Energetic dysregulations in psychotic disorders: Targets for new therapeutics

Converging findings point to brain- and body-wide energetic dysregulation in psychotic disorders, implicating metabolic abnormalities across different levels of investigation, including genetic, cellular, postmortem, and in vivo neuroimaging studies. The present review synthesizes this literature documenting aberrant energy production and use, specifically related to mitochondrial and redox dysregulation, in psychotic disorders. Mitochondrial DNA, copy number variants, polygenic risk, and candidate genes involved in metabolic pathways converge on glycolytic, mitochondrial, redox, and oxidative stress mechanisms. Consistent with these findings, cell studies, primarily from ex vivo brain tissue samples and induced pluripotent stem cells (iPSC), show misdistribution and structural fragmentation of mitochondrial networks and dysregulation in the expression of proteins involved in several metabolic processes. Inherent dysregulations, at the genetic and cellular level, may affect both neuronal and glial health, as observed at the tissue level. Neuroimaging studies demonstrate metabolic dysregulations in vivo, including central insulin resistance and redox and bioenergetic aberrations that are associated with cognitive impairment and altered brain networks. We also consider the effects of antipsychotic medications on energy metabolism. Finally, we propose a framework for future work and treatment approaches to target energetic dysregulations, including existing metabolic treatments. The metabolic mechanisms that interact to produce and perpetuate aberrant neuronal health and functioning in psychotic disorders are complex. Nevertheless, the findings highlight pathways that might be targeted for the development of novel treatments, providing an opportunity to develop more efficacious and better-tolerated interventions.