Evidence map for lactate-related mechanisms relevant to exercise-based antidepressant research.
| Mechanistic domain | Core evidence | Depression-relevant inference | Evidence strength and key limitation | Key refs |
|---|---|---|---|---|
| Peripheral lactate kinetics | Exercise intensity, modality, training status, and recovery influence lactate peak, AUC, time-to-peak, and clearance. | Links external exercise dose to internal metabolic response. | Established exercise physiology; not depression-specific and influenced by nutrition, sleep, sex, age, fitness, medication, and metabolic health. | [4–12] |
| Brain lactate uptake | Human physiology and MRS studies show brain lactate uptake during exercise or elevated arterial lactate. | Supports peripheral-central metabolic communication. | Human physiological evidence; mostly non-depressed samples and not direct proof of antidepressant mechanism. | [41, 59–65] |
| MCT transport | MCT1, MCT2, and MCT4 mediate lactate transport across BBB, astrocytes, and neurons. | Provides a transport route for lactate movement between blood, glia, and neurons. | Strong molecular/translational evidence; transporter expression and function may vary by region, disease state, and training. | [29, 30, 41] |
| ANLS and glial-neuronal coupling | Astrocyte-derived lactate supports neural activity, memory, and plasticity. | Relevant to depression-related circuits requiring metabolic support during cognitive control and effort. | Mechanistic evidence is substantial but direct clinical evidence in MDD remains limited. | [20, 21, 27, 28, 31–34, 70–72] |
| Plasticity signaling | Lactate can influence BDNF, CREB, SIRT1, Arc, c-Fos, Zif268, and NMDA-related signaling. | May support activity-dependent remodeling after exercise. | Mostly preclinical/cellular evidence; direction and magnitude in human MDD are uncertain. | [28, 34–38] |
| HCAR1-VEGF neurovascular pathway | Exercise-induced lactate can signal through HCAR1 to induce VEGF and angiogenesis in experimental models. | Links exercise metabolism to vascular and neurogenic adaptation. | Preclinical evidence; clinical relevance and dose-response in depression are unproven. | [39] |
| Glial-immunometabolic regulation | Lactate affects microglia, inflammation, phagocytosis, and histone lactylation. | May modulate neuroinflammatory aspects of fatigue and motivational symptoms. | Context-dependent mechanisms; lactate can have divergent immune effects depending on concentration, duration, cell type, and disease state. | [43–46] |
| Antidepressant-like behavior | Peripheral or acute lactate administration produces antidepressant-like effects in animal models. | Direct preclinical support for behavioral relevance. | Animal evidence; cannot be interpreted as direct clinical antidepressant efficacy. | [40, 74] |
| Lactate paradox | Regional dmPFC/dACC lactate is associated with physical effort-based decision-making in humans. | Warns against the claim that more lactate is always beneficial. | Human neuroimaging evidence is correlational; directionality, task demand, and confounding remain unresolved. | [73] |
| Translational exercise dosing | Exercise physiology studies show that blood lactate responses vary with exercise intensity, modality, training status, and recovery. | We propose that lactate kinetics be prospectively evaluated as candidate physiological feedback variables for characterizing internal metabolic response, tolerability, and putative responder phenotypes in future MDD exercise trials. | Hypothesis-generating only; prospective validation in MDD is required before lactate-informed dosing can be considered a clinical prescription strategy. | [4–12] |
ANLS: astrocyte-neuron lactate shuttle; AUC: area under the curve; BBB: blood-brain barrier; BDNF: brain-derived neurotrophic factor; CREB: cAMP response element-binding protein; dACC: dorsal anterior cingulate cortex; dmPFC: dorsomedial prefrontal cortex; HCAR1: hydroxycarboxylic acid receptor 1; MCT: monocarboxylate transporter; MDD: major depressive disorder; MRS: magnetic resonance spectroscopy; NMDA: N-methyl-D-aspartate; SIRT1: sirtuin 1; VEGF: vascular endothelial growth factor.