Reprogramming brain bioenergetics in depression: an integrative framework linking creatine, branched-chain amino acids, and exercise to neuroplasticity, cognitive function, and depression-related outcomes.

Depression represents a multifaceted neuropsychiatric disorder distinguished by disruptions in cerebral energy metabolism, neurotransmitter communication, neuroplasticity, and cognitive processes. An increasing body of literature indicates that integrative non-pharmacological interventions aimed at metabolic and neurochemical pathways may present promising adjunctive strategies for ameliorating depressive manifestations and concomitant cognitive impairments. This review explores the prospective combined effects of creatine supplementation, branched-chain amino acids (BCAAs), and physical exercise as a multimodal bioenergetic intervention for the management of depression. Creatine is pivotal in maintaining neuronal energy equilibrium via the phosphocreatine system, thereby facilitating mitochondrial functionality and adenosine triphosphate availability within neural cells. BCAAs may influence central fatigue and exercise performance through competitive inhibition of tryptophan transport across the blood-brain barrier. Importantly, this mechanism primarily reflects acute exercise-related serotonergic responses associated with central fatigue and should not be considered mechanistically equivalent to the chronic serotonergic dysfunction observed in major depressive disorder. Accordingly, within the context of depression, BCAAs are discussed as indirect modulators of mental health outcomes through their effects on fatigue perception, exercise tolerance, and adherence to physical activity, rather than as direct serotonergic antidepressant interventions. Concurrently, consistent engagement in physical exercise activates critical neuroplasticity-associated signaling pathways, which are instrumental in promoting hippocampal neurogenesis and enhancing stress resilience. Emerging empirical evidence derived from both experimental and clinical investigations suggests that the combined application of these interventions may exert complementary influences on brain bioenergetics, neuroplasticity, exercise capacity, and cognitive function. Collectively, this integrative paradigm highlights the potential of creatine supplementation, BCAAs, and physical exercise to support depression-related outcomes through distinct yet complementary mechanisms involving bioenergetic regulation, enhanced exercise capacity, neuroplastic adaptations, and improved cognitive and emotional functioning.