β-hydroxybutyrate in depression: Neuropharmacological mechanisms and therapeutic potential

Major depressive disorder (MDD) is a prevalent and disabling illness marked by high rates of recurrence, suicide, and self-harm, yet current first-line antidepressants remain inadequate for a substantial proportion of patients. An increasing number of preclinical studies now indicate that β-hydroxybutyrate (BHB) has significant antidepressant potential, and several candidate mechanisms have been proposed, including NLRP3 inflammasome inhibition, HDAC inhibition, GPR109A activation, and enhancement of BDNF-dependent neuroplasticity. However, translation to the clinic remains constrained: evidence in humans is limited to small ketogenic-diet trials and cross-sectional observations rather than controlled studies of BHB itself, it is unclear whether exogenous BHB can reproduce the full antidepressant profile of the ketogenic diet, and the mechanistic hypotheses vary considerably in their level of experimental support. This review synthesizes the biosynthesis and transport of BHB, critically evaluates the evidence linking BHB to depression across animal and human studies, and appraises the relative strength of the proposed neuropharmacological mechanisms. We further outline the safety considerations, monitoring needs, and delivery strategies relevant to clinical translation, and identify the specific evidence gaps that must be addressed before BHB-based interventions can be tested as antidepressants in humans.