Mitochondrial dysfunction and disrupted cerebral energy metabolism have been increasingly linked to the pathophysiology of schizophrenia. Preclinical studies suggest that certain atypical antipsychotics may exacerbate mitochondrial dysfunction by inhibiting respiratory complex I, contributing to adverse effects. Risperidone, a dopamine D2/serotonin 5-HT2 antagonist, and aripiprazole, a partial dopamine D2 agonist, were selected because of their contrasting pharmacological profiles and reported differential effects on mitochondrial complex I activity. Despite these findings, the clinical implications remain poorly understood. This randomised controlled trial aims to evaluate and compare the biochemical and clinical effects of risperidone and aripiprazole on mitochondrial dysfunction in patients with schizophrenia.

In this randomised, open-label, parallel-arm clinical trial, 60 patients with schizophrenia who were drug-naïve or had not taken any antipsychotic drugs for at least 4 weeks before recruitment were randomly assigned to risperidone or aripiprazole treatment for 12 weeks, with inclusion of an additional group of 30 healthy individuals for baseline comparisons. The primary outcome is the change in mitochondrial respiratory chain complex I concentration in platelets, and secondary outcomes include serum lactate, pyruvate, creatine kinase levels and Newcastle Mitochondrial Disease Adult Scale (NMDAS) scores. Clinical efficacy and safety are evaluated using the Positive and Negative Syndrome Scale (PANSS) and monitoring treatment-emergent adverse events. Intention-to-treat analysis will be done for all parameters using suitable statistical tools.

Ethical approval was obtained from the Institutional Ethics Committee and the study conformed to the provisions of the Declaration of Helsinki and ICMR’s national ethical guidelines for biomedical and health research involving human participants (2017). Written informed consent will be obtained from the legally authorised representative of the patients. Results will be disseminated through peer-reviewed publications and conferences to inform safer treatment strategies for schizophrenia.

NCT06236451.