Role of neuro-immunological factors in the pathophysiology of mood disorders: Implications for novel therapeutics for treatment resistant depression

Abstract

Mood disorders are associated with persistently high rates of morbidity and mortality, despite the widespread availability of antidepressant treatments. One limitation to extant therapeutic options has been that nearly all approved antidepressant pharmacotherapies exert a similar primary action of blocking monoamine transporters, and few options exist for transitioning treatment resistant patients to alternatives with distinct mechanisms. An emerging area of science that promises novel pathways to antidepressant and mood-stabilizing therapies has followed from evidence that immunological factors play major roles in the pathophysiology of at least some mood disorder subtypes. Here we review evidence that the compounds that reduce the release or signaling of neuroactive cytokines, particularly IL-1β, IL-6, and TNF-α, can exert antidepressant effects in subgroups of depressed patients who are identified by blood-based biomarkers associated with inflammation. Within this context we discuss the role of microglia in central neuroinflammation, and the interaction between the peripheral immune system and the central synaptic microenvironment during and after neuroinflammation. Finally we review data using preclinical neuroinflammation models that produce depression-like behaviors in experimental animals to guide the discovery of novel neuro-immune drug targets.