Antidepressant Medications May Have Alternate Use

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 (UniversitГ©
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, RenГ© Hen, Catherine Belzung

Biological Psychiatry (2008). 64[4]:
pp 293 - 301.

doi:10.1016/j.biopsych.2008.02.022



Click
Here to View Journal Website



Written by: Peter M Crosta



View drug information on Prozac Weekly.