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Pharmacogenetics is concerned with the genetic basis for interindividual differences in the clinical reponse to drugs. The study of genetic polymorphism in drug metabolism has been an area of particular interest. A genetic polymorphism is a monogenic or mendelian trait that exists in the population in at least two phenotypes (and presumably in at least two genotypes), the rarest of whom exists in at least 1%–2% (Vogel and Motulsky 1982). Thus, two phenotypes are discernible in the case of genetic polymorphism in drug metabolism: a slowly metabolizing phenotype who may develop toxic plasma (tissue) concentrations when a standard dose regimen is employed and a rapidly metabolizing phenotype who may develop subtherapeutic concentrations.

Antidepressant drugs have not been classified very systematically and no commonly accepted nomenclature has been developed. Classification has been based upon criteria as different as the time of development of the drugs, their chemical structure, their biochemical properties, and their behavioral effects.

The dose-effect relationship is a basic element in all research in experimental pharmacology. In clinical pharmacology, the central role of the dose-effect concept has usually been acknowledged, but the actual demonstration of dose-effect relationships in clinical drug research is often extremely difficult. In the early years after the introduction of imipramine and subsequently other tricyclic antidepressants (TCA), the dose-effect problems were not infrequently discussed in the clinical reports, usually on the basis of uncontrolled clinical assessments (Delay and Deniker 1959; Ayd 1959). However, towards the end of the 1960s, the question of appropriate dosing appeared to receive little attention, clinically or in research trials. In a larger review attempting to identify variables important for the therapeutic efficacy of TCA, the dose was not even considered (Smith et al. 1969). At that time, the demonstration of pronounced variations in steady state levels in patients on standard TCA (Sjoqvist et al. 1968) gave rise to a series of studies on concentration-effect relationships during the following two decades. For the introduction of new antidepressants, there is an increasing demand for data on the dose-effect relationship. In this situation, it seems awkward that our knowledge about the dose-effect relationship for the usual control therapy, TCA, is rather limited. Also for the clinical use of TCA, the dose-effect issue has been reintroduced by some authors in the 1980s (Quitkin 1985; Roose et al. 1986; Goethe et al. 1988). However, in clinical trials, this problem is seldom even discussed as a source of bias or variability.

The discovery of a common genetic polymorphism in the oxidation of sparteine and debrisoquine (Mahgoub et al. 1977; Eichelbaum et al. 1979) has created new interest in the role of genetic factors for individual variations in the oxidation of psychotropic drugs, notably tricyclic antidepressants.

A recent count suggests that there are more than a hundred compounds at various stages of development as possible new antidepressants. These include “pure” norepinephrine and serotonin reuptake inhibitors. Most of these compounds, however, have not reached the stage of clinical research at which it would be wise, from a clinical point of view, to discuss their efficacy or draw conclusions on toxicity and unwanted side effects. This is especially evident for the pure norepinephrine reuptake blockers.

In the course of development of new drugs there is a tendency to think and plan, on both conscious and unconscious levels, on the basis of the experience with existing therapeutics. Often, therefore, the development of new antidepressants has been based on knowledge collected with tricyclic antidepressants or MAO inhibitors. The experimental pharmacodynamics of tricyclics in particular has played a dominant role in the development of models for the mode of action of antidepressants and hence in the development of rational drugs with selective effects. On the clinical side our planning is also influenced by earlier experience, when side effects are recorded or when pharmacokinetic studies are designed, for example. Our experience with earlier drugs should be the inspiration and not the limitation of our research on new compounds. What we must do, then, is distil the essence of the earlier experience that can be expected to be relevant for the new drugs.

The use of human liver microsomal preparations as a tool in drug metabolism research has potentials in a number of areas, not least in pharmacogenetics.The testing of different compounds for their ability competitively to inhibit the oxidation of model compounds such as sparteine/debrisoquine or mephenytoin is a particularly useful primary screening procedure (Otton et al. 1983,1984; Boobis et al. 1983; von Bahr et al. 1985; Inaba et al. 1984,1985; see Table 1). Substances not acting as inhibitors of the sparteine/debrisoquine oxygenase can safely be excluded as substrates of this P450 isozyme and will, accordingly, not exhibit the corresponding monogenetic polymorphism in metabolism in vivo. There appear to be no false negatives contradicting this assumption. However, if a compound is extensively bound to tissue components in the in vitro preparation, apparent high K i values may lead to the erroneous conclusion that the compound is a weak in vitro inhibitor. Among the substances that act as competitive inhibitors of this oxygenase (Table 1), several different tricyclic antidepressants and β-blockers are notable substrates of this oxygenase and show in vivo the corresponding oxidation 1982).Several neuroleptics, both phenothiazines, thioxanthenes, and butyrophenones appear to be potent inhibitors of the metabolism of typical tricyclic antidepressants, such as imipramine, desipramine, amitriptyline and nortriptyline. These neuroleptics include chlorpromazine, perphenazine, thioridazine, levomepromazine, fluphenazine, chlorprothixene and haloperidol. Studies on the effect of perphenazine on formation and excretion of metabolites of imipramine and desipramine suggested that the major effect was an inhibition of the 2-hydroxylation of imipramine and, in particular, desipramine (Fig. 2; Gram 1975). This has been confirmed in studies on imipramine metabolite levels in plasma (Brosen et al. 1986)