© Priory Lodge Education Limited, 1996.
Version 1.0
Version 1.0 first published 10:52 PM on 21/06/96


A DOUBLE BLIND TRIAL COMPARING CLOMIPRAMINE AND SERTRALINE IN THE TREATMENT OF MAJOR DEPRESSION


R. A. Edwards B.M., B.Ch., M.A., F.R.A.N.Z.C.P.,
Consultant Psychiatrist, Hastings
And
G.L. Newburn M.B.,Ch.B., F.R.A.N.Z.C.P.,
Consultant Psychiatrist, Rotorua.

Correspond with:
Dr. R. A. Edwards,
Psychiatric Unit,
Memorial Hospital,
Hastings,
New Zealand.
Email : rode@central.co.nz


Abstract
Introduction
Method
Results
Conclusions
References

Abstract

Sertraline has been compared with tricyclic antidepressants but not with clomipramine, the most serotonergic of this group. In this study 32 patients presenting as outpatients with a major depressive episode were treated with sertraline or clomipramine in a single-blind study. Efficacy was measured using the Hamilton and the Zung rating scales and by Clinical Global Assessment. Tolerability was judged using Clinical Global Ratings and side effects were recorded individually. Both groups showed a marked improvement with no overall difference between groups. Although side effects occurred with equal frequency in the two groups, the profile of side effects of the two drugs was different. Average drug dosages were relatively low in this study and the sexual dysfunction noted as a side effect in higher dose studies of Sertraline did not occur.

Introduction

It has been hypothesised for nearly 25 years that biogenic amines are involved in the aetiology of affective disorder. The central amine neurotransmitters most carefully focused on in this regard have been the indoleamines and catecholamines. Serotonin's importance in depressive illness has been strongly indicated by CSF receptor binding and neuroendocrine studies, although their interpretation at times can be difficult [1]. Additionally it has been suggested that a selective disorder of serotonin metabolism may be associated with suicidal behavior in depressed patients [2].

Sertraline is a highly selective serotonin uptake inhibitor with only weak effects on the reuptake of dopamine and noradrenaline. Its major metabolite N-desmethylsertraline has only one tenth the potency of sertraline and is thus effectively inactive in in vivo animal models normally indicative of antidepressant and electrophysiological activity. The mean elimination half life of sertraline in man is about 26 hours [3].

Sertraline has been shown to be an effective antidepressant in double blind placebo control studies [ 4-5 ]. A large multi-centre study compared the effects of sertraline as compared to amitriptyline and placebo in the treatment of DSM III defined major depression [4]. Sertraline was as effective as amitriptyline in relieving the symptoms of depression and both were significantly more effective than placebo. A further study in elderly depressed patients [5] showed sertraline to be as effective as amitriptyline in treating DSM III major depression in this age group.

Both studies [ 4,5 ] suggested sertraline was better tolerated than amitriptyline despite using protocols which escalated the doses of both active drugs to the maximum tolerated by the patient. Sertraline was associated with a significantly lower incidence of anticholinergic side effects than amitriptyline but a higher incidence of gastro-intestinal side effects including nausea, anorexia and loose stools. Male sexual dysfunction and insomnia were also noted as side effects of sertraline in these high dosage studies.

Whereas sertraline is an extremely potent serotonin uptake inhibitor, amitriptyline is a mixed agent with more effect on noradrenergic systems than on serotonergic ones. Indeed amitriptyline may have only 1-2% of the potency of sertraline on 5-HT reuptake [3]. Clomipramine however is the most serotonergic of the tricyclics with 20% of the potency of sertraline on 5HT inhibition and would seem to be a more equivalent comparator drug. The present study was designed to compare the efficacy and tolerability of sertraline and clomipramine in an outpatient population of depressed patients.

Method

This was potentially a double blind study. Owing to packaging difficulties, the medication capsules for the two arms of the study differed. If patients had previously been on clomipramine, they could potentially have recognized which medication they were taking. The investigator remained blind for the study drug throughout the study. Enquiry after the study did not indicate that any patients had recognized their medication and thus the study may reasonably be considered double blind.

Outpatients with a diagnosis of DSM III major depression and meeting the inclusion criteria for the study each took part in a washout phase of no more than two weeks. Patients still meeting the study criteria at the end of this period were then randomly assigned to sertraline 50mg or clomipramine 50mg nocte. All patients received a full physical and psychiatric examination at commencement of the study. Inclusion criteria included DSM III diagnosis of major depression, Hamilton Depression Rating Scale ( HAMD ) score of 18 or higher and aged 18 to 75 years. Other than a hypnotic, patients were not allowed other psychotropic medication. Exclusion criteria were a) patients with another DSM III diagnosis; b) patients with a drop of 25% of baseline or scoring below 18 on the HAMD at the end of washout; c) patients with more than minimal psychotic symptoms; d) suicidal patients e) patients addicted to alcohol or other drugs f) patients with major physical illness; g) potentially pregnant females; h) patients in whom tricyclics were contraindicated e.g. narrow-angle glaucoma, prostatism, etc.; i) patients on depot neuroleptics j) patients who had received Electroconvulsive Therapy prior to entering the study. All patients gave full informed consent and ethical committee approval was obtained at both a regional and national level.

Patients were seen every two weeks for a ten week period. At each visit the HAMD, the Zung depression scale and clinical global impression based on psychiatric examination were measured as criteria of efficacy. Side effects and tolerability were assessed by clinical global impression and by direct enquiry. Medication doses could be titrated upwards in 50mg increments, if clinical response was poor, to a maximum dosage of 150mg per day. Patients experiencing undue side effects could have medication reduced by 50mg increments if the side effects were not too severe and they wished to continue in the trial. Patients were then maintained on their optimum dose for at least four weeks.

The major outcome indicators used in the study were the HAMD and the Zung Depression Scale. Changes in the two treatment groups between the post-washout scores and the final score recorded during the study were compared using Wilcoxon's 2 sample test. P values of p = 0.05 or less were considered statistically significant.

Results

Thirty two patients were entered in the study and completed a minimum of two weeks on active medication ( clomipramine 15 patients, sertraline 17 patients ). Other than a tendency for patients in the sertraline group to be slightly heavier, there was no significant difference between the groups on demographic characteristics. The average duration of therapy was 52 days in the clomipramine group and 55 days in the sertraline group.

Demographic Characteristics
SertralineClomipramine
Age (yrs) (S.D.)45.0 (17.6)44.0 (16.0)
Mass (kg) (S.D.)84.0 (17.0)72.0 (16.0)
Gender (F:M)10:710:5
Mean Duration of Therapy55 days52 days

The mean HAMD scores at the end of washout were similar in the two groups ( mean 24.1 for clomipramine and 23.5 for sertraline ). Post washout Zung scores were also similar ( mean 55.3 for clomipramine and 53.1 for sertraline). The mean daily dose of medication at the end of the trial was clomipramine 67mg and sertraline 85mg.

There was a marked improvement in patients of both groups shown by the change in HAMD scores, change in Zung scores and Clinical Global Impression Effectiveness scale.

SertralineClomipramine
HAMD scores post washout23.524.1
HAMD scores week 10 visit2.85.9
Percentage Reduction88.975.02
Mean change (1st to last visit) (SD)16.2 (8.3)18.0 (8.2)
Zung scores post washout53.155.3
Zung scores week 10 visit34.938.8
Percentage reduction34.229.84
Mean change (1st to last visit) (SD)13.1 (10.8)14.8 (13.1)
p<0.0003p<0.0004
Clinical Global Impression (Efficacy)*76%67%

* No. of Patients rated Complete Remission, Marked Improvement or Improved at last visit.

There was no overall difference between the two groups on any of the main parameters of efficacy. An intent to treat analysis based in the sum of the HAMD and the Zung scores reported during the entire study likewise showed no significant differences between the two groups.

Side Effects
SertralineClomipramine
CGI- Tolerability
% rated Excellent of Good at last visit8260
No. Patients withdrawn for adverse events21
% of patients reporting any adverse event70%53%
Individual Adverse Events
Constipation03
Nausea43
Sedation53
Postural Hypotension13
Dry mouth32
Diarrhoea20
Headache31
Other67
Total2422

Adverse events occurred with approximately equal frequency in both treatment groups. Severe side effects leading to premature discontinuation of treatment were uncommon, occurring in two patients in the sertraline group ( abdominal pain, nausea and vomiting in both patients ) and one in the clomipramine group ( excessive sedation ). Side effects related to postural hypotension and constipation were commoner in the clomipramine group, whereas nausea, diarrhoea and headache were commoner in the sertraline group.

On the Clinical Global Impression scale for Tolerability the tolerance was rated as excellent or good in 82% of patients in the sertraline group and in 60% of patients in the clomipramine group.

Conclusions


This was a small study carried out in two provincial centres. Based on the relatively small number of patients enrolled, the value of statements regarding statistical significance is limited. Bearing this in mind, based on three measures of efficacy employed in this study it is reasonable to conclude that sertraline and clomipramine are equally effective in the treatment of depression. The final scores on these measures were very similar and the course of the remission week by week was the same for the two groups. Both drugs were very effective in relieving depressive symptoms and the change in HAMD scores from entry to end point of the trial was particularly large. The average maximum dose of each medication taken during the trial is noteworthy as this was less for both drugs than the average maximum dose used in other studies. Comparison of HAMD initial scores did not indicate any difference in severity of depression between this and other studies [ 5, 6 ]. Similarly demographic characteristics and response times to medication seemed unremarkable in this study compared to others.

It is noteworthy that male sexual dysfunction and insomnia observed in previous studies of sertraline and amitryptiline [ 5, 6 ] were not evident in the current study. As previous studies had a somewhat higher average dose of sertraline, this may indicate that sertraline may cause such effects only at higher dosages and that a clinically effective dose of 50 or 100mg may be free of such side effects.

The side effect profile of sertraline and clomipramine show some differances which allows greater flexibility in prescribing habits of clinicians and hopefully leads to better acceptability of antidepressant treatment for patients suffering from this condition.

References


1) Melzer H Y & Lowy M T. The Serotonin Hypothesis of Depression in : Melzer H Y, Editor. Psychopharmacology the Third Generation of Progress, Raven Press, New York, 1987 pp. 513-526

2) Asberg M, Traskman L & Thoren P, 5HIAA in the Cerebrospinal Fluid: A Biochemical Suicide Predictor?, Archives of General Psychiatry, 1976, 33: 1193-97.

3) Heym J & Koe B K, Pharmacolgy of Sertraline: A Review, Journal of Clinical Psychiatry, 1988, 49-8 Supplement: 40-45.

4) Reimherr F W, Chouinard G, Cohn C K, Cole J O, Itil T M, La Pierre Y D, Masco H L & Mendels J. Antidepressant Activity of Sertraline: A Double Blind Placebo and Amitriptyline Controlled Multi Centre Comparison Study in Outpatients with Major Depression, Journal of Clinical Psychiatry, 1990, 51.12 Supplement P: 18-27.

5) Cohn C K, Shrivastava R, Mendels J, Cohn J B, Fabre L F, Claghorn J L, Dessain E C, Itil T M & Laudin A. A Double Blind Multi Centre Comparison of Sertraline and Amitriptyline in Elderly Depressed Patients. Journal of Clinical Psychiatry, 1990, 51: 12 Supplement B: 28-33

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