J Affect Disord. 2025 Dec 29:121079. doi: 10.1016/j.jad.2025.121079. Online ahead of print.

ABSTRACT

INTRODUCTION: Major Depressive Disorder (MDD) is a prevalent psychiatric condition frequently associated with metabolic dysfunction. Metabolic interventions, including the ketogenic diet (KD), have shown potential antidepressant effects; however, rigorous clinical evaluation remains limited. This pilot study aimed to assess the feasibility, safety, tolerability, and preliminary clinical efficacy of a medically supervised ketogenic diet (MSKD) in individuals with moderate to severe depression.

METHODS: An open-label, single-arm, 14-week pilot feasibility trial was conducted virtually through Kingston General Hospital, Ontario, Canada. Participants underwent a two-week KD induction phase, followed by a 12-week follow-up phase under the supervision of a registered dietitian. Feasibility outcomes included adherence (sustained nutritional ketosis defined by blood ketones ≥0.5 mmol/L), tolerability, recruitment, and retention rates. Clinical outcomes were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), Generalized Anxiety Disorder-7 scale (GAD-7), and Snaith-Hamilton Pleasure Scale (SHAPS).

RESULTS: From an initial 89 interested individuals, 11 (12.4 %) participants were enrolled and began the intervention. Of these, 8 (72.7 %) successfully completed both induction and maintenance phases, all maintaining nutritional ketosis. Adherence was high, with no dropouts during the maintenance phase. Mild and transient side effects were reported primarily during induction. Clinically significant reductions were observed in depressive symptoms (change from the baseline MADRS score estimate from the model was 23.33 points, 95 % CI: 17.95-28.71; p < 0.001). remission in 87.5 %), anxiety symptoms (GAD-7 mean reduction of 8.8 points, p = 0.005), and anhedonia (SHAPS mean reduction of 4.8 points, p = 0.001).

DISCUSSION: This pilot study demonstrated robust feasibility, safety, and tolerability of a medically supervised ketogenic diet in individuals with moderate to severe depression. Preliminary findings indicate significant improvements in depressive symptoms, anxiety, and anhedonia, supporting further investigation in larger, randomized controlled trials.

TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05558995.

PMID:41475571 | DOI:10.1016/j.jad.2025.121079

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