Recognition that inflammation may represent a common mechanism of disease has been
extended to include neuropsychiatric disorders including major depression. Patients
with major depression have been found to exhibit increased peripheral blood inflammatory
biomarkers, including inflammatory cytokines, which have been shown to access the
brain and interact with virtually every pathophysiologic domain known to be involved
in depression, including neurotransmitter metabolism, neuroendocrine function, and
neural plasticity. Indeed, activation of inflammatory pathways within the brain is
believed to contribute to a confluence of decreased neurotrophic support and altered
glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity
and loss of glial elements, consistent with neuropathologic findings that characterize
depressive disorders. Further instantiating the link between inflammation and depression
are data demonstrating that psychosocial stress, a well-known precipitant of mood
disorders, is capable of stimulating inflammatory signaling molecules, including nuclear
factor kappa B, in part, through activation of sympathetic nervous system outflow
pathways. Interestingly, depressed patients with increased inflammatory biomarkers
have been found to be more likely to exhibit treatment resistance, and in several
studies, antidepressant therapy has been associated with decreased inflammatory responses.
Finally, preliminary data from patients with inflammatory disorders, as well as medically
healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their
signaling pathways may improve depressed mood and increase treatment response to conventional
antidepressant medication. Translational implications of these findings include the
unique opportunity to identify relevant patient populations, apply immune-targeted
therapies, and monitor therapeutic efficacy at the level of the immune system in addition
to behavior.