Results suggest a cause and effect relationship between inflammatory cytokines and symptoms relevant to a number of psychiatric illnesses including mood and anxiety disorders, as well as schizophrenia. In addition, data indicate that immune cells may have a critical role in neuronal integrity and the prevention of developmental diseases including Autism Spectrum Disorders (ASD). These findings highlight the nuanced role of the immune system in brain health and illness, and emphasize the exciting potential of neurotherapeutics that target the immune system to treat neuropsychiatric disorders.

A recent clinical trial was conducted to determine whether antagonism of the inflammatory cytokine tumor necrosis factor (TNF) would reduce depressive symptoms in patients with treatment resistant depression (TRD), thereby testing the cytokine hypothesis of depression (Raison et al, 2013). Interestingly, only TRD patients with a baseline peripheral blood concentration of C-reactive protein (CRP—a readily available biomarker of inflammation) >5 mg/l exhibited a clinically significant response to infliximab compared with placebo, indicating that within TRD patients, there appears to be a subgroup of individuals whose depressive symptoms are driven by TNF-induced inflammation in a cause and effective manner. Plasma concentrations of TNF and its soluble receptors as well as peripheral blood expression of TNF-regulated genes also discriminated infliximab responders vs nonresponders as did genes that regulate gluconeogenesis and lipid metabolism, suggesting an interaction between inflammatory pathways and pathways related to the metabolic syndrome in predicting response to cytokine antagonism (Figure 1) (Mehta et al, 2013). Symptom dimensions that improved in infliximab vs placebo-treated patients with CRP >5 mg/l included anhedonia, psychomotor retardation, and anxiety. These behaviors are common to multiple psychiatric illnesses and are thought to be mediated by specific brain regions, such as the basal ganglia and dorsal anterior cingulate cortex, which are targets of inflammatory cytokines (Miller et al, 2013). These findings suggest that cytokines may have specific effects on symptoms domains across disorders, and that relevant patients for immune-targeted therapies can be identified by plasma inflammatory biomarkers or gene expression profiles related to inflammation and the metabolic syndrome.

Figure 1
figure 1

Gene expression pathways that significantly predicted antidepressant response to infliximab. Genes at baseline that were significantly predictive of infliximab treatment response (50% reduction in 17-item Hamilton Depression Rating Scale at any point during the study; n=148, 1.2-fold change, P⩽0.01) were involved in pathways related to glycolysis and gluconeogenesis, cholesterol and sphingolipid transport, and apoptosis through tumor necrosis factor (TNF)-related signaling pathway as assessed using Metacore and Wikipathways. Reprinted from Mehta et al, 2013, with permission from Elsevier.

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Regarding the participation of the immune system in neuronal integrity, data has indicated that T cells have a fundamental role in learning and memory as well as neurogenesis. For example, T-cell deficient mice perform poorly in multiple cognitive tasks, including the Morris water maze, and exhibit impaired neurogenesis in an enriched environment (Ziv et al, 2006). The mechanisms of these effects appear to be related to the ability of T cells to produce IL-4, which stimulates the release of growth factors from astrocytes, and promotes the conversion of microglia and macrophages from an inflammatory M1 phenotype to a neuroprotective M2 phenotype (Derecki et al, 2010). Complementing these data are recent findings that transplantation of wild-type microglia into a genetically induced mouse model of Rhett’s syndrome markedly attenuated disease development including impaired open-field behavior and rotarod performance, decreased body weight, and reduced lifespan. (Derecki et al, 2012). In most cases, Rhett’s syndrome, an ASD, is the result of a mutation of the MECP2 gene that encodes a methyl-CpG-binding protein that is expressed in multiple cell types including neurons, where in mutated form, it leads to neuronal dysfunction. The mutated MECP2 gene is also expressed in glial cells including microglia. Interestingly, transplantation of wild-type microglia (lacking the mutated MECP2 gene) markedly reduced disease expression, indicating the importance of microglia in neuronal integrity and disease development in ASD.

Taken together, these data highlight the multiplicity of roles played by the immune system in neuropsychiatric disorders, and indicate that managing immune responses represents a new era in neuropsychopharmacology and immunology.

FUNDING AND DISCLOSURE

The authors declare no conflicts of interest. Andrew H Miller has served as a consultant for Abbott Laboratories, AstraZeneca, GlaxoSmithKline, Lundbeck Research USA, F. Hoffmann-La Roche Ltd, Johnson and Johnson, Schering-Plough Research Institute, and Wyeth/Pfizer Inc. and has received research support from Centocor Orthotec Services LLC, GlaxoSmithKline, and Schering-Plough Research Institute. Jennifer C Felger has nothing to declare.