Neurogenesis creation of new neurons critical to antidepressant action

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The seminal studies by Duman and co-workers14 on neurogenesis may help to explain why antidepressants typically take a few weeks to have an effect and may indicate why a rapid-acting antidepressant may not be a viable propositition.14 These workers created a strain of 5HT1A'knockout' mice that as adults show anxiety-related traits, such as a reluctance to begin eating in a novel environment. While unaffected by chronic treatment with the SSRI fluoxetine, the mice became less anxious after chronic treatment with TCAs that act via another neurotransmitter, NE, suggesting an independent molecular pathway. While chronic fluoxetine treatment doubled the number of new hippocampal neurons in normal mice, it had no effect in the knockout mice. The tricyclic imipramine boosted neurogenesis in both types of mice, indicating that the 5HT1A receptor is required for neurogenesis induced by fluoxetine but not imipramine. Chronic treatment with a 5HT1A-selective drug confirmed that activating the 5HT1A receptor is sufficient to spur cell proliferation. An extension of this work using the SSRI fluoxetine in a transgenic cell line from dentate gyrus showed that the SSRI does not affect division of stem-like cells but increases division of amplifying neuroprogenitor cells that results in new neurons in dentate gyrus. This effect was specific for dentate gyrus.30 Although these findings strengthen the case that neurogenesis contributes to the effects of antidepressants, the authors caution that ultimate proof may require a 'cleaner' method of suppressing this process, such as transgenic techniques that will more precisely target toxins to the hippocampal circuits involved. Ultimately, these results suggest that strategies aimed at stimulating hippocampal neurogenesis provide novel avenues for the treatment of anxiety and depressive disorders. However, the Holy Grail of current treatment strategies is to develop antidepressants with a fast onset of action. In this light, the neurogenesis hypothesis, also reported in antipsychotic drug treatment (see 6.02 Schizophrenia), would therefore not support this approach.

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Conquering Fear In The 21th Century

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