A Neuro-endocrine-immune Network Perspective on Transcranial Direct Current Stimulation for Metabolic Dysregulation in Schizophrenia

Individuals with schizophrenia (SCZ) frequently exhibit glycolipid metabolic disorders. This clinical issue cannot be fully explained by the high metabolic risk associated with antipsychotic medications alone. It is increasingly recognized to involve complex multi-system interactions, particularly those linking the central nervous system with peripheral endocrine and immune regulation. Existing interventions have shown limited efficacy, underscoring the need for novel adjunctive strategies. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation (NIBS) technique that modulates cortical excitability, has accumulated preliminary evidence for metabolic regulation in non-psychiatric populations and has generated several mechanistic hypotheses. However, direct evidence regarding its efficacy in SCZ remains limited, and the lack of comparison with existing interventions has hindered the recognition of its neurobiological mechanisms and potential advantages. Current challenges include methodological limitations, outcome heterogeneity, and insufficient mechanistic understanding, highlighting the need for further research and standardization of this clinical intervention. In light of these gaps, we synthesize the latest evidence on the metabolic and weight regulatory effects of tDCS, and further propose an integrative neuro-endocrine-immune network framework to conceptualize how central neuromodulation may influence peripheral metabolic regulation through interconnected biological systems. Moreover, we identify key methodological limitations in current tDCS research and outline directions for improvement, aiming to enhance the quality of future direct evidence. This framework provides a theoretical direction for future interventional studies applying tDCS to glycolipid metabolic disorders in SCZ, while acknowledging that further direct evidence is still warranted.