Antidepressant Medications May Have Alternate Use

Editor's Choice
Main Category: Depression
Also Included In: Biology / Biochemistry
Article Date: 28 Aug 2008 - 0:00 PDT

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A new study published in the August 15th issue of Biological Psychiatry finds that hippocampal neurogenesis (neuron birth in the hippocampus part of the brain) might be used by the monoaminergic antidepressants (related to the secretion of monoamine neurotransmitters such as dopamine and serotonin) to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the hypothalamo-pituitary-adrenal (HPA) axis and related neuropeptides (amino acid chains).

Results from studies of antidepressant medications over the past several years have been mixed, and Alexandre Surget (Université François Rabelais de Tours, Tours, France) and colleagues wonder if it is time to abandon corticotrophin releasing factor-1 (CRF1) antagonists as antidepressants - ones that recently failed in a large clinical trial - or time to analyze the agents from a different perspective. It has been known that depression and anxiety disorders are linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis as well as structural changes within the hippocampus itself. Animal studies in mice have shown that unpredictable chronic mild stress (UCMS) can reignite these effects, and UCMS-induced changes - including downregulation of hippocampal neurogenesis - can be reversed by antidepressant (AD) treatment. Knowing that stress-related disruption of hippocampal neurogenesis can be reversed is important to the actions of available AD medications. Surget and colleagues investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs.

One result of the study revealed that eliminating hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays; that is, reduced neurogenesis does not cause stress-related behavioral deficits. The researchers also show the existence of both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Using two experimental approaches for treating depression, blockade of the CRF1 receptor or the vasopressin-1B (V1B) receptor, the researchers show their efficacy in reversing the impact of stress on behavior even when neurogenesis is disrupted. Corresponding author Catherine Belzung, Ph.D., clarifies that, "We now report evidence that restoration of the functioning of the stress axis may be the key to how these new antidepressant approaches might work."

Surget and colleagues' findings indicate that neurogenesis disruption may be causing CRF1 receptor antagonists to be effective in treating stress-related behavioral disturbances even in a context where other antidepressants do not work.

John H. Krystal, M.D. (Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System) writes in a comment that, "These findings lend weight to the hope that CRF1 antagonists might play a role in the treatment of antidepressant-resistant symptoms of depression or posttraumatic stress disorder. If so, CRF1 antagonists could fulfill an important unmet need...We do not need another Prozac, but we urgently need to find ways to help the large number of patients who fail to respond adequately to our available treatments."

Drug-Dependent Requirement of Hippocampal Neurogenesis in a Model of Depression and of Antidepressant Reversal
Alexandre Surget, Michael Saxe, Samuel Leman, Yadira Ibarguen-Vargas, Sylvie Chalon, Guy Griebel, René Hen, Catherine Belzung
Biological Psychiatry (2008). 64[4]: pp 293 - 301.
doi:10.1016/j.biopsych.2008.02.022

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Written by: Peter M Crosta


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