Cognitive Impairment in Psychotic Disorders Is Associated with Brain Reductive Stress and Impaired Energy Metabolism as Measured by 31P Magnetic Resonance Spectroscopy

Abstract

Background and Hypothesis Convergent evidence shows the presence of brain metabolic abnormalities in psychotic disorders. This study examined brain reductive stress and energy metabolism in people with psychotic disorders with impaired or average range cognition. We hypothesized that global cognitive impairment would be associated with greater brain metabolic dysregulation. Study Design Participants with affective and non-affective psychosis (n = 62) were administered the MATRICS Consensus Cognitive Battery (MCCB) and underwent a 31P-magnetic resonance spectroscopy scan at 4T. We used a cluster-analysis approach to identify 2 clusters of participants with and without cognitive dysfunction. We compared clusters on brain redox balance or reductive stress, measured by the ratio of nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH, in addition to creatine kinase (CK) enzymatic activity and pH. Study Results The mean (SD) age of participants was 25.1 (6.3) years. The mean NAD+/NADH ratio differed between groups, with lower NAD+/NADH ratio, suggesting more reductive stress, in the impaired cognitive cluster (t = −2.60, P = .01). There was also a significant reduction in CK activity in the impaired cognitive cluster (t = −2.19, P = .03). Intracellular pH did not differ between the 2 cluster groups (t = 1.31, P = .19). The clusters did not significantly differ on severity of mood and psychotic symptomatology or other measures of illness severity. Conclusions Our results demonstrate that psychotic disorders with greater cognitive impairment have greater brain metabolic dysregulation, with more reductive stress and decrease in energy metabolic rate markers. This provides new evidence for the potential of emerging metabolic therapies to treat cognitive deficits in psychotic disorders.