The therapeutic effect of the tricyclic antidepressants is subject to marked interindividual differences in response. Only 50 to 70% of depressed patients usually benefit from treatment. The antidepressive effect is most clearly drug-related in endogenous depressions and less convincing in other types of depression. However, even within diagnostically homogenous groups of depressed patients, the antidepressive effect is variable. Some of this variability may be explained by the pronounced interindividual variation in pharmacokinetics of tricyclic antidepressants, in particular variation in steady state plasma levels.Studies with nortriptyline in endogenous depressions have indicated that a therapeutic effect is only achieved when the plasma level is above 50 and below 150 to 180&mgr;g/L, above which patients respond poorly. For imipramine, most patients respond well when plasma levels of imipramine + desipramine are above 200 to 240&mgr;g/L. Very high plasma levels do not appear to impair the antidepressive effect of imipramine. The present data on other antidepressants are less clear.For nortriptyline and imipramine, as well as other antidepressants, there is a need for more studies on larger patient populations comprising different diagnostic categories, and designed and conducted with careful consideration of the number of methodological problems involved in interpreting plasma level/effect relationships. The use of plasma level monitoring in cases of intoxication with tricyclic antidepressants is potentially useful, but studies in this area are limited.