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. 2025;32(1):36-48.
doi: 10.1159/000542979. Epub 2024 Dec 19.

KETO-MOOD: Ketogenic Diet for Microbiome Optimization and Overcoming Depression - A Protocol for a Randomized Controlled Trial

Katarzyna Hongler  1 , Astrid Lounici  1 , Erin Maurer  1 , Ueli Lanz  1 , Orsolya Szathmari  1 , Yvonne Reuter  1 , Sandra Nussbaum  1 , Ines Steinborn  1 , Annika Haedrich  2 , Melina A Mölling  3 , Ulf Wein  1 , Iona Bocek  1 , Luca Hersberger  4 , Annette B Brühl  1 , Undine E Lang  1 , Timur Liwinski  1
Affiliations

KETO-MOOD: Ketogenic Diet for Microbiome Optimization and Overcoming Depression - A Protocol for a Randomized Controlled Trial

Katarzyna Hongler et al. Neuroimmunomodulation. 2025.

Abstract

Introduction: Major depressive disorder (MDD) significantly impacts millions worldwide, with limited success in achieving remission for many patients, leading to high disease burden and increased suicide risk. Psychotherapy and antidepressants, although effective, do not provide relief for all, prompting the search for alternative treatments. Ketogenic diets have demonstrated positive effects on brain health. Our study aims to investigate the efficacy of the ketogenic diet in alleviating MDD symptoms, filling a critical gap in psychiatric treatment options and offering a novel dietary approach with potential to mitigate disease burden and enhance mental well-being.

Methods: This phase 2 randomized controlled trial will evaluate the efficacy of a 10-week program of dietitian counseling and ketogenic meal provision versus an intervention with similar dietetic contact promoting a healthy, insulin-lowering, non-ketogenic diet. The primary outcome is the change in the Patient Health Questionnaire nine-item depression score. Secondary outcomes include cognitive and affective mindfulness, self-efficacy, sleep, cognitive function, work and social adjustment, and various immunological, metabolic, and microbiome markers at weeks 6 and 10.

Conclusion: This study addresses a critical gap in depression treatment by exploring the ketogenic diet's potential as a metabolic mood enhancing intervention. Given the global impact of depression and limitations of current therapies, this research is valuable for exploring previously underappreciated neuroprotective and metabolic mechanisms and clinical benefits.

Keywords: Ketogenic diet; Ketogenic metabolic therapy; Metabolic psychiatry; Microbiome; Nutritional therapy.

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Conflict of interest statement

K.H. is the founder and CEO of flexiMENTE Health and Resilience Coaching. A.L. is the founder of MyKetoBrain. E.M., U.L., and O.S. are partners at Mason & Lanz Metabolic Solutions, while Y.R. serves as a consultant. T.L. is a medical advisor to Mason & Lanz Metabolic Solutions. The authors recognize the importance of adhering to general nutritional guidelines and advocate for dietary modifications only when there is a clear health rationale, supported by professional guidance from experts in dietary counseling and therapy. Authors who practice dietary counseling provide a range of tailored approaches, from standard public health recommendations to therapeutic dietary restrictions – including carbohydrate restriction – when supported by evidence (e.g., for conditions such as obesity or metabolic syndrome). Individual dietary practices vary among the authors and have also changed over time; for instance, some have personally explored both carbohydrate-based vegan diets and animal-based ketogenic diets.

Figures

Fig. 1.
Fig. 1.
Participant flow through the study.
See this image and copyright information in PMC

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