Introduction

Mood disorders are chronic and recurrent psychiatric conditions that affect emotions, energy, and motivation. Mood disorders include depressive disorders and bipolar disorders. Depression affects more than 264 million people worldwide. In the United States, major depressive disorder (MDD) affects approximately 7% of the adult population in a given year [1]. Bipolar Disorder (BD) is also a chronic mental health condition with a lifetime prevalence of approximately 1.5–2.4% [2] and a high risk of recurrence. In recent years, there has been an increase in the rates of mood disorders [2, 3]. Moreover, many people do not respond adequately to standard treatments, which usually include medications and psychotherapy. It is estimated that 30% of people with major depressive disorder and bipolar depression are resistant to treatment [4•], while many remain at risk for illness recurrence and disability [5, 6]. There is thus an urgent need to develop new treatment modalities for mood disorders.

Recent evidence points to the potential for metabolic therapies to improve symptoms and functional outcomes in mood disorders [7]. The ketogenic diet is one such metabolic therapy, which is an eating pattern low in carbohydrate, high in fat, and moderate in protein that results in increased synthesis of ketone bodies (β-hydroxybutyrate, acetone, acetoacetate) leading to ketosis. It is a 100-year-old, evidence-based treatment for epilepsy [8]. The ketogenic diet has been demonstrated to reduce and remit seizures, including in treatment-resistant epilepsy [9]. The production of ketone bodies provides the brain with an alternate fuel source to glucose. Ketone bodies bypass several crucial steps in glucose transport and glycolysis and ketosis provides ketones as an alternative source of Acetyl CoA to enable the tricarboxylic acid cycle when glucose metabolism is impaired, and this reduces glycolytic energy production and consequently lactate accumulation. The ketogenic diet directly addresses metabolic dysfunction by lowering both blood glucose levels and insulin secretion [10]. Interestingly, other treatments for epilepsy are routinely used in the treatment of mood disorders, with some anticonvulsant medications being FDA-approved for the treatment of bipolar disorder, while others are routinely used off-label for the treatment of mood disorders more broadly. There is growing interest in the use of the ketogenic diet as a treatment for mood disorders.

There is compelling evidence that the ketogenic diet can target underlying pathophysiologic mechanisms in mood disorders. This article aims to assess the status of the use of the ketogenic diet in bipolar disorder and explore its potential as a therapeutic approach for mood disorders. In this review, we hope to present data from randomized clinical trials, case series and new areas of research in recent years.

Pathophysiologic Targets of the Ketogenic Diet in Mood Disorders

Multiple biological mechanisms have been proposed as potential contributors to mood disorders, encompassing mitochondrial dysfunction, inflammatory pathways, oxidative stress, and insulin resistance [11,12,13,14]. The ketogenic diet is known to improve all of these.

Mitochondrial Dysfunction

Mitochondria, integral cellular structures, play critical roles in numerous biological functions, particularly in the generation of energy. Within the brain, where ATP consumption is elevated and storage capacity is limited [15], mitochondria play a vital role in regulating neuronal activity, influencing both short-term and long-term neuronal plasticity, bolstering cellular resilience, and facilitating behavioral adaptations [16,17,18]. There is converging evidence for energy dysregulation in mood disorders [19, 20]. Studies using brain 31P magnetic resonance spectroscopy have identified abnormalities related to redox regulation and bioenergetics, including NAD + /NADH imbalance [19] and decreased generation of ATP with energy demand [19, 20]. Recently, therapies with the potential to improve mitochondrial function have been investigated as complementary therapies alongside existing pharmacological treatments for mood disorders [21].

The ketogenic diet has been shown to enhance mitochondrial biogenesis and function, a process vital for energy production, by increasing the expression of genes involved in energy metabolism. This dietary approach shifts the body's energy reliance from glucose to ketone bodies, which are more efficient substrates for mitochondria, leading to improved energy efficiency and cellular health [22, 23]. Studies by Veech and colleagues have shown an improvement in mitochondrial function with the ketogenic diet [24, 25]. Furthermore, the ketogenic diet can reduce oxidative stress and inflammation, further supporting mitochondrial function and overall cellular resilience [22, 26, 27].

Inflammation

A substantial body of evidence suggests associations between inflammation and mood disorders [28,29,30,31,32]. Heightened levels of inflammatory markers, including tumor necrosis factor (TNF) alpha, C-reactive protein, and interleukins IL-1, IL-2, IL-6, and IL-10 are observed in individuals with MDD and BD [29].

The ketogenic diet has been associated with significant reductions in inflammatory biomarkers. A meta-analysis by Masood et al. highlighted the diet's efficacy in reducing C-reactive protein, a key marker of inflammation, across several studies, suggesting a systemic anti-inflammatory effect. Another meta-analysis by Li et al. of 44 randomized, controlled trials found that adherence to a ketogenic diet can improve inflammatory biomarkers, including TNF-α and IL-6 [33, 34].

Oxidative Stress

Recent studies provide growing evidence that oxidative stress may be a fundamental mechanism in bipolar disorder [14, 35, 36•]. Reactive oxygen species (ROS) naturally arise as by-products of cellular energy metabolism and function. The majority of these free radicals are generated during oxidative phosphorylation and are subsequently neutralized through a series of biochemical pathways [37]. Levels of oxidative damage are linked to mood states, with both manic and depressed states exhibiting heightened oxidative stress, while euthymic states do not. Meta-analyses indicate a notable rise in specific ROS among individuals with bipolar disorder [38, 39]. Persistent cellular damage is likely to result in disruptions in neurotransmission, potentially leading to the manifestation of symptoms observed in bipolar disorder.

Consuming a ketogenic diet has been shown to impact mitochondrial functions and oxidative stress [40,41,42]. The beneficial impacts of ketones and the ketogenic diet on oxidative stress via the augmentation of the NAD + /NADH ratio have been extensively recorded in animal studies, ex vivo experiments, and cellular models [43, 44].

Obesity and Insulin Resistance

Major depressive disorder and bipolar disorder are conditions characterized by symptom profiles that can affect appetite, energy, sleep, and motivation [45]. The prevalence of obesity in individuals with MDD and BD is nearly double compared to the general population [46].

Extensive research has focused on unravelling the mechanisms linking mood disorders and obesity, suggesting that various facets of depression's neurobiology may contribute to an elevated risk of obesity [47]. Longitudinal studies validate that depression during adolescence significantly predicts higher body mass index (BMI) in adulthood, while individuals with obesity are also at increased risk of MDD compared to those within a healthy weight range [48]. Pharmacotherapy serves as a significant mediator in the relationship between depression, bipolar disorder, and obesity, frequently causing sedation and heightened appetite, thereby impacting both physical health and treatment adherence [49, 50]. Moreover, weight gain and the medical comorbidities it brings about might diminish the probability of favorable clinical responses to pharmacological treatments [50].

People with BD face a threefold higher risk of diabetes compared to the general population [51]. This cannot be attributed solely to the side effects of BD medications, as there is also a high prevalence of type 2 diabetes (T2DM) in medication-naïve patients [52]. Given the substantial occurrence of insulin resistance in BD, coupled with findings indicating compromised neuronal glucose metabolism and the association with diabetes comorbidity, neuronal insulin resistance likely plays a role in the development of BD. Evidence from research suggests that hyperinsulinemia in BD is associated with hyperinsulinemia in the brain, which may inhibit oxidative phosphorylation and result in a shift toward glycolytic energy production and mitochondrial dysfunction.

The ketogenic diet directly addresses metabolic dysfunction by lowering both blood glucose levels and insulin secretion [53, 54]. A meta-analysis revealed a reduction in fasting blood glucose levels and HbA1c rates following a ketogenic diet intervention compared to pre-intervention levels [55]. Reports indicate improvements in mood, energy, sleep, mental clarity, and affective stability associated with the adoption of low-carbohydrate and ketogenic diets in individuals with type 2 diabetes and obesity [56]. Hence, the ketogenic diet might hold significant relevance in the management of mood disorders.

Bipolar Disorder

1-Case Reports and Case Series

Several case reports and case series suggest that the ketogenic diet may play a role in the treatment of bipolar disorder.

One was of a 27-year-old male diagnosed with bipolar affective disorder with rapid cycling who was treated with ketogenic diet therapy for 2 years in addition to pharmacotherapy after no response to depressive symptoms in 4 years of pharmacotherapy [57]. After the first year of treatment, the patient's mood improved and stabilized, cognitive functions and concentration improved and anxiety disappeared. In the second year of treatment, the beneficial effects continued. The patient experienced complete remission of his chronic depression, even with a reduction in pharmacologic treatment [57].

Another case report was a 69-year-old woman with bipolar II symptoms who started a ketogenic diet. After two years on the diet, the patient noticed a decrease in her anxiety, anger attacks and depressive symptoms [58]. Another patient in the same case report was a 30-year-old woman with type II bipolar illness. After experiencing the side effects of multiple medications, she started using the ketogenic diet. She reported experiencing mood-stabilizing effects after treatment [58].

In another case report, a 33-year-old single man diagnosed with schizoaffective disorder showed persistent positive and negative symptoms despite multiple drug trials. Over the course of a year, he predominantly adhered to a ketogenic diet and noted a decrease in both types of symptoms. Throughout the diet, his functionality notably improved [59]. The second case was of a 31-year-old woman with a psychiatric history encompassing major depression and anorexia nervosa, ultimately diagnosed with schizoaffective disorder. Despite undergoing electroconvulsive therapy and numerous drug trials, her positive and negative symptoms persisted. By the fourth month of adhering to the ketogenic diet, she experienced a reduction in both types of symptoms [59].

In another case study [60], a 60-year-old woman diagnosed with type 1 bipolar disorder started a ketogenic diet for treatment-resistant mood and psychotic symptoms. She experienced significant improvement in mood and anxiety symptoms [60].

In another case, a 49-year-old woman with a history of early-onset, treatment-resistant bipolar disorder had been managed with various mood stabilizers and neuroleptic medications. Alongside antipsychotic treatment, the patient followed two distinct ketogenic diets. However, there was no discernible clinical improvement, weight loss or urinary ketosis noted during this time. Although this case report suggested that the ketogenic diet failed to improve her symptoms, she never achieved urinary ketosis, implying that she never fully complied with the treatment [61].

A larger case series included 31 adults with treatment-resistant major depressive disorder, bipolar disorder, and schizoaffective disorder. They were prescribed a ketogenic diet [62]. Twenty-eight patients were able to adhere to the diet. Overall, all of the patients adherent to the diet experienced at least some improvement in symptoms, with 43% of the patients achieving clinical remission of illness [62]. In addition, 10 patients diagnosed with schizoaffective disorder reported improvement in positive and negative symptoms [62].

2-Clinical Trials

Two recent clinical trials indicate encouraging outcomes in utilizing the ketogenic diet for bipolar disorder treatment. One pilot study was conducted to assess the feasibility and acceptability of implementing the ketogenic diet in people with bipolar disorder [63••]. Participants, aged 18 and 70 years, were clinically euthymic for a minimum of three months. Out of 26 enrolled participants, 20 adhered to the diet until their 6- to 8-week follow-up, with 18 completing the entire 8-week intervention period. Most participants successfully achieved and sustained ketosis, with ketosis present in 91% of all daily ketone readings, suggesting a high level of adherence to the diet. One-third of participants experienced reduction in psychiatric symptoms and 95% participants had improvement in cardiometabolic risk parameters. Higher blood beta-hydroxybutyrate levels were associated with improvement in mood and energy levels, along with reduced impulsivity and anxiety [64••]. All but one of the participants (n = 20) for whom baseline and follow-up data were completed lost weight during the intervention period. 52.6% of participants achieved significant weight loss (≥ 5% body weight). Participants' mean BMI decreased by 5.3% and mean systolic blood pressure decreased by 7.4 mmHg. During the period of diet cessation, one-third of participants who reported reduced mood variability chose to stay on the ketogenic diet. Adverse events were predominantly mild and manageable. The study documented 11 minor side effects, such as fatigue, constipation, drowsiness, and hunger, alongside one serious adverse event, which involved euglycemic ketoacidosis in a participant using an SGLT2 inhibitor [63••]. This research identified lactate as a biomarker, suggesting that increased levels of lactate may indicate impaired oxidative phosphorylation and a compensatory increase in glycolysis. The study revealed noteworthy changes in metabolites, including decreased lactate levels, increased citrate (which contributes to oxidative phosphorylation through the tricarboxylic acid cycle), and heightened levels of the ketone body beta-hydroxybutyrate. These findings suggest that ketosis may prompt a transition towards heightened mitochondrial activity, enhanced oxidative phosphorylation, and reduced glycolysis [64••].

A 4-month pilot study was conducted to investigate the effects of KD on individuals with schizophrenia or bipolar disorder. Twenty-three participants were enrolled in a single-arm study. Based on ketone levels in this study, fourteen participants were fully adherent to the diet (above 80% of the time ketone measures > 0.5), six participants were semi-adherent (ketones > 0.5 above 60–80% of the time), and one participant was nonadherent (ketones > 0.5 < 50% of the time.) Results showed improvements in metabolic health and no participant met criteria for metabolic syndrome at the end of the study. In psychiatric measures, participants with schizophrenia showed a 32% reduction in Brief Psychiatric Rating Scale scores. Overall Clinical Global Impression (CGI) severity improved by an average of 31%. 79% of all participants improved by at least 1 point on CGI (92% for those who were adherent with treatment and 50% for those who were semi-adherent). According to the Clinical Mood Monitoring assessments, the proportion of participants who were on neuroleptic medication at baseline and in recovery increased from 33% at baseline to 75% at the end of the study. In the adherent group, 100% were in recovery at the end of the study. Overall, for both the bipolar and schizophrenia populations, 43% of participants achieved improvement during the study (50% for adherent and 33% for semi- adherent). Cohort-wide psychiatric improvements included increased life satisfaction (17%) and improved sleep quality (19%) These results suggest that the intervention had a positive impact on participants' mental health and well-being. Moreover, beneficial changes in weight, body composition and metabolic markers, including insulin sensitivity, were also observed in a metabolically vulnerable population. Common side effects of the ketogenic diet such as headaches, fatigue and constipation were documented at baseline. These side effects decreased significantly and reached minimal or negligible levels after the third week of the study [65••].

Major Depression

Preclinical Studies

Preclinical studies have suggested potential efficacy of the ketogenic diet in alleviating depressive symptoms in animal models.

One line of research suggests that the ketogenic diet can enhance the presence of Akkermansia, a probiotic, in the gut of rodents [66, 67]. In animal stress models, this augmentation of Akkermansia has exhibited properties akin to antidepressants, suggesting a potential role of the ketogenic diet in fostering antidepressant effects [68].

Another study analyzed the brain structure and behavior of mice exposed to KD during gestation followed by a standard diet (SD) after birth [69]. Adult offspring exposed to KD showed reduced susceptibility to anxiety and depression and exhibited increased levels of physical activity compared to their counterparts exposed to both prenatal and postnatal SD. These results suggest that prenatal exposure to KD programs the neuro-anatomy of offspring and influences adult behavior.

The impact of medium- and long-chain ketogenic diets on cerebral electrical activity and the propagation of cortical spreading depression (CSD) [70] has also been examined. Weaned rats were divided into three groups: one received a control diet, the other a medium-chain triglyceride KD and the third a long-chain triglyceride KD. Results indicated that short-term KD treatment significantly reduced the rate of CSD spread compared to the control group. However, long-term administration of KD showed no effect on the CSD rate, suggesting that short-term KDs have a favorable impact on reducing cerebral excitability in young animals [70].

Finally, other evidence suggests that the ketogenic diet may have antidepressant properties, evidenced by rats on the diet showing reduced "behavioral despair" in the Porsolt test, a model for depression, compared to those on a control diet [71].

Case Reports and Case Series

As detailed in a case study, a 65-year-old female diagnosed T2DM and major depressive disorder engaged in a 12-week ketogenic diet regimen [72]. Following the intervention, notable improvements were evident across both physiological and psychological realms. Alongside reductions in HbA1C and blood glucose levels, the patient reported amelioration of depressive symptoms and enhanced adherence to diabetes management. Notably, after the 12-week period, medication usage decreased by 75%. Moreover, the patient experienced heightened self-assurance, increased self-efficacy, elevated energy levels, enhanced sleep quality, and greater bodily stability [72].

In another case report, a 21-year-old female with obesity, a mood disorder, and comorbid conditions including emotion dysregulation, body dysmorphic disorder, and an eating disorder, underwent a 4-week ketogenic diet. Following the 4-week dietary regimen, notable improvements were observed, including stabilized mood, decreased anxiety, and normalization of the circadian rhythm. Additionally, the patient reported the absence of suicidal thoughts, alongside recorded weight loss [73].

In a study of individuals with chronic epilepsy, a retrospective survey was carried out among those who adhered to the Modified Atkins Diet (MAD) for a minimum of 1 month and up to 2 years. The MAD involves restricting net carbohydrates to 20 g per day while permitting high fat and unlimited protein intake [74]. Consequently, a reduction in depressive and anxiety symptoms was noted among the participants, with this decrease directly correlating with the duration of the diet. Additionally, it was observed that some individuals who did not experience a reduction in seizures opted to continue the diet due to the observed improvement in their mood and anxiety. Notably, changes in seizure frequency did not exhibit a significant correlation with alterations in measures of depression or anxiety severity. This implies that the noted improvement cannot solely be attributed to a decrease in seizures [74].

Clinical trials

Significant results of ketogenic diet were found in clinical trials conducted in groups of patients showing depressive symptoms with previous comorbidity.

In a randomized, controlled, 4-month trial of the ketogenic diet in children and adolescents aged 1–18 years old diagnosed with epilepsy, it was observed that KD patients initially exhibited higher levels of mood symptoms. However, at the 4-month follow-up, the children experienced a decrease in anxiety, tension, and hostility levels [75]. Regarding social-emotional functioning, individuals in the KD group demonstrated decreased levels of anxious and mood disorder behavior after 4 months, a change that was not associated with improvements in seizure control. Furthermore, an enhancement in their overall functionality was noted at the 4-month mark, which was not linked to the reduction in seizures [75].

In another randomized, controlled trial, overweight or obese adults participated in a 6-week controlled feeding intervention involving hypocaloric diets, which comprised approximately 75% of their energy expenditure. The KD groups were divided into two: the first group received ketone salt (KD + KS; n = 12) twice daily, while the second group received a mineral-free, flavor-matched placebo (KD + PL; n = 13) [76]. Additionally, a third group of age- and BMI-matched adults was subsequently assigned to the isoenergetic low-fat diet (LFD; n = 12) for comparison with the KD. Mood assessments were conducted using the abbreviated Profile of Mood States and Visual Analog Mood Scale questionnaires. A noteworthy interaction between diet and time was observed regarding depression scores. Specifically, the results indicated that the KD + PL group exhibited higher depression scores compared to the KD + KS group at week 2. While there was a non-significant increase in depression scores for the LFD group at week 4, it's important to note that throughout the study, the KD + KS group consistently demonstrated lower depression scores compared to the other groups [76••].

A substantial non-randomized, open-label investigation examined alterations in depressive symptoms over 2 years among 262 predominantly non-depressed individuals with Type 2 diabetes. These participants engaged in a continuous remote care intervention focused on carbohydrate restriction. Subclinical depressive symptoms declined within the initial 10 weeks and persisted for up to 2 years. This study suggests that an increase in blood ketone levels, which serve as a marker for adherence to a low-carbohydrate diet, is associated with a reduction in depressive symptoms [77••].

Discussion

The ketogenic diet reveals an intriguing intersection between metabolic health and psychiatric conditions. The synthesis of evidence from preclinical studies, case reports, and clinical trials underscores the potential of dietary interventions as a treatment for mood disorders.

Central to the discussion is the ketogenic diet's mechanistic underpinnings, which suggest a multifaceted approach to mitigating mood disorder pathology. Mitochondrial dysfunction, inflammation, oxidative stress, and insulin resistance are key biological mechanisms implicated in the etiology of mood disorders. The ketogenic diet's ability to enhance mitochondrial function, reduce inflammation and oxidative stress, and improve insulin sensitivity presents a novel pathway through which dietary interventions can impact psychiatric health. Notably, the diet's efficacy in epilepsy—a condition with established therapeutic overlaps with mood disorders—further validates the potential translational benefits of this dietary approach to mental health.

The evidence presented in this review, particularly from case reports and series, indicates variable yet promising outcomes for individuals with bipolar disorder and major depressive disorder. While some case reports illustrate remarkable improvements in mood stabilization, cognitive function, and overall quality of life, others highlight the challenges and limitations, including adherence to the diet and variability in response. These findings underscore the necessity for individualized assessment and monitoring when considering the ketogenic diet as a treatment for mood disorders.

Clinical trials add a layer of rigor to the evaluation of the ketogenic diet's impact on mood disorders, with studies showing improvements in mood, energy levels, and metabolic health biomarkers. These trials, however, also emphasize the importance of monitoring for potential adverse effects and the need for further research to optimize dietary protocols and identify patient populations most likely to benefit.

The growing body of evidence supporting the ketogenic diet's role in mood disorder treatment aligns with a broader shift towards integrative approaches in psychiatry, which encompass lifestyle and dietary modifications alongside conventional pharmacotherapy and psychotherapy. This holistic perspective acknowledges the complex interplay between brain function and metabolic health, offering a more comprehensive approach to mental health care.

The ketogenic diet presents a promising, albeit preliminary, treatment for mood disorders. The diet's potential to address key pathological mechanisms common to both mood disorders and metabolic dysregulation warrants further investigation. Future research should focus on larger, well-designed clinical trials to confirm these preliminary findings, elucidate mechanisms of action, and identify predictive markers of response to dietary interventions. Ultimately, the integration of dietary strategies into mental health care could offer a more nuanced and personalized approach to treating mood disorders, potentially improving outcomes for individuals for whom conventional treatments are insufficient.