Alterations in lipid, redox, and energy metabolism in recent onset psychosis: a metabolomics study in non-smoking individuals and matched controls

Psychotic disorders are associated with systemic metabolic alterations, but these associations may be confounded by smoking. We investigated plasma metabolites in 47 non-smoking recent onset psychosis patients and 36 matched (on age, sex and ethnicity) healthy controls using untargeted LC MS metabolomics. We applied univariate, multivariate and pathway analyses, with subgroup exploration in patients that were diagnosed with schizophrenia spectrum disorder (SSD) specifically. We identified 28 significantly altered metabolites predominantly reflecting lipid metabolism (elevated saturated free fatty acids, glycerol 3 phosphate, conjugated bile acid), redox imbalances (decreased L cysteine, L cystine and taurine) and energy metabolism (reduced pyruvate). These alterations remained significant after adjusting for sex, antipsychotic treatment and metabolic syndrome parameters. Enrichment analyses highlighted taurine/hypotaurine metabolism, alanine/aspartate/glutamate pathways and fatty acid biosynthesis in psychosis. Within the SSD subgroup (n = 28), metabolic perturbations were more pronounced, showing stronger depletion of reducing equivalents and elevated free fatty acids. These findings indicate a specific systemic metabolic signature in psychosis independent of smoking, sex, antipsychotic medication or metabolic syndrome. The pattern suggests mitochondrial dysfunction and increased oxidative stress, accompanied by compensatory lipid mobilization. These findings identify redox and energy metabolism as promising targets for future pharmacological or metabolic interventions in SSD.