The Glutamate Hypothesis of Schizophrenia: Current Evidence and Implications for Precision Psychiatry

Abstract The dopamine hypothesis of schizophrenia, dominant for over five decades, has limitations in explaining the full spectrum of symptoms, particularly cognitive deficits and treatment-resistant psychosis. The glutamate hypothesis has emerged as a complementary and increasingly supported framework for understanding schizophrenia pathophysiology. This review synthesizes current evidence regarding glutamatergic dysfunction in schizophrenia and its implications for precision psychiatry. We examine neurobiological mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction, neuroimaging biomarkers including magnetic resonance spectroscopy and functional connectivity abnormalities, immunological evidence including anti-NMDA receptor antibodies, and pharmacological interventions targeting the glutamate system. We discuss how glutamatergic biomarkers may stratify patient populations, predict treatment response, and guide personalized therapeutic approaches. Emerging evidence suggests that glutamatergic dysfunction represents a convergence point for multiple pathophysiological pathways in schizophrenia, offering novel opportunities for biomarker-driven diagnosis and treatment selection. This comprehensive overview provides a foundation for implementing precision psychiatry approaches based on glutamatergic dysfunction in clinical settings.