Evaluating the efficacy and mechanisms of a ketogenic diet as adjunctive treatment for people with treatment-resistant depression: A protocol for a randomised controlled trial

Min Gao; Megan Kirk; Eva Lash; Heather Knight; Moscho Michalopoulou; Nicola Guess; Michael Browning; Scott Weich; Philip Burnet; Susan A Jebb; Richard Stevens; Paul Aveyard

doi:10.1016/j.jpsychires.2024.04.023

Evaluating the efficacy and mechanisms of a ketogenic diet as adjunctive treatment for people with treatment-resistant depression: A protocol for a randomised controlled trial

J Psychiatr Res. 2024 Apr 15:174:230-236. doi: 10.1016/j.jpsychires.2024.04.023. Online ahead of print.

Authors

Affiliations

¹ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; NIHR Oxford Health Biomedical Research Centre, Warneford Hospital, Oxford, UK. Electronic address: min.gao@phc.ox.ac.uk.
² Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; NIHR Oxford Health Biomedical Research Centre, Warneford Hospital, Oxford, UK.
³ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
⁴ Department of Psychiatry, University of Oxford, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK.
⁵ School of Health and Related Research, University of Sheffield, Sheffield, UK.
⁶ Department of Psychiatry, University of Oxford, Oxford, UK.
⁷ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; NIHR Oxford Health Biomedical Research Centre, Warneford Hospital, Oxford, UK; NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.

PMID: 38653031
DOI: 10.1016/j.jpsychires.2024.04.023

Abstract

Background: One-third of people with depression do not respond to antidepressants, and, after two adequate courses of antidepressants, are classified as having treatment-resistant depression (TRD). Some case reports suggest that ketogenic diets (KDs) may improve some mental illnesses, and preclinical data indicate that KDs can influence brain reward signalling, anhedonia, cortisol, and gut microbiome which are associated with depression. To date, no trials have examined the clinical effect of a KD on TRD.

Methods: This is a proof-of-concept randomised controlled trial to investigate the efficacy of a six-week programme of weekly dietitian counselling plus provision of KD meals, compared with an intervention involving similar dietetic contact time and promoting a healthy diet with increased vegetable consumption and reduction in saturated fat, plus food vouchers to purchase healthier items. At 12 weeks we will assess whether participants have continued to follow the assigned diet. The primary outcome is the difference between groups in the change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 6 weeks. PHQ-9 will be measured at weeks 2, 4, 6 and 12. The secondary outcomes are the differences between groups in the change in remission of depression, change in anxiety score, functioning ability, quality of life, cognitive performance, reward sensitivity, and anhedonia from baseline to 6 and 12 weeks. We will also assess whether changes in reward sensitivity, anhedonia, cortisol awakening response and gut microbiome may explain any changes in depression severity.

Discussion: This study will test whether a ketogenic diet is an effective intervention to reduce the severity of depression, anxiety and improve quality of life and functioning ability for people with treatment-resistant depression.

Keywords: Ketogenic diet; Metabolic psychiatry; Nutrition; Treatment-resistant depression.