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
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.
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.
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.
| Sertraline | Clomipramine | |
|---|---|---|
| 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) | 10:7 | 10:5 |
| Mean Duration of Therapy | 55 days | 52 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.
| Sertraline | Clomipramine | |
|---|---|---|
| HAMD scores post washout | 23.5 | 24.1 |
| HAMD scores week 10 visit | 2.8 | 5.9 |
| Percentage Reduction | 88.9 | 75.02 |
| Mean change (1st to last visit) (SD) | 16.2 (8.3) | 18.0 (8.2) |
| Zung scores post washout | 53.1 | 55.3 |
| Zung scores week 10 visit | 34.9 | 38.8 |
| Percentage reduction | 34.2 | 29.84 |
| Mean change (1st to last visit) (SD) | 13.1 (10.8) | 14.8 (13.1) |
| p<0.0003 | p<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.
| Sertraline | Clomipramine | |
|---|---|---|
| CGI- Tolerability | ||
| % rated Excellent of Good at last visit | 82 | 60 |
| No. Patients withdrawn for adverse events | 2 | 1 |
| % of patients reporting any adverse event | 70% | 53% |
| Individual Adverse Events | ||
| Constipation | 0 | 3 |
| Nausea | 4 | 3 |
| Sedation | 5 | 3 |
| Postural Hypotension | 1 | 3 |
| Dry mouth | 3 | 2 |
| Diarrhoea | 2 | 0 |
| Headache | 3 | 1 |
| Other | 6 | 7 |
| Total | 24 | 22 |
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.
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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