It appears that alterations in the immunoinflammatory system are both causative and consequential. For example, it is now established that exposure to second trimester infection increases an offspring’s risk for MDD, bipolar disorder, schizophrenia, autism, as well as mental retardation. It has also been reported that the immunoinflammatory “genetic architecture” (e.g. single nucleotide polymorphisms (SNIPs) and mRNA may be different in individuals who are “at risk” for mood disorders or other brain illness, as well as individuals who are probands.8

Interventional research has indicated that immunoinflammatory activation is associated with alterations in brain structures subserving disparate domains of psychopathology. For example, immunoinflammatory activation is associated with increase in depression measures, anhedonia measures, as well as cognitive impairment.9,10

A neurobiological correlation with the foregoing phenotypic measures has been the observation that neural inflammation is associated with activation of nodal structures (e.g. Broadmann’s area 24) as well as cognitive control/ emotional circuits and networks relevant to affect regulation, emotional control, and neural cognitive performance.11 At the neurochemical level, it has been convincingly established that immunoinflammatory activation results in altered release, availability, and reuptake of classic monoamines.

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For example, neuroinflammation results in an activation of the kyneurinine with resulted elevation of highly neurotoxic metabolites, e.g. quinolinic and relative reduction of tryptophan availability for monoaminergic synthesis.12 Moreover, via effects on tyrosine hydroxylase as well as tetrahydrobiopterin levels, neural inflammation results in a relative reduction in norepinephrine and dopamine signalling.

Conventional antidepressant therapies, such as selective serotonin reuptake inhibitors (SSRIs), exert an influence on the immunoinflammatory system. Compelling proof-of-concept data of the foregoing assertion is provided by replicated evidence indicating that SSRI therapy reduces the odds ratio for incident major depressive episodes in medically ill patients receiving interferon therapy.13,14,15

A growing body of literature has explored the possibility that anti-inflammatory agents may be capable of mitigating depressive symptoms in subsets of individuals. A recently completed meta-analysis synthesizing data related to anti-inflammatory agents in depression provided suggestive evidence, albeit undergoing heterogeneity of results.16