Perspectives on the ketogenic diet as a non-pharmacological intervention for major depressive disorder

Abstract Objective: Major depressive disorder (MDD) is a prevalent mood disorder characterized by persistent low mood and anhedonia, significantly impacting cognitive function and daily living. Despite available pharmacological treatments, nearly one-third of individuals with MDD do not achieve adequate symptom relief with conventional treatments. The ketogenic diet (KD), a high-fat, low-carbohydrate diet that induces ketosis, has emerged as a potential non-pharmacological intervention for MDD. The objective of this study was to provide a comprehensive perspective on the current knowledge and gaps regarding the potential antidepressant effect of the KD, emphasizing its safety, efficacy, and mechanistic pathways. Methods: This narrative review synthesizes data from preclinical and clinical studies on the effects of KD on mood, cognitive function, and its potential as an antidepressant. Mechanistic insights from animal and human studies are explored to elucidate possible pathways through which KD may exert its effects on MDD. Results: Evidence from animal models suggests that KD may reduce depressive-like behaviors and improve cognitive function. Preliminary human studies, including case reports and observational studies, indicate potential benefits such as mood stabilization, increased energy, and reduced depression severity. Proposed mechanisms include immune-inflammatory regulation, correction of mitochondrial dysfunction, and neurotransmitter modulation. However, key gaps remain, particularly regarding the therapeutic window, long-term efficacy, and specific mechanisms of action in MDD. Conclusions: KD represents a promising avenue for further investigation as a non-pharmacological treatment of MDD. Further research is needed to establish its clinical utility, identify predictors of response, and assess its feasibility as a treatment option for MDD.