From Insulin Resistance to Mitochondrial Failure: A Staged Model of Impaired Metabolic Flexibility in Schizophrenia

Schizophrenia is a highly heritable neuropsychiatric disorder whose pathophysiology remains poorly understood. While neurotransmitter, neurodevelopmental, synaptic, and dysconnectivity hypotheses explain important aspects of the disorder, growing evidence suggests that metabolic dysfunction also plays a central role. This narrative review synthesises evidence from genetics, cell signalling, molecular neuroscience, and metabolism to propose a theoretical framework linking insulin resistance and mitochondrial dysfunction to schizophrenia. We argue that genetic susceptibility and environmental risk factors converge to produce insulin resistance, impaired insulin signalling, and chronic metabolic stress. Reduced insulin signalling suppresses PI3K/AKT activity, while nutrient overload initially hyperactivates mTORC1 independently of PI3K/AKT. Together, these abnormalities shift cellular metabolism away from oxidative metabolism, promote neuroinflammation, impair mitophagy, disrupt mitochondrial dynamics, and increase oxidative stress. Progressive mitochondrial dysfunction subsequently reduces ATP production and downregulates mTORC1, resulting in persistent bioenergetic impairment. We propose that these metabolic abnormalities provide mechanistic links to hallmark features of schizophrenia, including GABAergic and dopaminergic dysfunction, abnormal neurodevelopment, synaptic pathology, cortical structural changes, and disrupted brain connectivity. Finally, we suggest that schizophrenia differs from mood disorders through greater prenatal neurodevelopmental disruption and reduced mitochondrial repair capacity, producing more severe and persistent metabolic dysfunction.