Mitochondrial dysfunction in schizophrenia and its modulation by atypical antipsychotic drugs: A randomized controlled trial

Background Recent evidence increasingly links schizophrenia to mitochondrial dysfunction, implicating altered mitochondrial respiratory and metabolic processes in its pathophysiology. Preclinical data suggest that atypical antipsychotics may inhibit mitochondrial respiratory chain complex I (MRCC I), raising concerns regarding mitochondrial impairment despite clinical efficacy. Hence, this study was conducted to evaluate mitochondrial dysfunction associated with schizophrenia and to compare changes during treatment with risperidone and aripiprazole. Methods In this randomized, open-label, clinical trial, 60 patients with schizophrenia were allocated to either risperidone or aripiprazole for 12 weeks. A healthy control group ( n = 30) was recruited for baseline biochemical comparisons. The outcome measures were the change in platelet MRCC I, serum lactate, pyruvate, lactate:pyruvate (L:P) ratio, creatine kinase, Positive and Negative Syndrome Scale (PANSS), Newcastle Mitochondrial Disease Adult Scale (NMDAS), responder rate, and treatment-emergent adverse events (TEAEs). Results At baseline, schizophrenia patients exhibited significantly higher levels of MRCC I, lactate, pyruvate, and L:P ratio compared to healthy controls, consistent with underlying mitochondrial dysregulation. After 12 weeks of therapy, both risperidone and aripiprazole significantly reduced MRCC I concentration (−2.66 vs −3.13 nmol/10 8 platelets), with no inter-group difference ( p = 0.508). Serum lactate and L:P ratio increased significantly, while serum pyruvate remained unchanged. PANSS scores improved significantly in both groups, with comparable responder rates. NMDAS scores showed no significant change. TEAEs were mostly mild and more frequent with risperidone, though not statistically significant. Conclusion Schizophrenia is associated with alterations in mitochondrial-related biochemical markers suggestive of disrupted cellular bioenergetics. Treatment with risperidone and aripiprazole was associated with changes in these markers, without differences between groups. These findings reflect altered bioenergetic status and warrant further investigation using functional assays. Trial registration ClinicalTrials.gov identifier: NCT06236451.