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In a double-blind multi-centre study of general practice patients with DSM-III-R major depressive disorder, sertraline (50 or 100 mg/day) was compared with dothiepin (75 or 150 mg/day) and with placebo. There were 83, 96 and 90 patients evaluated in the respective treatment groups; treatment lasted 6 weeks. Patients were assessed on the MADRS, CGI, and Leeds Self-rating Scales. Statistically significant differences (p < 0.05) between sertraline and placebo were found on MADRS and CGI but not the Leeds Scales. In the mild subgroup analyses, there were no significant differences between sertraline and placebo. However, clear significant differences (p < 0.05) between sertraline and placebo were present in the severe subgroup. Dothiepin failed to achieve a statistically significant difference from placebo on any analyses. Seventy-six per cent of patients were treated with 50 mg sertraline and 81% of patients received 150 mg dothiepin. Both sertraline and dothiepin were generally well tolerated; the most frequent side effects with sertraline were nausea, dizziness and headache; with dothiepin the most frequent side effects were dry mouth, somnolence and headache.

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In this double-blind study in primary care patients, the efficacy and safety of sertraline, an antidepressant which is a selective inhibitor of serotonin re-uptake, was compared with clomipramine. Patients with DSM-III-defined major depression and with significant anxiety randomly received 50-150 mg of either sertraline (N=51) or clomipramine (N=55) once daily for 6 weeks. The mean final daily dose was 63.5 mg sertraline and 60.6 mg clomipramine. Seventy five percent of sertraline-treated and 79% of clomipramine-treated patients were maintained on the lowest dose of 50 mg once daily. The mean scores of all the rating scales (HAM-D, HAM-A, HAD, CGI) showed similar efficacy between the treatments in reducing the symptoms of depression and anxiety. Clomipramine was less well tolerated than sertraline with a greater overall incidence of side effects, or significantly greater incidence of anticholinergic side effects and significantly more patient withdrawals due to side effects; 18% in the clomipramine group compared with 4% in the sertraline group. The results indicate that sertraline is an effective agent to use in primary care patients with depression and associated symptoms of anxiety and is better tolerated than the tricyclic comparator clomipramine.

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A group of 480 patients, aged 19-78 with an HRSD score of at least 17 and who met DSM-III criteria for major depressive disorder were studied. Patients were given placebo for a one-week single-blind run-in period, after which sertraline was administered for eight weeks. This was followed by 44 weeks in which patients received sertraline or placebo on a double-blind, randomised basis. Patients were assessed periodically using the 17-item HRSD and the Clinical Global Impression scales. During the entire double-blind period 24 (13.0%) sertraline patients relapsed compared with 48 (45.7%) placebo patients (P less than 0.001). The protective effect of sertraline was maintained throughout the 44 weeks. The study provides evidence that sertraline prevents relapse of the index episode of depression as well as recurrence of further episodes and has few side-effects.

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The treatment of depression with antidepressant agents must be continued beyond the acute phase, until the response is complete. The precise length of this continuation phase is still debated, but most authors estimate that it should last for between 4-6 months after apparent recovery. If antidepressants are withdrawn sooner, the original depression will return (relapse) in a proportion of patients. Relapse rates on placebo are high, whether patients are first-time or recurrent depressives. Most depressions are recurrent and long-term treatment therefore ensures that the changes of a new episode of illness developing are reduced. The importance of this aspect of efficacy is recognized and new antidepressants are being tested in long-term prophylactic studies. A long-term efficacy study has shown that sertraline was significantly more effective than placebo in preventing both relapse and recurrence.

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The clinical trial programme of sertraline, a selective serotonin re-uptake inhibitor, has shown the drug to have a favourable safety and toleration profile. In contrast, the tricyclic antidepressant, amitriptyline, produced a significant level of side effects, particularly anticholinergic. The side-effect profile of sertraline was similar in young and old, and individual side effects did not make a notable contribution to the discontinuation rate. The incidence of side effects was related to both dosage and dosage regimen. An initial dose of 50 mg increased at 2-weekly intervals to 100 mg and then 200 mg daily produced a very low incidence, no side effect occurring with a frequency greater than 10%. In the long term (after 8 weeks' study), sertraline was well tolerated with little difference in side-effect reporting from placebo. There were no significant problems with safety. Sertraline was without effect on vital signs or electrocardiogram, and had no clinically relevant effects on laboratory values. In contrast to amitriptyline there was no significant effect on body weight. The overall incidence of mania was 0.4% and skin rash less than 2%. There were no cases of drug-related convulsions. Overdose with sertraline (four cases) was satisfactorily overcome with no significant sequelae and without the need for intensive monitoring.

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The authors review the literature in an attempt to evaluate the relationship between serotonin and depression. Animal studies show that the administration of tryptophan (the precursor of serotonin) increased serotonin synthesis and influenced behavior. Low plasma tryptophan levels have been found in patients with endogeneous depression. Postmortem studies have shown an association between lowered hindbrain serotonin levels and suicide among depressed persons. The decreased serotonin levels in blood platelets during depression mirrored the neuronal changes. Tricyclic antidepressants inhibited platelet serotonin uptake and reduced imipramine binding sites on the platelets. A positive correlation between depression rating scores and platelet aggregatory response has been reported. Serotonin stimulated release of prolactin and growth hormone, although the prolactin response was less marked in depression. A marker for depressive illness is still sought, but it is likely to be related in some way to serotonin.

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The authors review preclinical data; clinical pharmacology data; and efficacy data of sertraline, a novel serotonin uptake inhibitor. Both in vitro and in vivo, sertraline is a potent and specific serotonin uptake inhibitor (possessing up to 10 times the activity of similar agents). Chronic dosing produces down-regulation of beta-adrenergic receptors. In man, sertraline inhibits platelet serotonin uptake and is devoid of obvious cardiac effects. The plasma half-life of sertraline is 25 hours. Studies on psychomotor performance show little or no effect at doses up to 100 mg, whereas 200 and 400 mg appear to possess some sedating action. Sertraline exhibits acute antidepressant effects in the dose range 50 to 200 mg/day; in addition, in the same dose range it prevents recurrence of depression. Its side-effect profile is similar to that of drugs of the same class (dry mouth, nausea, and diarrhea being the most prominent); it lacks the obvious anticholinergic and sedating effects of amitriptyline.

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1 Fluvoxamine and clovoxamine, two new potential antidepressants were given to 27 healthy male volunteers in a double-blind, placebo controlled, three-way crossover study. 2 Neither compound affected the electrical intervals of 24 h ambulant electrocardiographic monitoring with the exception of a small increase in R-R interval. 3 There were no changes in blood pressure measurements. 4 The only notable unwanted symptom was nausea for both fluvoxamine and clovoxamine.

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Thirty patients were treated in a randomised double-blind efficacy study of fluvoxamine and chlorimipramine. The dose range for both drugs was 50-300 mg in divided daily doses. Mean daily doses were higher for fluvoxamine than chlorimipramine. Generally the baseline recordings were comparable for both drug groups. Fluvoxamine was superior to chlorimipramine in all the rating scales used without achieving statistical significance. Chlorimipramine, but not fluvoxamine, caused a significant decrease in blood pressure. There were no significant effects on ECG or laboratory variables. There was no significant relationship between plasma levels of either compound or metabolite and clinical response. Chlorimipramine exerted more unwanted effects than fluvoxamine. Autonomic effects of fluvoxamine were minimal in comparison with chlorimipramine. Chlorimipramine patients required more concurrent anxiolytic medication than fluvoxamine. Both drug groups required a significant amount of concurrent hypnotic medication.

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