Ketogenic Diet as an application for adjunct Mental Health Treatment for Bipolar Disorder

Ketogenic Diet as an application for adjunct Mental Health Treatment for Bipolar Disorder

In Brief:

• The Ketogenic Diet improves brain energy metabolism.
• The Ketogenic Diet has mood stabilizing effects.
• The Ketogenic Diet reduces markers of Inflammation and directly induces anti-inflammatory molecules.
• Early indications suggest that the Ketogenic Diet can successfully be used to reduce symptoms and improve outcomes of Mental Health Disorders such as Bipolar Disorder and Neurodegenerative diseases.

Summary:

Despite the lack of large-scale randomized controlled clinical trials, early indications suggest significant applications of successfully treating and managing mental health disorders such as Bipolar Disorder with the Ketogenic Diet.

Introduction:

The Ketogenic Diet has been shown in multiple studies to have beneficial outcomes, not only in people with epilepsy, but also in those with mental health and neurodegenerative disorders, including the likes of Bipolar Disorder (1). The emerging evidence suggests that the benefits are offered by elevated brain ketones stabilizing mood and enhancing mitochondrial function. (2) Issues with neuronal energy metabolism and oxidative stress are features in the pathophysiology of mental health and neurodegenerative disorders, including bipolar disorder; (3,4)  both of which are shown to have been improved by the Ketogenic Diet. The Ketogenic Diet as it relates to Bipolar disorder and potential considerations is something that I would like to focus this report on.

Mechanisms of the Ketogenic Diet and Bipolar Disorder:

A case series by Palmer et al (2021) reported that patients with bipolar disorder who adhered to a ketogenic diet displayed notable reductions in mood instability; including some who experienced full remission. (5)

Another small pilot study showed patients with a reported improvement in mood regulation and also a reduced reliance on psychiatric medications, while maintaining a state of nutritional ketosis. (6)

This is not surprising, given the extent of the numerous mechanisms involved in brain and body metabolism which are impacted positively by being in a state of nutritional ketosis. These effects range from GABA upregulation, (7) the inhibition of excitatory neurons, the anti-inflammatory outcomes, biomarkers (8) and effects of beta hydroxybutyrate systemically and in the brain.(9) This includes the suppression of NLRP3 (9) inflammasomes and cytokines such as IL1B),(9) the inhibition of reactive oxygen species in the blood and indirectly increasing the expression of antioxidant enzymes. (10)

The increased GABA activity subsequently reducing glutamate excitotoxicity as well as a modulation of brain derived neurotrophic factor (BDNF) levels (commonly dysregulated in mood disorders) are thought to be potential mechanisms to support this improvement. (11, 12)

Elevated levels of beta-hydroxybutyrate is also shown to create neurological efficiencies, e.g. less byproducts of glucose metabolism in the brain and mitochondrial biogenesis (2). Betahydroxybutyrate has also been shown to have potentially neuroprotective effects, including protecting the blood brain barrier as well as inducing protein solubility of damaging proteins and their byproducts; which protects the brain from this otherwise damaging ordeal. (Proteostasis) (13) 

Concerns, Side effects and Considerations:

The ‘’Keto flu”” is a range of symptoms that can manifest during the adaptation period of switching from a glucose fuelled diet to a Ketogenic diet, but are typically transient, and among healthy individuals can be managed well with minimal risk. This could include lethargy, headaches and temporary blood sugar issues that may require moderating with sensitive individuals, as well as possible hormonal and sleep issues. Other side effects can arise in some due to ingesting large quantities of MCT’s as part of their Ketogenic Diet; such as GI distress, cramping and diarrhea. (14) Anyone with any history of Diabetes or Pre-Diabetes should consult their General Practitioner or a Specialist before embarking on this diet themselves, to manage any possible complications, and in this case ketones should be monitored, to be aware of any rare curveballs, such as ketoacidosis.

Uric acid is something that can increase during this transitory period and also something that should be considered and potentially monitored, when a ketogenic diet is adopted long term. (15) The short term risk of gout is possible due to the acute increased levels of uric acid. Kidney stones can develop over time in some individuals if the diet isn’t managed with care. This risk can be mitigated with electrolyte management, for example increased daily sodium of 1-2 grams (daily intake of 4-5 grams) (10) and a maintenance potassium intake of 3-4 grams per day as well as increased water levels.

Another consideration is the commonly acute increase in total cholesterol markers; namely Total Cholesterol, Total:HDL ratio and LDL. A study conducted by Dr Matt Budoff provided some mid-length insights (a mean of 4.7 years of follow-up) revealing a statistically significant cohort of Lean Mass Hyper Responders (LMHR) that did not develop any increased atherosclerosis on a ketogenic diet (Carbohydrate Restricted Diet) despite a significant increase in LDL-C and and HDL-C, as well as the cholesterol carrier; ApoB. Budoff showed that in this cohort there was no correlation between the increased LDL-C, ApoB and Cardiovascular disease risk; as was previously generally understood. (All patients in the study were already negative for genetic hypercholesterolemia, had normal blood pressure, and weren’t on any lipid altering medications.) (16)

The Coronary Artery Calcium (CAC) scoring system was used to identify calcified plaque in the participants arteries as well Computed Tomography Angiography (CCTA) to determine that there was no visible or measurable increase in the burden of plaque in the LMHR after spending an average of 4.7 years on the Ketogenic (Carbohydrate Restricted Diet). (16)

This study provided some insights that suggests that the development of plaque may be more influenced by factors such as inflammation, insulin resistance and metabolic status. The implications of this suggest that typical cardiovascular risk scoring models do not apply to Lean Mass Hyper Responders, although longer term studies are necessary to determine the long term outcomes. In this cohort the participants triglycerides were low and were reduced during the ketogenic diet. This is likely because of the mechanism of oxidation of free fatty acids resulting from the depletion of glycogen stores. (16)

This aligns with ideas presented by Ken Sikaris at the Melbourne Pathology Conference which rather identifies triglycerides as the culprit lipids marker of CVD rather than Cholesterol. (17)

A systematic review and meta-analysis of 8 Randomised Controlled Trials looked at the hypothesis of the Ketogenic diet decreasing symptoms of anxiety and depression and resulted in no measurable decrease in anxiety and depression in participants without a mood disorder on a Low Carbohydrate Diet. (18) The results were mixed between literature that was reviewed and analyzed. (18)

It is important to note that according to this review the Low Carbohydrate diet was defined as less than 45% of calories in the diet coming from Carbohydrates (19) so was not necessarily ketogenic at all. One study referenced <26% of Calories coming from Carbohydrates. This highlights the importance of defining and differentiating between a Low Carbohydrate Diet (LCB), a Very Low Carbohydrate Diet (VLCD) (20) and A Ketogenic Diet. And also the importance of assessing the macronutrient breakdown. In order to determine the effects of the Ketogenic Diet, measuring the levels of ketone bodies present in the blood and brain is imperative to determine whether the participants are actually in a state of nutritional Ketosis or not. The study highlighted that caloric restriction was also a significant factor as to whether the VLCD or LCD showed any benefits on anxiety and depression. (18) Diet Quality was also not accounted for in these studies, so it is impossible to determine the level of processed foods versus unrefined whole foods and the types of carbohydrates that were being consumed by participants. The fact that the participants didn’t have a mood disorder also doesn’t rule out these diet approaches improving depression and anxiety in those with a prevalent mood disorder, such as bi-polar disorder.

Personal Experience/Anecdote:

In recent years I have experimented on myself with both fasting and with the ketogenic diet. This was with the goal of longevity, overall health and body composition goals.

Anecdotally, I can report that fasting was unsustainable and induced sleep issues and subsequently a hypomanic response within as little as 48-72 hours (potentially due to adrenal dysregulation/a cortisol, serotonin and melatonin imbalance and high allostatic load without adequate fueling). When transitioning to a modified ketogenic diet, (75% of calories from Fat, 20% from Protein and 5% from Carbohydrates) I was able to successfully regulate my sleep and subjectively experienced a range of positive mood and energy benefits over the course of several weeks. I adhered to the Strict but Modified Ketogenic diet for approximately 7-8 weeks with minimal issues and many benefits. (Calories remained high)

The benefits included an improved sense of mood stability and wellbeing and a significantly noticeable improvement in brain clarity and cognitive function. I noticed a steady state of ketosis showing on a ketone breath monitor for essentially the entire 7-8 weeks. Approximately 4.0+mmol/L. Since then I have found a carb-appropriate diet more sustainable and functional as a staple.

Conclusions and Limitations:

Although not necessarily a complete cure for all, The Ketogenic Diet has promising applications for many people with Mental Health and Neurodegenerative Disorders, such as Bipolar Disorder. (21, 22)

There are significant limitations to the current research, so this must be considered when assessing the data and this report. This indicates the need for more clinical data and randomized controlled studies in this area.

Albeit it is relatively difficult to study and isolate the variables, due to the current therapeutic treatment models for such mental health conditions and variety of pharmacology that is typically administered.

Despite the lack of large-scale randomized controlled clinical trials, there is a growing body of literature showing the Ketogenic Diet used as a successful adjunctive or alternative therapeutic approach to treat and manage Bipolar Disorder. This has been applied in cases where patients are resistant to more pharmaceutical based treatment protocols.

References:

1. Needham N, Campbell IH, Grossi H, Kamenska I, Rigby BP, Sharon Anne Simpson, et al. Pilot study of a ketogenic diet in bipolar disorder. British Journal of Psychiatry Open. 2023 Oct 10;9(6).

2. Bough KJ, et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol. 2006;60(2):223-235. doi:10.1002/ana.20942.

3.Sarnyai Z, Palmer CM. Ketogenic Diet for Schizophrenia : Clinical Implication. Curr Opin Psychiatry. 2020;33 (5) : 488-492.

4. Bostock ECS, Kirby KC, Taylor BV. The current status of the Ketogenic Diet in Psychiatry. Front Psychiatry. 2017; 8:43.

5.Palmer CM, Gilbert – Jaramillo J, Westman EC. The Ketogenic Diet and remission of severe Psychiatric symptoms in adults with Schizophrenia, Bipolar and Schizoaffective Disorder: A Case Series. Front Psychiatry. 2021; 12: 760590.

6. Campbell IC, Slyepchencko A, St – Pierre J Kasper S, Berk M. A potential role for the Ketogenic Diet in Bipolar Disorder. Bipolar Disord. 2021; 23 (8) : 739748.

7. Yudkoff M, Daikhin Y, Nissim I, Horyn O, Lazarow A, Luhovyy B, et al. Response of brain amino acid metabolism to ketosis. Neurochem Int. 2007 Jul;50(2): 176–82. doi:10.1016/j.neuint.2006.08.005.

8. Kossoff EH, et al. The ketogenic diet and inflammatory biomarkers in children with refractory epilepsy. Epilepsy Res. 2018;142:111-116. doi:10.1016/j.eplepsyres.2018.06.005.

9. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nat Med. 2015 Mar;21(3):263–9. doi:10.1038/nm.3804.

10. Athinarayanan SJ, Roberts CGP, Vangala C, Shetty GK, McKenzie AL, Weimbs T, et al. The case for a ketogenic diet in the management of kidney disease. BMJ Open Diabetes Research and Care [Internet]. 2024 Apr 1;12(2):e004101. Available from: https://drc.bmj.com/content/12/2/e004101

11. Rusek M, Pluta R, Uamek-Kozio M, Czuczwar SJ. Ketogenic Diet in Alzheimer’s Disease. Int J mol Sci. 2019;20 (16) : 3892.

12. Murphy P, Likhodii SS, Hatheway C, Burnham WM. Effect of the Ketogenic Diet on the activity level in an animal model of depression. Epilepsy Behaviour. 2005; 6 (3): 388-392.

13. García-Velázquez L, Massieu L. The proteomic effects of ketone bodies: implications for proteostasis and brain proteinopathies. Frontiers in molecular neuroscience. 2023 Jul 27;16.

14. Harvey CJDC, Schofield GM, Williden M. The Lived Experience of Healthy Adults Following a Ketogenic Diet: A Qualitative Study. Harvey C, editor. Journal of Holistic Performance[Internet]. 2018 May 4;1(2463-7238):1–21. Available from: https://www.holisticperformance.institute/courses/take/journal-of-holistic-performance/pdfs/52889169-the-lived-experience-of-healthy-adults-following-a-ketogenic-diet-a-qualitative-study

15. Lecocq FR, McPhaul JJ. The effects of starvation, high fat diets, and ketone infusions on uric acid balance. Metabolism. 1965 Feb;14(2):186–97.

16. Budoff, M, Manubolu, V, Kinninger, A. et al. Carbohydrate Restriction-Induced Elevations in LDL-Cholesterol and Atherosclerosis: The KETO Trial. JACC Adv. 2024 Aug, 3 (8) .https://doi.org/10.1016/j.jacadv.2024.101109

17. Australasian College of Nutritional and Environmental Medicine. Evolving Landscapes of Nutrition in Medicine [Conference]. 2019 May 24-26; Pullman Melbourne on the Park, Melbourne, VIC. Presentation by: Ken Sikaris,Melbourne Pathology.

18. Varaee H, Darand M, Hassanizadeh S, Hosseinzadeh M. Effect of low-carbohydrate diet on depression and anxiety: A systematic review and meta-analysis of controlled trials. Journal of Affective Disorders. 2023 Mar;325:206–14.

19. Low Carbohydrate Diet – an overview | ScienceDirect Topics [Internet]. http://www.sciencedirect.com. Available from: https://www.sciencedirect.com/topics/medicine-and-dentistry/low-carbohydrate-diet

20. Milazzo N, Michaux M, Examine.com. Ketogenic Diet information. Vetted by experts, based on the latest research [Internet]. Examine.com. 2024 [cited 2025 Jun 6]. Available from: https://examine.com/diets/keto/?show_conditions=true#is-nutritional-ketosis-the-same-as-ketoacidosis 

21. Needham N, Campbell IH, Grossi H, Kamenska I, Rigby BP, Sharon Anne Simpson, et al. Pilot study of a ketogenic diet in bipolar disorder. British Journal of Psychiatry Open. 2023 Oct 10;9(6)

22. Phelps JR, Siemers SV, Wurtman RJ. Neurochemical effects of ketogenic diet in bipolar disorder: A pilot study. Neuropsychopharmacology. 2013;38(5):1156-1163. doi:10.1038/npp.2013.3.