Clinical studies show better response rates of patients with depression and schizophrenia to combinations of atypical antipsychotics and antidepressants, compared to responses to either type of drugs alone. Animal studies demonstrate that some antipsychotics and antidepressants increase neurogenesis and BDNF expression in the hippocampus, which is reduced in volume in patients with depression or schizophrenia. We hypothesized that the better therapeutic effects of combined treatment seen in schizophrenia and depression patients are related to the additive or synergistic effects of combined treatment on hippocampal neurogenesis and BDNF expression. To test this hypothesis, we investigated the effects of chronic administration of quetiapine, venlafaxine, and their combination, on hippocampal cell proliferation and BDNF expression in rats, when subjected to chronic restraint stress (CRS) during the last 2 weeks of a 3-week drug administration period. We found (1) CRS decreased hippocampal cell proliferation and BDNF expression; (2) chronic administration of quetiapine or venlafaxine dose-dependently prevented these decreases in hippocampal cell proliferation and BDNF expression caused by CRS (6 h/day for 14days); (3) the combination of lower doses of quetiapine (5mg/kg) and venlafaxine (2.5mg/kg) increased hippocampal cell proliferation and prevented BDNF decrease in stressed rats, whereas each of the drugs exerted mild or no effects; (4) individual higher doses of quetiapine (10mg/kg) or venlafaxine (5mg/kg) exerted effects comparable to those produced by their combination. These results support our hypothesis and can lead to future studies to develop new therapeutic approaches for treatment-resistant depression and the negative symptoms of schizophrenia. © 2006 Wiley-Liss, Inc.