Oince the discovery in the late 1950's of imipramine (Tofranil®), the first tricyclic antidepressant (TCA), and iproniazid, the first monoamine oxidase inhibitor (MAOI), many other TCAs and MAOIs, now being considered the classical antidepressants, have become available. Their effectiveness has been shown in numerous studies, although according to nowadays standards well designed studies (placebo-controlled, defined diagnostic groups, the use of standardized rating scales) with these compounds are relatively scarce.

From the early 1980's the so called modern antidepressants have been introduced: the selective serotonin re-uptake inhibitors (SSRIs), the reversible selective monoamine oxidase-A inhibitors (RIMAs) and a variety of other compounds. All these drugs have been registered after their effectiveness had been shown in well designed, placebo-controlled studies. In defining the efficacy of antidepressants, registration authorities consider two aspects important: statistical evidence and clinical relevance.

A survey of the history of psychopharmacotherapy is presented.

In Antiquity some psycho-active plant extracts were already known . Since the rise of chemistry in early nineteenth century, sedative drugs were synthesized first. Since the fifties of this century the four groups of psychotherapeutic drugs proper, anxiolytics, hypnotics, antipsychotics and antidepressants have been discovered.

Astute clinical or preclinical observation and the understanding of coincidences, serendipity, has been the basis of these discoveries. Since the prototypes were discovered, no real breakthroughs have been achieved.

In this article the value of the tyramine conjugation test (TCT) as a predictor of the response to antidepressive medication is reviewed. The TCT seems of little discomfort for the patient, is easy to perform and is suggested to have a high sensitivity and specificity. In addition, there are indications that a decreased tyamine conjugation could be a traitmarker for the vulnerability of depression. Hypotheses concerning the, as yet unclear etiology of the decreased tyramine are reviewed.

An attempt is made to relate drug and non-drug antidepressive interventions to brain processes. In the present context two concepts are proposed: vulnerability towards depressogenic factors and depression as a state of the brain. Accordingly, it is assumed that the current antidepressants make the brain less vulnerable by inhibiting monoaminergic neurons and by reducing the number or efficacy of their postsynaptic receptors. In contrast, electroconvulsive therapie and sleep-deprivation affect primarily the state of the brain and can produce spectacular (but often short lasting) improvements. It is proposed that the combination of the two aspects may lead to fast and lasting antidepressive effects.

For all controlled studies that bear upon the analgesic-effect of antidepressants, a meta-analysis was conducted to get an estimation of the effect size and to get a sight on the possible modes of action. For this purpose both content and methodological variables were coded for each study. The mean size of the analgesic effect is 0.63. This means that the average patient getting an antidepressant has less pain than 74% of the patients getting a placebo. However because of selective drop-out and the use of psychometri-cally inadequate pain scales, this may be an over-estimation. Real analgesic qualities of antidepressive agents seem to offer the most plausible explanation for the effect, but the importance of serotonin reuptake blocking is not confirmed. A main objection, however, is that in all studies the depression variable was insufficiently controlled at inclusion. Because both the estimation of the effect size as the explanation of the effect are confounded with methodological doubts, it is concluded that further studies need to be done to overcome these difficulties.

A case report is presented of a 72 year old woman, who has been treated for a depression with amitriptyline. During the treatment an orofacial dyskinesia develloped. Data in the literature concerning a possible link between the manifestation of orofacial dyskinesia and treatment with antidepressants were mainly found to be case reports. A closer study of the total in all of 25 case reports reveals that the antidepressant is often at most one of more possible determinants of the movement disorder. Particularly, it was frequently noted that patients were treated with other drugs or that the use of other drugs was not specified. A controverse exists in the literature whether or not a so called spontaneous orofacial dyskinesia is found in high frequency in elderly people. For clinical practice the advice is given that, in case an orofacial dyskinesia arises during antidepressant treatment, attention should be paid to other provoking factors in the first place.

Lithium was added to imipramine in case of a 55-year old depressed woman who didn't respond to imipramine alone. There was a clear improvement within a few days on 900 mg lithium carbonate a day (lithium plasmalevel 0.9 mmol/l). However when after two weeks the lithium dose was reduced to 600 mg a day (lithium plasmalevel 0.5 mmol/l), an almost immediate relapse followed. On resuming lithium in the old dose the depression disappeared again. After four weeks the second attempt at reducing and eventually stopping the lithium appeared to be successful. Half a year after cessation of lithium imipramine was also stopped. More than a year afterwards there hasn't been a depression again.

In this case, after a fast potentiation of imipramine by lithium, a relapse followed when the lithium dose was reduced. It seems to be that even a high and successful starting dose of lithium needs to be continued for some time in order to prevent a relapse.

Food and Drug Administration, World Health Organisation and Committee on Proprietary Medicinal Products have published guidelines with recommendations how to conduct clinical trials. The guidelines for the clinical evaluation of antidepressant drugs contain a great variety of recommendations how to design phase I, phase II and phase III trials. Especially the pharmaceutical industry will follow these guidelines as much as possible to make the chances to register a new chemical entity as optimal as possible. While FDA and CPMP guidelines are primarily meant to be read by representatives from the pharmaceutical industries, the WHO guidelines give mainly information for clinicians. For the psychiatrist with interest in clinical research on antidepressants it is mandatory to know about the existence of these different guidelines. Fundamental differences between the guidelines do not exist; the methodological and ethical problems concerning placebo-use and relapse-recurrence problems are especially emphasized in the CPMP-guidelines.

Since the introduction of the monoamine oxydase inhibitors and the first tricyclic antidepressant (TCA) imipramine in the late fifties, the treatment of depressive disorders has been changed dramatically. Althought a great variety of antidepressants such as TCA's, selective serotoninte-re-uptake inhibitors (SSRI's) mianserin, trazodone, mirtazapine, moclobemide and venlafaxine has become available, the exact mode of action is not revealed as yet, and classification should be done according to the interference of antidepressants with central monoaminergic processes.

As to the potential of causing interactions, special attention has to be given to the SSRI's because of their interference with the CYP450 isozyme system. Therapeutic monotoring is recommended for the TCA's. The choiseforan antidepressant should be based on various factors like symptomatology and severity of the depression, potential interactions and somatic and/or psychiatric comorbidity.

Extensive clinical research has demonstrated that TCA's are the most effective for major depression with melancholia (vital depression) and depressive disorders in the elderly.