Summary:
Major depressive disorder (MDD) is a common mental health condition associated with persistent low mood, reduced pleasure or interest, fatigue, changes in sleep and appetite, and suicidal thoughts. Although selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed, many individuals do not achieve full symptom improvement. People with MDD are also more likely to experience metabolic conditions, suggesting a possible link between metabolic dysfunction and depression. Dietary interventions, particularly the ketogenic diet (KD), have been investigated due to associations between unhealthy diets high in ultra-processed foods and increased depression risk. The ketogenic diet is a high-fat, very low-carbohydrate diet that induces ketosis, a metabolic state in which ketone bodies become the body’s primary energy source instead of glucose. Proposed mechanisms for the KD include improved brain energy metabolism, enhanced mitochondrial function, antioxidant effects, neuroprotection, and changes in neurotransmitter activity. This study was a pilot trial conducted virtually in Canada to examine the feasibility and acceptability of a medically supervised KD in adults with moderate to severe depression. Participants completed a two-week induction phase followed by a 12-week maintenance phase under the guidance of a registered dietitian. 11 participants commenced the intervention and 8 completed the full program. All participants who completed the study maintained nutritional ketosis, with high adherence and no dropouts during the maintenance phase. Significant improvements were observed in depressive symptoms, anxiety, and low pleasure and enjoyment scores. Overall, this pilot study found that a medically supervised KD was safe, tolerable, and achievable for adults with moderate to severe depression. The findings also suggested potential benefits for depressive symptoms such as anxiety and low enjoyment and pleasure, supporting the need for larger randomised controlled trials to further evaluate its effectiveness.
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.
Article Publication Date: 06/01/2026
DOI: 10.1016/j.jad.2025.121079
