The effects of the novel tricyclic antidepressant lofepramine were compared with that of its principal metabolite desipramine. In double-bind clinical trials, lofepramine has been shown to be as effective as desipramine and other comparator tricyclic antidepressants in the treatment of endogenous and reactive depression, but there are some differences between them. Thus the acute toxicity of lofepramine is approximately one-fifth that of its metabolite; lofepramine is a less potent muscarinic receptor antagonist than desipramine (verified by clinical studies in volunteers and depressed patients); lofepramine is less likely to produce conduction defects than desipramine. Neurochemical studies show that both lofepramine and its metabolite are potent noradrenaline uptake inhibitors in vitro and evidence is presented to suggest that lofepramine may release this amine following chronic administration in vivo; both drugs slightly increase serotonin turnover under these conditions and down-regulate cortical beta-adrenoceptor function. Unlike desipramine and most clinically effective antidepressants, lofepramine was inactive in attenuating the hyperactivity of olfactory bulbectomized rats in the "open field" apparatus, and in reversing acute clonidine induced hypomotility. From such tests it appears unlikely that the active metabolite, desipramine, is formed in the brain in sufficient concentrations after chronic lofepramine administration to make a substantial contribution towards the pharmacological activity of the parent compound.