96,97 Disruption of normal cycling of ovarian hormones has been implicated in the higher rates of depression in women relative to men, and indicates that abnormal estrogen levels and/or signaling could be involved in the pathophysiology of depression. Novel and selective estrogen ligands could prove useful for

reversing the atrophy of neurons caused by stress, as well as the behavioral symptoms of depression. Another area that has received attention is the role of elevated inflammatory responses in depression. This hypothesis is supported Inhibitors,research,lifescience,medical by studies demonstrating that serum levels of proinflammatory cytokines, most notably IL-1β, IL6, and TNFα, are increased in depressed patients.98,99 In addition, BVD-523 mw cytokines can produce sickness behavior, including fatigue and decreased appetite that

could account Inhibitors,research,lifescience,medical for some symptoms of depression.100 Elevated inflammatory cytokines also contribute to other illnesses, including cardiovascular disease, diabetes, and obesity, that have high rates of comorbidity with depression.101 Together these studies demonstrate a role of inflammatory cytokines in the pathophysiology of depression, and identify novel therapeutic targets. This includes the use of antagonists and agents that block the production of cytokines. For example, there are now reports demonstrating Inhibitors,research,lifescience,medical that peripheral administration of an antibody (Inflixamab), or TNF α receptor-fusion protein (Etanercept) that neutralizes TNFα, produces antidepressant responses.102,103 Preclinical studies also show that blocking or neutralizing IL-1β produces Inhibitors,research,lifescience,medical antidepressant actions in cellular and behavioral models.101,104 There is also evidence that blockade of purinergic 2X7 (P2X7) receptor, which activates the inflammasome to stimulate the processing and release of IL-iβ, produces antidepressant effects.101 ft is not clear at

this point if induction of inflammatory cytokines contributes Inhibitors,research,lifescience,medical to neuronal atrophy, but there is evidence that activated microglia participate in dendrite pruning in support of this possibility.105 The targets and concepts discussed represent the major areas related to the pathophysiology of depression that are currently being investigated for drug development. Taken together, these breakthroughs represent significant potential for a new era of novel therapeutic target development for the treatment of depression. almost Acknowledgments The research was supported by grants from the NIMH MH089983, MH96891, and the Dowshen Program for Neuroscience.
We feel that ongoing discourse between mental health clinicians and neuroscientists is beneficial both for scientific progress in neuroscience and mental health treatments. Neuroscientists may benefit from being educated about clinical models of mental disorders and advances in the nosography of these disorders.