Ketogenic Diet May Modestly Improve Treatment-Resistant Depression
Key Clinical Summary
- A UK randomized clinical trial found that a ketogenic diet (KD) led to greater improvement in depressive symptoms versus a matched control diet at 6 weeks in adults with treatment-resistant depression (TRD).
- The study of 88 participants showed a statistically small between-group difference on the 9-item Patient Health Questionnaire (PHQ-9) at 6 weeks (mean difference −2.18; P = .05), with no significant differences in secondary outcomes at 12 weeks.
- No serious adverse events were reported, but clinical relevance remains uncertain, warranting further research before routine clinical use.
A randomized clinical trial (RCT) conducted in the United Kingdom that assessed whether a ketogenic diet could offer therapeutic benefit in adults with treatment-resistant depression (TRD) found a modest improvement in depression measures versus control diet at week 6. Results were published in JAMA Psychiatry.
Study Findings
The RCT enrolled 88 adults (mean age 42.1 years; 69% women) with TRD, defined as a persistent, at least moderately severe depressive episode despite at least 2 adequate antidepressant treatments. Participants were randomized 1:1 to either a ketogenic diet ([KD]; high-fat, low-carbohydrate [<30 g/day]) or a phytochemical diet control that offered the option for extra fruit and vegetable intake and replaced saturated fats with unsaturated fats. Each group received weekly individual dietetic support to maintain weight stability and monitor adherence
Both groups experienced marked reductions in depression severity by week 6. The KD group saw a mean (SD) PHQ-9 decrease of −10.5 (7.0) versus −8.3 (5.1) in the control group. The between-group difference in PHQ-9 change at 6 weeks was −2.18 (95% CI, −4.33 to −0.03; P = .05; Cohen d −0.68; 95% CI -1.35 to -0.01), favoring the KD. At 12 weeks, between-group differences in PHQ-9 measured −1.85 (95% CI, −4.04 to 0.33; P = .10; Cohen d, -0.58; 95% CI, -1.26 to 0.10). Secondary outcomes, including anxiety, anhedonia, cognitive impairment, quality of life, and functional measures, showed no significant differences.
Adherence to assigned diets varied over time, and no serious adverse events were reported in either group.
Clinical Implications
These findings suggest that a ketogenic diet may offer modest short-term depressive symptom reduction beyond a nutritionally credible control diet in adults with TRD, but the clinical significance remains unclear. The primary outcome difference at 6 weeks reached marginal statistical significance, while secondary and longer-term outcomes did not. Clinicians should note that dietary interventions, especially extreme carbohydrate restriction, require careful consideration of patient metabolic health, adherence feasibility, and potential nutritional deficits.
Given the trial’s remote implementation and structured support, results may not generalize to routine outpatient care without dietetic resources. Additionally, the mechanism by which ketosis might influence mood—potentially through metabolic, inflammatory, or neurotransmitter pathways—remains theoretical and requires further elucidation. The absence of serious adverse events is reassuring but not sufficient to recommend widespread adoption. Future larger, controlled trials are needed to confirm efficacy, define optimal patient selection, and assess longer-term outcomes before integrating KD into routine TRD management.
Expert Commentary
Lead author Min Gao, PhD, of the Nuffield Department of Primary Care Health Sciences, University of Oxford, commented that while the KD showed greater improvement than control at 6 weeks, “the clinical relevance is uncertain, as the mean effect size was modest and not evident in secondary analyses.”
Reference
