Chapter 4 - Anti-Inflammatory and Immune-Modulatory Therapeutic Approaches in Major Depression

Abstract

High levels of several proinflammatory components of the immune system such as interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), or neopterin in patients suffering from major depression (MD) point to the involvement of an inflammatory process in the pathophysiology of MD. Direct and indirect effects of cytokines on the neurotransmitter storage and release—mediated by microglia cells and astrocytes—are discussed. The tryptophan/kynurenine metabolism mediates the activity of the immune system and the serotonergic and glutamatergic neurotransmissions. The enzyme indoleamine 2,3-dioxygenase (IDO)—a key enzyme of this metabolism in the central nervous system (CNS)—is driven by pro- and anti-inflammatory cytokines and degrades serotonin. Moreover, neuroactive kynurenines such as kynurenic acid and quinolinic acid act on the glutamatergic neurotransmission as N-methyl-d-aspartate (NMDA)—antagonists and agonists, respectively. Alterations of the serotonergic, noradrenergic, and glutamatergic neurotransmissions are associated with low-level neuroinflammation. Epidemiological and clinical studies point to a key role for inflammation as risk factor for MD. A large-scale epidemiological study in MD clearly demonstrates that severe infections and autoimmune disorders are lifetime risk factors for MD. Neuroinflammation in the prefrontal cortex, the nucleus accumbens, and the insula has been shown in MD by in vivo positron emission tomography. Further support comes from the therapeutic benefit of anti-inflammatory compounds in MD such as the cyclo-oxygenase-2 (COX-2) inhibitors or TNF-α antagonists. On the other hand, antidepressants have anti-inflammatory and immunomodulatory intrinsic effects. The beneficial effect of both, COX-2 inhibitors alone and of the approach of anti-inflammatory treatment in MD, has been shown in meta-analyses in the meantime.