Synergetic effects of quetiapine and venlafaxine in preventing the chronic restraint stress-induced decrease in cell proliferation and BDNF expression in rat hippocampus.
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 14 days); (3) the combination 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) individual higher doses of quetiapine (10 mg/kg) or venlafaxine (5 mg/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.
Xu
Haiyun
H
Neuropsychiatry Research Unit, Department of Psychiatry, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
Chen
Zhong
Z
He
Jue
J
Haimanot
Samson
S
Li
Xiaokun
X
Dyck
Lillian
L
Li
Xin-Min
XM
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002908:Chronic Disease; D003511:Cyclohexanols / Q000494:pharmacology*; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D003987:Dibenzothiazepines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000069348:Quetiapine Fumarate; D051381:Rats; D012149:Restraint, Physical; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000069470:Venlafaxine Hydrochloride
D014150:Antipsychotic Agents; D019208:Brain-Derived Neurotrophic Factor; D003511:Cyclohexanols; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride