Major depressive disorder (MDD), which is a leading psychiatric illness across the world, severely affects quality of life and causes an increased incidence of suicide. Evidence from animal as well as clinical studies have indicated that increased peripheral or central cytokine interleukin-6 (IL-6) levels play an important role in stress reaction and depressive disorder, especially physical disorders comorbid with depression. Increased release of IL-6 in MDD has been found to be a factor associated with MDD prognosis and therapeutic response, and may affect a wide range of depressive symptomatology. However, study results of the IL6 genetic effects in MDD are controversial. Increased IL-6 activity may cause depression through activation of hypothalamic-pituitary-adrenal axis or influence of the neurotransmitter metabolism. The important role of neuroinflammation in MDD pathogenesis has created a new perspective that the combining of blood IL-6 and other depression-related cytokine levels may help to classify MDD biological subtypes, which may allow physicians to identify the optimal treatment for MDD patients. To modulate the IL-6 activity by IL-6-related agents, current antidepressive agents, herb medication, pre-/probiotics or non-pharmacological interventions may hold great promise for the MDD patients with inflammatory features.

Schizophrenia has been primarily associated with dopamine dysfunction, and treatments have been developed that target the dopamine pathway in the central nervous system. However, accumulating evidence has shown that the core pathophysiology of schizophrenia might involve dysfunction in dopaminergic, glutamatergic, serotonergic, and gamma-aminobutyric acid (GABA) signaling, which may lead to aberrant functioning of interneurons that manifest as cognitive, behavioral, and social dysfunction through altered functioning of a broad range of macro- and microcircuits. The interactions between neurotransmitters can be modeled as nodes and edges by using graph theory, and oxidative balance, immune, and glutamatergic systems may represent multiple nodes interlocking at a central hub; imbalance within any of these nodes might affect the entire system. Therefore, this review attempts to address novel treatment targets beyond the dopamine hypothesis, including glutamate, serotonin, acetylcholine, GABA, and inflammatory cytokines. Furthermore, we outline that these treatment targets can be possibly integrated with novel treatment strategies aimed at different symptoms or phases of the illness. We anticipate that reversing anomalous activity in these novel treatment targets or combinations between these strategies might be beneficial in the treatment of schizophrenia.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.