An investigation of the antidepressant properties of lofepramine and its desmethylated metabolites in the forced swim and olfactory bulbectomized ratmodels of depression

The purpose of this study was to examine the metabolites of lofepramine (LO F), namely desipramine (DMI), desmethyl desipramine (DDMI) and desmethyl lo fepramine (DML) in the forced swim and olfactory bulbectomized (OB) rat mod els of depression. In the first study, subacute treatment with DMI (10 mg/k g) and DML (20 mg/kg), but not LOF, reduced the immobility time in the forc ed swim test. In the "open field", chronic (14 day) treatment with all drug s attenuated the hyperactivity associated with olfactory bulbectomy. In the second experiment, a lower dose of DML (10 mg/kg) demonstrated activity fo llowing subacute treatment in the forced swim and following chronic treatme nt in the OB model. In addition, DDMI (10 mg/kg) was active in both models. From these results, it can be concluded that, at the doses employed, LOF a nd it's desmethylated metabolites, DMI, DML and DDMI, exhibits activity in the OB model. In contrast, lofepramine but not it's desmethylated derivativ es is inactive in the forced swim test, perhaps suggesting the requirement of metabolic conversion of LOF to reveal antidepressant activity in this mo del. (C) 1999 Published by Elsevier Science B.V./ECNP.