International Congress Series 1287 (2006) 206 – 212

www.ics-elsevier.com

Recent advances in the psychopharmacology

of psychosomatic medicine
A.N. Singh
Department of Psychiatry, Queen’s University, Hotel Dieu Hospital, 166 Brock St., Kingston, Ontario, Canada

Abstract. The art and science of psychopharmacological treatment of psychosomatic disorders have
expanded greatly in the past two decades. Novel drugs of an exciting nature, alternative uses of
existing drugs, combination strategies and specialized needs of patients have brought sophistication
and enhanced therapeutic sciences. Psychopharmacological advances in psychosomatic medicine
have been in the areas of anorexia nervosa, bulimia, anxiety disorder, major depression, insomnia
and management of somatization. This paper will discuss these advancements. Objective: To
enhance the knowledge of psychopharmacological advances in psychosomatic disorder. D 2006
Elsevier B.V. All rights reserved.

Keywords: Psychopharmacology; Psychosomatic medicine; Psychosomatic disorder; Recent advances

Psychopharmacological treatment in psychosomatic disorder has expanded greatly in the

past decade. Novel drugs of an exciting nature, alternative use of existing drugs, com-
bination of therapies in order to meet patients’ specialized needs have enhanced the quality
of care; thereby, the quality of life. Psychopharmacological advances in psychosomatic
medicine have been in the areas of:

(a) Anxiety disorders

(b) Eating disorders
(c) Depression disorder
(d) Insomnia
(e) Migraine
(f) Management of somatization.

E-mail address: singha@post.queensu.ca.

0531-5131/ D 2006 Elsevier B.V. All rights reserved.

doi:10.1016/j.ics.2005.11.095
 A.N. Singh / International Congress Series 1287 (2006) 206–212 207

1. Anxiety disorders
Recent research activities have confirmed the need of diagnostic subtyping for the
appropriate treatment of anxiety disorders. Pharmacotherapy with antianxiety drugs
remains the mainstay of treatment, but concomitant non-pharmacological treatment should
be considered for all anxiety sufferers.
1.1. Panic disorders
The goal here is to control panic disorder in the short-term and then continue long-term
maintenance treatment if needed. Recent advances in this area are the utilization of
(a) SRI [1] agents, (b) utilization of SNRI agents, and (c) using Buspirone and atypical
antipsychotic-like Risperidone and Quetiapine.
Venlafaxine XR, Paroxetine and Cipramil remain my choice. The side effects of SSRI
and SNRI in many panic patients necessitate that the starting dose should be usually half
of the normal range of dosage. Sexual side effects are the most common side effects of
the above drugs, particularly on maintenance therapy; hence in these patients, Viagra, if
not contraindicated, should be used. The discontinuation of these drugs should be
gradual and of tapering design to avoid the occurrence of serotonin withdrawal
syndrome. Buspirone has not been successful in panic disorders [2]. However,
Risperidone and Seroquel in small doses have shown better results because of their
serotonin antagonistic properties. Carbamazepine and Valproic acid have been reported
to be effective in case reports [3].

1.2. Generalized anxiety disorders

Venlafaxine, Paroxetine and Cipramil are the recent drugs to be significantly
effective in generalized disorders. Partial Benzodiazepine receptor agonists like
Bretazenil and Abcernil have shown effectiveness and also possess a low risk for
dependence.

1.3. Obsessive–compulsive disorder

Recent drugs that have been significantly effective in this disorder are Fluoxetine,
Paroxetine, Sertraline and Fluvoxamine [4]. Recent studies in SRIs have revealed that
OCD symptoms may improve in 2 to 3 weeks or maybe delayed between 4 and 6
weeks; hence, the duration of treatment for control of symptoms usually should be of
10 to 12 weeks. The effects doses of SRIs are also in the range of 40 to 60 mg in
Fluoxetine and Paroxetine and 150 to 200 mg in Sertraline. OCD is a chronic illness;
hence, duration of treatment depends upon the clinical condition of individual
patients.

1.4. Post-traumatic stress disorder (PTSD)

SRIs have been effective in controlling the positive symptoms of PTSD, like re-
experiencing the events and arousal, but negative symptoms like withdrawal and
avoidance do not respond [5]. Beta-blockers are of effective use in controlling persistent
symptoms of automatic arousal. Carbamazepine [6] and Valproate [7] improve irritability,
anger and aggressive outbursts in PTSD patients.
208 A.N. Singh / International Congress Series 1287 (2006) 206–212

2. Eating disorders
2.1. Anorexia nervosa
In anorexia nervosa the main therapeutic goals are threefold:

(1) to stimulate the appetite and increase weight gain

(2) dietary advice
(3) treating underlying disorders which precipitate anorexic tendencies like depression,
obsessive compulsive disorder, personality disorder and substance abuse.

Drugs chosen for the treatment of anorexia nervosa are those which promote weight
increase and also resolve underlying precipitating causes. Tricyclic antidepressants like
amitriptyline, clomipramine, trimipramine, norpramin and tetracyclic antidepressants like
maprotiline remain the favoured drugs, while antipsychotics like chlorpromazine,
pimozide and sulpride are also utilized. Benzodiazepines in small doses during the weight
gain process are beneficial for controlling reactive anxiety. The benzodiazepines most
appropriate in this phase remain sublingual lorazepam and alprazolam. Cyproheptadine, a
serotonin antagonist, which increases weight, has also been utilized in daily doses of 12–
32 mg a day with a statistically significant result. The moclobemide second generation of
monamine oxidase inhibitor group of drugs (called RIMA class) might help patients with
anorexia nervosa, but further studies to confirm efficacy are needed.
Recent uncontrolled studies have supported the effectiveness of Fluoxetine in the dose
range of 20–80 mg a day. The duration needed in these patients is about a year. Naltrexone
in a dose of 100 mg twice a day has shown effectiveness in reducing purging/binge eating
in both anorexic and bulimia patients. Atypical antipsychotic, olanzapine, and NASSA
agent, Mirtazapine, in my patients have shown significant therapeutic efficacy.
Individual psychotherapy and family therapy have been tried with some success.
Overall, the recent trend has been to combine pharmacotherapy with individual
psychotherapy, family therapy and dietary advice for better and total management of
anorexia nervosa.
2.2. Bulimia nervosa
In bulimia nervosa antidepressants, particularly of the newer serotonin reuptake types
like fluoxetine have been remarkably and significantly successful. In Canada, the Health
Protection Branch has recently given new indication of antibulimic property to fluoxetine.
Other newer SRI drugs like fluvoxamine, Sertraline and Paroxetine are also beneficial to
bulimia patients. Naltrexone, a long acting oral narcotic antagonist, has also been found
effective in reducing binge eating and vomiting symptoms in antidepressant-treated
refractory patients. The dosage utilized falls in the range of 200–300 mg a day. In bulimia
nervosa, apart from pharmacotherapy, the utilization of cognitive behavioural treatments
either individually or in group, have been of significant help in improving eating
behaviour and attitude about body shape and weight. Recent study has shown the
superiority of combined drug and cognitive behavioural therapy over behaviour therapy.
Thus, the future management of bulimia patients lies in combined therapies, which include
pharmacotherapy, cognitive behaviour therapy and dietary advice.
 A.N. Singh / International Congress Series 1287 (2006) 206–212 209

3. Recent advances in depression disorders

Recent advances in the treatment of depression have demonstrated wider therapeutic
activities, improved safety, tolerability, selectivity and reduced adverse reaction profiles
[8]. These newer antidepressants can be classified as:

1) SSRIs
2) SNRIs
3) NARIs
4) NaSSA
5) RIMA.
3.1. Selective serotonin reuptake inhibitors (SSRI)
The SSRIs are chemically distinct from traditional antidepressants like tricyclic,
tetracyclic and monoamine oxidase inhibitors, but share the common route of selective and
potent inhibition of neuronal reuptake of serotonin, and have none or very little effect on
neuronal reuptake of norepinephrine, acetylcholine and histamine. Thus, these drugs have
less sedative, anticholinergic and cardiovascular effects than other antidepressants of
tricyclic and tetracyclic class. Fluoxetine, fluroxamine, sertraline, indalpine, Paroxetine,
alproclate, femorxetine and choroxamine belong to SSRI group of drugs. Overall, SSRI
have equal therapeutic efficacy, but possess a better side effect profile, thus, making them
more acceptable to patients. The common side effects of SSRI are nausea, anorexia,
agitation, headache and sexual disorders.
3.2. Serotonin and noradrenaline reuptake inhibitor (SNRI)
This new class of drugs act on both noradrenergic and serotonergic neurotransmitters
and may have a number of benefits to other antidepressants. They lack actions on
adrenergic, muscarinic or histamine receptors, which are responsible for many of the
adverse effects of older antidepressants. This group consists of Venlafaxine, Duloxetine
and Milnacparan. Duloxetine has equal effects on both nor-adrenergic and serotonergic
neurotransmitters, whereas venlafaxine has more strong action on serotonin and
milnacipran on noradrenergic. The side effects profile is similar to SSRIs.
3.3. Selective noradrenaline reuptake inhibitor (NARI)
Reboxetine belongs to this group and is the first nontricyclic selective nonadrenaline
reuptake inhibitor. It mediates its therapeutic effect by increasing the action of
noradrenaline in the brain without significant interaction with muscarinic, alpha1-
adrenergic, H1-histaminergic receptors that mediate the classic side effects of the tricyclic
antidepressant (TCAs). The side effect profile of reboxetine is consistent with a
noradrenergic agent that possesses weak anticholinergic and serotonergic activity.

3.4. Noradrenergic and specific serotonergic antidepressants (NaSSA)

Mirtazapine represents this group. The antidepressant effect of the drug is a result of
increased neurotransmission of both noradrenergic and serotonergic neurotransmitters. The
efficacy has been reported similar to older antidepressants. Mirtazapine develops
210 A.N. Singh / International Congress Series 1287 (2006) 206–212

neutropenia of reversible type, which is nonprogressive in nature and dose related. The
adverse effects related to the anticholinergic system and cardiac effects are low.
3.5. RIMA
It is a newly developed class of monoamine oxidase inhibitor drugs, which combine
primarily with reversible monoamine oxidase-A inhibitor and belongs to the benzamide
family. Unlike RIMA, classical monamine oxidase inhibitors are irreversible enzyme
inhibitor drugs without the selectivity for the two isoenzymes MAO-A and MAO-B.
Moclobemide is the first derivative of the RIMA class of drugs. Moclobemide shows no
affinities for muscranic, dopaminergic, serotoninergic, adrenergic opioid or benzodiazepine
receptors, and acts primarily on isoenzyme MAO-A with reversible binding. Clinical
studies have confirmed that it is nearly devoid of tyramine interaction of producing
hypertension crisis very unlike the earlier irreversible MAOI drugs. Comparative clinical
studies have confirmed the significant therapeutic efficacy in depression and further
research is continuing to evaluate its efficacy in panic attacks and anxiety. Drug interaction
with molclobemid is seen with cimietidine, selegiline, pethidine and clomipramine and
daily dose ranges between 150 and 450 mg.

4. Insomnia
Therapeutic use of benzodiazepine hypnotics for insomnia have become limited due to
the development of tolerance, dependence and rebound. Recent advances in the treatment
of insomnia lie in the discovery of bnon-benzodiazepine hypnoticsQ [9].
4.1. Non-benzodiazepine hypnotics
This group of drugs is non-benzodiazepine receptor agonists and chemically unrelated
to benzodiazepines. However, these drugs act through benzodiazepine receptors. Three
drugs belonging to three subgroups are in the process of changing the pharmacotherapy of
insomnia. These drugs are:

1) cyclopyrrolone—Zopiclone
2) imidazopyridine—Zolpidem
3) pyrazolopyrimidine—Zaleplon.

4.1.1. Zopiclone
Zopiclone modulates the action of the neurotransmitter, GABA, to produce its hypnotic
effect. It also binds only to a distinct site on the GABA/chloride ion channel complexes
located in the cerebral cortex, cerebellum and hippocampus, and not to peripherally
located complexes. The efficacy of this drug is to enhance sleep induction, maintenance,
reduces sleep latency and nocturnal awakening, enhances the quality of stages 3 and 4
sleep and produces sleep which mimics natural sleep. The therapeutic advantages of
Zopiclone over benzodiazepine hypnotics are as follows:

(i) Predominantly primary action orientated drug, no significant secondary action (no
receptor affinities to serotonin, dopamine, peripheral benzodiazepine sites, ~1, ~2
and adrenergic receptors).
 A.N. Singh / International Congress Series 1287 (2006) 206–212 211

(ii) Markedly reduced activity for amnesia or memory disturbance.

(ii) Reduced affinities for tolerance and dependence.
(iv) Markedly reduced effect on psychomotor activities and cognition.
(v) Absence of confusion in elderly.
(vi) Lack of accumulation.
(vii) Stage 3 of sleep is increased, thus, the only hypnotic which increases the total
duration of deep sleep.
(viii) No effect on stage 4 and little or no effect on REM sleep.

No reduction of dose is required for elderly patients.

4.1.2. Zolpidem
This drug is not available in Canada, but is in the USA. This drug reduces sleep latency
and prolongs the total sleep time. Rebound insomnia is seen in this drug after
discontinuation and infrequently produces daytime sedation or amnesia. This drug
shortens the sleep latency, prolongs total sleep time, but has very little or no effect on sleep
stages. The development of tolerance and physical dependence has rarely been observed
and under unusual circumstances. Absorption of Zolpidem with food shows lower oral
bioavailability in comparison to taken without food when about 70% of oral bioavailability
is found. Zolpidem elimination half-life is 1.5 to 2.4 h, but unlike Zopiclone, Zolpidem has
a longer half-life in the elderly and a shorter half-life in children.

4.1.3. Zaleplon
Zaleplon is clinically unrelated to benzodiazepine and binds differently to the
benzodiazepine type I site on the raminobutyric acid subtype A (GABA)/chloride ion
channel complex. Zaleplon is rapidly absorbed and reaches peak plasma concentration in
about 1 h, which is also its half-life. The adverse reactions of this drug are minimal of all
members of this group and no rebound insomnia and no psychomotor retardation in
daytime have been observed in the patients taking this drug. Neither tolerance nor
dependence has been observed after stopping this drug. The sleep latency is decreased by
the use of this drug, which enhances the quality of sleep.

5. Migraine
Recent advances in migraine therapy has been the development of sumatriptan, which is a
5-hydroxytryptamine-like receptor agonist [10]. Sumatriptan mediates selective vasocon-
striction within carotid arterial circulation supplying intracranial and extracranial tissues
such as brain and meninges. Mechanism of antimigraine activity could, thus, involve
vasoconstriction of dura blood vessels. This drug has remarkable activity in controlling the
acute pain of migraine. Imitrex can be given orally in a dose of 100 mg or by subcutaneous
injection in 6 mg doses. Patients who do not respond to the oral dose should not have any
more tablets. The maximum oral dose in 24 h is 300 mg or by injection 12 mg a day.
This drug should not be used in patients suffering from (a) any heart disorders, (b)
hemiplegic and basilar migraine, (c) patient receiving MAOI, selective 5-HT reuptake
inhibitors and lithium, and (d) cerebrovascular disorders. Intravenous route causes coronary
vasospasm, hence, should not be used.
212 A.N. Singh / International Congress Series 1287 (2006) 206–212

6. Management of somatization
In recent years in the area of psychosomatic medicine somatizing patients are on the
increase. Physical symptoms are many in these patients, but no organic basis is found,
thus, leaving the physician to investigate the presence of acute psychosocial stressors with
or without the presence of anxiety, depression and pain separately or in combination.
Somatization at this point is regarded as a general process by which bodily symptoms
may be used as a culturally sanctioned idiom of distress to implicate problems of family,
work, school, financial or other problems.
Pharmacotherapeutic intervention is limited here in most cases, but illness behaviour
reducing coping mechanisms are to be treated here with insight orientated psychotherapy
and cognitive therapy. Family therapy and behaviour therapy are also utilized. However,
ruling out medical conditions with non-specific symptoms and planning to care rather than
cure should be the objective. Establishing a primary therapist with regular visits to
educate, to produce insight to remove the co-existing anxiety and depression and finally to
enhance coping mechanisms are the successful steps for the treatment of somatizing
patients.

7. Conclusion
Advances in the psychopharmacological treatment have been satisfactory, but further
researches are still needed to find ideal drugs for the treatment of the above disorders,
which should have enhanced therapeutic benefit with a minimal or no adverse reaction
profile.

References

[1] W. Boyer, Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating panic attacks:
a meta-analysis, Int. Clin. Psychopharmacol. 10 (1995) 45 – 49.
[2] D.V. Sheehan, et al., Is buspirone effective for panic disorder? J. Clin. Psychopharmacol. 10 (1990) 3 – 11.
[3] P.E. Keck Jr., et al., Antiepileptic drugs for the treatment of panic disorder, Neuropsychobiology 27 (1993)
150 – 153.
[4] J.W. Jefferson, J.H. Greist, The pharmacotherapy of obsessive–compulsive disorder, Psychiatr. Ann. 26
(1996) 2002 – 2209.
[5] J.M. Silver, D.P. Sandberg, R.E. Hales, New approaches in the pharmacotherapy of post-traumatic stress
disorder, J. Clin. Psychiatry 51 (Suppl. 10) (1990) 33 – 38.
[6] S. Lipper, et al., Preliminary study of carbamazepine in post-traumatic stress disorder, Psychosomatics 27
(1986) 849 – 854.
[7] F.A. Fesler, Valproate in combat-related post-traumatic stress disorder, J. Clin. Psychiatry 52 (1991) 361 – 364.
[8] A.N. Singh, A.K. Jainer, Recent advances in the treatment of depression, J. Indian Med. Assoc. 1 (1999)
19 – 24.
[9] A.N. Singh, Recent Advances in the Pharmacotherapy of Insomnia (in press).
[10] A.N. Singh, Pharmacological therapy in psychosomatic medicine, Jpn. J. Psychosom. Med. 32 (1992)
589 – 598.