Episode 237: Ketogenic Diet Review and Update with Dr. Matt Bernstein
Matt Bernstein, MD; David Puder, MD
Joining today’s episode is Dr. Matt Bernstein, the Chief Executive Officer of Accord and a leading voice in metabolic psychiatry, a field exploring how metabolism, nutrition, circadian rhythms, and exercise influence brain function and mental health. A summa cum laude graduate of Columbia University and a trained psychiatrist from the MGH McLean Psychiatry Residency Program, he has held leadership roles at McLean Hospital and Ellenhorn, organized the first public conference on metabolic psychiatry in 2023, and serves on the clinical advisory board of Metabolic Mind.
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Editor: Joanie Burns, PMHNP
Reviewer: Erika Vega, MD, Liam Browning
Metabolic Interventions for Psychiatric Conditions: Reassessing Treatment Strategies Through a Metabolic Lens
Introduction
A surge in public interest, evidenced by popular YouTube channels (e.g., Lauren Kennedy West with 300K+ subscribers; Metabolic Mind with 60K subscribers) and high‐view interviews as well as successful books by experts like Dr. Georgia Ede and Chris Palmer, reflects a growing belief that targeting metabolic dysfunction may offer a more sustainable path to mental health. This interest is particularly compelling given the shortcomings of current pharmacotherapies, which, while effective in acute symptom management, often yield suboptimal functional outcomes and carry significant metabolic and neurological side effects.
I. Foundations in Neurology: Evidence from Epilepsy
A. The Ketogenic Diet in Pediatric and Adult Epilepsy
The ketogenic diet (KD) has been a cornerstone of treatment for refractory epilepsy for over a century. Originally introduced in 1921 by Wilder at the Mayo clinic (Höhn et al., 2019) to mimic the metabolic effects of fasting, the KD rapidly gained acceptance for its ability to reduce seizure frequency and severity—especially in children with treatment-resistant epilepsy.
Key Findings in Pediatric Epilepsy:
Multiple randomized controlled trials (RCTs) and meta-analyses have demonstrated the efficacy of the KD in pediatric populations. For example, Neal et al. (2008) conducted a landmark RCT (145 children ages 2-16) showing that children with drug-resistant epilepsy on the classic KD experienced a 75% reduction in seizure frequency, with nearly 38% of patients achieving greater than a 50% reduction in seizures compared to 6% of controls (28/73 vs 4/72 patients, p<0.0001). In many cases, prolonged adherence to the KD has resulted in complete seizure freedom in up to 30% of patients (Freeman et al., 2007; Neal et al., 2008). Additionally, two Cochrane reviews by Martin‐McGill et al. (2018 and 2020) confirmed that the KD is effective in reducing seizure frequency in children with drug-resistant epilepsy, noting improvements not only in seizure control but also in quality of life and cognitive outcomes over long-term follow-up.
Sustained Seizure Control After Diet Discontinuation:
Notably, several studies have reported that the beneficial effects of the KD may extend beyond the period of strict dietary adherence. For instance, Martinez et al. (2007) observed that a majority of children who achieved seizure control on the KD maintained their improved outcomes even after tapering the diet. Another study (Patel et al., 2010) found that excellent seizure control actually improved from 52% to 79% after an average of 6 years post-discontinuation of the diet. These findings suggest that early seizure control in pediatric epilepsy may be predictive of long-term remission even after dietary discontinuation.
Diverse Dietary Approaches:
Over time, variations of the KD have been developed, such as the modified Atkins diet (MAD) and the low glycemic index treatment (LGIT), which offer greater flexibility while preserving the core metabolic benefits. These alternative protocols have expanded the applicability of metabolic therapy in both pediatric and adult epilepsy, providing clinicians with additional tools to tailor treatment to individual patient needs.
Findings in Adult Epilepsy:
Although the majority of research has focused on pediatric populations, the KD has also been applied in adult patients with epilepsy. A meta-analysis by Ye et al. (2015) indicates that adults with intractable epilepsy can benefit from the KD, with more than 50% efficacy rate with the classic KD and slightly lower response rates, but higher compliance with a modified Atkins diet (MAD).
B. Clinical Implications for Psychiatry
The well-validated efficacy of KD in epilepsy supports the rationale for exploring its “off label” use in psychiatry. In both fields, treatments that modulate neuronal excitability and energy metabolism offer the potential to improve clinical outcomes with fewer long-term side effects. Psychiatrists frequently employ treatments that originated in clinical neurology. Valproic acid and lamotrigine originated as FDA approved treatments for epilepsy and were later studied and approved by the FDA as treatments for bipolar disorder. Vagus nerve stimulation was originally approved for epilepsy but later won approval by the FDA as treatments for major depression and obesity.
II. The Bidirectional Relationship Between Metabolic and Brain Disorders
A robust body of evidence indicates that metabolic disorders, including diabetes, insulin resistance, and cardiovascular disease, are closely intertwined with mental health disorders such as depression, bipolar disorder, and schizophrenia. This bidirectional relationship implies that metabolic dysregulation can predispose individuals to psychiatric conditions and vice versa.
Longitudinal Evidence Linking Metabolic Dysfunction to Psychiatric Outcomes
Perry et al. (2021) provided compelling longitudinal data in a large cohort of children. Their study found that those with the highest levels of insulin and other metabolic abnormalities in childhood had a significantly increased risk of developing mental health disorders in young adulthood, such as schizophrenia and major depressive disorder. This research underscores the importance of early metabolic health in predicting later psychiatric outcomes.
In a complementary study, Pan et al. (2010) examined a cohort of women over time and found a bidirectional association between depression and type 2 diabetes. Women with a history of depression were more likely to develop diabetes and, conversely, those with diabetes had an elevated risk of subsequent depression. These findings emphasize that mood disorders and metabolic disturbances share common physiological pathways, such as chronic inflammation, dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, and impaired insulin signaling.
Meta-analytic research by Luppino et al. (2010) further corroborates this bidirectional link. Their systematic review and meta-analysis showed that obesity not only increases the risk of developing depression but that depression can lead to subsequent weight gain and metabolic syndrome. This reciprocal relationship suggests that metabolic dysregulation and mental illness are interconnected via overlapping biological mechanisms.
The convergence of evidence from these diverse studies highlights that poor metabolic health in early life is a predictor of later psychiatric morbidity and that the presence of mental health disorders further exacerbates metabolic risk.
These studies collectively suggest that early metabolic dysregulation is not only a marker, but may be a modifiable risk factor for later mental health disorders.
Implications of the Bidirectional Relationship
The evidence supports a model in which metabolic and psychiatric disorders are interconnected through shared pathophysiological processes. Chronic inflammation, oxidative stress, poor mitochondrial function and impaired insulin signaling are common threads that link these conditions. Recognizing the bidirectional relationship has several important clinical implications:
Early Intervention: Screening for metabolic abnormalities in childhood and early adulthood may allow for the early identification of individuals at risk for developing psychiatric disorders.
Integrated Treatment Approaches: Interventions that address metabolic dysfunction such as the ketogenic diet, exercise, mindfulness and circadian rhythm alignment could potentially mitigate the development or severity of mental health disorders. In fact, there are multiple case reports and case series demonstrating dramatic clinical benefits of ketogenic diets, as discussed in Section V below, and the evidence for the power of exercise as a metabolic and mental health intervention has been well documented elsewhere (see also Episodes 10, 96, 142, 165, 179, and 230). Mindfulness interventions and circadian rhythm alignment also have been demonstrated to improve both mental and metabolic health, but a presentation of the evidence for these interventions is outside the scope of this review.
Holistic Patient Care: Understanding the interplay between metabolic and psychiatric health underscores the need for integrated care models that simultaneously address both physical and mental health (see also Episode 207).
In summary, the convergence of data from multiple longitudinal studies not only reinforces the association between metabolic dysregulation and mental illness, but also provides a compelling rationale for employing metabolic interventions as part of a comprehensive treatment strategy in psychiatry.
III. Metabolic Health and Functional Outcomes in Serious Mental Illness
Patients with serious mental illnesses (SMIs) such as schizophrenia, bipolar disorder, and major depressive disorder (MDD) are at significantly increased risk for metabolic disturbances. These patients exhibit higher rates of obesity, insulin resistance, type 2 diabetes, dyslipidemia, and cardiovascular disease compared to the general population. These metabolic abnormalities contribute substantially to the reported 15–20 year reduction in life expectancy observed among these individuals.
A. Metabolic Dysregulation in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder
Recent studies have consistently shown that the prevalence of metabolic syndrome is alarmingly high in patients with SMIs. For instance, Mazereel, et al. (2020) reviewed how psychotropic medications exacerbate obesity and metabolic syndrome in these populations, while Barton et al. (2020) reported significantly higher rates of metabolic syndrome and diabetes in psychiatric inpatients compared with the general population. In schizophrenia, systematic reviews (e.g., Rognoni et al., 2021) confirm that second-generation antipsychotic drugs are associated with significant metabolic and cardiovascular side effects. Similar challenges are observed in bipolar disorder, where studies such as Vancampfort et al. (2013) have confirmed the high metabolic risk in that population that is exacerbated by second-generation antipsychotics.
B. Adverse Metabolic Effects of Psychotropic Medications
Psychotropic medications are often necessary for managing acute psychiatric symptoms, but they frequently exacerbate underlying metabolic dysfunction. Key observations include:
Antipsychotics: Second-generation antipsychotics such as clozapine, olanzapine, quetiapine and risperidone are well documented to induce weight gain, hyperglycemia, and dyslipidemia (Bernardo et al., 2021; Rognoni et al., 2021). These side effects contribute to a significantly elevated risk of metabolic syndrome and cardiovascular disease in patients with schizophrenia and bipolar disorder, as well as those with other conditions such as major depressive disorder and anxiety disorders (OCD, PTSD), where these medications are also used at increased frequencies.
Mood Stabilizers:
Valproic acid and lithium are both associated with significant weight gain. One review of a few studies reported the effect is greater with lithium (Dols et al., 2013) while a small prospective cohort trial found that valproic acid had significantly greater weight gain than lithium over a 6 month period (Banihashem et al., 2022).
Antidepressants: Several recent studies have shown that antidepressant treatment, particularly with certain SSRIs, is associated with weight gain, reduced muscle mass, and heightened cardiometabolic risk (Andersson et al., 2024). Such metabolic side effects can further impact overall health and functional recovery in patients with major depressive disorder.
These findings underscore the importance of regularly monitoring metabolic parameters in patients receiving psychotropic medications and employing integrated treatment approaches that address both psychiatric and metabolic health.
C. Improved Long-Term Functional Outcomes Through Progressive Antipsychotic Dose Reduction
Research suggests that long-term functional outcomes may be significantly improved by systematically reducing antipsychotic dosages in stable patients. Wunderink et al. (2013) demonstrated that first-episode psychosis patients who underwent structured antipsychotic dose reduction in the first two years achieved better social and vocational recovery five years later compared to those maintained on higher doses in the first two years. Key mechanisms may include:
Reduced Dopamine Blockade: Given the importance of dopamine signaling to reward and motivation, lowering doses of medications that block dopamine receptors may alleviate cognitive and negative symptoms.
Mitigation of Metabolic Side Effects: Decreasing antipsychotic dosage can stabilize weight and may improve insulin sensitivity.
IV. Patient Selection for Metabolic Interventions
Identifying patients who may benefit most from metabolic interventions is critical. Categories to consider include:
Patients stable on psychiatric medications with inadequate symptom relief and/or with poor metabolic health: These individuals often experience incomplete functional recovery which may be due to insufficient symptom reduction, medication side effects, and metabolic dysfunction. Metabolic interventions may allow for improved symptom control, safer medication reductions, and improved functional outcomes.
Patients preferring holistic approaches: Some individuals opt for non-medical treatments for many reasons. Some are concerned about the side effects of medications and other treatments such as ECT or TMS. Some are drawn to treatments that are considered more natural such as those rooted in diet and exercise.
Patients intolerant to psychiatric medications: Many individuals have tried medications and could not tolerate the side effects or did not like the way they subjectively felt on these medications. For these patients, metabolic therapies may provide an alternative route to symptom relief and functional recovery.
Additional categories: This may include individuals with comorbid metabolic diseases (e.g., diabetes, obesity, PCOS, etc.) who might derive dual benefits from a program of metabolic interventions.
V. Evidence for Metabolic Interventions in Psychiatry
Over the last few years, accumulating research has highlighted the therapeutic potential of metabolic interventions—particularly the ketogenic diet (KD)—in managing psychiatric conditions such as bipolar disorder, schizophrenia, and major depressive disorder (MDD). Below is a summary of key studies and their clinical significance. There are additional studies documenting the benefits of ketogenic diets in anorexia nervosa (Calabrese et al., 2022), autism spectrum disorders (Schrickel et al., 2025), alcohol withdrawal symptoms (Wiers et al., 2021 and 2024), and dementia (Anderson et al., 2025). Of note, most of these studies did not have a control group and therefore could be subject to multiple types of bias.
A. Summary of Key Studies
Design & Population: The TRIO-BD study was a randomized, quadruple-masked, placebo-controlled clinical trial that evaluated the effects of treating insulin resistance with metformin in patients with treatment-resistant bipolar depression.
Findings: The study demonstrated that reversing insulin resistance through metformin treatment led to a significant improvement in depressive symptoms, with a higher proportion of patients achieving remission compared to the placebo group. Importantly, the clinical improvement was strongly correlated with improvements in metabolic parameters, including HOMA-IR scores (fasting insulin, fasting glucose), suggesting that the antidepressant effect of metformin may be mediated through enhanced insulin sensitivity.
Clinical Significance: This study highlights the critical role of metabolic health in the management of treatment-resistant depression and suggests that targeting insulin resistance may be a viable therapeutic strategy. The findings support the broader hypothesis that metabolic interventions, including dietary approaches like the ketogenic diet, could provide significant psychiatric benefits by addressing underlying metabolic dysfunction.
Design & Population: A 4-month pilot trial involving patients with bipolar disorder and schizophrenia.
Adherence: High adherence (80–100% ketosis) correlated with more pronounced improvements in both psychiatric and metabolic parameters.
Bipolar disorder: 76% (16 out of 21 participants)
Schizophrenia spectrum disorders (including schizophrenia and schizoaffective disorder): 24% (5 out of 21 participants)
Participants maintained their usual psychotropic medications throughout the trial without restrictions on dose adjustments with their doctor.
Participants were not asked to track calories; instead, they were instructed to limit their carbohydrate intake to approximately 20 grams daily (excluding fiber), consume one cup of vegetables and two cups of salad per day, and were encouraged to drink eight glasses of water daily.
Adherence was defined by blood ketone levels: adherent participants had ketone levels between 0.5 – 5 mM for 80–100% of measurements.
Findings: Participants adhering to a KD experienced a 32% reduction in psychotic symptoms (in schizophrenia), a significant improvement in mood symptoms in those with bipolar (with greater adherence to the diet associated with more improvements), improvements in life satisfaction, global functioning and marked metabolic improvements (e.g., reduced weight, visceral adipose tissue and insulin resistance).
Fourteen participants were fully adherent to the diet (ketone levels >0.5 in at least 80% of measurements), six were partially adherent (ketone levels >0.5 between 60–80% of the time), and one participant was non-adherent.
Metabolic Outcomes:
10% average weight reduction
11% reduction in waist circumference
Reduction of Fat Mass Index by 17%
36% reduction in visceral adipose tissue for adherent participants
27% reduction in HOMA-IR (insulin resistance measure) among adherent participants.
High-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, decreased by 23% overall
Triglycerides reduced by 25% in adherent participants
LDL cholesterol increased by 21%; however, this was primarily large buoyant LDL rather than small dense LDL, suggesting lower cardiovascular risk
Complete resolution of metabolic syndrome criteria in all participants initially diagnosed
HbA1c reduced by 3.6% overall and 4.9% in adherent participants
17% improvement in insulin sensitivity
Psychiatric Outcomes:
Schizophrenia participants experienced a 32% reduction in psychotic symptoms (Brief Psychiatric Rating Scale).
Participants with bipolar disorder specifically saw an increase in the proportion classified as “recovered or recovering,” going from 38% to 81%, with 100% of adherent bipolar participants reaching a “recovered or recovering” state.
Clinical Global Impression (CGI) scores improved by an average of 31%.
Among those with baseline symptoms, 79% showed clinically meaningful improvement.
Overall improvements in depression (PHQ-9 score reduced by 33%), anxiety (GAD-7 reduced by 8.9%), sleep quality (PSQI improved by 19%), and global functioning (GAF improved by 17%).
Qualitative patient feedback highlighted significant personal improvements such as reduction in anxiety attacks, mood stabilization better than previous medications (e.g., lamotrigine), increased sexual activity after years of inactivity, and subjective feelings of significant recovery.
Clinical Significance: Demonstrates the potential for KD to address both psychiatric and metabolic dimensions of illness in severely ill outpatients, paving the way for randomized controlled studies in similar populations.
Common ketogenic diet-related side effects (e.g., fatigue, constipation, headache) were mostly transient, resolving within 3 weeks.
Design & Population: A retrospective analysis of 31 inpatients with refractory mental illness in a psychiatric hospital who received a ketogenic diet with regular psychiatric care.
Bipolar disorder type II: 13 patients (42%)
Schizoaffective disorder: 12 patients (39%)
Major depressive disorder: 7 patients (23%)
Among the 28 patients who adhered to the diet for over two weeks, urine ketone testing was conducted once during the intervention and showed positive results in 18 patients (64%). Dietary adherence was rated as excellent for 11 patients (39%), good for 12 patients (43%), and fair for 5 patients (18%).
Findings: KD intervention led to substantial reductions in Hamilton Depression Rating Scale, Montgomery-Åsberg Depression Rating Scale scores, Positive and Negative Symptom Scale and Clinical Global Impression, with effect sizes far surpassing those typically reported for medication trials. Metabolic parameters improved and a majority of patients had their medication doses decreased during the study.
Depression: Substantial reductions in depression severity scores:
HAM-D: Reduced from 25.4 to 7.7 (69% improvement).
MADRS: Reduced from 29.6 to 10.1 (67% improvement).
Psychosis: For patients with schizoaffective disorder, PANSS scores improved from 91.4 to 49.3 (45% improvement).
Clinical Global Impression (CGI-S): Improved from 4.9 to 2.0, with 43% achieving clinical remission.
64% of patients had their psychotropic medication doses reduced during the intervention.
Clinical Significance: Suggests that metabolic therapies can yield robust psychiatric symptom improvements in treatment refractory inpatients, opening opportunities for randomized controlled studies in similar populations.
Limitations:
Retrospective design, small sample size, lack of randomization or control group, and potential biases (e.g., expectancy, selection bias).
Short and variable duration of KD adherence (ranging from 15–248 days).
In conclusion, the Danan et al. (2022) study provides compelling preliminary evidence supporting the ketogenic diet’s therapeutic potential for severe, treatment-refractory mental illness, aligning well with calls for more rigorous future studies.
Design & Population: A retrospective case series examining personalized ketogenic metabolic therapy in outpatients with depression and anxiety in 3 adults age 32 to 36.
Adherence defined by achieving and maintaining capillary BHB ≥0.8 mmol/L and GKI <6.
Integrated support system: bi-weekly consultations, virtual groups, daily food journaling, nature activities, community engagement, and ongoing psychiatric follow-up.
Findings: Complete remission of mood and anxiety symptoms within 7–12 weeks, accompanied by significant metabolic enhancements.
Notable improvements in associated psychiatric conditions, including cessation of binge eating behaviors and obsessive-compulsive symptoms.
Anxiety symptoms generally remitted earlier than depression (within 2–6 weeks).
Clinical Significance: Illustrates how KD can rapidly improve mood disorders, potentially decreasing the need for polypharmacy.
Design & Population: A pilot study for 6-8 weeks of a KD in euthymic bipolar disorder, assessing clinical, metabolic, and magnetic resonance spectroscopy (MRS) findings.
Findings: There were significant correlations between ketone levels and mood, energy, anxiety and impulsivity. Significant reductions were seen in weight and systolic blood pressure. MRS showed significant reductions in glutamine, glutamate and myo-inositol in relevant brain regions.
Decreased glutamate + glutamine (Glx):
11.6% decrease in anterior cingulate cortex (ACC, p=0.025)
13.6% decrease in posterior cingulate cortex (PCC, p<0.001)
Glutamate (Glu) and glutamine (Gln), collectively called Glx, are key excitatory neurotransmitters and neuromodulators. Elevated glutamate is frequently observed in mood disorders like bipolar disorder and depression, suggesting excessive neuronal activity, excitotoxicity, or dysregulated energy metabolism.
A significant reduction of Glutamine in the anterior cingulate cortex (ACC, a region involved in emotional regulation and cognitive control) and posterior cingulate cortex (PCC, important for self-reflection, rumination, and emotional processing) indicates that a ketogenic diet (KD) might reduce excitatory neurotransmission or normalize glutamate-related disturbances. Clinically, this might help stabilize mood, reduce anxiety, and mitigate symptoms of emotional dysregulation common in bipolar disorder.
Decreased total choline in ACC (p=0.004) and PCC (p<0.001)
Total choline (tCho) measured via spectroscopy is associated with cell membrane metabolism, myelination, and membrane turnover. Elevated choline often suggests increased cellular turnover, inflammation, or metabolic stress.
The observed reduction in choline in the ACC and PCC suggests a decrease in cellular turnover or reduced inflammation and neuronal stress. This may reflect an improvement in neuronal integrity or reduced inflammatory processes—potentially beneficial changes in bipolar disorder.
Reduced myo-inositol in PCC (p=0.025)
Myo-inositol (mI) is involved in cell signaling, particularly in phosphoinositide signaling pathways associated with mood regulation and insulin sensitivity. Elevated myo-inositol often reflects disturbed signal transduction and metabolic dysfunction and is associated with bipolar disorder, depression, and anxiety disorders.
A reduction in myo-inositol, especially in the PCC, may reflect improved insulin signaling, reduced inflammation, or improved neurochemical regulation associated with mood stabilization.
No significant metabolite changes in the right dorsolateral prefrontal cortex (RDLPFC).
Clinical Significance: MRS revealed changes in brain energy metabolism suggestive of improved neuronal bioenergetics. Clinically, this underscores the possibility of achieving better functional outcomes through targeted metabolic therapies.
Note. Reprinted from “A pilot study of a ketogenic diet in bipolar disorder: Clinical, metabolic and magnetic resonance spectroscopy findings”, by Campbell et al., 2025, BJPsych Open, 11, e34, 1–8.
Note the step up in improvement, better modeled by a non-linear step up.
B. Relevance to Clinical Practice and Functional Outcomes
Dual Benefits on Metabolic and Psychiatric Health:
Each of these studies underscores the capacity of metabolic interventions to address both core psychiatric symptoms and the metabolic side effects commonly associated with psychotropic medications. This dual action is particularly valuable for patients with severe mental illness (SMI), who often experience significant metabolic comorbidities.Potential for Medication Optimization and Reduced Side Effects:
The large effect sizes observed (e.g., Calabrese et al., 2024 and Danan et al., 2022) suggest that KD and other metabolic therapies can provide robust symptom relief, thereby creating opportunities to lower psychotropic dosages. Such dose reductions may mitigate long-term adverse effects (including metabolic dysregulation) and promote better functional recovery.Enhanced Quality of Life and Functional Recovery:
Improvements in mood and psychotic symptoms, coupled with metabolic stabilization, can lead to gains in social, vocational, and cognitive functioning. Studies like Wunderink et al. (2013) have shown that judicious medication reduction supports better long-term outcomes. Metabolic interventions, by further alleviating medication-induced metabolic strain, may amplify these benefits.
C. Conclusion: Pathway to Optimal Outcomes
Collectively, these studies reinforce the growing awareness that metabolic interventions—particularly the ketogenic diet—hold promise as potent adjunctive or alternative treatments in severe mental illness. By targeting both psychiatric symptoms and metabolic dysfunction, clinicians can aim for improved functional outcomes that extend beyond mere symptom management. As future research continues to elucidate the underlying mechanisms and refine patient selection criteria, metabolic therapies may become a cornerstone of comprehensive care for individuals with schizophrenia, bipolar disorder, and major depressive disorder.
VI. Mechanistic Insights: How Ketogenic Diets Improve Brain Health
Ketogenic metabolic therapies confer benefits through several interrelated biological pathways. Due to the success of ketogenic diets in improving clinical benefits in epilepsy, there has been tremendous interest in trying to understand the mechanisms underlying this phenomenon. There is now an extensive literature that has accumulated in this area, giving clinicians confidence that these interventions have a strong basis in relevant neuroscience.
1. Alternative Energy Substrate Provision
Ketone Bodies as Fuel: In states of glucose hypometabolism, often associated with insulin resistance, ketone bodies (e.g., beta-hydroxybutyrate) provide a stable energy source for neurons, generate fewer reactive oxygen species, and help stabilize neuronal excitability (Newman & Verdin, 2017; Veech, 2004).
2. Anti-inflammatory and Antioxidant Effects
Inflammasome Inhibition: BHB inhibits the NLRP3 inflammasome, reducing pro-inflammatory cytokines (Youm et al., 2015).
Oxidative Stress Reduction: Ketone metabolism increases the NAD⁺/NADH ratio, boosting endogenous antioxidant defenses (Newman & Verdin, 2017).
3. Enhanced Mitochondrial Function and Biogenesis
Mitochondrial Efficiency: Activation of PGC-1α promotes mitochondrial biogenesis and improves ATP production, crucial for synaptic plasticity (Anderson et al., 2025; Rho, 2017). In addition to their well‐known role in ATP production, mitochondria are also crucial regulators of brain function through their involvement in neurotransmitter release, intracellular calcium homeostasis, and retrograde signaling that influences nuclear gene transcription and synaptic plasticity, processes that are essential for neuroprotection and have been implicated in the pathophysiology of various mental health disorders (Picard & McEwen, 2018).
4. Neurotransmitter Modulation
Balancing Excitation and Inhibition: KD increases GABA synthesis while reducing glutamate excitotoxicity, thus stabilizing neural networks (Anderson et al., 2025).
5. Epigenetic Regulation and Neurotrophic Support
Histone Deacetylase (HDAC) Inhibition: BHB’s inhibition of HDACs leads to increased histone acetylation and upregulation of neuroplasticity-related genes (e.g., brain-derived neurotrophic factor (BDNF)) (Newman & Verdin, 2017).
6. Modulation of the Gut-Brain Axis
Microbiome Changes: KD alters gut microbiota composition, reducing systemic inflammation and producing neuroactive metabolites (Olson et al., 2018).
7. Improved Insulin Sensitivity
Restoration of Insulin Signaling: Agents like metformin enhance both peripheral and central insulin sensitivity, which is linked to better cognitive function and can improve treatment resistant bipolar depression (Calkin, et al., 2022). Ketogenic diets have been shown to be a potent way to restore insulin sensitivity (Hallberg et al., 2018).
VII. Ideal Metabolic Treatment Plan: A Multimodal Approach
While there is emerging evidence that the ketogenic diet on its own can markedly improve outcomes in serious mental illness and a large body of evidence that exercise can be an excellent treatment for mild to moderate depression, it is intriguing to consider that an approach that combines multiple interventions could have an even greater impact.
Mindfulness practices have been shown to have a wide range of benefits, including decreasing distressing emotions, depressive symptoms, and perceived stress, as well as increasing positive psychological and physical well-being markers. These benefits are at least partially mediated through safety signaling, during which energetic resources are directed toward cellular optimization and away from energy-demanding stress states (Crosswell et al., 2024)
Circadian rhythm alignment plays a crucial role in regulating hormonal cycles and metabolic processes. When internal clocks are properly synchronized, the timed release of hormones, such as cortisol, insulin, and melatonin, is optimized, which promotes efficient glucose metabolism and improves insulin sensitivity. Moreover, this alignment enhances sleep quality and stabilizes neural circuits involved in mood regulation, thereby reducing the risk of depression and anxiety. For instance, Scheer et al. (2009) demonstrated that circadian misalignment impairs glucose tolerance and insulin sensitivity, suggesting that restoring circadian regularity may counteract these metabolic disruptions and support better mental health.
A proposed quartet of lifestyle interventions to create the ideal conditions for metabolic and mental health improvement:
An Individualized Well-Formulated Ketogenic Diet: Including a predominance of whole foods, adequate high quality protein, healthy fats, plentiful fiber and phytonutrients from a variety of vegetables. It also may involve eliminating foods to which the individual is sensitive (can commonly mean gluten, dairy and other foods to which many individuals are sensitive).
Individualized Exercise Plan: Including resistance training, high-intensity interval training (HIIT), and aerobic training, all of which have independent benefits on metabolic health, mental health, and neuroplasticity. This should be geared to the fitness level and preferences of the individual, and ideally both time efficient, enjoyable and progressive in intensity over time.
Mindfulness Practices: This can include a variety of options such as meditation, prayer, visualization, chanting, yoga, Tai Chi and Qigong. Technology such as biofeedback devices (Heartmath, the Muse) can be useful tools to facilitate the ability to achieve deep rest states in some individuals.
Circadian Rhythm Alignment: Through strategies such as morning sunlight exposure and more time outside, regular sleep and meal times, and minimizing all blue-light before bedtime and overnight.
Each modality independently improves both metabolic and mental health and, when combined, they may yield synergistic benefits that further enhance overall clinical outcomes.
VIII. Special Populations and Contraindications
A. Special Populations
Ketogenic diets and other metabolic interventions have demonstrated benefits in populations with comorbid conditions:
Diabetes and Obesity: Improved glycemic control and weight loss (Hallberg et al., 2018).
Polycystic Ovarian Syndrome (PCOS): Beneficial hormonal and metabolic effects (Mavropoulos et al., 2005).
Migraine Headaches: Reduction in migraine frequency and intensity (Tereshko et al., 2023).
Autism Spectrum Disorder: Improvements in behavior and cognitive function in some cases (Schrickel et al., 2025).
Mild Cognitive Impairment and Neurodegenerative Conditions: Enhanced brain energy metabolism and improvements in cognition and functioning (Anderson et al., 2025).
Substance Abuse Disorders: Reduced withdrawal symptoms and cravings (Wiers et al., 2021 and 2024).
Pregnancy: Data regarding the safety of ketogenic diet (KD) use during pregnancy are limited and predominantly originate from contexts involving epilepsy and metabolic disorders. Current evidence consists mostly of small case reports, observational data, and animal studies, making definitive risk assessments challenging and individualized. Animal studies, such as Sussman et al. (2013), have shown significant alterations in fetal organ growth (e.g., enlarged hearts, reduced brain size), changes in brain structure, impaired neuronal density, and delayed neurological development linked to maternal KD, raising concerns about potential developmental impacts. In humans, observational studies like epidemiological research by Desrosiers et al. (2018) noted increased neural tube defect risks associated with very low carbohydrate intake, potentially due to decreased folate consumption. Kramer and Smith (2021) provided a contrasting perspective, reporting a successful KD pregnancy outcome in a case of metabolic disorder (Glut1 deficiency syndrome), highlighting the importance of individualized and supervised clinical management. Recent reviews by Miłosz et al. (2025) reinforce these concerns, noting risks of nutritional deficiencies, metabolic disturbances, increased genome methylation variability, ketoacidosis, and developmental abnormalities, balanced by therapeutic benefits in specific contexts such as epilepsy, PCOS, and Glut1 deficiency. While most direct human evidence from epilepsy and metabolic disorder contexts reports generally favorable short-term outcomes, isolated minor anomalies and nutritional deficiencies (particularly folate and essential vitamins) have been noted. Experts thus emphasize careful monitoring and nutritional supplementation. KD therapy may offer therapeutic benefits in carefully selected and medically supervised scenarios; however, broader and long-term studies are essential to clarify its safety profile during pregnancy (Van der Louw et al., 2017; Miłosz et al., 2025).
B. Contraindications
While KD can be highly effective, it is not appropriate for everyone. Contraindications include:
Certain Metabolic Disorders: Inborn errors of metabolism that impair fat oxidation. These are rare and typically discovered in early childhood.
Medications Requiring Glycemic Stability: Some drugs (e.g., SGLT2 inhibitors) may need to be adjusted to avoid adverse effects like euglycemic ketoacidosis.
Severe Liver or Pancreatic Disease: May impair fat metabolism.
IX. Practical Tips and Clinical Pearls (Clinical Opinion Section)
Patient Selection: Ideal candidates include those with insufficient functional recovery, poor metabolic health, and/or medication intolerances. An assessment of someone’s motivation to engage in these types of lifestyle interventions is a crucial first step in the process.
Multidisciplinary Support: Effective implementation often requires collaboration among psychiatrists, dietitians, primary care providers, mental health professionals, personal trainers, family, and other community supports.
Monitoring and Assessment: Regular metabolic assessments including weight, vital signs, blood glucose, lipids, thyroid panel, insulin resistance score, specific micronutrients, daily ketones.
Medication monitoring and adjustment: Careful attention needs to be paid to certain medications such as:
Lithium, valproic acid and carbamazepine (and other medications with narrow therapeutic indices) may need to be adjusted in the early KD adaptation period, when diuresis and fluid shifts are common.
Anti-hypertensives may need to be lowered as blood pressure typically improves with the ketogenic diet, sometimes rapidly.
Diabetes medications may need to be lowered as early as the first few days, as some carry a risk of hypoglycemia when carbohydrate intake is severely restricted. Collaboration with an endocrinologist and the use of a continuous glucose monitor are strongly recommended.
Patient Education/Close Collaboration: Use clear, accessible language to explain how metabolic therapies work and their potential benefits. There may need to be close collaboration with patients and members of the care team, especially in the early stages, to avoid adjustment effects (“keto flu”) and to ensure that the plan is being followed appropriately
Individualized Pace of Implementation: Some individuals may benefit from a step-wise or gradual implementation process. This is especially true when attempts at implementing the whole plan at once seem overwhelming and may enhance long-term adherence. One may start with small dietary changes and a modest exercise program. It is important to notice and celebrate the early metabolic and mental health improvements and build on the progress that has been made by adding more interventions. On the other hand, there may be advantages in many individuals to engaging in an immersive and comprehensive approach from the beginning, as it allows for rapid and noticeable benefits, which can greatly enhance motivation.
Adjusting Psychotropic Medications: Careful consideration should be given to reducing doses of psychotropic medications if the expected improvement is occurring in metabolic and mental health, always in a controlled and monitored manner.
Medication Potentiation: As things are improving on a metabolic plan, clinicians and patients sometimes see an increase in physical symptoms, which are best understood as the effects of medication potentiation. While there is little research in this area, clinicians theorize that there may be enhanced bioavailability or altered pharmacokinetics (possibly due to changes in cytochrome P450 enzyme activity from a high-fat diet) which may lead to increased drug effects. With antipsychotics, one may see increased sedation, orthostatic hypotension, or even new extrapyramidal symptoms (EPS). Similarly, for mood stabilizers and antidepressants, potentiation might lead to heightened side effects such as increased sedation or other side effects typical of that particular medication.
Individualized Plans: Emphasize the importance of personalized treatment plans that factor in patient preferences and comorbidities.
X. Future Directions and Clinical Integration
The rapid pace of research in metabolic psychiatry promises further clarity on optimal protocols and long-term outcomes. Ongoing randomized controlled trials with advanced imaging and biomarker analyses will help delineate which patient subgroups benefit most and which protocols are most effective. Ultimately, integrating metabolic interventions into standard psychiatric practice may lead to a paradigm shift toward personalized, biologically-based treatments. See the following table for some of the studies that are in progress at this time:
Note. Ongoing studies in metabolic psychiatry. Adapted from "Metabolic Mind," by the Baszucki group, 2025 (https://www.metabolicmind.org/research). Copyright 2024 by Metabolic Mind.
Supplements for Ketogenic Diet
Sodium:
Amount: 3,000–5,000 mg per day: Approximately 1.5–2 teaspoons of added salt daily, especially during the first 4 weeks.
Reason: Keto reduces insulin, causing the kidneys to excrete more sodium and water. Glycogen depletion also leads to less water and more diuresis. Increased sodium intake prevents fatigue, muscle cramps, headaches (“keto flu”), and dizziness.
Potassium:
Amount: 3,000–4,700 mg per day
Reason: When insulin levels drop due to carbohydrate restriction, the kidneys not only excrete more sodium but also potassium. This renal potassium excretion is often secondary to sodium loss, causing an increased need for potassium replacement. Helps maintain electrolyte balance, prevents muscle cramps, heart palpitations, and weakness.
Sources:
Ideally, potassium should come from dietary sources rather than supplements. However, it’s important to consult your doctor, as excessive potassium intake can lead to health complications.
Avocado (~700 mg per avocado)
Spinach (~500–800 mg per cooked cup)
Salmon (~500 mg per 6 oz serving)
Potassium chloride supplement (e.g., “lite salt”) if needed (¼ teaspoon ~700 mg potassium)
Magnesium:
Amount: Aim for 300–400 mg/day ideally, mostly through foods.
Reason: It is estimated that more than 50% of Americans may be deficient in magnesium which is a cofactor for more than 300 enzymes that regulate diverse reactions in the body. Magnesium is required for energy production, contributes to the structural development of bone and is required for the synthesis of DNA, RNA, and the antioxidant glutathione. Magnesium also plays a role in the active transport of calcium and potassium ions across cell membranes, a process that is important to nerve impulse conduction, muscle contraction, and normal heart rhythm.
Sources
Pumpkin seeds: ~150 mg per 1 oz (28 g)
Spinach: ~150–160 mg per cooked cup
Swiss chard: ~150 mg per cooked cup
Almonds: ~75–80 mg per 1 oz (23 almonds)
Dark chocolate (70–85%+ cacao): ~65 mg per 1 oz square
Avocado: ~60 mg per medium avocado
Hemp seeds: ~70 mg per 2 tablespoons
Chia seeds: ~95 mg per 2 tablespoons
Mackerel: ~80 mg per 3 oz serving
Brazil nuts: ~105 mg per 1 oz (6–7 nuts)
Optimize Hydration During Keto Adaptation
In the first weeks of adapting to a ketogenic diet, increasing water intake is often beneficial and, along with the above electrolytes, should prevent the side effects of this adaptation phase, also known as the “keto flu”. This can include effects such as headaches, muscle aches or cramps, low energy, nausea and brain fog. While there is some debate over whether one should “drink to thirst” or to attempt to meet a certain volume of water, a reasonable quantity of water in the first two weeks of adaptation is 0.5 oz. per pound of body weight along with electrolyte supplementation through diet or other means. So, that would be 100 oz. for a 200 pound person or 60 oz for a 120 pound person.
Labs to Do When Starting the Ketogenic Diet
Strongly Recommended Baseline Labs (need periodic rechecking):
Comprehensive Metabolic Panel (CMP)
Why: Evaluates kidney and liver function, electrolyte status, and baseline glucose, essential because keto affects fluid and electrolyte balance and can impact liver metabolism.
Complete Blood Count (CBC)
Why: Screens for anemia, infection, inflammation, or blood disorders. Helpful due to dietary shifts affecting nutrient status and absorption.Fasting Lipid Panel
Why: Provides baseline cholesterol levels (HDL, LDL, triglycerides) and monitors changes in cardiovascular risk markers due to the high-fat content of keto diets.Vitamin D (25-OH Vitamin D)
Why: Many people are deficient and it is vital to maintain immune, bone, and metabolic health. Helps identify deficiency and potential need for supplementation.
Vitamin B12
Why: Essential for nerve health, cognitive function, and red blood cell production. Helps identify baseline status and potential need for supplementation.Carnitine Levels
Why: Critical for transporting fatty acids into mitochondria for fat metabolism. Low levels impair the effectiveness of the ketogenic diet and are also associated with depression, causing fatigue or muscle weakness.Thyroid Stimulating Hormone (TSH)
Why: Thyroid hormones regulate metabolism; keto diets can slightly affect thyroid function. Monitoring helps prevent thyroid-related metabolic slowdown.Hemoglobin A1c (HbA1c)
Why: Establishes baseline glucose control and identifies insulin resistance or prediabetes; tracks keto’s effect on long-term glucose metabolism.
Magnesium (RBC Magnesium preferred)
Why: Keto diets can induce magnesium deficiency due to increased renal excretion and dietary restriction, causing muscle cramps, fatigue, and anxiety. Use caution when interpreting magnesium blood tests and clinical assessment may be more accurate.
Optional Labs Helpful for Deeper Nutritional and Metabolic Assessment (available at standard laboratories):
Iron Panel (Total Iron, Iron Binding Capacity, Ferritin)
Why: Identifies iron deficiency or overload. Iron deficiency is common in the general population (especially in menstruating women), and impairs mitochondrial function. Iron overload is common in those who are supplementing with iron.
Homocysteine
Why: Elevated levels indicate increased cardiovascular risk and potential deficiencies in B vitamins (folate, B12), which is common in the general population.Uric Acid
Why: Keto may initially elevate uric acid levels, increasing gout risk. Helpful to monitor, particularly in susceptible individuals.Celiac Disease Screening Panel (Tissue Transglutaminase AB IgA and Immunoglobulin A)
Why: Screens for underlying gluten sensitivity or celiac disease, which can impact nutrient absorption and gut health, especially important if the ketogenic diet doesn’t resolve digestive issues.Copper and Ceruloplasmin
Why: Assess copper status; imbalance can affect energy metabolism, neurological health, and iron utilization. Useful in restrictive or highly selective diets. Excess free copper is also common in the general population and is associated with anxiety and other psychiatric symptoms, as it is an essential cofactor for the enzyme that converts dopamine to norepinephrine.hs-CRP (High-sensitivity C-Reactive Protein)
Why: Evaluates systemic inflammation; helpful for assessing cardiovascular risk and inflammation status, potentially improved by the ketogenic diet.HOMA-IR (or Fasting Insulin)
Why: Directly measures insulin sensitivity and metabolic health. The ketogenic diet commonly improves insulin resistance; baseline is valuable for tracking metabolic progress.Additional Thyroid Studies (Free T3, Free T4, Reverse T3, Thyroid Antibodies)
Why: Provides comprehensive thyroid function assessment, especially useful if symptoms of low metabolism, fatigue, or weight stagnation occur despite dietary compliance.
Conclusion
The extensive evidence from the well-established efficacy of the ketogenic diet in epilepsy to emerging data in psychiatric populations supports the promise of metabolic interventions in mental health. With the potential for effect sizes exceeding those of conventional medications (as demonstrated by Danan et al., 2022), and a robust mechanistic rationale spanning energy metabolism, inflammation, mitochondrial function, and neurotransmitter balance, metabolic therapies offer a transformative potential. When implemented in a multimodal, patient-centered approach, these interventions may not only reduce psychiatric symptoms and side effects, but also improve overall functional recovery and quality of life.
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