Approximately 50% of patients with a major depressive episode fail to achieve remission with first-line antidepressant treatments. Second-line treatment strategies for such patients include lithium augmentation of antidepressants, particularly with tricyclic antidepressants. The neurobiological mechanisms underlying the therapeutic effects of lithium augmentation are not yet fully understood. Unravelling these mechanisms could aid the development of more effective antidepressant drugs. In the present study, we investigated whether chronic treatment with a combination of lithium and the tricyclic antidepressant, desipramine, could produce antidepressant-like behaviour in a mouse strain (BALB/cOLaHsd) that exhibited reduced sensitivity to the behavioural effects of chronic desipramine treatment in the novelty-induced hypophagia test. Since chronic treatment with antidepressant drugs increases the proliferation of newly-born cells in the hippocampus, and hippocampal cell proliferation is required for the behavioural effects of at least some antidepressants in neohypophagia tests, the present study also investigated whether lithium plus desipramine increased cell proliferation in the hippocampus. Chronic treatment with lithium plus desipramine but neither drug alone, induced antidepressant-like behaviour and increased hippocampal cell proliferation, thus suggesting that increased hippocampal cell proliferation may be a mechanism underlying lithium augmentation of antidepressants. Moreover, since BALB/cOLaHsd mice respond to lithium plus desipramine but not to either drug alone, they may become useful in the development of a mouse model of treatment-refractory depression for which there is an unmet need. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.