Today’s Dietitian
Vol. 28 No. 5 P. 22
The ketogenic diet (KD) is well-known for its efficacy in treatment-resistant epilepsy. However, in recent years, applications of the ketogenic diet have been expanding, and the emerging field of metabolic psychiatry is one example of this expansion.
Metabolic psychiatry is a burgeoning area of research that explores “the critical interrelationships among nutrition, metabolic function (eg, brain metabolism, insulin sensitivity, diabetic processes, and body weight, among other factors), inflammation, and mental health.”1
In clinical practice, this typically describes treating individuals with severe mental illness (including major depression, bipolar disorder, and schizophrenia) with ketogenic metabolic therapy (KMT), often alongside other metabolically beneficial strategies such as circadian rhythm support and physical activity.
History of KD in Mental Illness
The use of KD in mental illness is not entirely new. In 1965, Abel Pacheco and colleagues conducted a pilot study exploring KD in schizophrenia treatment.2 However, research in this area paused for several decades until a 2009 case report reopened the discussion.3 Several subsequent case studies showcased individuals with schizophrenia and bipolar disorder who experienced dramatic improvements in symptoms while following KD.4–6
Over the past decade, public interest in KD has grown, and several new pilot trials, case studies, and retrospective analyses have been published.7–12
Although research on KMT for mental illness is still in its early stages, its safety and efficacy in epilepsy is well-established.13 “Over the past 100 years of use, ketogenic diets have evolved to accommodate individual needs, to maximize tolerance and to minimize adverse effects,” says Beth Zupec-Kania, RDN, CD, founder of Ketogenic Therapies, LLC. Recent research is working to understand underlying mechanisms of how KD might improve mental health.
The Metabolic Theory of Major Mental Illness
Proponents of the metabolic theory of major mental illness, popularly known as the “Brain Energy Theory,” argue that mental disorders are essentially metabolic disorders of the brain which can be optimally treated using metabolic approaches.14
Brain metabolism is the process by which the brain produces energy and maintains its structure. Research suggests that problems in neurometabolism may be present in severe mental illness, including major depression, schizophrenia, and bipolar disorder.15
Of course, there are many other important factors at play in mental health—neurotransmitter dysregulation, genetics, hormone imbalances, and trauma, for example. The metabolic theory of major mental illness does not discount these factors. Instead, researchers seek to understand how underlying neurometabolic dysfunction might create an environment primed for the development of serious mental illness.
Mitochondrial Dysfunction in Severe Mental Illness
Mitochondrial dysfunction appears to be a common factor in severe mental illness. Bipolar disorder, schizophrenia, and major depressive disorder are frequently associated with mitochondrial dysfunction in postmortem brain analyses.16 Abnormalities in mitochondrial DNA appear to be more frequent in serious mental disorders.17,18 In bipolar disorder, lower brain levels of ATP and higher levels of lactate in the frontal lobe and cerebrospinal fluid have been observed, suggesting decreased metabolic efficiency.19
Brain imaging studies on individuals with severe mental illness frequently find region-specific alterations in glucose metabolism, possibly due to mitochondrial dysfunction and insulin resistance. 16,17,20,21 Additionally, animal models of mitochondrial dysfunction tend to show aberrations in brain function and behavior, and individuals with mitochondrial disease are more likely to have cooccurring psychiatric disorders.16
Insulin Resistance, Inflammation, and Oxidative Stress
Mitochondrial dysfunction is closely linked to insulin resistance, oxidative stress, and inflammation. Reduced mitochondrial function appears to be a risk factor in the development of insulin resistance. Insulin sensitivity may be weakened by production of free radicals by damaged mitochondria and subsequent oxidative stress.22,23 Conversely, existing insulin resistance can weaken mitochondrial function, hamper energy production, and increase oxidative stress.22,24
The link between insulin resistance and mental illness may be related to the known effects of insulin resistance on the brain: decreasing glucose metabolism in the brain, increasing neuroinflammation, and precipitating neuronal damage and cell death.25 Insulin resistance within the brain itself is linked to cognitive dysfunction, mood changes, and neurodegeneration.26
Inflammation in the rest of the body can impact brain health, as well. Systemic inflammation can weaken blood-brain barrier function, allowing potentially hazardous molecules into the brain.27 Blood-brain barrier dysfunction appears to be common in psychiatric disorders, including schizophrenia and major depressive disorder, and can worsen oxidative stress and inflammation within the brain.28
KD and Brain Energy Production
Mitochondrial function is incredibly important within the brain, because neurons need a great deal of energy to produce their intense electrical activity. That energy is typically consumed in the form of glucose, the preferential fuel source of the brain.
But glucose is not the brain’s only energy source.29 Ketone bodies, including beta-hydroxybutyrate (BHB) and acetoacetate, can produce more ATP than glucose.30 Thus, when mitochondrial function is impaired, ketone bodies might act as a more efficient energy substrate.
By replenishing the brain energy deficit, KD can help restore core brain functions. The metabolic shift from glucose utilization to ketone production also reduces circulating insulin levels.15
Additionally, KD-induced improvements in mitochondrial function may reduce free radical production, leading to decreased oxidative stress and neuroinflammation. KD may also improve blood-brain barrier function,31 increase glutathione levels to help prevent oxidative damage, and boost brain-derived neurotropic factor (BDNF), an important factor in neuroimmune health and neuroplasticity.32 BHB and acetoacetate also scavenge free radicals, directly reducing oxidative stress.32
Glutamate and GABA
Neurotransmitter synthesis, transport, and catabolism are closely linked with overall brain metabolism,33 potentially leading to the co-occurrence of brain energy and neurotransmitter dysregulation commonly seen in mental illness.
Levels of the neurotransmitters glutamate and gamma-aminobutyric acid (GABA) are commonly dysregulated in mental illness, as well as in other neurological and neurodegenerative diseases.15,34 Maintenance of optimal glutamate concentrations is vital to prevent either energy depletion at one extreme or excitotoxicity at the other.35 However, in severe mental illness, glutamate levels in certain brain regions can rise, while GABA levels are frequently low.34 Elevated glutamate levels can cause neuronal stress and damage, as well as impair neuroplasticity.35
While the relationship between nutritional ketosis and glutamate is not fully understood, KD appears to improve both glutamate and GABA levels.15 Research suggests that KD reduces excitatory transmission and promotes a more inhibitory, GABAergic state by remodeling neuronal synapses in the hippocampus.36
KMT Clinical Trials
While relatively few clinical trials have been published to date, a recent surge in funding has led to a handful of clinical case series and pilot trials, as well as multiple active clinical trials. Thus far, generalizability of study results is limited by small sample sizes, lack of a control arm, and short intervention time frames. Several studies also faced high dropout rates.
However, researchers have generally found good tolerance of KD alongside significant improvements in psychiatric symptoms and metabolic health,7,9,12 or, at minimum, maintenance of a balanced mood while on KD.8 Some studies also found improvements in brain glutamate and glutamine levels in specific brain regions,37 as well as improvements in BDNF levels.12
Is KD the Right Choice for My Client?
While the research backing KMT for mental illness may be growing, it is not an appropriate therapy for everyone.
Absolute contraindications, according to one or more sources, include pregnancy, breastfeeding, severe heart failure, severe inherited hypercholesterolemia, severe hypertriglyceridemia, liver failure, acute or chronic pancreatitis, porphyria, use of SGLT2 inhibitors, pyruvate kinase deficiency, and fat metabolism disorders (such as primary carnitine deficiency or organic acidurias).38
Relative contraindications may present increased risk of adverse outcomes or side effects with KD and require a higher level of supervision if the initiating the diet These include cerebrovascular disease, cachexia, CVD, cholecystectomy, history of kidney stones, renal disease, active or severe infection, type 1 and type 2 diabetes mellitus (particularly with use of insulin or antihyperglycemic medications), severe GERD, substance abuse, osteopenia/osteoporosis, respiratory failure, underweight status, hyperlipidemia, antihypertensive medication use, disordered eating, and secondary carnitine deficiency.38
In the absence of contraindications, individuals with serious mental illness may benefit from KMT, whether or not they show evidence of metabolic dysfunction outside the brain.38
Additionally, individuals who don’t want, can’t tolerate, or haven’t responded to psychiatric medications might make particularly good candidates for KMT. A recent expert consensus paper recommends KMT be offered to all suitable patients with serious mental illness, if they wish, and suggests KMT as an adjunct to first-line treatment.38
Reframing “Noncompliance”
Since KD therapy does require substantial lifestyle modification, it can be challenging to follow consistently. Highly motivated individuals with good social support are most likely to succeed with KD implementation.38 Unfortunately, some individuals with mental illness may have poorer social support, fewer material resources, lower self-efficacy, and challenges with energy levels, mood, and motivation, potentially making KMT more difficult.
Client-centered care is crucial when clients have difficulty with dietary change. Modifying the intervention to better suit the individual might mean providing better education; providing more tools to manage side effects; or adjusting meal plans for preferences, finances, or abilities. It also means being ready to stop KD altogether and try something else if the client prefers.
The RDN’s Role in KMT
Having support from a cohesive interdisciplinary treatment team (including a prescribing clinician and nutrition professional at minimum) is important in safely initiating KD. Prescribers often need to adjust medications once the diet is started.38 Dietitians can support the client with both dietary education and semistructured meal plans depending on what ketogenic ratio or dietary formulation is chosen.
KD can take a variety of forms, ranging from the strict 4:1—4g of fat for every 1g of protein and carbohydrate combined—up to the more liberal 1:1 KD, and even alternative approaches such as the Modified Atkins Diet (MAD). “In older children and adults, a more liberal approach is typical to allow flexibility and better adherence. As a consultant in a short-term trial in adults with bipolar disorder and now a long-term trial in children, we’ve found that a simple ketogenic meal pattern resulting in consistent low ketosis is doable in motivated families and can improve mental health significantly,” Zupec-Kania says.
MAD may be a practical approach for individuals with mental illness, as it does not require strict weighing, measuring, or calorie and protein restrictions. It allows 15 g/day of carbohydrate for the first month, and then 20 g/d long-term. Versions of MAD, sometimes with moderate protein restrictions, have been used in the clinical research described above with good results.7
Regardless of the ketogenic approach selected, assistance from a dietitian is crucial in achieving ketosis through a nutrient-dense, whole food-based diet. “A dietary pattern that includes mostly whole foods is always ideal and in alignment with ketogenic diets,” says Zupec-Kania. However, because the diet is low in fruits, whole grains, pulses, and vegetables, it can be low in certain nutrients, such as fiber, magnesium, folate, B12, vitamin C, vitamin D, potassium, calcium, phosphorus, and sometimes even sodium.39,40 “The best way to offset this is to encourage low-carb vegetables as the main carbohydrate source,” she says. The RDN can help clients optimize the nutrient density of their diet and recommend supplemental sources of nutrients they might be missing.
Dietitians should also monitor anthropometric data, laboratory data, and nutrition-focused physical examination findings to ensure that nutrient needs are met. Laboratory testing typically includes a complete blood count, comprehensive metabolic panel, fasting lipid panel, fasting insulin, vitamin B12, vitamin D3, carnitine panel, and additional personalized testing as needed.38
Additionally, dietitians can support clients holistically with lifestyle guidance. Establishing consistent meal and sleep schedules and increasing physical activity can produce remarkable improvements in mental wellbeing. Alongside KD, these interventions can help improve metabolic health, neurometabolism, and psychiatric symptoms.41,42
Managing Side Effects
Dietitians can also assist clients with managing side effects of KD. For example, RDNs should emphasize adequate fluids and electrolytes to prevent dehydration and electrolyte imbalance, sometimes experienced as the “keto flu.”
“Low carbohydrate intake has a diuretic effect, which can draw out sodium and potentially other minerals, especially in people who exercise or live in warm climates. Regular salt intake is advised, especially in people who are consuming minimally processed foods,” Zupec-Kania says.
Constipation is another common concern with KD, so dietitians can proactively educate clients on promoting good bowel hygiene with fluids, low-carbohydrate sources of fiber, and physical activity.
Cholesterol levels are another common concern with KD. For some clients, lipids decrease significantly while on KD. However, other clients, particularly of the phenotype known as lean mass hyperresponders, may experience dramatic increases in LDL cholesterol. While the actual cardiovascular risk associated with this increase is unclear,43 dietitians should closely monitor lipid panels in conjunction with the primary care provider and recommend dietary and lifestyle strategies to optimize cardiovascular health. For example, exercising and increasing intake of polyunsaturated fatty acids, soluble fiber, and plant sterols and stanols may improve cholesterol levels.
Weight changes may also occur with KD. Typically, initial weight loss occurs as the body reduces muscle glycogen and water storage.44 If weight loss continues in clients who are not attempting to lose weight or for whom weight loss is unsafe, the RDN should modify the diet plan to increase caloric intake.
Monitoring for Effectiveness and Safety
The authors of a recent consensus paper warn that during the early weeks of KD initiation, some individuals may experience worsening of certain psychiatric symptoms, such as mood swings, insomnia, fatigue, anxiety, mania, or irritability. Clients should be counseled to reach out immediately to the care team for support if these symptoms arise. This allows the care team to ensure the client’s safety, as well as evaluate for underlying causes of the symptoms, such as electrolyte imbalance, hypoglycemia, hyperketonemia, or diet-drug interactions.38
During the first three to four months on KD, the goal is to achieve and maintain ketosis in a range that adequately manages symptoms. Expert consensus suggests serum BHB levels of at least 0.5 mmol/L, with the potential for greater symptom improvement with at least 1 mmol/L.38 Initial research suggests a correlation between a higher degree of ketosis and greater improvement in mental health symptoms.37
Experts suggest self-monitoring ketosis using fingerstick (capillary) testing, typically at least once per day at around the same time of day. For those on glucose-lowering medications, more frequent testing or even continuous glucose and ketone monitoring may be necessary. Once adequate levels of ketosis are achieved and consistently maintained, clients can monitor as needed.38
While some patients’ symptoms may improve within a few weeks, others may need several months on KMT before seeing a significant change. Evidence-based guidelines have yet to be established, but expert consensus recommends that individuals with mental illness remain in ketosis for at least three to four months consecutively before concluding that KD was ineffective.38
Illness-specific symptom inventories, such as the Hamilton Depression Rating Scale for depression,45 the Brief Psychiatric Rating Scale for schizophrenia,46 and the Affective Lability Scale for bipolar disorder,47 can help the care team monitor changes in psychiatric symptoms. Taken together with the client’s subjective experience, these measures can help ascertain the effectiveness of KMT.
Summary
While research in KMT is still lacking, metabolic treatments for psychiatric disorders offer an interesting and exciting way for RDNs to get involved in mental health. Future clinical research in metabolic psychiatry may set the stage for an even more integral role for dietitians in the field of mental health.
— Erica Golden, RDN, IFNCP, is a clinical dietitian, author, and educator specializing in mental health and digestive disorders. In her private practice, Nourished Mind Nutrition, she uses integrative, trauma-informed care to support clients with depression, anxiety, irritable bowel syndrome, and disordered eating. Golden is the author of the continuing education books Trauma-Informed Care: An Integrative Nutrition Approach to Empowered Healing and Nutrition and Mental Health: Integrative Approaches for Diet, Dysfunction, and the Gut-Brain Axis.
References
1. Barch DM. Special Section: Metabolic Psychiatry. Biol Psychiatry Glob Open Sci. 2023;3(4):580-581.
2. Pacheco A, Easterling Ws, Pryer Mw. A pilot study of the ketogenic diet in schizophrenia. Am J Psychiatry. 1965;121:1110-1111.
3. Kraft BD, Westman EC. Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: a case report and review of the literature. Nutr Metab (Lond). 2009;6:10.
4. Phelps JR, Siemers SV, El-Mallakh RS. The ketogenic diet for type II bipolar disorder. Neurocase. 2013;19(5):423-426.
5. Palmer CM. Ketogenic diet in the treatment of schizoaffective disorder: two case studies. Schizophr Res. 2017;189:208-209.
6. Palmer CM, Gilbert-Jaramillo J, Westman EC. The ketogenic diet and remission of psychotic symptoms in schizophrenia: two case studies. Schizophr Res. 2019;208:439-440.
7. Danan A, Westman EC, Saslow LR, Ede G. The ketogenic diet for refractory mental illness: a retrospective analysis of 31 inpatients. Front Psychiatry. 2022;13:951376.
8. Needham N, Campbell IH, Grossi H, et al. Pilot study of a ketogenic diet in bipolar disorder. BJPsych Open. 2023;9(6):e176.
9. Sethi S, Wakeham D, Ketter T, et al. Ketogenic diet intervention on metabolic and psychiatric health in bipolar and schizophrenia: a pilot trial. Psychiatry Res. 2024;335:115866.
10. Laurent N. Retrospective case study: ketogenic metabolic therapy in the effective management of treatment-resistant depressive symptoms in bipolar disorder. Front Nutr. 2024;11:1394679.
11. Laurent N, Bellamy EL, Hristova D, Houston A. Ketogenic metabolic therapy in the remission of chronic major depressive disorder: a retrospective case study. Front Nutr. 2025;12:1549782.
12. Decker DD, Patel R, Cheavens J, et al. A pilot study examining a ketogenic diet as an adjunct therapy in college students with major depressive disorder. Transl Psychiatry. 2025;15(1):322.
13. Palmer CM. The ketogenic diet and metabolic treatments for neuropsychiatric disorders. BJPsych Open. 2025;11(3):e94.
14. Palmer CM. Brain Energy: A Revolutionary Breakthrough in Understanding Mental Health – and Improving Treatment for Anxiety, Depression, OCD, PTSD, and More. Dallas, Texas: BenBella Books, Inc; 2022.
15. Sethi S, Ford JM. The role of ketogenic metabolic therapy on the brain in serious mental illness: a review. J Psychiatr Brain Sci. 2022;7(5):e220009.
16. Ni P, Ma Y, Chung S. Mitochondrial dysfunction in psychiatric disorders. Schizophr Res. 2024;273:62-77.
17. Townsend L, Pillinger T, Selvaggi P, et al. Brain glucose metabolism in schizophrenia: a systematic review and meta-analysis of 18FDG-PET studies in schizophrenia. Psychol Med. 2023;53(11):4880-4897.
18. Zuccoli GS, Saia-Cereda VM, Nascimento JM and Martins-de-Souza D (2017) The energy metabolism dysfunction in psychiatric disorders postmortem brains: focus on proteomic evidence. Front Neurosci. 2017;11:493.
19. Jeong H, Dimick MK, Sultan A, et al. Peripheral biomarkers of mitochondrial dysfunction in adolescents with bipolar disorder. J Psychiatr Res. 2020;123:187–193.
20. Su L, Cai Y, Xu Y, Dutt A, Shi S, Bramon E. Cerebral metabolism in major depressive disorder: a voxel-based meta-analysis of positron emission tomography studies. BMC Psychiatry. 2014;14:321.
21. Wu C, Ren C, Teng Z, et al. Cerebral glucose metabolism in bipolar disorder: a voxel-based meta-analysis of positron emission tomography studies. Brain Behav. 2021;11(5):e02117.
22. Sangwung P, Petersen KF, Shulman GI, Knowles JW. Mitochondrial dysfunction, insulin resistance, and potential genetic implications. Endocrinology. 2020;161(4):bqaa017.
23. Liao J, He W, Li L, et al. Mitochondria in brain diseases: Bridging structural-mechanistic insights into precision-targeted therapies. Cell Biomaterials. 2025;1:100016.
24. Sergi D, Naumovski N, Heilbronn LK, et al. Mitochondrial (dys)function and insulin resistance: from pathophysiological molecular mechanisms to the impact of diet. Front Physiol. 2019;10:532.
25. Soltani S, Dolatshahi M, Soltani S, et al. Relationships between brain glucose metabolism patterns and impaired glycemic status: a systematic review of FDG-PET studies with a focus on Alzheimer’s disease. Hum Brain Mapp. 2025;46(4):e70180.
26. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14(3):168-181.
27. Beltrán-Velasco AI, Clemente-Suárez VJ. Impact of peripheral inflammation on blood-brain barrier dysfunction and its role in neurodegenerative diseases. Int J Mol Sci. 2025;26(6):2440. Published 2025 Mar 9.
28. Kealy J, Greene C, Campbell M. Blood-brain barrier regulation in psychiatric disorders. Neurosci Lett. 2020;726:133664.
29. Rae CD, Baur JA, Borges K, et al. Brain energy metabolism: A roadmap for future research. J Neurochem. 2024;168(5):910-954.
30. Arima Y. The impact of ketone body metabolism on mitochondrial function and cardiovascular diseases. J Atherosclerosis Thromb. 2023;30(12):1751–1758.
31. Dyńka, D., Kowalcze, K., & Paziewska, A. The role of ketogenic diet in the treatment of neurological diseases. Nutrients. 2022;14(23): 5003.
32. Chang YB, Baleja JD. The role of the ketogenic diet in modulating biochemical pathophysiology in psychiatric and neurodegenerative disorders. Int J Mol Sci. 2026;27(11):4932.
33. Andersen JV. The Glutamate/GABA-glutamine cycle: insights, updates, and advances. J Neurochem. 2025;169(3):e70029.
34. Zhang J, Toulopoulou T, Li Q, et al. Charting brain GABA and glutamate levels across psychiatric disorders by quantitative analysis of 121 1H-MRS studies. Psychol Med. 2024;54(15):4071-4082.
35. Pal MM. Glutamate: The master neurotransmitter and its implications in chronic stress and mood disorders. Front Hum Neurosci. 2021;15:722323.
36. Stunault MI, Deng P, Periandri EM, et al. Ketogenic diet dampens excitatory neurotransmission by shrinking synaptic vesicle pools. Preprint. bioRxiv. 2025;2025.06.04.657883.
37. Campbell IH, Needham N, Grossi H, et al. A pilot study of a ketogenic diet in bipolar disorder: clinical, metabolic and magnetic resonance spectroscopy findings. BJPsych Open. 2025;11(2):e34.
38. Ede G, Bernstein M, Calabrese L, et al. Awareness and best practices in using ketogenic therapy to treat serious mental illness: a modified Delphi consensus. Front Nutr. 2026;13:1749406.
39. Tsang E, Webster R, Mohammad S, et al. The nutritional adequacy of the ketogenic diet in paediatric epilepsy: Detailed nutrient analysis and dietary recommendations. Clin Nutr ESPEN. 2025;69:274-285.
40. Crosby L, Davis B, Joshi S, et al. Ketogenic diets and chronic disease: weighing the benefits against the risks. Front Nutr. 2021;8:702802.
41. Marano G, Acanfora M, Conci L, et al. A chrono-metabolic approach to mental health: current perspectives on circadian rhythms, gut microbiota, and microbial metabolites in mood disorders. Metabolites. 2026;16(6):400.
42. Heissel A, Heinen D, Brokmeier LL, et al. Exercise as medicine for depressive symptoms? A systematic review and meta-analysis with meta-regression. Br J Sports Med. 2023;57(16):1049-1057.
43. Budoff M, Manubolu VS, Kinninger A, et al. Carbohydrate restriction-induced elevations in ldl-cholesterol and atherosclerosis: The KETO Trial. JACC Adv. 2024;3(8):101109.
44. Burén J, Svensson M, Liv P, Sjödin A. Effects of a ketogenic diet on body composition in healthy, young, normal-weight women: a randomized controlled feeding trial. Nutrients. 2024;16(13):2030.
45. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62
46. Lukoff D, Liberman RP, and Nuechterlein KH. Symptom monitoring in the rehabilitation of schizophrenic patients. Schizophrenia Bulletin. 1986;12(4):578-602.
47. Aas M, Pedersen G, Henry C, et al. Psychometric properties of the Affective Lability Scale (54 and 18-item version) in patients with bipolar disorder, first-degree relatives, and healthy controls. J Affect Disord. 2015;172:375-380.