Schizophrenia, a disease of impaired dynamic metabolic flexibility: A new mechanistic framework

•Findings of bioenergetic abnormalities require re-conceptualization of schizophrenia.•These abnormalities are present in the brain and in the periphery at first episode.•Central and systemic impairments during the disease course need to be reconciled.•We propose that schizophrenia is a disease of impaired dynamic metabolic flexibility.•This theoretical framework and testable hypothesis open the way to novel treatment. Schizophrenia is a chronic, neurodevelopmental disorder with unknown aetiology and pathophysiology that emphasises the role of neurotransmitter imbalance and abnormalities in synaptic plasticity. The currently used pharmacological approach, the antipsychotic drugs, which have limited efficacy and an array of side-effects, have been developed based on the neurotransmitter hypothesis. Recent research has uncovered systemic and brain abnormalities in glucose and energy metabolism, focusing on altered glycolysis and mitochondrial oxidative phosphorylation. These findings call for a re-conceptualisation of schizophrenia pathophysiology as a progressing bioenergetics failure. In this review, we provide an overview of the fundamentals of brain bioenergetics and the changes identified in schizophrenia. We then propose a new explanatory framework positing that schizophrenia is a disease of impaired dynamic metabolic flexibility, which also reconciles findings of abnormal glucose and energy metabolism in the periphery and in the brain along the course of the disease. This evidence-based framework and testable hypothesis has the potential to transform the way we conceptualise this debilitating condition and to develop novel treatment approaches.