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Review
The Potential Role of the Ketogenic Diet in Serious Mental Illness: Current Evidence, Safety, and Practical Advice
by Joanna Rog,Zuzanna Wingralek, Katarzyna Nowak,Monika Grudzień ,Arkadiusz Grunwald ,Agnieszka Banaszek andHanna Karakula-Juchnowicz

J. Clin. Med. 2024, 13(10), 2819; https://doi.org/10.3390/jcm13102819
Published: 10 May 2024

Abstract
The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that mimics the physiological state of fasting. The potential therapeutic effects in many chronic conditions have led to the gaining popularity of the KD. The KD has been demonstrated to alleviate inflammation and oxidative stress, modulate the gut microbiota community, and improve metabolic health markers. The modification of these factors has been a potential therapeutic target in serious mental illness (SMI): bipolar disorder, major depressive disorder, and schizophrenia. The number of clinical trials assessing the effect of the KD on SMI is still limited. Preliminary research, predominantly case studies, suggests potential therapeutic effects, including weight gain reduction, improved carbohydrate and lipid metabolism, decrease in disease-related symptoms, increased energy and quality of life, and, in some cases, changes in pharmacotherapy (reduction in number or dosage of medication). However, these findings necessitate further investigation through larger-scale clinical trials. Initiation of the KD should occur in a hospital setting and with strict care of a physician and dietitian due to potential side effects of the diet and the possibility of exacerbating adverse effects of pharmacotherapy. An increasing number of ongoing studies examining the KD’s effect on mental disorders highlights its potential role in the adjunctive treatment of SMI.
Keywords: ketogenic diet; nutritional intervention; bipolar disorder; major depressive disorder; schizophrenia; nutritional psychiatry; psychiatric disorders; mental health; serious mental illness

1. Introduction
The ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet [1]. With the reduced intake of glucose, fat becomes an energy substrate, leading to increased ketogenesis. Oxidation of fatty acids in the mitochondria produces large amounts of energy with acetyl coenzyme A (acetyl-CoA) production. The efficiency of the Krebs cycle is reduced, and the production of mainly three ketone bodies is increased: acetoacetate, acetone, and β-hydroxybutyrate [2,3]. Thus, following the KD leads to intensified production of ketones, which become the main source of energy for the central nervous system [3] and can provide up to 60–70% of the brain’s energy requirements [4,5]. The metabolic state during the KD is described as “nutritional ketosis”. There are many modifications of KD [1]. The classic KD contains 80% fat, dominated by long-chain fatty acids, 15% protein, and 5% carbohydrates [3]. The high-protein KD (Modified Atkins Diet: MAD), known as the Atkins diet, is less restrictive than the traditional KD. The MAD contains 15% carbohydrates with unlimited protein and fat, which makes compliance easier for the patient [3,6]. Meanwhile, reducing long-chain fatty acids and increasing medium-chain fatty acids accelerates triglyceride absorption. This increases the amount of produced ketone bodies per kilocalorie and improves mitochondrial metabolism [1,7,8]. The very low-calorie KD (VLCKD) limits daily carbohydrate intake to 20–50 g or less than 10% of the macronutrients in a 2000 kcal per day [9]. Another modification includes the use of low-glycemic-index products in a high-fat diet [10,11]. In the cyclic KD (CKD), periods of the KD and the high-carbohydrate diet are alternated [12]. A growing number of studies highlight the positive effects of the KD on the composition of the gastrointestinal microbiome [13], mitochondrial activity [14,15,16], neurotransmitter synthesis, and inhibition of neurodegenerative processes [17], as well as modulating oxidative stress and inflammation [18,19,20,21]. At the same time, the increase in the amount of ketone bodies contributes to the “sparing” of glucose. As a result, it can be used to a greater extent in protective antioxidant or glycogenesis processes [22,23,24]. The use of a KD can potentially improve the response to treatment and reduce the symptoms of serious mental illness (SMI): bipolar disorder (BD) [15], schizophrenia (SZ) [25], and major depressive disorder (MDD) [26]. More and more evidence highlights the importance of nutrition in maintaining mental health. Many mechanisms engaged in the pathophysiology of mental illness are affected and modulated by nutrition [27]. Based on these experiences, nutritional psychiatry has been created [28]. Dietary patterns, nutrients, and food products have potential positive effects on mental health outcomes, including the Mediterranean diet; high intakes of vegetables, fruits, and other plant-based products; fermented foods; unsaturated omega-3 fatty acids; vitamin D; zinc, folate, or probiotics; and many others [27]. Mechanisms such as brain glucose hypometabolism, increased oxidative stress and inflammation, dysfunction in neurotransmitter synthesis, and mitochondrial metabolism have been described in the pathogenesis of mental disorders [17,29]. The KD leads to improved carbohydrate and lipid metabolism, which may inhibit the metabolic disturbances that may occur with many antidepressants and antipsychotic medications [15,30]. In 2018, the International Study Group established the KD as an effective nonpharmacologic intervention for epilepsy. The study, published in 2024, suggests that for the protocols aimed at achieving ketosis as a partial mechanism of therapeutic action, the phrase “ketogenic diet therapy” should be used. There are many indications that the KD may become part of the treatment for many conditions beyond neurological diseases [31]. Therefore, the aim of the study is to determine the potential therapeutic effect of KD in SMI.

2. Materials and Methods
The studies included in the narrative review were selected from the PubMed, Google Scholar, and Scopus databases from repository inception to 23 March 2024. To collect model and human studies that evaluated the impact of the KD on MDD, BD, and SZ, the following keywords were used: “ketogenic diet”, “ketosis”, “ketone bodies”, “low carbohydrate diet”, “Atkins diet”, “LCHF”, “KLCHF”, “LC/KD”, “serious mental illness”, “psychiatric diseases”, “schizophrenia”, “major depressive disorder”, and “bipolar disorder”. The study selection was as follows: (1) clinical trials, meta-analyses, animal model research, and case reports were included; (2) articles not written in English, conference abstracts only, review articles, duplicated papers, or papers that do not relate to BP, MDD, or SZ were excluded.

3. Therapeutic Effect of the Ketogenic Diet in Schizophrenia
3.1. Etiopathogenesis and Potential Role of the Ketogenic Diet
Several mechanisms take place in the process of SZ that lead to impaired synaptic communication. The frequent remodeling of synapses and neurons is very energy intensive, while the brain’s main energy substrate is glucose. Glucose is converted into adenosine triphosphate (ATP) through glycolysis in the cytoplasm, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation in the mitochondria [32]. The greatest part of ATP energy is needed to reverse ion movements that cause postsynaptic responses [33]. Glucose metabolism produces glutamate and gamma-aminobutyric acid (GABA). Deficits in glucose and synaptic energy supply can disrupt communication and cause abnormal brain function and behavior [34]. The dysregulation of systemic glucose metabolism is observed in SZ [35], and transcriptomic, proteomic, and metabolomic studies have repeatedly shown the glycolysis pathway as being disturbed in both the brain and cerebrospinal fluid of patients with SZ [36,37,38]. Chouinard et al. demonstrated abnormal brain bioenergetics in individuals with SZ using 31P magnetic resonance spectroscopy [39]. A variety of glycolysis-related enzymes have been identified to be dysregulated in SZ [38,40] and its translational animal models, including pharmacological and genetic glutamate/NMDA receptor hypofunction models [36,41,42]. In first-onset, antipsychotic-naive patients with SZ, systemic glucose metabolism anomalies can lead to hyperglycemia, decreased glucose tolerance, and increased resistance to insulin [43,44,45]. These findings indicate that a metabolic-based treatment that bypasses damaged glycolytic pathways and impaired mitochondrial activity may have beneficial therapeutic effects [35]. By bypassing glycolysis, providing alternative energy substrates in the form of ketone bodies, and resetting the processes underlying glucose and energy metabolism, the KD positively impacts normalization of brain energy metabolism [46,47,48]. Additionally, it inhibits histone deacetylases and promotes metabolic regulation [35]. The KD improves neuronal function by lowering glutamate toxicity, increasing GABA inhibitory tone, and decreasing reactive oxygen species (ROS) production [49]. The mechanisms of action of the KD also include optimizing mitochondrial metabolism and neurotransmitter function, strengthening neural network stability, and improving oxidative stress and inflammation. The metabolic, neuroprotective, and neurochemical impacts of the KD may give symptomatic relief to people with SZ [17,50].
Moreover, in recent years, the gut microbiota diversity of patients with SZ has been compared to gut microbiota of healthy individuals. In comparison to the healthy gut, facultative anaerobic bacteria such as Lactobacillus fermentum, Alkaliphilus oremlandii, Cronobacter sakazakii/turicensis, and Enterococcus faecium were identified among individuals with SZ [51]. Authors suggest that a personalized and targeted modulation of intestinal microbial diversity by prebiotics (non-digestible fiber) might be a treatment option for management of SZ [52]. The KD considerably impacts the variety and count of the gut microbiome, which is linked to reduced blood glucose levels and increased blood ketone levels [53].
The etiopathogenesis of SZ and the potential role of the ketogenic diet In its treatment are summarized in Figure 1. An overlapping mechanism of the pathogenesis of SMI and the therapeutic mechanism(s) of the KD on SMI should be considered.