The purpose of this study was to examine the metabolites of lofepramine (LOF), namely desipramine (DMI), desmethyl desipramine (DDMI) and desmethyl lofepramine (DML) in the forced swim and olfactory bulbectomized (OB) rat models of depression. In the first study, subacute treatment with DMI (10 mg/kg) and DML (20 mg/kg), but not LOF, reduced the immobility time in the forced swim test. In the "open field", chronic (14 day) treatment with all drugs attenuated the hyperactivity associated with olfactory bulbectomy. In the second experiment, a lower dose of DML (10 mg/kg) demonstrated activity following subacute treatment in the forced swim and following chronic treatment 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 and it's desmethylated metabolites, DMI, DML and DDMI, exhibits activity in the OB model. In contrast, lofepramine but not it's desmethylated derivatives is inactive in the forced swim test, perhaps suggesting the requirement of metabolic conversion of LOF to reveal antidepressant activity in this model. (C) 1999 Published by Elsevier Science B.V./ECNP.