A Ketogenic Diet for Treatment-Resistant Depression: A Randomized Clinical Trial

TL;DR

A 6-week ketogenic diet showed slightly better improvement in depression symptoms than a control diet in people with treatment-resistant depression.

Contribution

First randomized clinical trial showing a ketogenic diet may offer modest antidepressant benefits in treatment-resistant depression.

Findings

The ketogenic diet group showed a greater reduction in depression scores at 6 weeks compared to the control group.

No serious adverse events were reported in the trial.

The effect size was modest and not consistently seen in secondary outcomes.

Abstract

This randomized clinical trial assesses the effect of a ketogenic diet on mental health outcomes in individuals with treatment-resistant depression.

Does a ketogenic diet (KD; high fat, low carbohydrate) vs a control diet improve mental health outcomes in individuals with treatment-resistant depression (TRD)?

In this randomized clinical trial of 88 UK participants with TRD, both the KD and control groups reported rapid improvements in depression. After 6 weeks, the improvement was greater in the KD group than in the control group.

This randomized clinical trial suggests that KDs may be effective as an adjunctive treatment for TRD.

Preclinical evidence and case reports suggest potential therapeutic benefits of ketogenic diets (KDs) in the treatment of depression, but evidence from well-controlled randomized clinical trials (RCTs) is lacking.

To assess the efficacy of a KD compared with a control diet in adults with treatment-resistant depression (TRD).

This RCT was conducted between February 22 and June 15, 2024. Participants aged 18 to 65 years with TRD and a score of 15 or greater on the 9-item Patient Health Questionnaire (PHQ-9) from across the UK were included.

Participants were randomized 1:1 to one of two 6-week dietary interventions: (1) KD of prepared foods providing less than 30 g of carbohydrates per day with weekly individual dietetic support or (2) a control (phytochemical [phyto]) diet with vouchers to purchase 1 extra serving of vegetables or fruit and replace saturated fats with unsaturated fats, with equal dietetic support. The last follow-up was at 12 weeks.

The primary outcome was the between-group difference in change in PHQ-9 score from baseline to week 6. Secondary outcomes included PHQ-9 score at 12 weeks, depression remission, anxiety, anhedonia, cognitive impairment, quality of life, and functional outcomes.

The study included 88 participants (mean [SD] age, 42.1 [13.1] years; 61 women [69%]): 44 in the KD group and 44 in the phyto diet group. Depression severity decreased markedly in both groups; the mean (SD) change in PHQ-9 score from baseline to week 6 was −10.5 (7.0) in the KD group and −8.3 (5.1) in the phyto group. The mean between-group differences in PHQ-9 score at 6 and 12 weeks were −2.18 (95% CI, −4.33 to −0.03; P = .05; Cohen d, −0.68; 95% CI −1.35 to −0.01) and −1.85 (95% CI, −4.04 to 0.33; P = .10; Cohen d, −0.58; 95% CI, −1.26 to 0.10), respectively. There were no differences in secondary outcomes between the KD and phyto groups. No serious adverse events occurred.

In this RCT, a KD had antidepressant benefits compared with a well-matched control diet at 6 weeks. However, the clinical relevance is uncertain, as the mean effect size compared with the control was modest and not evident in secondary analyses.

ClinicalTrials.gov Identifier: NCT06091163

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