Nonlinear kinetics of trimipramine in depressed patients

An increase of the dose of trimipramine (TM) results in a markedly disproportionate increase of the steady-state plasma concentration of the major active metabolite desmethyltrimipramine (DMT). Ten patients receiving 75 mg/day of TM had a mean steady-state plasma concentration of 53.8 ng/ml TM and 26.3 ng/ml DMT. Ten others receiving 150 ng/ml TM had a mean concentration of 122.5 ng/ml TM and 133.8 ng/ml DMT. This is most likely due to the saturation within therapeutic dosage range of the subspecies of cytochrome P-450 responsible for hydroxylation of DMT. Available data on metabolism of tricyclic antidepressants shows that the hydroxylation of desmethylimipramine (desipramine) but not that of desmethylamitriptyline (nortriptyline) reaches saturation within therapeutic dosage range. Clinicians should take into consideration the possibility of dose-dependent kinetics when adjusting the dose of tricyclic antidepressants. This finding highlights the value of monitoring of blood levels of antidepressants.