Mechanisms of Exercise Training in Ameliorating Cognitive Function in Patients With Depression: A Narrative Review of Molecular Targets and Clinical Prescriptions

Abstract

Depression is frequently accompanied by core cognitive impairments, notably in executive function and memory. Although the ameliorative effects of exercise training have been widely corroborated, the evidence regarding its underlying mechanisms remains fragmented. To provide a comprehensive and integrated view, this review proposes a testable, cross-scale “peripheral-central-behavioral” hypothetical mechanistic model to explain the effects of exercise on cognition. The core theoretical contribution of this study lies in explicitly postulating a “molecule-structure-function” cross-level mediation hypothesis. The exercise-induced upregulation of peripheral neurotrophic factors must be mediated by a core “structural mediator”, specifically the enhanced white matter integrity of key tracts, to ultimately drive the “electrophysiological output” of optimized cerebral information processing efficiency. Furthermore, this model proposes the temporal cascade effects of neuro-psychological interactive regulation, distinguishing between early subacute HPA axis normalization and mid-to-long-term reward system activation. Crucially, recognizing the profound translational gap between biological mechanisms and clinical application, this review emphasizes that optimal exercise prescriptions cannot be dictated solely by physiological targets. Addressing the heterogeneity of depressed individuals, we propose a precision intervention framework that meticulously balances neurobiological efficacy by tailoring specific modalities and optimal dose-response thresholds to distinct depression subtypes. Ultimately, this review provides a theoretical framework for future stratified randomized controlled trials (RCTs) based on longitudinal multimodal co-measurements, paving the way for clinically viable, predictable, and highly individualized exercise prescriptions.