As a result of their slow onset of action, the difficulty of assessing dose-effect, and the marked interindividual variability of steady-state plasma concentration, tricyclic antidepressants present a special challenge, as well as opportunity, for therapeutic drug monitoring. As shown particularly by the twin studies of Alexanderson, the most important factor responsible for interindividual variation is metabolism; in comparison, differences in binding to plasma proteins are much less significant. Despite the problems posed by the complexity of action of tricyclic antidepressants and their active metabolites on noradrenaline and serotonin metabolism and on monoaminergic receptor sites mdash; as well as the heuristic difficulty calling for a combination of analytical, clinical, pharmacological, and psychiatric expertise mdash; some headway is being made in our understanding the responses of patient populations to this family of drugs. The following conclusions are drawn: (a) monitoring of the plasma concentration of some tricyclics in some types of depressives may improve the clinical use of these drugs; (b) such measurements are valuable mainly in non-responders to normal therapeutic doses; and (c) there seem to exist biochemical subgroups of depressive patients for whom drug choice must be tailored.
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