@article{10.37349/en.2026.1006142,
abstract = {Exercise is an effective non-pharmacological intervention for depressive symptoms, but the biological mechanisms underlying its intensity-dependent and symptom-specific effects remain incompletely defined. This review proposes the “lactate window” hypothesis as a testable mechanistic model, not as an established clinical prescription strategy. Lactate is a plausible candidate link because it is tightly related to exercise intensity, functions as an oxidative substrate and signaling molecule, and participates in brain energy metabolism, astrocyte-neuron metabolic coupling, neuroplasticity, neurovascular signaling, and glial-immunometabolic regulation. Major depressive disorder (MDD) is associated with altered brain energy metabolism, mitochondrial dysfunction, pH abnormalities, and disrupted glial-neuronal support, which may be particularly relevant to fatigue, anhedonia, low motivation, psychomotor slowing, and impaired effort-based decision-making. However, lactate should not be interpreted as uniformly beneficial. Preclinical work suggests that acute L-lactate can produce antidepressant-like effects, whereas human neuroimaging findings indicate that regional lactate in motivation-related cortical circuits may be associated with reduced willingness to exert physical effort. We therefore distinguish three evidence levels: established physiological findings, plausible mechanistic pathways, and hypothesis-generating clinical applications. The proposed lactate window is operationally defined by dynamic features of the response, including blood lactate peak, area under the curve (AUC), time-to-peak, clearance, recovery kinetics, an exploratory lactate-to-rating of perceived exertion (RPE) index, affective response, next-day fatigue, sleep, and adherence. The clinical goal is not to maximize lactate, but to identify a tolerable, recoverable metabolic challenge that may support adaptive brain remodeling. Future trials should test whether lactate kinetics predict antidepressant response beyond conventional exercise dose and whether such effects are strongest for energy-, motivation-, and effort-related symptom dimensions. Because direct clinical evidence in MDD remains limited, lactate-informed exercise prescription should currently be framed as a research agenda requiring prospective validation.},
author = {Kong, Jianda},
doi = {10.37349/en.2026.1006142},
journal = {Exploration of Neuroscience},
elocation-id = {1006142},
title = {The “lactate window” hypothesis: exercise-induced lactate dynamics in neurometabolic remodeling and symptom-dimensional exercise prescription for depression},
url = {https://www.explorationpub.com/Journals/en/Article/1006142},
volume = {5},
year = {2026}
}