Synergetic Effects of Quetiapine and Venlafaxine in Preventing the Chronic Restraint Stress-Induced Decrease in Cell Proliferation and BDNF Expression in Rat Hippocampus Haiyun Xu, 1,2 Zhong Chen, 1,3 Jue He, 1 Samson Haimanot, 1 Xiaokun Li, 2 Lillian Dyck, 1 and Xin-Min Li 1,2 * ABSTRACT: Clinical studies show better response rates of patients with depression and schizophrenia to combinations of atypical antipsy- chotics 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 hip- pocampus, 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, ven- lafaxine, 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 14 days); (3) the com- bination of lower doses of quetiapine (5 mg/kg) and venlafaxine (2.5 mg/kg) increased hippocampal cell proliferation and prevented BDNF decrease in stressed rats, whereas each of the drugs exerted mild or no effects; (4) indi- vidual higher doses of quetiapine (10 mg/kg) or venlafaxine (5 mg/kg) ex- erted 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. V VC 2006 Wiley-Liss, Inc. KEY WORDS: antidepressants; antipsychotics; hippocampus; cell proliferation; BDNF INTRODUCTION There are clinical reports that combinations of atypical antipsychotic drugs (APDs) and antidepressants are more effective for treatment-resis- tant depression patients and in treating the negative symptoms of schizophrenia. For example, the atypical APD olanzapine or risperidone enhanced the thera- peutic response of depression to fluvoxamine (a selec- tive serotonin reuptake inhibitor) (Hirose and Ashby, 2002). In another report, fluvoxamine improved nega- tive symptoms when added to ongoing antipsychotic treatment (Silver and Nassar, 1992). Similarly, fluoxe- tine, another SSRI, improved negative symptoms in patients with schizophrenia (Goff et al., 1995). In animal studies, chronic administration of antide- pressants have been shown to increase neurogenesis (Malberg et al., 2000; Kodama et al., 2004) and brain-derived neurotrophic factor (BDNF) expression (Nibuya et al., 1995; Xu et al., 2003) in the hippo- campus, a brain region that plays critical roles in learning and memory, and which is compromised in patients with depression (Sheline et al., 1996) and schizophrenia (Weiss et al., 2005). Atypical APDs also stimulate neurogenesis in adult rat brain (Wakade et al., 2002; Kodama et al., 2004) and upregulate BDNF expression in the hippocampus (Bai et al., 2003; Fumagalli et al., 2003). BDNF is widely distributed in the brain, and syn- thesized predominantly in neurons; its expression is highest in the hippocampus and in the cerebral cortex (Ernfors et al., 1990; Hofer et al., 1990; Wetmore et al., 1990). In addition to providing neurotrophic support for cholinergic neurons, BDNF has been pro- posed to have a potential role in promoting the func- tion and survival of dopaminergic, GABAergic, norad- renergic, and serotonergic neurons (for review, see Connor and Dragunow, 1998). The expression of both the BDNF gene and its corresponding protein has been shown to be regulated by a number of pro- cesses, such as seizures, restraint stress, neurotransmit- ter actions, and second messenger cascades, including cAMP (Humpel et al., 1993; Wetmore et al., 1994; Lindefors et al., 1995; Nibuya et al., 1995, 1996; Smith et al., 1995; Vaidya et al., 1997; Bain et al., 2004; Xu et al., 2004). Neurogenesis is a process of generating functionally integrated neurons from progenitor cells (Ming and Song, 2005). In most mammals, active neurogenesis occurs throughout life in the subventricular zone of the lateral ventricles and in the subgranular zone 1 Neuropsychiatry Research Unit, Department of Psychiatry, College of Medicine, University of Saskatchewan, Saskatoon, Canada; 2 Laboratory of Neuropharmacology, School of Pharmaceutical Science, Wenzhou Medical College, Zhenjiang, China; 3 Department of Orthopedics, Zhu- jiang Hospital, Southern Medical University, Guangzhou, China Grant sponsors: Canadian Institutes of Health Research; Canadian Psychi- atry Research Foundation; Saskatchewan Health Research Foundation; Schizophrenia Society of Saskatchewan; Royal University Hospital Foundation. *Correspondence to: Xin-Min Li, Neuropsychiatry Research Unit, 103 Wiggins Road, Saskatoon, S7N 5E4 Canada. E-mail: Xin-Min.Li@usask.ca. Accepted for publication 31 March 2006 DOI 10.1002/hipo.20184 Published online 1 May 2006 in Wiley InterScience (www.interscience. wiley.com). HIPPOCAMPUS 16:551–559 (2006) V VC 2006 WILEY-LISS, INC.