Co-Treatment with Diazepam Prevents the Effects of Fluoxetine on the Proliferation and Survival of Hippocampal Dentate Granule Cells

Background: Selective serotonin reuptake inhibitors (SSRI) often produce increased anxiety during the first weeks of treatment before the clinical antidepressant response, and these symptoms are commonly treated with benzodiazepines. Selective serotonin reuptake inhibitors increase proliferation of neuronal progenitors in rodent hippocampus after a delay of approximately 2 weeks. Methods: We have used this delayed increase in neurogenesis, as detected with both a rapid dot-blot method and with immunostaining, as a model of the delayed clinical antidepressant effects. Results: Whereas the SSRI fluoxetine alone significantly increased both neurogenesis and survival of newborn cells when administered for 2-3 weeks, co-treatment with diazepam and fluoxetine completely blocked the increase in both neurogenesis and survival. Furthermore, neurogenesis was not increased when fluoxetine and diazepam were first co-administered for 2 weeks and then fluoxetine was given alone for 2 additional weeks. Moreover, we show that daily administration is necessary for neurogenesis, because injection of fluoxetine for up to 1 week failed to increase neurogenesis, when assayed at 14 days from the first injection. Conclusions: These results suggest that benzodiazepines might interfere with the clinical effects of fluoxetine or that increased neurogenesis is not a valid model for the delayed onset of the clinical antidepressant effects.