The integrated bioenergetic-interoceptive model of schizophrenia-spectrum disorders

Schizophrenia has traditionally been conceptualized as a heterogeneous neurodevelopmental disorder involving neurotransmitter dysregulation, synaptic dysfunction, and large-scale brain network abnormalities. However, a growing body of convergent evidence indicates that schizophrenia is embedded in broader, system-level physiological dysregulation involving metabolic, immune, endocrine, gastrointestinal, autonomic, and interoceptive alterations. This article proposes an integrated bioenergetic-interoceptive model of schizophrenia-spectrum disorders, in which the disorder is understood as a disturbance of predictive allostatic regulation under energetic constraint. According to the model, reduced metabolic flexibility, altered cerebral bioenergetics, cumulative allostatic load, microbiome-gut-brain axis dysregulation, and disturbed interoceptive timing converge on late-maturing, energetically demanding association networks that support salience attribution, self-referential processing, cognitive control, social cognition, and embodied self-experience. Within this framework, the mismatch between energy demand and available capacity constitutes a functionally proximal energetic constraint on adaptive brain-body regulation, whereas impaired metabolic flexibility represents one possible dynamic mechanism underlying this constraint. Gut-immune-metabolite signaling is interpreted as a modulatory input system that may alter the reliability and metabolic cost of interoceptive inference. Gastric, cardiac, respiratory, and vagal rhythms may constitute candidate timing mechanisms through which bodily signals contribute to the temporal organization of the embodied self. The model further posits that neotenous association cortical systems and large-scale networks—including the default mode, salience, frontoparietal, cingulo-insular, and self-referential systems—are particularly vulnerable to convergent metabolic, inflammatory, autonomic, and interoceptive stressors. The model reframes schizophrenia as a multisystem disturbance of predictive brain-body regulation and delineates testable directions for future multimodal biomarker research and for adjunctive interventions targeting bioenergetic, inflammatory, autonomic, gut-brain, and interoceptive mechanisms.