Elsevier

Life Sciences

Volume 6, Issue 17, 1 September 1967, Pages 1895-1903
Life Sciences

Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds

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Abstract

Imipramine counteracts the “depressive syndrome” evoked by reserpine in rats at a time when the brain contains little imipramine (I) but high levels of the active metabolite desmethylimipramine (DMI). Since the reserpine syndrome in animals has certain similarities to depression in man, it has been suggested that imipramine, at least partly, exerts its antidepressant effect in man through the formation of DMI. Both drugs are useful in the treatment of endogenous depression with little difference between the two regarding the onset of action. Nortriptyline (NT), the desmethylated metabolite of amitriptyline (AT), has also been introduced into clinical practice as an antidepressant. All four drugs are useful in certain cases of depression but not in others. The reasons for the individual differences in therapeutic response are unknown. Angst demonstrated that certain families were resistant to the action of imipramine. However, the mechanism of this therapeutic resistance was not analyzed. Differences in the rate of metabolism of the tricyclic antidepressants could explain the individual differences in the clinical response to these drugs. Studying such possibilities, Hammer et al. measured the plasma concentrations of DMI in eleven depressed patients and found a 36-fold difference between the lowest and highest steady-state level. Similar individual differences have now been found to occur with NT. In addition, we have determined the plasma levels of DMI and NT, which are built up in vivo during administration of the corresponding tertiary compounds imipramine and amitriptyline.

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