA. Based on its mode of action,
it may also have antidepressant effects, although these have not been the
focus for regulatory approval. There does not appear to be the same potential
for abuse with this type of agent compared to psychostimulants, presumably
because dopamine release is not increased. Bupropion may be considered for
children with comorbid depression and ADHD, where its dopamine and/or
NE uptake blocking effects may help both syndromes (Tables 11.4 and 11.5).
Duloxetine, mirtazapine and agomelatine have yet to be evaluated in
younger age groups.
Table 11.4 Dosing of dual-action antidepressants*
Medication Initial dose (mg) Target dose (mg) Dose range (mg)†
Bupropion 100 150 200–450

Mirtazapine 15 30 30–45
*Adapted with permission from Shugart and Lopez, 2002.

†High end of range may exceed recommended upper limits in formularies and should be used with
caution.
Table 11.5 Recommendations for pharmacotherapy of MDD in

children and adolescents
First Fuoxetine Level 1
Second Citalopram; escitalopram; sertraline Level 2
Third Bupropion; MAOIs Level 3
Not recommended TCAs Level 1

Paroxetine Level 2
Venlafaxine Level 3
Nefazodone Level 3
Maintenance therapy
There have been very few antidepressant maintenance trials in children and
adolescents; sertraline was effective in one trial that lasted 20 weeks. Safety
concerns about the SSRI class need to be resolved before other agents can be
recommended. So far, recommendations about maintenance therapy in this
population are derived from trials in adult populations, although the same
case can be made for children as for adults, that the goals of therapy are to
obtain and maintain remission. As in adults, discontinuation should follow a
tapering regimen.
Electroconvulsive therapy (ECT) in children and

adolescents
Based on limited data, the use of ECT in teenagers with depression or mania
is effective and relatively well tolerated. Rates of improvement and
side-effects appear comparable to those reported for adults. There are

insufficient data on the use of ECT in children, and there is insufficient clini-
cal experience with children to inform the development of guidelines.
In practice, ECT should be reserved for the treatment of adolescents who
are suffering from a treatment-resistant depressive or manic illness of such
severity that the medical condition of the patient is compromised, or when
the patient is at imminent risk for suicide. In such cases, it is prudent to
obtain a second opinion from a psychiatrist who is not involved in the care
of the patient. Practical aspects for the use of ECT are summarized in Table
11.6. A comprehensive medical and psychiatric history and physical exami-
nation should also be conducted. Informed consent from both patient and
legal guardian should be obtained prior to the use of ECT. Guidelines for
the use of ECT in adolescence are currently under development by the
American Academy of Child and Adolescent Psychiatry.
Resistance to ECT can be defined as an absence of response after 12 treat-
ments, of which six were bilateral. There is evidence to show that relapse
rates following ECT are high in patients who are restarted on an
Table 11.6 Suggestions for the use of ECT in children and

adolescents
1. Choice of anesthetic: Thiopentone, methohexitone and propofol (associated with

shorter seizures in young people) are preferred in combination with
suxamethonium as the muscle relaxant
2. Device and dosing: As young people have low seizure thresholds, machines that
are capable of delivering low doses should be used. Brief-pulse, not sine-wave,
machines are preferred
3. Electrode position: There are no data correlating improvement with electrode
placement. Unilateral placement may be as effective and may result in fewer
cognitive side-effects but bilateral may be associated with a more rapid onset of
improvement. Change position to unilateral if the patient becomes confused
following bilateral treatment, or change from unilateral to bilateral after six to eight
treatments if there is no improvement
4. Electroencephalogram (EEG) monitoring and recording seizure length: This is
particularly important in this population, and prolonged seizures (> 2 minutes)
should be terminated with diazepam or additional general anesthetic
5. Number of treatments: Similar to those for adults, usual range being six to 12
treatments. The absence of any signs of improvement after six to eight treatments
is an indication to discontinue
Table 11.7 Recommendations for the use of ECT in children and

adolescents
ECT is third-line treatment for adolescents but may be considered earlier Level 3
in acutely suicidal, psychotic or treatment-resistant patients
There is weak evidence to support ECT use in prepubertal children Level 4
antidepressant that was previously ineffective. Therefore, treatment with

an antidepressant from a different class should be considered. The effec-
tiveness of maintenance ECT to prevent relapse or recurrence has not been
evaluated in children and adolescents (Table 11.7).
In adolescents, side-effects with ECT are common in the postictal period
but are usually transient. Headaches occur most frequently and should be
treated conservatively. When the cognitive effects of ECT were evaluated,
there were no long-lasting effects on various neurocognitive functions,
although short-term effects (lasting up to two months) on memory have
been noted. See Chapter 8 for a more detailed discussion of ECT.
Conclusions
The controversy about risks and benefits of treatment for depression in chil-
dren and adolescents will require further study before it can be resolved.
There is also a need to compare the relative effectiveness of antidepressants
and evidence-based psychotherapies as well as to evaluate the benefits of
maintenance treatments in children and adolescents. Regardless of treatment
choice, close monitoring during therapy of depression is important, especially
at the beginning of treatment when symptom severity is highest and side-
effects may be experienced before any benefits of treatment are noticed.
Currently, for depression of mild to moderate severity in children and ado-
lescents, clinical management or evidence based psychotherapy alone is rec-
ommended. Fluoxetine is indicated (in addition to psychotherapy) when the
depression is more severe or chronic, or comorbidity is present, or when there
is limited response or access to psychotherapy. Other SSRIs can be used if
these first line recommendations are not effective. Other newer antidepres-
sants and ECT should be reserved as third line treatments.
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Chapter 12
Depression in late life
Introduction
Most recommendations for the treatment of depression are based on evi-
dence derived from studies of middle-life populations. Historically, this
information has been applied to special populations, including the elderly,
without adequate evaluation of efficacy, tolerability or safety. Yet there are
age-related differences in the prevalence of depression, its clinical presenta-
tion and various aspects of treatment. The goal of this chapter is to provide a
critical evaluation of the available data on epidemiology and treatment
options as they pertain to managing depression in older adults.
The assessment and management of depression in the elderly involves
several challenges. The very old are more sensitive to adverse effects of
pharmacotherapy, for reasons ranging from pharmacokinetic and pharma-
codynamic properties of the agents to inherent biological differences in an
aging body and brain. Although several of the stereotypes about depression
in this group, compared to younger adults (e.g. poorer response to treat-
ment and greater risks of chronicity), have turned out to be largely
unjustified, depression in the elderly continues to cause substantial mor-
bidity and mortality. Frequent medical comorbidity and the not uncom-
mon need for complex multidrug regimens contribute to underdetection of
mood disorders in the elderly. Reluctance to voice concerns about one’s
mental health or to utilize mental health services are also significant issues
among the elderly, who often grew up with more stigmatized beliefs about
mental illnesses and psychiatric treatments than subsequent generations.
Biased assumptions persist among healthcare providers, who sometimes
view depression as normal in the context of medical or mental impairment
or declining socioeconomic power and reduced independence, which can

result in an overlooked diagnosis and a missed opportunity to make a dif-
ference with treatment.
Epidemiology
The belief that depression is a natural or even inevitable consequence of
aging is unfounded. Multiple studies suggest that the current and lifetime
prevalences of major depressive disorder (MDD) in later life (age 65 years
and over) are significantly lower than at younger ages. For example, one-
year prevalence rates for men and women, respectively, in the Epidemiologic
Catchment Area (ECA) study were only 0.4 per 100 and 1.4 per 100, i.e.
about one-third of the rates seen in younger or mid-life groups. Of course,
higher rates are observed in specific treatment settings, including hospital
wards and nursing homes. Patients at particular risk include those with
chronic debilitating illnesses, including dementia. There also appears to be a
late-life onset variant of dysthymia that is thought to be linked to the cumu-
lative burden of illness on brain function. As the most serious outcome of
depression, suicide rates in the elderly differ from those of mid-life adults.
Specifically, elderly white men have the highest suicide rates of all socio-
demographic groups. There has, nevertheless, been a reduction in overall
suicide rates in the elderly during the past few decades.
Treatment
Psychotherapy
Various psychotherapies have been adapted for treatment of late-life depres-
sion, including several forms of cognitive behavior therapy (CBT), interper-
sonal psychotherapy (IPT) and psychodynamic psychotherapy (see Table
12.1). One meta-analysis found that CBT was an effective treatment as com-
pared to waiting list or no-treatment control groups, but psychodynamic
psychotherapy was not. Before concluding that psychodynamic psychother-
apy is not a useful treatment for depressed elders, it is important to keep in
mind the potential impact of the ‘allegiance effect’ to bias studies: in this
case few of the studies of psychodynamic therapy were conducted or super-
vised by advocates of this form of treatment. Results of another meta-analy-
sis of a broader grouping of time-limited psychotherapy studies suggested
efficacy because response rates to psychotherapy were significantly higher
Depression in late life 157
Table 12.1 Recommendations for psychotherapy in late-life MDD
First CBT and IPT for mild-to-moderate depression Level 2
than those observed in placebo-control groups in double-blind trials of anti-

depressant medications. However, as there were no direct comparisons
between psychological and pharmacological treatments included in this
meta-analysis, confidence in the conclusion is limited by the simple fact that
studies of psychotherapy and pharmacotherapy may enroll different types of
elderly depressed patients.
Only a small number of controlled studies of psychotherapy in older
depressed patients have included both an active comparator (pharmacother-
apy) and a double-blind placebo. In the first study, patients with bereavement-
related major depressive episodes were randomly assigned to either an
antidepressant or a psychotherapy, singly or in combination. Overall, nor-
triptyline was significantly more effective than placebo, whereas IPT was not.
The combination tended to be more effective than nortriptyline alone. In the
second study, patients who were depressed following myocardial infarction
were randomized to either citalopram or placebo and to either IPT or clinical
management using a factorial design. After 12 weeks of study therapy, the
effects of the selective serotonin reuptake inhibitor (SSRI) were clinically and
statistically significant; non-significant trends actually favored clinical man-
agement alone over IPT. In the only relevant published placebo-controlled
study of treatment of late-life dysthymia and minor depression, a study based
in primary care comparing paroxetine and problem-solving therapy, results
overall favored the pharmacotherapy. However, the inconsistency of the effect
of this brief psychosocial intervention was noteworthy, varying from the least
to the most effective treatment group across the clinical sites of the trial.
Maintenance psychotherapy
Reynolds and colleagues have conducted the only long-term studies evaluat-
ing the role of IPT, alone and in combination with antidepressants, for the
prevention of recurrent depression in later life. The first study, which utilized
nortriptyline, was open to patients aged 60 and older. The second study,
which used paroxetine, was limited to patients 70 and older. In both trials
patients had initially received acute-phase therapy with the combination of

IPT and antidepressants, and did not relapse during four months of continu-
ation therapy. The randomized experiments thus did not begin until patients
had fully recovered from the index episode of depression. In both studies,
patients who were withdrawn from both medication and psychotherapy had
the poorest outcomes, with those remaining on both therapies having the
lowest risk of recurrence. In the first study, the advantage of combined treat-
ment (as compared to the monotherapies) was particularly evident among
those patients aged 70 and above, who were less likely to remain well on
monotherapies than the patients aged 60–69. In the second study, IPT did
not perform as well as in the first; patients on IPT alone were nearly as likely
to suffer recurrences as patients on placebo.
Pharmacotherapy
Antidepressant pharmacotherapy has become the cornerstone of manage-
ment of depression in late life. Evidence from a number of meta-analyses doc-
uments convincingly that antidepressant medications are effective treatments
of late-life depression. The newer medications were found to be as effective as
tricyclic antidepressants (TCAs) in these analyses, and generally are associ-
ated with fewer discontinuations due to severe adverse events and a lower
burden of side-effects. Thus, because the SSRIs are the most widely used anti-
depressants across all age groups, they also are generally used first in late-life
depression. Although not available in the USA, moclobemide has been
studied extensively in this population, and, where available, is a first line
treatment in depressed elders.
Among the newer medications, no significant differences in efficacy across
classes of antidepressants were revealed in these meta-analyses. However,
results from a pooled analysis of eight randomized controlled trials (RCTs)
suggested that therapy with the dual-action agent venlafaxine might result
in higher remission rates than observed with the SSRIs. Although none of
the studies included in the pooled analysis were specifically designed to
examine treatment outcomes in the elderly, this finding held true across age
groups, with the difference being particularly large among postmenopausal
women not taking hormone replacement. The safety and tolerability of ven-
lafaxine has not been studied extensively in frail elders, although one pub-
lished trial that compared venlafaxine and sertraline observed that the SSRI
was significantly better tolerated than the immediate-release formulation of
the serotonin and norepinephrine reuptake inhibitor (SNRI). Clinical experi-
ence with the extended-release formulation of venlafaxine therapy with

healthier older depressed patients has been reassuring. A similar conclusion
was reached in a post hoc analysis of the older participants of double-blind
studies of duloxetine, the second SNRI to be widely introduced.
There is also evidence that escitalopram may have stronger antidepressant
effects than citalopram and, possibly, other SSRIs in controlled studies of
depressed patients, but the impact of such differences specifically in older
patients has not yet been examined. These differences are hypothesized to be
the result of stereochemically mediated differences in binding at the sero-
tonin transporter.
Without consensus about a specific pharmacotherapy of first choice for
treatment of late-life depression, medications are more likely to be deter-
mined by individual physicians’ experiences and differences in side-effect
profiles. This is appropriate because vulnerability to the adverse effects of
pharmacotherapy is a major concern when treating the elderly and concerns
are not restricted to any specific antidepressant class.
Anticholinergic effects (constipation, urinary retention, dry mouth, blurred
vision and cognitive impairment) and postural hypotension, which can cause
falls and, secondarily, hip fractures, are of particular concern when TCAs are
used to treat the elderly. For those at risk for dementia, anticholinergic effects
can unmask cognitive difficulties, and, in the extreme, can provoke a delir-
ium. TCAs also have quinidine-like effects on cardiac conduction, which can
worsen otherwise benign bundle branch blocks, can cause tachycardia and
can have a relatively high lethality index, which makes them dangerous in
overdose.
Within the TCA class, nortriptyline and desipramine are generally preferred
for the treatment of depression in late life, because these medications tend to
cause fewer anticholinergic and antihistaminic side-effects. Moreover, blood
level/treatment response relationships for TCAs have been relatively well
studied, which permits somewhat greater precision in titrating to higher
doses. Nevertheless, the overall side-effect burden of the secondary amine
TCAs is still greater than that of the SSRIs. For example, nortriptyline has anti-
cholinergic effects that are an order of magnitude stronger than those of
paroxetine, which is the most anticholinergic of the SSRIs. Thus, even the
secondary amine TCAs are now widely considered to be a second or third line
therapy for depression in late life.
Although the SSRIs are now generally preferred over the TCAs because of
safety considerations, there are some other concerns that are relevant to treat-
Table 12.2 Recommendations for pharmacotherapy in late-life MDD
First Moclobemide Level 1

Citalopram; bupropion; escitalopram; fluvoxamine; Level 2
paroxetine; sertraline; venlafaxine; mirtazapine
Second Fluoxetine; nortriptyline Level 1

Desipramine; trazodone Level 2
Third Amitriptyline; imipramine Level 1

Clomipramine; doxepin; maprotiline Level 2
Phenelzine; tranylcypromine Level 2
Maintenance-phase treatment
Elderly patients should continue maintenance Level 1
pharmacotherapy for at least two years
ment of the frail elderly. Foremost among these are bradycardia, the syn-
drome of inappropriate excretion of antidiuretic hormone (SIADH) and
balance difficulties, which can cause falls. To these more serious side-effects
must be added the common treatment-emergent complaints, such as sexual
dysfunction, nausea, diarrhea and other gastrointestinal complaints and
insomnia. Venlafaxine (which, at lower doses, can be thought of as an SSRI)
has similar side-effects, with an additional concern of elevated blood pressure
at higher doses (Table 12.2).
Among the other newer antidepressants, bupropion, moclobemide, nefa-
zodone and mirtazapine are distinguished from the SSRIs and venlafaxine by
a relatively low incidence of sexual side-effects. Mirtazapine has beneficial
effects on sleep, which can be a bonus for many older depressed patients,
whereas bupropion and moclobemide are essentially non-sedating.
Mirtazapine is the most antihistaminic of all the newer antidepressants, and,
as a result, can cause oversedation and weight gain. Interestingly, in one
recent clinical trial, response to mirtazapine was superior to response to
paroxetine among patients who expressed the APOE4 gene, which is impli-
cated in the risk of dementia and cerebrovascular disease. Nefazodone is
seldom used today because it has been associated with a rare incidence of
liver failure.
The non-selective monoamine oxidase inhibitors (MAOIs), tranyl-
cypromine and phenelzine, are considered third-choice therapies for late-life
depression, largely because of the need for dietary restrictions to avoid the so-
called ‘cheese effect’, i.e. a hypertensive crisis triggered by ingestion of the
amino acid tyramine. The MAOIs can also cause a range of troublesome side-
effects, with orthostatic hypotension being the most serious in late-life
patients. Nevertheless, these medications were found to be significantly more
effective than the RIMA (reversible inhibitor of monoamine oxidase A)
moclobemide in one meta-analysis. This analysis was not confined to studies
of late-life depression, however, in which the tolerability advantage of
moclobemide may have been more salient. It remains to be seen whether the
new transdermal formulation of selegiline is useful in late-life depression.
Although selegiline is approved in low (MAO-B) selective doses for treatment
of Parkinson’s disease (i.e. 5–10 mg/day orally), antidepressant activity
requires much higher, non-selective oral doses (i.e. >30 mg/day). Transdermal
administration eliminates inhibition of MAO-A in the gut and, by skipping
first-pass metabolism, minimizes MAO-A inhibition in the liver. Thus, trans-
dermal delivery permits a high, non-selective level of MAO inhibition in the
brain, with much less risk of dietary interactions. There are, however, two
remaining issues that have dampened clinical enthusiasm: (1) the US Food
and Drug Administration (FDA) has approved therapy without dietary restric-
tions only at the initial, minimum therapeutic dose (6 mg/24 hours), while
higher doses (i.e. 9–12 mg/24 hours) are often needed for patients with diffi-
cult-to-treat depression; and (2) relative freedom from dietary interactions
does not convey any protection from the potential for drug–drug interactions,
which can include potentially lethal cases of serotonin syndrome when high
doses of selegiline are used in close temporal proximity to SSRIs or SNRIs.
Washouts of at least one week are thus necessary when switching from reup-
take inhibitors and, because of the long elimination half-life of its metabolite
(norfluoxetine), at least five weeks are needed following cessation of fluoxe-
tine therapy.
Pharmacokinetic factors and propensity to cause drug–drug interactions are
also important when considering which newer antidepressant to prescribe.
SSRIs vary in their effects on the various cytochrome P450 (CYP) isoenzymes,
thus resulting in significant differences in propensity to cause drug–drug
interactions (see Chapter 6). This is particularly important in elderly patients
who have often been prescribed multiple medications for various comorbid
physical conditions. Sertraline, citalopram, escitalopram, venlafaxine,
mirtazapine and also agomelatine are considered to have lower potential for
this type of drug–drug interaction.
Maintenance pharmacotherapy
The need for maintenance treatment after successful antidepressant therapy
in the elderly is at least as important as it is for younger adults. Moreover,
elderly patients may be even more likely to relapse after discontinuing anti-
depressants, so most antidepressant responders should receive maintenance
pharmacotherapy for at least two years (see Chapter 2). In a four-year
outcome study of elderly patients with MDD, higher anxiety scores at the
time of response and longer time to treatment response were risk factors for
recurrence. Therefore, treatment of residual anxiety symptoms may improve
the long-term treatment outcome.
With one exception, controlled studies of the SSRIs have documented sus-
tained efficacy. There are few studies to compare the effectiveness of specific
maintenance treatments in the elderly, and none specifically contrasting
various types of newer antidepressants (e.g. SSRI vs. SNRI) and none compar-
ing a newer antidepressant against an older standard such as nortriptyline.
Phenelzine was superior to nortriptyline in a placebo-controlled, one-year
maintenance study of elderly patients with depression, although high drop-
out rates compromised this study. As noted earlier, there is evidence from
the first study of Reynolds and colleagues that nortriptyline is an effective
maintenance pharmacotherapy, especially at higher serum levels and in
combination with IPT. The TCA dosulpin has also been shown to be effective
for prevention of recurrent depression in late-life depression.

Electroconvulsive therapy (ECT) is a safe, rapidly effective and well-tolerated
treatment for severe forms of MDD (see Chapter 8). It has been repeatedly
shown to be a useful treatment in late-life depression, even in the presence
of significant medical comorbid conditions. In some regions, ECT is used
preferentially for the treatment of patients who are less able to tolerate pro-
longed response times to pharmacotherapy (i.e. intensely suicidal patients or
those who are essentially starving to death from disinterest in food). ECT is
the treatment of first choice for severe depressive episodes with psychotic
features, and should always be considered when multiple antidepressant
trials have been ineffective. Good ECT practice in the elderly requires careful
pre-anesthetic medical consultation and management, minimization of con-
comitant pharmacotherapy that may adversely affect cognition and vigilant
monitoring of intra- and post-ECT cardiac status.
Factors influencing the choice of bilateral versus unilateral electrode place-

ment are similar to those in younger groups, balancing the higher probability
of response, fewer missed seizures (and thus less required exposure to anes-
thetics) and longer times to relapse in bilateral placements with correspond-
ingly greater likelihood of confusion, memory impairment or delirium.
Conclusion
Although prevalence rates for depression in late life are lower compared to
middle life depression, comorbid depression and medical illness is a frequent
problem in the elderly and often adds complexity to pharmacotherapy. In
general the same treatments that work in middle late life are effective in the
elderly, although there is a substantially smaller evidence base. The use of
ECT is disproportionately higher in this population compared to younger age
groups.
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Chapter 13
Psychiatric and physical

comorbidities in
depression
General principles
Major depressive disorder (MDD) is such a common condition in the
general population that its co-occurrence with other Axis I (psychiatric),
Axis II (personality) and Axis III (physical) disorders is to be expected.
However, MDD occurs much more often than would be expected by
chance in many conditions (Figures 13.1 and 13.2). Clinicians can expect
General population 5
Schizophrenia 25
Alcohol abuse 26
Drug abuse 35
Personality disorders 35
Attention deficit disorder 40
Anxiety disorders 50
Bulimia nervosa 65
Anorexia nervosa 84
0 20 40 60 80 100
% of sample with MDD

Figure 13.1 Prevalence of MDD in other Axis I disorders.
General population 5
Alzheimer's disease 11
HIV/AIDS 12
Heart disease 17
Stroke 23
Myocardial infarct 25
Diabetes 27
Cancer 42
Parkinson's disease 51
0 10 20 30 40 50 60
% of sample with MDD
Figure 13.2 Prevalence of MDD in chronic disease. HIV, human
immunodeficiency virus; AIDS, acquired immune deficiency syndrome.
that many patients with MDD will have comorbid conditions. Left
untreated, depression can contribute to poor compliance for treatment of
other medical conditions, increase length of hospital stays and increase
mortality.
There are many common diagnostic and treatment issues associated with
comorbid depression, regardless of the specific comorbid condition. The
diagnosis of depression is often difficult to make in the presence of comor-
bidity. Depressive symptoms frequently accompany other illnesses, and the
primary condition may have symptoms that are common to MDD. For
example, anxiety symptoms such as panic attacks can occur or worsen
during a major depressive episode (MDE). Mood instability is a common
symptom in personality disorders and can be misdiagnosed as depressive
mood. In physical illnesses such as cancer, fatigue and lack of energy may
not be a valid symptom of depression. In these situations, other depressive
symptoms such as anhedonia, loss of interest and feelings of guilt may be
helpful in making a diagnosis of comorbid MDD.
Despite the high frequency of comorbidity, there are very few controlled
studies of treatment. MDD with comorbidity is usually more difficult to treat,
runs a more chronic course, has greater impairment of function and is associ-
ated with greater risk of suicide compared with MDD alone. Unfortunately,
most randomized controlled trials of MDD specifically exclude comorbid
Psychiatric and physical comorbidities in depression 169
conditions, so results cannot be generalized to patients with comorbidity.

Many studies focus only on depressive symptoms and do not include formal
comorbid depressive disorders. Psychotherapeutic interventions are often tar-
geted at the primary condition, which may also reduce secondary depressive
symptoms. Similarly, studies of antidepressants for comorbidity can be com-
plicated by other medications used in treating the primary disorder.
Not surprisingly, response and remission rates with monotherapy treat-
ments are generally lower in patients with comorbidity. Combined treatment
with pharmacotherapy and psychotherapy is usually indicated for optimal
outcome. In the following sections, evidence-based treatment recommenda-
tions for both psychotherapy and pharmacotherapy are summarized for Axis
I, II and III comorbidities.
Axis I comorbidities
Depression is frequently comorbid with other psychiatric disorders (see
Figure 13.1). Among the Axis I disorders, anxiety disorders (panic disorder,
generalized anxiety disorder, post-traumatic stress disorder, obsessive com-
pulsive disorder and social anxiety disorder) and eating disorders are most
commonly associated with MDD. In some conditions, such as schizophrenia,
it is very difficult to separate symptoms of depression from symptoms of the
primary condition, such as negative symptoms. Specific symptom scales
(such as the Calgary Depression Scale) can be useful in making an MDD
diagnosis.
Treatment
In the treatment of Axis I comorbidities, some of the same medication prin-
ciples apply as for people with medical illnesses. For example, people with
anxiety disorders are often hypersensitive to somatic sensations. Thus, lower
initial doses and slower dose titration are helpful strategies to minimize their
experience of medication side-effects. In most cases, however, full therapeu-
tic doses are required for optimal response. Evidence based treatments of
selected Axis I comorbidities are summarized in Table 13.1.
Axis II comorbidities
Personality disorders and dimensions also have a complex relationship with
MDD. An estimated 30–50% of patients with MDD have a diagnosable
Table 13.1 Recommendations for the treatment of MDD with

comorbid Axis I (psychiatric) disorders
Treatment choice
Condition Psychotherapy Pharmacotherapy
Anxiety CBT (Level 3) SSRIs and novel agents (Level 3)

disorders • panic disorder: start with lower initial doses
• OCD: aim for higher doses
Substance use Motivational Fluoxetine; imipramine; desipramine (Level 2)

disorders interviewing (Level 3) Avoid benzodiazepines (Level 3)
Avoid interactions: MAOIs with opiates; SSRIs
with MDMA; fluoxetine/paroxetine and
codeine (opiate withdrawal); bupropion SR
(increased seizure risk)
Eating CBT (Level 2) Bulimia nervosa: fluoxetine (Level 2); phenelzine

disorders (cautions apply) (Level 2)
Anorexia nervosa: TCAs and SSRIs (Level 3)
Schizophrenia Adjunctive CBT treats Imipramine; sertraline (Level 2)

negative and positive Other SSRIs (Level 3)
symptoms (Level 2) SSRIs may help negative symptoms (Level 2)
Atypical antipsychotics (olanzapine;
risperidone) treat depressive symptoms in
acute psychosis (Level 1)
Clozapine reduces suicide events (Level 2)
Attention CBT may be useful as Bupropion SR (Level 3)

deficit adjunctive treatment Atomoxetine (Level 4)
disorder (Level 3) Fluoxetine; sertraline as adjunctive treatment
for depressive symptoms only (Level 3)
Dementia BT (Level 2) Citalopram; fluoxetine; sertraline (Level 2)

Amitriptyline; clomipramine (Level 2)
ECT (Level 3)
SSRI, selective serotonin reuptake inhibitor; OCD, obsessive compulsive disorder; MAOI,
monoamine oxidase inhibitor; CBT, cognitive behavior therapy; BT, behavior therapy; TCA, tricylic
antidepressant; ECT, electroconvulsive therapy; MDMA, methylenedioxymethamfetamine
(Ecstasy).
personality disorder. There is some evidence that premorbid personality

dimensions such as neuroticism confer vulnerability to depression. However,
MDD can also result in regression and exacerbation of premorbid personality
dimensions. In many studies, effective treatment of MDD leads to an
Table 13.2 Recommendations for the treatment of MDD comorbid

with Axis II (personality) disorders
Psychotherapy
Combined psychotherapy and pharmacotherapy may have superior outcomes Level 3
The combination of Cognitive Behavioral Analysis System of Psychotherapy Level 2
(CBASP) and pharmacotherapy was particularly effective in a group of patients
with ‘chronic depression’, many of whom met criteria for Axis II disorders
Dialectical behavior therapy is beneficial for mood symptoms associated with Level 2
borderline personality
Pharmacotherapy
Fluoxetine (in borderline personality) Level 2
Monoamine oxidase inhibitors (MAOIs) Level 3
Olanzapine and risperidone (as adjunctive treatment) Level 3
improvement in personality traits, and patients may no longer meet criteria

for a personality disorder once they have recovered from an MDE. Evidence
based treatments of Axis II comorbidities are summarized in Table 13.2.
Treatment
Most attention has been focused on depression in relation to borderline per-
sonality disorder. In two clinical trials, one in the USA and one in New
Zealand, the presence of a Cluster B diagnosis before treatment predicted a
positive antidepressant response to fluoxetine compared to those without a
comorbid diagnosis, although a subsequent meta-analysis suggested a thera-
peutic disadvantage for pharmacotherapy in depressed patients with comor-
bid personality disorders. In addition, electroconvulsive therapy (ECT)
outcome in depressed patients with comorbid borderline personality disor-
der was significantly worse than in depressed patients with or without other
personality disorders.
The role of psychotherapy is of particular importance, either alone or
combined with pharmacotherapy, in treating axis II comorbidities. Psycho-
educational and skills-oriented approaches to psychotherapy have been rec-
ommended for patients with chronic depression and comorbid personality
disorders. Modified forms of cognitive behavior therapy (CBT), including
dialectical behavior therapy (DBT), have been developed for patients with
borderline personality disorder. The Cognitive Behavioral Analysis System of
Psychotherapy was specifically developed for the treatment of chronic

depression, and was found to have significant effects on psychosocial func-
tioning independent of change in depressive symptoms. Evidence based
treatments of Axis II comorbidities are summarized in Table 13.2.
Axis III comorbidity

Depression is common, and increasingly recognized as an important risk factor
in the mortality and functional impairment of patients with comorbid physi-
cal illness (see Figure 13.2). Depression can worsen outcomes in medical con-
ditions by several potential mechanisms: (1) behavioral inactivation and lack
of motivation seen in depression may affect adherence to medications or other
important treatments (such as exercise for diabetes); (2) there may be an
increase in negative behaviors associated with depression (e.g. poor diet,
smoking, etc.); (3) interpersonal problems experienced by people with depres-
sion may affect ability to engage with health professionals and rehabilitation
programs; and (4) biological manifestations of depression, such as immune
dysfunction, decreased heart rate variability, impaired circadian rhythms and
disrupted sleep patterns, may specifically affect physical health.
There is particular interest in the relationship between cardiovascular
disease and depression. Depression is a significant risk factor for developing
coronary artery disease (CAD), and depressed patients are four times as likely
to have a myocardial infarction (MI). Depression is also associated with
increased mortality in patients with CAD, possibly due to alterations in the
hypothalamic–pituitary–adrenal axis, increased platelet activation and coag-
ulability, increased levels of proinflammatory cytokines or decreased heart
rate variability. In the first six months after an MI, there is a three- to four-
fold increase in mortality among those patients with MDD, which makes it
second only to heart failure as a poor prognostic indicator.
Treatment
Despite the high prevalence and importance of depression in physical
illness, there are very few large randomized controlled trials (RCTs) of med-
ically ill patients with defined comorbid depression (with the exception of
CAD – see below). In general, antidepressants appear to be effective treat-
ments in patients with MDD and general medical illnesses. A systematic
review conducted through the Cochrane collaboration showed that antide-
pressants are effective for depression comorbid with a wide range of medical
Table 13.3 Recommendations for MDD comorbid with Axis III

(physical) disorders
Treatment choice
Condition Psychotherapy Pharmacotherapy
General medical Social support; psychotherapy Selective serotonin reuptake

disorders (elderly) (Level 1) inhibitors (SSRIs); novel
antidepressants; tricyclic
antidepressants (TCAs);
psychostimulants (Level 1)
Cardiac disease Cognitive behavior Citalopram; sertraline (Level 1)

therapy (CBT) (Level 2) Nortriptyline (Level 2)
Interpersonal psychotherapy
(IPT) no more effective
than placebo, therefore
not recommended
Cancer No studies found Fluoxetine; mianserin; paroxetine

(Level 2)
Amitriptyline; desipramine (Level 2)
Diabetes CBT (Level 2) Fluoxetine; sertraline (Level 2)

Nortriptyline (Level 2) and other
norepinephrine-acting TCAs may
worsen glucose control, therefore
not recommended
HIV/AIDS IPT; group social support; Fluoxetine (Level 1)

CBT (Level 2) Paroxetine; desipramine; imipramine
(Level 2)
Sertraline (Level 3)
Parkinson’s disease No studies found Nortriptyline; desipramine (Level 2)

Paroxetine; sertraline (Level 3)
Stroke disease CBT no more effective than Citalopram; fluoxetine; nortriptyline;

placebo, therefore not sertraline (Level 1)
recommended (Level 2) Psychostimulants (Level 3)
conditions, and are generally well tolerated by patients with medical illness.
Evidence-based treatment recommendations for comorbid medical condi-
tions are summarized in Table 13.3.
There are numerous studies of psychological treatment for cancer. While
several studies have shown reductions in depressive and anxiety symptoms
with CBT and other treatments, none has specifically examined patients
with a comorbid diagnosis of MDD. There is limited information on antide-
pressant effects in cancer patients with comorbid depression, although posi-
tive results with mianserin, fluoxetine and paroxetine have been reported.
Three large RCTs have examined the treatment of depression in patients
with CAD. In the SADHART study (Sertraline AntiDepressant Heart Attack
Randomized Trial), sertraline was compared with placebo in the treatment of
MDD post-MI. The antidepressant was effective in reducing symptoms of
depression, and overall showed better outcomes than placebo on a number
of cardiovascular system measures. Although sertraline did not significantly
reduce mortality or other cardiac events, this study was not adequately
powered to detect these differences. Another study, ENRICHD (Enhancing
Recovery in Coronary Heart Disease Patients), examined CBT (augmented by
sertraline for severe depression non-responders after five weeks) for post-MI
MDD. CBT modestly improved depressive symptoms compared to usual care
(which may have included antidepressants), but did not affect cardiac out-
comes. A post hoc analysis, however, found that the subgroup taking sertra-
line did show reductions in mortality and cardiac events. The third RCT
compared citalopram, interpersonal psychotherapy (IPT) and the combina-
tion in patients with CAD and MDD. Citalopram, but not IPT, was superior
to pill placebo in reducing symptoms of depression. There was no added
benefit of IPT over clinical management in this study. In summary, selective
serotonin reuptake inhibitors (SSRIs) such as sertraline and citalopram are
effective for MDD comorbid with CAD, with some evidence suggesting that
both depression and cardiac outcomes may be improved with treatment.
CBT, but not IPT, also appears to have benefit for these patients.
There are some important considerations with the use of specific medica-
tions for depression comorbid with other medical illnesses (see Table 13.4).
For example, nortriptyline is effective in treating people with diabetes and
depression but it has been found to worsen glucose control, while fluoxetine
not only improved mood but also improved glycemic control. The effect of
psychotropic medication-related weight gain on insulin resistance is always
an important issue to be considered. On the other hand, amitriptyline and
dual-action antidepressants also play an important role in treating chronic
painful physical conditions.
One important caution in using antidepressants in physically ill patients is
the risk of adverse events of particular antidepressants and potential interac-
tions with other drugs.
Table 13.4 Safety concerns for the use of antidepressants in

physically ill patients
Avoid antidepressants with:
• potential interactions with the physical illness, e.g. tertiary amine TCAs in cardiac
disease or bupropion in epilepsy
• side-effects that may exacerbate the physical illness, e.g. nortriptyline or
mirtazapine in diabetes
• potential interactions with other drugs used to treat the physical illness, e.g.
fluvoxamine with quinidine.
Start low, go slow and keep going, i.e. start with lower than usual doses of medications
and titrate up slowly but continue to full therapeutic doses as needed.
Conclusions
Comorbidities are the rule rather than the exception among patients with
mood disorders, yet few clinical trials have been carried out to assess out-
comes in patients with psychiatric and physical comorbidities. A notable
exception is the Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) study, where real-world patients received sequenced treatments. A
valuable contribution from this project will be results comparing treatment
outcomes for patients with and without Axis I, II or III comorbidities. In
general, comorbidity with depression tends to predict less favorable thera-
peutic outcomes. For optimal patient care, it is important that treatment
selection is informed by careful assessment of all three axes. In medically ill
patients, it is important to evaluate the impact of antidepressant treatment
not only on mood symptoms but also on other physical outcome criteria.
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Index
Page references in italics refer to Figures and Tables
adherence 16, 16 assertiveness 35

adolescence see children and adolescents atomoxetine in children and adolescents
α2-adrenoceptor antagonism 55 148
agomelatine 56 attention deficit hyperactivity disorder
in anxious depression 67, 68 (ADHD) 148
in melancholia 65 atypical depression 17, 78, 129
in winter depression 67 management 63, 63
agomelatine 75, 82, 83 atypicals as augmentation therapies 98
in children and adolescents 148 augmentation therapy 45, 98
in elderly people 162 automatic negative thoughts 33, 34
optimization 96
side-effects 85, 86 Beck Depression Inventory 17, 29
alcohol abuse\130 Beck’s model of cognitive therapy 30
allegiance effect 156 befloxatone 51
all-or-none thinking 33 behavior therapy 35
allosteric serotonin reuptake inhibitor vs. cognitive therapy 39
(ASRI) 53, 81 behavioral rehearsal 35
amine uptake blocking agents 51–5 benzodiazepines
amitriptyline 51, 79 in anxious depression 68
comorbidities 174 ECT and 109
in psychotic major depression 66 bereavement 3, 5
anhedonia 35, 64, 168 bibliotherapy 39–40
anticonvulsants, ECT and 109 bipolar disorder 5
antidepressant, choice of 14–16 postpartum depression and 136
classification by mechanism of action bradycardia 160
75, 76 breastfeeding 138–9
evolution of 49–50, 49 bupropion 52, 75, 82
psychotherapy in combination with in children and adolescents 148
42–4 in combination 100
anxious depression 67–8, 68 in elderly people 160
anxiety disorder 44 optimization 96
aripiprazole 98 in pregnancy 133
178 Index
bupropion (cont.) Cognitive Behavioral Analysis System of

in premenstrual dysphoric disorder 131 Psychotherapy (CBASP) 13, 35–6,
side-effects 82, 84, 86 44, 69, 171–2
switching 94 cognitive therapy 31, 32–4
in winter depression 67 vs. behavioral therapy 39
burden of illness 1 vs. interpersonal psychotherapy 38
buspirone 99 phases of treatment 33–4, 34
response/remission in 45
Calgary Depression Scale 169 in switching 94
cancer 168, 172–3 cognitive triad 33
carbamazepine, ECT and 109 collaborative empiricism 33
cheese reaction 51 combination strategies 100, 101
children and adolescents, depression in combination therapy 98
ECT 149–51 comorbidity 167–75
maintenance therapy 149 Axis I 169
pharmacotherapy 147–9, 148 Axis II 169–72
psychotherapies 145–6, 146 Axis III 172–4
risk factors 145, 146 gender and 130
chlomipramine 52 management 10, 11–12
chlorpromazine 51 compliance 16, 16
choice of antidepressants, factors conflict resolution 35
influencing 75 continuation phase psychotherapy 41–2
chronic depression 68–70, 69 coronary artery disease (CAD) 172
citalopram 52, 53, 81 cost of depression 1
augmentation 94, 98, 99 course of depression 1
in children and adolescents 147 cross-over 97
comorbidities 174
in elderly people 157, 159, 161 Daily Record of Dysfunctional Thoughts
in postpartum psychosis 139 34
in pregnancy 133 deep brain stimulation 114–15
in premenstrual dysphoric disorder dehydroepiandrosterone 122
131, 132 delayed onset of antidepressant action
remission after 93 56–7, 56–7
in winter depression 67 dementia 156
clomipramine 53, 79 depression neurocircuitry 114
augmentation 99 desipramine 53, 79
in anxious depression 68 in combination 97, 100
in melancholia 64 overdose 88
clonazepam in anxious depression 68 in premenstrual dysphoric disorder
cognitive behavior therapy (CBT) 13, 32 131
in adolescents 146 switching 98
in Axis II comorbidity 171 desvenlafaxine succinate (DVS) 81
in children\145–6 in menopause 140
in depression during pregnancy 133 diabetes 174
in elderly people 156 diagnosis 2–4
interpersonal psychotherapy vs. 38 diagnostic instruments 4–5
in postpartum depression 136 dialectical behavior therapy (DBT) 171
women and 130 diaphragmatic breathing 35
Index 179
disability adjusted life years (DALYs) 1, 2 in pregnancy 135

discontinuation and discontinuation- prevention of relapse following 110
emergent symptoms 88 in psychotic major depression 66
docosahexanoic aicd (DHA) 120 treatment parameters 106–8
dosulphin in elderly people 162 unilateral (UL-ECT) 107
double depression 68 electroencephalogram (EEG) 107
drug–drug interactions 86–7 emotional reasoning 33
DSM-IV-TR (SCID) 5 enzyme inhibitors 50
dual-action antidepressants 53–5, 75, 79 eosinophilia myalgia syndrome 121
in children and adolescents 147–8, escitalopram 52, 53, 81
149 in elderly people 161
during pregnancy 133 in melancholia 65
duloxetine 53, 54, 75, 79, 81 in pregnancy 133
in children and adolescents 148 in premenstrual dysphoric disorder
drug–drug interactions 86 131, 132
in melancholia 65 in winter depression 67
optimization 96 estrogen replacement therapy 140–1
side-effects 86 evening primrose oil,
dysthymic disorder 68 in premenstrual dysphoric disorder
132
eating disorders 130 evidence based antidepressant selection
Edinburgh Postnatal Depression Scale 61–70, 62
(EPDS) 137 exercise 125, 126
eicosapenaenoate (EPA) 120, 121
elderly people, depression in 155–63 fatigue 3
ECT 162–3 first generation antidepressants 75–80
epidemiology 156 fluoxamine 86
maintenance pharmacotherapy 162 fluoxetine 53, 54, 57
maintenance psychotherapy 157–8 in adolescents 146
pharmacotherapy 158–62, 160 in anxious depression 68
psychotherapy 156–7, 157 in atypical depression 63
treatment 156–63 in Axis II comorbidity 171
electroconvulsive therapy (ECT) 55, in breastfeeding 139
105–10 in children and adolescents 147, 148,
adverse effects 108 151
in Axis II comorbidity 171 in chronic depression 68
bilateral (BL-ECT) 107 in combination 98, 100, 122
in children and adolescents 149–51, comorbidities 174
150–1 discontinuation 88
in combination with antidepressants drug–drug interactions 86
109 in melancholia 65
efficacy and indications 105–6 in menopause 141
in elderly people 162–3 optimization 97
gender differences in response 131 in postpartum depression 136
indications 107 in postpartum psychosis 139
maintenance 109, 109 in pregnancy 133, 134
management of seizure activity 108 in premenstrual dysphoric disorder
in postpartum psychosis 138 131
180 Index
fluoxetine (cont.) interpersonal deficits 36

in recurrent brief depression 69 interpersonal psychotherapy (IPT) 13,
side-effects 85, 86 36–7
switching 97 in children and adolescents 146
washout period 78, 97 cognitive behavioral therapy vs. 38
in winter depression 67 cognitive therapy vs. 38
fluparoxan 55 in elderly people 156, 157, 158
fluvoxamine gender and 130
in anxious depression 68 phases of treatment 36, 37
discontinuation 88 involuntary admission 11
in minor depressive disorder 69 involutional melancholia 139
in postpartum psychosis 139
in pregnancy 133 lesion based neurosurgery 115
side-effects 85 light therapy 67, 123–4, 125, 126
efficacy 123
gender differences in depression 129–30 maintenance and prevention 124
in treatment response 130–1 side-effects 124, 124
graded task assignment 35 treatment parameters 123
grief, unresolved 36 α-linolenic acid 120
group therapy, gender and 130 lithium
guided discovery 33 augmentation 94, 97, 98
Guillain-Barré syndrome 52 in combination 125
ECTs and 109, 110
haloperidol 98 in postpartum depression 137
Hamilton Depression Rating Scale lorazepam in anxious depression 68
(HDRS/HAM-D) 17, 18–19, 38, 65
hepatitis 52 maintenance response to treatment 17,
HIV 38 20
hopelessness 10 major depressive disorder (MDD)
hormone replacement therapy (HRT) management
140–1 goals 9–10, 9
Hospital Anxiety and Depression Scale phases 9–10, 10
(HADS) 17, 24–5 MAO-A 78, 161
hyperforin 120 maprotiline 52
hypericin 120 in minor depressive disorder 69
Hypericum perforatum 119–20 in premenstrual dysphoric disorder
side-effects 120 131
maternity blues 135
idazoxan 55 major depressive disorder
imipramine 51–2, 79 prevalence in other Axis disorders 167
in atypical depression 63 prevalence in chronic disease 168
in anxious depression 68 subtypes of 6
vs. cognitive therapy 41 treatment options for subtypes 63–8
vs. interpersonal psychotherapy 38, measurement-based care 17
42 meditation 40
interpersonal psychotherapy and 45 melancholia 64–5, 64, 65
inositol 120–1 memory retrieval 33
insomnia 3 menopause 139–41
Index 181
prevalence of depression 139–40 reversible 51

risk factors 140 side-effects 71
treatment 140–1 in tuberculosis 49, 50
metachlorophenylpiperazine 55 type A 50
methylphenidate 99 type B 50
mianserin 55 washout period before 78
in combination 100 Montgomery Asberg Depression Rating
comorbidities 174 Scale (MADRS) 17, 21–3, 65
mifepristone (RU486) in psychotic major Mood Disorders Questionnaire 5
depression 66 Motherisk Program 134–5
milnacipran 53, 75, 79, 81 myocardial infarction (MI) 172
side-effects 86
mind-reading 33 nefazodone 55
mindfulness based cognitive therapy in combination with CBASP 44
(MBCT) 40, 45 in chronic depression 68
Mini International Neuropsychiatric in elderly people 160
Interview (MINI) 5, 10, 14 in pregnancy 133
minor depressive disorder (mDD) 69, 70 nomifensine 52
mirtazapine 53, 55, 58, 82, 83 norepinephrine reuptake inhibitor (NRI)
in anxious depression 68 52
in children and adolescents 148 in menopause 140
in chronic depression 68 in pregnancy 133
in combination 100 norepinephrine transporter blockade 96
in elderly people 160, 162 norfluoxetine 53
in menopause 141 in elderly people 161
in pregnancy 133 nortriptyline 42, 52, 79
in recurrent brief depression 69 comorbidities 174
remission 95 ECT and 110
side-effects 85, 86 in elderly people 157, 158, 159, 162
switching to 94 IPT and 42
moclobemide 51, 53, 75 optimization 96
in anxious depression 68 in postpartum depression 136
in atypical depression 63 in pregnancy 133
in chronic depression 68 switching to 94
in elderly people 158, 160, 161
in melancholia 64, 65 obsessive compulsive disorder (OCD)
washout period 78, 97 145
in winter depression 67 olanzapine
modafinil 99 augmentation 98
monoamine oxidase inhibitors (MAOIs) in psychotic major depression 66
63, 75–8, 97 omega-3 fatty acids 120–1
in breast-feeding 138 omega-6 fatty acids 120
in children and adolescents 147 optimization 96
in chronic depression 68 overdose, safety in 88
dosing 76 overgeneralization 33
in elderly people 161
irreversible 50 panic attacks 168
in pregnancy 133–4 pargyline 50
182 Index
Parkinson’s disease 50, 78, 114 prevalence 138

in elderly people 161 pregnancy, depression during 132–5
paroxetine 52, 53, 57 pharmacotherapy 133–5
in anxious depression 68 prevalence 132–3
vs. behavioral therapy 39 psychotherapy 133
in children and adolescents 147, 148 premenstrual dysphoric disorder 131–2
in chronic depression 68 pharmacotherapy 131–2
comorbidities 174 prevalence 131
discontinuation 88 psychotherapy for 131
drug–drug interactions 86 symptoms 132
in elderly people 157, 158 prevalence 1, 2
interpersonal therapy and 42 PRIME-MD (Primary Care Evaluation of
in melancholia 64, 65 Mental Disorders) 4–5, 17
in minor depressive disorder 69 problem-solving therapy 35
in postpartum depression 136 in elderly people 157
in postpartum psychosis 139 in minor depressive disorder 69
in pregnancy 133, 134 progressive deep muscle relaxation 35
in premenstrual dysphoric disorder protriptyline 52
131, 132 psychoanalytic psychotherapy 30
in psychotic major depression 66 psychotic major depression 65–6, 66
in recurrent brief depression 70 psychodynamic psychotherapy,
side-effects 85, 86 in elderly people 156
Patient Health Questionnaire (PHQ) 17, psychoeducation 17, 29
26–7 psychotherapy 12–14, 15, 29–30
perphenazine in psychotic major along, indications for 31–2
depression 66 antidepressants in combination with
personality disorder 44 42–4, 43
personalization 33 depression-focused, effectiveness of
phenelzine 37–9
in atypical depression 63, 78 gender differences in response 130
in elderly people 161, 162 in Axis II comorbidity 171
switching 97 maintenance phase models 42, 42
phospholipids 120 preventive effects 40–1
physical symptoms, unexplained 3, 5 treatment overview and limitations
pindolol 57 30–1
augmentation 99
in combination 125 quetiapine
placebo 37 as augmentor 98
postnatal mood disorders 70, 135–7 in psychotic major depression 66
prevalence 135–6
postpartum depression (PPD) 134, 135–7 randomized controlled trials (RCTs) 30
pharmacotherapy 136–7 rapid eye movement (REM) 3, 85
prevalence 135–6 reboxetine 52, 75, 83
psychotherapy 136 in pregnancy 133
risk factors 136 in recurrent brief depression 69
postpartum psychosis (PPP) 135, 138–9 side-effects 83
pharmacotherapy and breast-feeding receptor-acting drugs 55–7
138–9 recurrence rates 1
Index 183
recurrent brief depression (RBD) 69–70, serotonergic syndrome 122

70 serotonin and norepinephrine reuptake
remission 17 inhibitor (SNRI) 53, 81–3
repetitive transcranial magnetic in children and adolescents 147
stimulation (rTMS) 110–12 dosing 83
combination with antidepressants 112 in elderly people 157, 158, 159
efficacy and indications 110–11 in pregnancy 133
treatment parameters 111 metabolism and weight change 85–6,
RIMA (reversible inhibitor of 85
monoamine oxidase A) 161 sexual function 86, 86
risperidone side-effects 83–6, 84
augmentation 98 sleep, alertness and neurocognition
in psychotic major depression 66 84–5
role disputes 36 switching 94
role playing 35 serotonin metabolism, gender and 130
role transitions 36 serotonin syndrome 51
sertraline 52
S-adenosyl methione (SAMs) 121 in anxious depression 68
schemas 32 in atypical depression 63
schizophrenia 49, 51 in children and adolescents 149
second generation antidepressants 80–3, in chronic depression 68
87 in combination 100
selective abstraction 33 comorbidities 174
selective serotonin reuptake inhibitor in elderly people 158, 161
(SSRI) 51, 52–3, 61, 75, 80–1 in melancholia 64
in anxious depression 67 in menopause 141
in breast-feeding 138 in minor depressive disorder 69
in children and adolescents 147–8, in postpartum depression 136
148 in postpartum psychosis 139
discontinuation 88 in pregnancy 133, 134
dosing 81 in premenstrual dysphoric disorder
in elderly people 159, 160 131, 132
metabolism and weight change 85–6, in psychotic major depression 66
85 side-effects 86
in menopause 141 switching 94
in minor depressive disorder 69 in winter depression 67
in pregnancy 133, 134 severity of depression 64, 64
in premenstrual dysphoric disorder six-month prevalence 1, 2
131 sleep deprivation 124–5, 126
sexual function 86, 86 combination and maintenance 125
side-effects 81, 82, 83–6 efficacy 124–5
sleep, alertness and neurocognition treatment parameters 125
84–5 sleep disturbance 3, 57
selegiline (L-deprenyl) 78 slow wave sleep (SWS) 3
in elderly people 161 social isolation 37
in Parkinson’s disease 50 socioeconomic costs 1
self-help manuals 34 Socratic questioning 33
sequential combined treatment 44–5 somatization disorders 130
184 Index
St John’s wort 119–20 limitation of 79–80

in premenstrual dysphoric disorder 132 in melancholia 64
STAR*D (Sequenced Treatment in menopause 141
Alternatives to Relieve Depression) in pregnancy 133, 134
results 93–5 in schizophrenia 49
Structured Clinical Interview 5 side-effects 80, 85
substance abuse 130 triiodothyronine 94
suicide 1, 88 in menopause 140
in the elderly 156 tryptophan 121–2
gender and 130 in augmentation 99
risk assessment 10–11, 13–14 depletion 125
support interventions 14, 15–16 tuberculosis 49, 50
switching 45, 96–7 tyramine 51
practical aspects 97–8
syndrome of inappropriate excretion of unipolar depression 5
antidiuretic hormone (SIADH) 160
vagus nerve stimulation 112–13
therapeutic alliance 11–12, , 14 valproic acid, ECT and 109
third generation antidepressants 80–3, venlafaxine 53, 54, 79, 81, 89
87 in anxious depression 67, 68
thought stopping 35 in children and adolescents 147, 148
tianeptine 83 in chronic depression 68
tranylcypromine 89 in combination 100
in combination 100 discontinuation 88
in elderly people 161 dose–response relationship 96
overdose 88 drug–drug interactions 87
in recurrent brief depression 69 in elderly people 158, 159, 160, 161
remission 95 in melancholia 65
switching 97 in menopause 140
in treatment resistant depression 78 overdose 88
in winter depression 67 in postpartum depression 136
trazodone 55, 83 in postpartum psychosis 139
in pregnancy 133 in pregnancy 133
Treatment of Depression Collaborative remission 95
Research Project (TDCRP) 38 side-effects 86
treatment outcome, monitoring 16–17 switching 94
treatment resistant depression 64, 64,
95–6 winter depression 70, 123–4, 129
vagus nerve stimulation and 112–13 treatment 67, 67
tricyclic antidepressants (TCAs) 51–2, women, depression in 129–42
55, 63, 79–80 reproductive cycle 129, 129
in breast-feeding 138 work loss 1, 3
in children and adolescents 147
in chronic depression 68 yoga 40
discontinuation 88
dosing 77 zimelidine 52
in elderly people 158, 159 ziprasidone 98

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Treating Depression Effectively Applying Clinical Guidelines, 2nd Edition

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Treating

Sidney H Kennedy MD FRCPC

Raymond W Lam MD FRCPC

David J Nutt DM FRCP FRCPsych FMedSci

Second edition published in the United Kingdom in 2007 by Informa Healthcare,

Tel: +44 (0)20 7017 5000

All rights reserved. No part of this publication may be reproduced, stored in a

Library of Congress Cataloging-in-Publication Data

Data available on application

ISBN-13: 978 0 415 43910 7

Distributed in North and South America by

Within Continental USA

Distributed in the rest of the world by

Composition by Scribe Design Ltd, Ashford, Kent, UK

About the authors vi

1 Prevalence, burden and diagnosis 1

3 Psychotherapies, alone and in combination 29

4 Evolution of antidepressant agents 49

5 Evidence based antidepressant selection across depressive

6 Practical issues in using antidepressants 75

7 Sequential pharmacotherapies and treatment-resistant 93

8 Neuromodulation and other physical treatments 105

9 Complementary, light, sleep deprivation and exercise therapies 119

10 Depression in women 129

11 Depression in children and adolescents 145

12 Depression in late life 155

13 Psychiatric and physical comorbidities in depression 167

Sidney H Kennedy MD FRCPC David J Nutt DM FRCP FRCPsych

Prevalence, burden and

Prevalence, course and burden of illness

% of general population with MDD

Figure 1.1 Six-month prevalence of MDD across different countries.

Table 1.1 Worldwide Disability Adjusted Life Years attributed to

WHO regions % of total DALYs Ranking in region

WHO – World Health Organization epidemiological subregions.

Table 1.2 DSM-IV-TR criteria for the diagnosis of major

B. The symptoms do not meet criteria for a mixed episode.

An answer of ‘Yes’ to either question should trigger a more detailed assessment.

Diagnostic instruments for clinical use

Table 1.3 Features that help distinguish between

Feature Bereavement Major depressive episode

(Primary Care Evaluation of Mental Disorders) takes approximately nine

Table 1.5 Specifiers of MDD according to DSM-IV-TR

Specifier Key features

With melancholic features Non-reactive mood, anhedonia, weight loss, guilt,

With atypical features Reactive mood, oversleeping, overeating, leaden

With psychotic features Hallucinations or delusions

With catatonic features Catalepsy (waxy flexibility), catatonic excitement,

With seasonal pattern Regular onset and remission of depressive episodes

Weissman MM, Bland RC, Canino GJ et al. Cross-national epidemiology of major

Wilson S, Argyropoulos S. Antidepressants and sleep; a qualitative review of the litera-

The management of major depressive disorder (MDD) involves establishing a

Set goals of treatment

Table 2.1 Nine principles of management for a major depressive

• Set clear goals for treatment

Table 2.2 The phases of treatment of depression

Phase Duration Objectives Activities

Acute 6–12 weeks Remission of symptoms Establish therapeutic alliance

Maintenance Six months Prevention of relapse Provide education

objectives and activities (Table 2.2). There is increasing recognition of the

Treat comorbid medical conditions

Assess suicide risk

Table 2.3 General medical conditions frequently associated with

Neurological disorders Endocrine disorders