A Pilot Study of a Ketogenic Diet in Bipolar Disorder: Clinical, Metabolomic and Magnetic Resonance Spectroscopy Outcomes

Background Bipolar disorder and epilepsy are treated with anti-seizure medications. Preliminary evidence indicates that a ketogenic diet (a metabolic treatment for epilepsy) may be effective in the treatment of bipolar disorder. Aims To explore the impact of a ketogenic diet on clinical outcomes, and metabolomic and brain magnetic resonance spectroscopy biomarkers. Methods Euthymic individuals with bipolar disorder (N=27) were recruited to a 6-8 week single-arm trial of a modified ketogenic diet and a range of metabolic and clinical outcome measures were assessed. Results There was a positive correlation between daily ketone levels and ecological momentary assessments of mood ( p < 0.001) and energy ( p < 0.001) and an inverse correlation between ketone levels and impulsivity ( p < 0.001) and anxiety ( p < 0.001). Mean weight fell by 4.2kg ( p < 0.001), mean BMI fell by 5.3% ( p < 0.001) and mean systolic blood pressure was reduced by 7.4 mmHg ( p < 0.041). Brain Glx (a putative marker of treatment response to anti-seizure medication) decreased by 13.1% in the posterior cingulate cortex (PCC) ( p < 0.001) and by 9.2% in the anterior cingulate cortex ACC ( p = 0.02). At the dietary cessation period, one third of participants, who reported reduced mood lability, opted to remain on a ketogenic diet. Conclusion The majority of participants had improved cardiometabolic risk parameters and approximately one third experienced improvement in psychiatric symptoms. The study findings are consistent with our a priori hypothesis of ketone bodies acting as an alternative metabolic substrate under conditions of impaired insulin signalling in a subgroup of patients with bipolar disorder. Practitioner Points A ketogenic diet may be effective in improving cardiometabolic risk factors and managing medication-induced weight gain. 95% of participants lost weight with a mean of 4.2kg ( p < 0.001) over 8 weeks. Ketone level was correlated to improved daily ecological momentary assessments of mood ( p < 0.001) and energy ( p < 0.001) and decreased impulsivity ( p < 0.001) and anxiety ( p < 0.001). Participants who opted out of the dietary cessation period to remain on the diet, and who had reduced Affective Lability Scores, were characterised by more pronounced insulin resistance (HOMA-IR + 27.19%) and higher fasting insulin (+ 19.26%) at baseline. Study Registration Number: ISRCTN61613198 ### Competing Interest Statement Dr Iain Campbell has a diagnosis of bipolar disorder and follows a ketogenic diet to manage his symptoms. His current fellowship is funded by the Baszucki Brain Research Fund. ### Clinical Trial ISRCTN61613198 ### Funding Statement This study was funded by the Baszucki Brain Research Fund. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study received a favourable ethical opinion from the South East Scotland Research Ethics Committee 02. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes