TDM and Pharmacogenetics of Tricyclic Antidepressants – The Original Ideas

The idea that interindividual differences in the effects of tricyclic antidepressants may be related to corresponding differences in their rate of metabolism (steady-state plasma concentrations, C_ss) arose in the mid sixties in the laboratory of chemical pharmacology at NIH, headed by the legendary B. B. Brodie. He stimulated the late Wolfgang Hammer and myself to perform the first pharmacokinetic studies of tricyclic antidepressants in man. We found a 36-fold interindividual difference in C_ss in 11 depressed patients and identified one individual as a slow hydroxylator of desmethylinpramine^(1). She was later found to be a poor hydroxylater of debrisoquine as well⁽²⁾. Twin-studies in the late sixties had already shown that the C_ss of tricyclic antidepressants was under genetic control⁽²⁾. Using crossover studies with different drug substrates we found that poor hydroxylation of debrisoquine, tricylic antidepressants and several neuroleptics was caused by the same mechanism, a polymorphic CYP2D6⁽³⁾. The clinical significance of these observations stems from the demonstration that the antidepressant effects of nortriptyline⁽⁴⁾ and imipramine⁽⁵⁾ are concentration dependent. The former study lead to the concept of a „therapeutic window“ for some tricyclics with two drug metabolic mechanisms involved in therapeutic failures, poor and ultrarapid metabolism explained by mutations and (multi) duplication of the CYP2D6 gene, respectively. This is the basis for the combined use of TDM and genotyping of CYP2D6 in individualization of the treatment with antidepressants and neuroleptics⁽⁶⁾.

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