Mitochondrial dysfunction in schizophrenia and psychotic disorders: Implications for antipsychotic drug mechanisms

Schizophrenia (SCH) is a severe neuropsychiatric disorder associated with complex neurobiological alterations and suboptimal therapeutic outcomes. Increasing evidence indicates that mitochondrial dysfunction may contribute to SCH pathophysiology through impaired energy metabolism, oxidative stress, altered calcium homeostasis, and dysregulation of neuronal function. This review aims to summarize current knowledge regarding mitochondrial abnormalities in schizophrenia and to explore their potential involvement in the mechanisms of action of antipsychotic drugs.

A comprehensive review of the current literature was performed, focusing on human studies, cellular and animal models investigating mitochondrial alterations in schizophrenia, as well as studies evaluating the effects of antipsychotic medications on mitochondrial structure and function.

Available evidence demonstrates structural, molecular, and functional mitochondrial abnormalities in schizophrenia, including alterations in mitochondrial density, respiratory chain activity, oxidative phosphorylation, ATP production, and redox regulation. Antipsychotic drugs influence mitochondrial pathways in a complex and drug-specific manner. Some antipsychotics may impair mitochondrial respiration and increase oxidative stress, whereas others may exert compensatory or protective effects. Mitochondrial alterations may also contribute to cognitive impairment, negative symptoms, treatment response variability, and metabolic adverse effects associated with antipsychotic therapy.

Mitochondrial dysfunction represents an important component of schizophrenia pathophysiology and a potential therapeutic target. The interaction between mitochondrial pathways and antipsychotic drug effects highlights mitochondria as a possible pharmacodynamic interface for personalized treatment strategies. Further in vivo studies and biomarker-based approaches are required to clarify drug-mitochondria interactions and improve therapeutic outcomes in schizophrenia.