The Involvement of TNF-α in Cognitive Dysfunction Associated with Major Depressive Disorder: An Opportunity for Domain Specific Treatments

Abstract

Major depressive disorder is a highly prevalent, chronic and recurring disorder, associated with substantial impairment in cognitive and interpersonal functions. Accumulating evidence suggests that inflammatory processes play an important role in the etio-pathogenesis, phenomenology, comorbidity and treatment of MDD. Suboptimal remission rates and the persistence of cognitive deficits contribute to functional impairment in MDD inviting the need for the development of mechanistically novel and domain specific treatment approaches. The MEDLINE/ Pubmed database was searched from inception to February, 9th, 2014 with combinations of the following search terms: 'TNF-alpha', 'depression', 'infliximab', 'etanercept', 'adalimumab', 'golimumab' and 'certolizumab'. Preclinical and clinical evidence linking TNF-α to MDD pathophysiology were reviewed as well as the current status of TNF-α modulators as novel agents for the treatment of MDD. Experimental models and clinical studies provide encouraging preliminary evidence for the efficacy of TNF- α antagonists in mitigating depressive symptoms and improving cognitive deficits. Further studies are warranted to confirm these data in larger randomized controlled trials in primary psychiatric populations. Translational research provides a promising perspective that may aid the development and/or repurposing of mechanism-based treatments for depressive symptoms and cognitive impairment in MDD.

Fig. (1)

Schematic representation of inflammatory pathways involved in neuroprogression. Peripheral pro-inflammatory stimuli activate microglial cells, which initiate an inflammatory cascade within the brain secreting cytokines, chemokines, adhesion molecules and reactive nitrogen and oxygen species (RNS and ROS). Astrocytes further amplify the immune response and are responsible of impaired neurovascular coupling and reduced trophic support to neurons and other glial cells. Immunoexcitotoxicity is mediated by the production of the NMDA agonist QUIN, increased TNF-mediated density and activity of AMPA and NMDA receptors and decreased Glu reuptake. The combined effect of immune mediators, nitrosative and oxidative burden and reduced production of growth factors leads foster mitochondrial dysfunction and consequent apoptotic death and impaired neuroplasticity. GLU, glutamate; IDO, indolamine 2,3 dioxygenase; 5HT, serotonin; IFN, interferon; IL, interleukin; NGF, nerve growth factor; BDNF, brain derived neurotrophic factor; NMDA, N-methyl-Daspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic calcium-permeable receptors; QUIN, quinolinic acid; RNS, reactive nitrogen species; ROS, reactive oxygen species; Th1, T Helper 1; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; CCL, C-C chemokine ligands; CXCL (C–X–C motif) ligand chemokine; MCP, monocyte chemotactic protein.

Fig. (2)

TNF-α enhances excitotoxicity via upregulation of glutaminase, suppression of glutamine synthetase, impaired glutamate reuptake and increased trafficking of AMPA calcium‐ permeable receptors to the synaptic membrane and endocytosis of GABA-A receptors. These mechanisms, in association with alterations in 5-HT, DA, NA mediated neurotransmission, promote glial dysfunction and neuronal degeneration.

Fig. (3)

Simplified diagrams of the structures of 5 TNF antagonists. Infliximab is a mouse/human chimeric monoclonal antibody of IgG1 isotype. Adalimumab and golimumab are fully human monoclonal antibodies. Certolizumab is a PEGylated Fab' fragment of a humanized IgG1 monoclonal antibody. Etanercept is a fusion protein of TNFR2 (p75) and the Fc region of human IgG1.