Some pharmacological aspects of desmethylclomipramine.

The N-desmethyl metabolites of imipramine and amitriptyline possess antidepressant activity in their own right. To test whether this is also true of desmethylclomipramine, studies have been carried out on appropriate models. Desmethylclomipramine was shown to be present in plasma in higher concentrations than the parent compound, to be strongly active in reversing or suppressing reserpine-induced hypothermia, to possess anticholinergic activity on gastrointestinal smooth muscle, inhibiting motility and antagonizing muscarinic receptors, though to a lesser extent than clomipramine. It is also a more potent inhibitor of noradrenaline and dopamine uptake than clomipramine is, though less potent in inhibiting 5-hydroxytryptamine uptake. The metabolite has antidepressant activity of its own, probably associated with its monoamine uptake inhibitory properties, and doubtless makes an important contribution to the efficacy of treatment of depression with clomipramine; for this reason plasma levels of the metabolite as well as those of the parent compound should be taken into account.