Bipolar disorder is a serious mental illness characterized by significant mood swings. Current strategies for prevention and management of bipolar disorder are suboptimal and new interventions are required. A ketogenic diet, a high-fat, very low-carbohydrate diet, is emerging as a potential therapeutic intervention for bipolar disorder. This article explores the rationale, evidence, and practical considerations surrounding the use of ketogenic diets in managing bipolar disorder.
Introduction to Ketogenic Diets
The ketogenic diet is a metabolic therapy that has been used for over a century, with established efficacy in treating refractory epilepsy. The diet involves drastically reducing carbohydrate intake and increasing fat consumption, which shifts the body's primary fuel source from glucose to ketones. This metabolic shift can have various effects on brain function and overall health.
Rationale for Ketogenic Diets in Bipolar Disorder
Several factors suggest that a ketogenic diet may benefit individuals with bipolar disorder:
- Shared Pathophysiology: Epilepsy and bipolar disorder may share common underlying mechanisms.
- Metabolic Burden: Bipolar disorder is associated with a high metabolic burden, including increased rates of obesity, type 2 diabetes, and cardiovascular disease.
- Medication Side Effects: Many first-line medications for bipolar disorder increase cardiometabolic risk, necessitating adjunctive treatment strategies.
- Metabolic Improvements: Ketogenic diets have been shown to improve cardiometabolic health outcomes in the general population.
- Brain Energy Metabolism: It is proposed that this diet may contribute to more stable energy production in the brain through the metabolism of ketones as an alternative energy source to glucose, thus overcoming issues of glucose metabolism and insulin resistance that are common among people with bipolar disorder.
Emerging Evidence
Preliminary data from case reports, observational studies, and pilot studies suggest that ketogenic diets may have beneficial effects in bipolar disorder.
Pilot Study on Feasibility and Acceptability
A pilot study was conducted to assess the feasibility and acceptability of a ketogenic diet intervention in euthymic patients with bipolar disorder. This single-group, non-randomized open interventional pilot study, with no control group, found that the diet was feasible and acceptable to participants.
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Study Design and Methods
- Participants: Individuals diagnosed with bipolar disorder, according to DSM-IV criteria, who had been in a period of clinical euthymia for at least 3 months.
- Exclusion Criteria: Included pregnancy, breastfeeding, active substance misuse, recent adherence to a ketogenic diet, adherence to a vegan diet, recent hospital admission, concurrent participation in other research studies, inability to complete baseline assessments, and a history of liver, kidney, or cardiovascular diseases.
- Assessments: Conducted at baseline and during the follow-up period (6-8 weeks). These included medical and medication histories, blood pressure, BMI, diagnostic interviews, and mental health symptom scales (ALS-18, BDI, YMRS). Quality of life was assessed using questionnaires tailored to capture data on health and social care resource utilization, household expenditure on food and beverages, and information on employment and absenteeism.
- Brain Imaging: Fasting venepuncture and MRS brain scans were conducted pre- and post-intervention. Brain MRI and spectroscopy were acquired using a 3-T clinical MRI scanner to assess the anterior cingulate cortex (ACC), right dorsolateral prefrontal cortex (RDLPFC), and posterior cingulate cortex (PCC).
- Dietary Intervention: A modified ketogenic diet with a macronutrient distribution of 60-75% calories from fats and 5-7% from carbohydrates, with the remainder sourced from protein. Adjustments to individual macronutrient ratios were made throughout the study by the study dietitian based on the attainment of ketosis and glucose levels.
- Monitoring: Participants engaged in daily self-monitoring of glucose and ketone levels using a KetoMojo device. Continuous actigraphy was deployed over a 9-week period to monitor rest/activity patterns.
- Support: Participants had weekly remote consultations with a dietitian, supplemented by additional contacts as needed. Behavioral strategies were integrated to enhance diet adherence.
Key Findings
- Mood Stability: All participants were clinically euthymic at baseline, and median scores at week 8 remained within the euthymic range, with no statistically significant changes in ALS, YMRS, and BDI scores.
- Correlation between Ketone Levels and Mood: A positive correlation was observed between daily ketone level and mood and energy scores, with a negative correlation between ketone levels and both impulsivity and anxiety. No correlation was observed with speed of thought.
- Weight Loss: Mean body weight and BMI decreased significantly.
- Metabolomics Analysis: Exploratory global metabolomics analysis showed a clear separation of the study groups in partial least squares discriminant analysis (PLS-DA), suggesting that reliable trends in participant metabolism could be observed within this data-set.
- Ketone Body Levels: The analysis comparing levels of metabolites between baseline and follow-up showed increases in β-hydroxybutyrate, β-ketopentanoate and acetone.
Stanford Medicine Study
In spring of 2024, Stanford psychiatrist and obesity specialist Shebani Sethi, MD, led a pilot study of 21 adults with bipolar disorder or schizophrenia who also had some kind of metabolic disorder and were prescribed antipsychotic medications. The participants were instructed to follow a ketogenic diet, with approximately 10% of the calories from carbohydrates, 30% from protein and 60% from fat. Before the trial, 29% of the participants met the criteria for metabolic syndrome. On average, the participants improved 31% on a psychiatrist rating of mental illness known as the clinical global impressions scale, with three-quarters of the group showing clinically meaningful improvement. The participants reported improvements in their energy, sleep, mood and quality of life. Sethi said more research is needed to conclusively demonstrate the efficacy of the dietary therapy and to detail the mechanisms underlying it.
University of Edinburgh Study
The University of Edinburgh researchers insist the keto diet can also up those with bipolar disorder. The researchers noted a link between increased ketone levels and improvements in mood, energy, impulsivity, and anxiety.
Process Evaluation of Ketogenic Diet Intervention
A mixed-methods process evaluation was conducted to explore the feasibility and acceptability of a ketogenic diet intervention for bipolar disorder. Semi-structured telephone interviews were carried out with 15 participants 1-2 months after completing a 6-8 week modified ketogenic diet intervention, and 4 research clinicians from the study team following the completion of data collection. Data were thematically analysed. Fidelity checklists completed by research dietitians were analysed using descriptive count and percentage statistics.
Key Findings
- Encouraging Entry and Supporting Exit: Recognizing and managing participants’ varied motives and expectations, including around weight loss and symptom alleviation.
- Challenging but Potentially Transformational: While it can be difficult to initiate and maintain a ketogenic diet day-to-day, many participants perceived physical and psychological benefits (e.g. significant weight loss, mood stability and enhanced ability to focus).
- Intervention Facilitators: Including a range of behavioural (e.g. goal setting), social (e.g. family and dietitians) and technological (e.g. apps for monitoring) support mechanisms.
- Intervention Barriers: Including dietary preferences, concerns about the diet and its impact, the testing burden and capacity of the delivery team.
- The Wider Context: The cost of living and sociocultural expectations was a crucial factor explaining differential experiences.
Overall, descriptive analyses indicated moderate-to-good fidelity to the behaviour change components of the study.
Practical Considerations for Implementing a Ketogenic Diet
Implementing a ketogenic diet requires careful planning and monitoring. Key considerations include:
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- Macronutrient Ratios: Adhering to the correct macronutrient ratios (60-75% fat, 5-7% carbohydrates, and the remainder from protein).
- Food Choices: Focusing on whole, unprocessed foods, including protein and non-starchy vegetables, and not restricting fats. A preference for unsaturated fats was advised.
- Ketone Monitoring: Regular monitoring of blood ketone levels to ensure the attainment of ketosis (target blood ketone level of 1-4 mmol/L and glucose levels of 4-7.8 mmol/L).
- Hydration and Supplementation: Increasing fluid intake and supplementing with a broad-spectrum multivitamin and mineral supplement, along with a calcium and vitamin D supplement.
- Adverse Effects Management: Educating participants on managing possible adverse effects, such as hypoglycemia or hyperketosis.
- Professional Supervision: Working with a qualified healthcare professional, such as a registered dietitian or psychiatrist, to individualize the diet and monitor for potential risks.
- Behavioral Strategies: Integrating behavioral strategies to enhance diet adherence, including adherence checklists guided by the COM-B framework.
Ongoing and Future Research
Several research studies are underway to further investigate the effects of ketogenic diets on bipolar disorder:
- UCLA Health Multi-Site Pilot Study: A multi-site pilot study is set to explore whether a ketogenic diet, when combined with mood stabilizing medications, helps stabilize mood symptoms in teenagers and young adults who have bipolar disorder.
- University of Pittsburgh Study: A research study to examine the effects of a ketogenic diet on the brain in people with bipolar disorder.
These studies aim to provide more robust evidence on the efficacy and mechanisms of ketogenic diets in treating bipolar disorder.
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