Existing antidepressants are unsatisfactory: they have limited efficacy, side-effects are a problem, and there is an appreciable degree of toxicity. However, nonpharmacological, psychological approaches to the treatment of depression also have their own drawbacks, so that the search for better antidepressant compounds continues.

A total of 1269 psychiatrists, from 15 European countries, completed a questionnaire assessing treatment choice in depressive and anxiety disorders, with particular focus on diagnostic and other factors determining use of monoamine oxidase inhibitors (MAOIs). Tricyclic and similar antidepressants were used most commonly — MAOIs were used as first-choice therapy for depressive or anxiety disorders only by a minority but were commonly a second-choice treatment for atypical depressives. Use was inhibited by interactions and side-effects rather than by perceived ineffectiveness. Cross-national differences in treatment were considerable but diagnostic differences in case history vignettes were much smaller.

It is widely accepted that depression shows a tendency to run in families. This is partly due to genetic influences — and the subject has been covered in recent reviews. This article, therefore, does not aim to recapitulate the genetic evidence but rather aims to elucidate the mode of transmission, to achieve an understanding of relevant gene-environment co-actions and interactions, and to describe attempts to identify and localise major genes.

Depression is a very common condition, and most depressed patients in many countries are treated by their General Practitioners. It is a frequent cause of suicide – one of the major causes of death in young adults – and is the disorder most commonly associated with deliberate self-poisoning, a large percentage of suicides being due to poisoning with drugs that are only available on prescription. Self-poisoning with older tricyclic antidepressants (TCAs) poses major clinical management problems, since the majority of patients who overdose with these agents do not reach hospital alive. Though there is no convincing evidence that any one antidepressant is more effective than others or more rapid in onset of therapeutic action, antidepressants do differ substantially in their side-effect profiles and in their toxicity in overdosage, those introduced before 1970 being relatively more toxic. Since suicide rates have been reduced by limiting the availability of toxic substances such as barbiturates and harmful domestic gas, restricting the use of older antidepressants in favour of newer, safer compounds for depressed patients being treated in general practice would also seem to be advisable.

The hypertensive crisis induced by the ingestion of cheese in subjects undergoing treatment with monoamine oxidase inhibitors (MAOIs) led to their virtual disappearance in many parts of the world. Three strategies to try and diminish the risk of this reaction have been developed: the combination of current (irreversible and non-selective) MAOIs with tricyclic antidepressants, the use of new selective MAOIs, and the use of new reversible MAOIs. The relative effectiveness of these different approaches can be assessed by the tyramine pressor test. The introduction of reversible and selective monoamine oxidase-A (MAO-A) inhibitors looks especially promising clinically.

The cheese reaction following use of the irreversible monoamine oxidase inhibitors (MAOIs) began to be reported in the UK with increasing frequency from about 1961. By 1965, the underlying mechanism (tyramine-provoked hypertension) had been essentially elucidated. Thereafter, this potentially severe side-effect could have been largely avoided by the use of fairly simple dietary precautions. Unfortunately, suspicion and fear burgeoned, and both the seriousness and the frequency of risk were dramatically inflated. This was a major factor in the subsequent general disuse of the irreversible MAOIs. Second-generation MAOIs which are selective for monoamine oxidase-A and B are now being synthesised and may eliminate the eventuality of hypertension without special dietary precautions.

The efficacy of antidepressants for panic disorders has had major effects on our understanding of the classification, pathophysiology, and treatment of anxiety disorders. Psychiatric practice has also been significantly affected, but important issues remain unresolved, such as the mechanisms of therapeutic effect, optimal duration of therapy to minimise relapse, and the interaction and sequencing of medication with cognitive behavioural treatments.

Administration of moclobemide – a relatively short-acting, reversible inhibitor of monoamine oxidase-A (MAO-A) – to experimental animals potentiates the pressor responses to intravenously injected tyramine, but such effects are moderate, short-lived, and much less apparent when the tyramine is given orally. The ability of moclobemide to potentiate the pharmacological actions of amine substrates for MAO-A in in vitro preparations is very weak, unless the drug is ‘activated’ by prior incubation with the tissues. However, animal experiments, both in vitro and in vivo, can give realistic indications not only of the mode of action of inhibitors of MAO and any toxicity, but also, in the case of MAO inhibitors, of the chance of potentially life-threatening hypertensive crises following inadvertent ingestion of amine-containing food or medicaments. Animal tests may also reveal any influence MAOIs have on amines released from non-neuronal stores.

The effect of moclobemide, a short-acting, reversible, preferential monoamine oxidase-A inhibitor in a 4-week therapeutic trial, on the sleep of ten depressed patients, was assessed by polysomnographic recordings. Compared with their time on placebo, patients receiving moclobemide showed improved sleep continuity, particularly during the intermediate and late stages of drug administration. The total increase in sleep time was comprised of larger amounts of stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. Withdrawal of moclobemide was followed by a further increase of REM sleep, although values did not surpass those sometimes observed in adults with normal sleep. In these patients, the symptoms of depression were rated as being significantly improved during the study period.

The older monoamine oxidase inhibitors (MAOIs) are mechanism-based, irreversible inhibitors of MAO; most inhibit both the A and B forms of MAO. Several of the drugs are hydrazine derivatives which have non-specific effects other than MAO inhibition. These properties convey disadvantages, which may be seen as serious, though infrequent, adverse events — the ‘cheese effect’, hepatotoxicity, amphetamine-like activity, orthostatic hypotension and anticholinergic effects. New, reversible MAOIs stem from a variety of chemical classes and are more specific in their effects, with relatively rapid onset of action, direct relationship between plasma concentration and pharmacological effect, and no prolonged carry-over phenomena.

Patients (n = 490) suffering from a major depressive episode according to DSM-III criteria were randomly allocated to groups receiving either moclobemide, imipramine, or placebo treatment. Subjects were treated as out-patients for 6 weeks. On overall assessment of efficacy and on results of the Hamilton Rating Scale for Depression, both moclobemide and imipramine were superior to placebo, but the differences between moclobemide and imipramine were not significant. Premature termination due to insufficient efficacy was more frequent with placebo than with moclobemide or with imipramine, these differences being significant. The overall assessment of tolerance clearly favoured placebo and moclobemide over imipramine. This was also reflected in the frequency of premature terminations due to poor tolerance, as well as in the frequency of adverse events, which were highest in the imipramine group. The only cardiovascular finding was an increase of the mean heart rate with imipramine, maximum at the end of week 1, while placebo and moclobemide displayed no relevant changes. There were no other important drug-related changes.

The antidepressant efficacy, tolerability, and safety of moclobemide, a reversible, monoamine oxidase-A inhibitor, were compared with those of imipramine in parallel groups of patients with a major depressive episode, in a 4-week, multicentre (17 centres), randomised study. A total of 381 patients were randomly allocated to either treatment; they were not required to avoid tyramine-rich foods. Drop-out rates were comparable in both groups at about 17%. Judged primarily on the HRSD, no significant differences in efficacy were observed between the groups, but the number of patients presenting with adverse events, as well as the total number of adverse events, was greater with imipramine. Cardiovascular tolerability was satisfactory and physical examination, body weight, and laboratory values were essentially unaffected in both groups.

The novel antidepressant, moclobemide, is a reversible inhibitor of monoamine oxidase (MAO) preferentially of monoamine oxidise-A (MAO-A); it emerged for study out of a series of lipid-lowering agents. In spite of its weak MAO-A inhibition in vitro, moclobemide is a potent inhibitor of MAO-A, in vivo; its in vivo activity is of short duration, in contrast to the extremely long-lasting inhibition, e.g. by tranylcypromine. Moclobemide only slightly potentiates the pressor effect of oral tyramine in freely moving rats, again in contrast to tranylcypromine; it is not anti-cholinergic and is free of hepatotoxicity. Published evidence on the preclinical pharmacology is reviewed.