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Potential new targets for antidepressant medications

August 27, 2008

The news about antidepressant medications over the past several years has been mixed. The bad news from large multicenter studies such as STAR*D is that current antidepressant medications are effective, but not as effective as one might hope. Thus, there is a significant need for new treatment mechanisms for depression. On that front, there has been mixed news as well. One of the most exciting new drugs to reach human clinical trials, one that blocks the corticotrophin releasing factor-1 (CRF1) receptor, did not work in a large clinical trial sponsored by Pfizer Pharmaceuticals. Is it time to abandon CRF1 antagonists as antidepressants or should we revisit these agents from a new perspective? It is in this context that a new paper by Alexandre Surget and colleagues, scheduled for publication in the August 15th issue of Biological Psychiatry, is particularly interesting.

Through prior work, it has been shown that the ability to reverse the stress-related disruption of hippocampal neurogenesis, the ability of the brain to make new nerve cells in adulthood, was important to the actions of our available antidepressant medications. In this new study, the researchers affirm the prior findings, but suggest that two experimental approaches to the treatment of depression, blockade of the CRF1 receptor or the vasopressin-1B (V1B) receptor, retain their efficacy in reversing the impact of stress on behavior even when neurogenesis is disrupted. Catherine Belzung, Ph.D., corresponding author on this article, further explains 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."

How can one reconcile these interesting research findings in animals with the lack of antidepressant efficacy of a CRF1 receptor antagonist in the Pfizer study? Is this approach simply ineffective in humans or might there be subgroups of patients who might be more likely to respond to a CRF1 antagonist? The Surget et al. data raise the possibility that CRF1 receptor antagonists might be effective in treating stress-related behavioral disturbances even in a context where other antidepressants do not work, perhaps due to disruption of neurogenesis. John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System, comments: "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." He adds that "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."

Elsevier