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The ketogenic diet and remission of psychotic symptoms in schizophrenia: Two case studies

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... Nem todos os mecanismos dos efeitos benéficos das DC nestas patologias são claros, mas supõe-se estarem relacionados com a melhoria do metabolismo energético (7,11,14,16,25), a redução do stresse oxidativo (7,11,14,16,55,70,71), a redução de processos imunológicos/inflamatórios (7,11,14,16,55,70,71), a modulação dos níveis de neurotransmissores (7,16,19,55,70,71), a modulação da função mitocondrial (19,55,(70)(71)(72), a modulação do microbioma Existe ainda algum debate acerca da segurança da restrição de HC a longo prazo (27). Todavia, as DC são geralmente consideradas seguras, e a maioria dos efeitos colaterais (10,25,48,85) é transitória e pode ser prevenida ou tratada com medidas simples (25,48), não se comparando às complicações resultantes dos fármacos utilizados em algumas condições neuropsiquiátricas (10). ...
... Nem todos os mecanismos dos efeitos benéficos das DC nestas patologias são claros, mas supõe-se estarem relacionados com a melhoria do metabolismo energético (7,11,14,16,25), a redução do stresse oxidativo (7,11,14,16,55,70,71), a redução de processos imunológicos/inflamatórios (7,11,14,16,55,70,71), a modulação dos níveis de neurotransmissores (7,16,19,55,70,71), a modulação da função mitocondrial (19,55,(70)(71)(72), a modulação do microbioma Existe ainda algum debate acerca da segurança da restrição de HC a longo prazo (27). Todavia, as DC são geralmente consideradas seguras, e a maioria dos efeitos colaterais (10,25,48,85) é transitória e pode ser prevenida ou tratada com medidas simples (25,48), não se comparando às complicações resultantes dos fármacos utilizados em algumas condições neuropsiquiátricas (10). ...
... Nem todos os mecanismos dos efeitos benéficos das DC nestas patologias são claros, mas supõe-se estarem relacionados com a melhoria do metabolismo energético (7,11,14,16,25), a redução do stresse oxidativo (7,11,14,16,55,70,71), a redução de processos imunológicos/inflamatórios (7,11,14,16,55,70,71), a modulação dos níveis de neurotransmissores (7,16,19,55,70,71), a modulação da função mitocondrial (19,55,(70)(71)(72), a modulação do microbioma Existe ainda algum debate acerca da segurança da restrição de HC a longo prazo (27). Todavia, as DC são geralmente consideradas seguras, e a maioria dos efeitos colaterais (10,25,48,85) é transitória e pode ser prevenida ou tratada com medidas simples (25,48), não se comparando às complicações resultantes dos fármacos utilizados em algumas condições neuropsiquiátricas (10). ...
Article
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As perturbações mentais estão a tornar-se mais prevalentes a nível global, e existe evidência de que a nutrição é um fator crucial no que diz respeito à sua prevalência e incidência. As abordagens de tratamento mais utilizadas, a psicoterapia e a psicofarmacoterapia, nem sempre são acessíveis, toleráveis ou eficazes no alívio dos sintomas. As dietas cetogénicas, restritas em hidratos de carbono, moderadas em proteína e ricas em gordura, são há muito utilizadas no tratamento de epilepsia refratária e, mais recentemente, têm vindo a ser investigadas no âmbito de muitas outras condições metabólicas, neurodegenerativas e do neurodesenvolvimento. Este trabalho pretende rever a evidência existente relativamente à utilização das dietas cetogénicas na prevenção e tratamento de perturbações mentais. Foi realizada uma pesquisa nas bases de dados PubMed e Scopus, de fevereiro a junho de 2022. Os estudos encontrados atribuem às dietas cetogénicas um efeito ansiolítico, antidepressivo, estabilizador do humor e antipsicótico, para além de reduções significativas na sintomatologia de várias outras perturbações, como autismo, ingestão compulsiva, hiperatividade e abuso de substâncias. Contudo, os estudos em humanos são escassos e de baixa qualidade. Em conclusão, a escassez de ensaios clínicos aleatorizados e controlados não permite traçar, neste momento, conclusões firmes sobre a eficácia das dietas cetogénicas nas perturbações mentais. No entanto, o seu carácter promissor justifica a realização de mais estudos.
... Several neurological diseases involve cerebral glucose hypometabolism, which is also observed in schizophrenia; thus, it is hypothesized the ketogenic diet may be metabolically favorable for brain function in schizophrenia. There is also evidence that it can reduce oxidative stress and inflammation Ketogenic diet • Reduce oxidative stress and inflammation [28] • Compensate for impaired cerebral glucose metabolism [28] • Reduction of positive and negative symptoms [29][30][31][32][33] • Possible benefits to metabolic or gastrointestinal health [29,30] Gluten-free diet • Avoid inflammatory reactions to gluten-containing foods in patients with non-Celiac gluten sensitivity and elevated antigliadin IgG antibodies [11][12][13][14][15] • Reduction of positive and negative symptoms [34][35][36] • Improvements in cognition [35] • Possible reduction of other gluten-related symptoms, such as gastrointestinal problems Probiotics and prebiotics • Improve microbiome composition and diversity [16][17][18] • Reduction of positive and negative symptoms [38][39][40] • Improvements in cognition [42,43] • Reduction of gastrointestinal symptoms [41] Omega-3 fatty acids • Support proper neurodevelopment and neural functioning, particularly cell membranes [23] • Reduce inflammation [23] • Reduction of positive and negative symptoms [45,46] • Reduced depression and anxiety [48,60] • Improvements in cognition [58,59] Vitamin D • Modulate GABA/glutamate balance [22] • Maintain proper calcium homeostasis [22] • Reduction of positive and negative symptoms [40,63 B vitamins • Support proper neurodevelopment [19] • Support neurotransmitter formation [19] • Prevention of cognitive decline [64] • Improvements in cognition [64] and animal studies suggest it may address GABA/glutamate imbalances seen in schizophrenia [28]. While evidence on the use of the ketogenic diet in schizophrenia from human studies is limited, there are some compelling results. ...
... Several neurological diseases involve cerebral glucose hypometabolism, which is also observed in schizophrenia; thus, it is hypothesized the ketogenic diet may be metabolically favorable for brain function in schizophrenia. There is also evidence that it can reduce oxidative stress and inflammation Ketogenic diet • Reduce oxidative stress and inflammation [28] • Compensate for impaired cerebral glucose metabolism [28] • Reduction of positive and negative symptoms [29][30][31][32][33] • Possible benefits to metabolic or gastrointestinal health [29,30] Gluten-free diet • Avoid inflammatory reactions to gluten-containing foods in patients with non-Celiac gluten sensitivity and elevated antigliadin IgG antibodies [11][12][13][14][15] • Reduction of positive and negative symptoms [34][35][36] • Improvements in cognition [35] • Possible reduction of other gluten-related symptoms, such as gastrointestinal problems Probiotics and prebiotics • Improve microbiome composition and diversity [16][17][18] • Reduction of positive and negative symptoms [38][39][40] • Improvements in cognition [42,43] • Reduction of gastrointestinal symptoms [41] Omega-3 fatty acids • Support proper neurodevelopment and neural functioning, particularly cell membranes [23] • Reduce inflammation [23] • Reduction of positive and negative symptoms [45,46] • Reduced depression and anxiety [48,60] • Improvements in cognition [58,59] Vitamin D • Modulate GABA/glutamate balance [22] • Maintain proper calcium homeostasis [22] • Reduction of positive and negative symptoms [40,63 B vitamins • Support proper neurodevelopment [19] • Support neurotransmitter formation [19] • Prevention of cognitive decline [64] • Improvements in cognition [64] and animal studies suggest it may address GABA/glutamate imbalances seen in schizophrenia [28]. While evidence on the use of the ketogenic diet in schizophrenia from human studies is limited, there are some compelling results. ...
... Their scores returned to baseline 2 weeks after discontinuing the diet, but both maintained reduced body mass indices as compared to baseline [29]. In a case series describing two patients with schizophrenia diagnoses and chronic, treatment-refractory psychotic symptoms, both started a ketogenic diet for nonpsychiatric reasons (weight loss and gastrointestinal problems, respectively), but experienced complete remission of their psychiatric symptoms on the diet and were able to discontinue antipsychotics [30]. Another case report described a patient with refractory hallucinations on antipsychotic treatment whose symptoms resolved within 3 weeks of starting a ketogenic diet without any change in medication and remained remitted for the next year on the diet [31]. ...
Article
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Purpose of Review This review aims to provide an overview of the pathophysiological basis for the use of nutritional strategies in the treatment of schizophrenia, outline the evidence for dietary intervention strategies, and discuss clinical considerations around their implementation. Recent Findings Inflammatory and metabolic mechanisms underlying the pathophysiology of schizophrenia are well-characterized and may provide promising treatment targets. Existing literature on dietary intervention strategies for schizophrenia provides evidence supporting the use of antiinflammatory diets, select vitamins and supplements, and more targeted approaches such as gluten-free or ketogenic diets in specific subsets of patients. Implementation of these strategies is limited by physician education on nutrition, inherent difficulties in researching nutrition, patient factors, and structural factors. Summary Nutritional approaches represent an important and potentially underutilized treatment strategy to reduce symptoms and improve quality of life for patients with schizophrenia.
... The utility of the ketogenic diet in patients with schizophrenia has been reported in several case-reports [181][182][183]; all of which have reported benefits of the diet to compliant individuals, with remission of symptoms, reductions in PANSS score, and weight loss. Albeit promising, no large studies have been conducted. ...
... Albeit promising, no large studies have been conducted. The latest published case report documented implementation of the ketogenic for two women with chronic schizophrenia [181]. One patient was on the ketogenic diet for 5 years, the other for 12 years prior to publication. ...
... One patient was on the ketogenic diet for 5 years, the other for 12 years prior to publication. Both of these patients had complete remission of their psychotic symptoms, are off of antipsychotic medication, and have regained independence [181]. Aside from schizophrenia, the ketogenic diet has been effectively used in several psychiatric disorders [184,185]. ...
Article
A substantial and diverse body of literature suggests that the pathophysiology of schizophrenia is related to deficits of bioenergetic function. While antipsychotics are an effective therapy for the management of positive psychotic symptoms, they are not efficacious for the complete schizophrenia symptom profile, such as the negative and cognitive symptoms. In this review, we discuss the relationship between dysfunction of various metabolic pathways across different brain regions in relation to schizophrenia. We contend that several bioenergetic subprocesses are affected across the brain and such deficits are a core feature of the illness. We provide an overview of central perturbations of insulin signaling, glycolysis, pentose-phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation in schizophrenia. Importantly, we discuss pharmacologic and nonpharmacologic interventions that target these pathways and how such interventions may be exploited to improve the symptoms of schizophrenia.
... 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]. ...
Article
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Purpose of Review The ketogenic diet is a low carbohydrate, moderate protein, and high fat diet which results in a metabolic state known as ketosis, in which fats are broken down into ketone bodies. The ketogenic diet is a 100-year-old evidence-based treatment for epilepsy and is gaining popularity as a treatment for various mental disorders, including mood disorders. Our objective is to explain the potential mechanisms through which ketogenic diets may improve the pathophysiology of mood disorders and provide a comprehensive review of recent clinical literature on the topic Recent Findings Mood disorders are associated with several proposed pathophysiological mechanisms, including mitochondrial dysfunction, oxidative stress, inflammation, and insulin resistance. The ketogenic diet shows promise in addressing these underlying pathophysiological mechanisms and emerging clinical data suggest that ketogenic diets may improve symptoms in people with mood disorders. Summary The ketogenic diet shows promise in the treatment of mood disorders. This metabolic intervention has the potential to directly target underlying disease mechanisms, potentially reduce the need for medications, and reduce common side effects and comorbidities, such as weight gain and insulin resistance.
... In individuals with SZ, the severity of symptoms was reduced (32% drop in Brief Psychiatric Rating Scale scores). Moreover, a case report by Palmer et al. presents two patients with SZ treated with the KD for 5 and 12 years [63]. The first patient, an 82-year-old female, saw a significant decrease in psychotic symptoms after 2 weeks of following the KD. ...
... She was taken off haldol-decanoate after a year of treatment and has been free of psychotic symptoms for the past five years without antipsychotic medication. The patient remains on a KD [63]. Kraft et al. reported the unexpected remission of long-standing SZ symptoms in a 70-year-old female patient after beginning a KD [64]. ...
Article
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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.
... The findings of studies of Palmer et al. (2019) and Gilbert-Jaramillo et al. (2018) contributed to the growing body of evidence, which showed KD as having therapeutic potential for individuals with schizophrenia. In the study by Palmer et al. (2019), two female patients with a long history of schizophrenia and psychotic symptoms experienced complete remission of their symptoms without the need for antipsychotic medications after several years on KD. ...
... The findings of studies of Palmer et al. (2019) and Gilbert-Jaramillo et al. (2018) contributed to the growing body of evidence, which showed KD as having therapeutic potential for individuals with schizophrenia. In the study by Palmer et al. (2019), two female patients with a long history of schizophrenia and psychotic symptoms experienced complete remission of their symptoms without the need for antipsychotic medications after several years on KD. These cases are particularly noteworthy given the chronic nature ...
Book
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This book contains seven chapters that present research on the ketogenic diet and its roles in neuroscience and cancer. Chapter one highlights the roles of the ketogenic diet in neuroprotection and biochemical processes involved in the control of epilepsy. Chapter two reviews the use of the ketogenic diet, a low-carb, high-fat regimen, as an adjuvant treatment for neurological diseases such as Parkinson’s disease. Chapter three discusses how the antioxidant properties of the ketogenic diet might benefit patients by potentially ameliorating the harmful consequences of Alzheimer’s disease. Chapter four examines abnormalities in the different molecular components of the GABAergic system in neuropsychiatric disorders as well as the beneficial effects the ketogenic diet on them. Chapters five and six discuss the ketogenic diet’s role in cancer prevention and neuroglia. Chapter 7 presents the effect of the ketogenic diet on NKCC1 cotransporter regional expression.
... Te literature also discusses the use of the KD in psychiatric diseases, such as severe anxiety, depression, active bipolar disorder with psychosis or schizophrenia. Ketones are potentially a neuroprotective factor, primarily due to reduction of infammation in the body and maintenance of stable blood glucose levels [67][68][69][70][71]. However, these studies are limited to single cases or small groups, and the duration of the diet is short. ...
Article
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The ketogenic diet (KD) is a special high-fat, very low-carbohydrate diet with the amount of protein adjusted to one’s requirements. By lowering the supply of carbohydrates, this diet induces a considerable change in metabolism (of protein and fat) and increases the production of ketone bodies. The purpose of this article is to review the diversity of composition, mechanism of action, clinical application and risk associated with the KD. In the last decade, more and more results of the diet’s effects on obesity, diabetes and neurological disorders, among other examples have appeared. The beneficial effects of the KD on neurological diseases are related to the reconstruction of myelin sheaths of neurons, reduction of neuron inflammation, decreased production of reactive oxygen species, support of dopamine production, repair of damaged mitochondria and formation of new ones. Minimizing the intake of carbohydrates results in the reduced absorption of simple sugars, thereby decreasing blood glucose levels and fluctuations of glycaemia in diabetes. Studies on obesity indicate an advantage of the KD over other diets in terms of weight loss. This may be due to the upregulation of the biological activity of appetite-controlling hormones, or to decreased lipogenesis, intensified lipolysis and increased metabolic costs of gluconeogenesis. However, it is important to be aware of the side effects of the KD. These include disorders of the digestive system as well as headaches, irritability, fatigue, the occurrence of vitamin and mineral deficiencies and worsened lipid profile. Further studies aimed to determine long-term effects of the KD are required.
... Although clinical trials have not yet demonstrated the efficacy of the ketogenic diet in bipolar disorder or major depressive disorder, a beneficial effect has been suggested by some case reports [8,33]. Several case reports have also noted the utility of the ketogenic diet in reducing the Positive and Negative Syndrome Scale (PANSS) scores in schizophrenia patients [8,[34][35][36]. Furthermore, exogenous ketone supplementation, through the administration of ketone esters or ketone salts, has surfaced as a promising therapeutic strategy for inducing ketosis, modulating metabolic pathways, and improving behavioral deficits in various animal models of neuropsychiatric diseases [20,29,37]. ...
Article
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The disruption of brain energy metabolism, leading to alterations in synaptic signaling, neu-ral circuitry, and neuroplasticity, has been implicated in severe mental illnesses such as schizophrenia, bipolar disorder, and major depressive disorder. The therapeutic potential of ketogenic interventions in these disorders suggests a link between metabolic disturbances and disease pathology; however, the precise mechanisms underlying these metabolic disturbances, and the therapeutic effects of metabolic ketogenic therapy, remain poorly understood. In this study, we conducted an in silico analysis of transcriptomic data to investigate perturbations in metabolic pathways in the brain across severe mental illnesses via gene expression profiling. We also examined dysregulation of the same pathways in rodent or cell culture models of ketosis, comparing these expression profiles to those observed in the disease states. Our analysis revealed significant perturbations across all metabolic pathways, with the greatest perturbations in glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC) across all three disorders. Additionally, we observed some discordant gene expression patterns between disease states and ketogenic intervention studies, suggesting a potential role for ketone bodies in modulating pathogenic metabolic changes. Our findings highlight the importance of understanding metabolic dysregulation in severe mental illnesses and the potential therapeutic benefits of ketogenic interventions in restoring metabolic homeostasis. This study provides insights into the complex relationship between metabolism and neuropsychiatric disorders and lays the foundation for further experimental investigations aimed at appreciating the implications of the present transcriptomic findings as well as developing targeted therapeutic strategies.
... Following that note, a ketogenetic diet intervention, which mainly consists of reducing carbohydrate intake and increasing fat intake, was associated with a decrease in positive and negative symptoms of schizophrenia (Danan et al. 2022). Two case studies also described how, after following a ketogenic diet, patients started to exhibit improvement in psychotic symptoms and mood, reduction in suicidal thoughts, and weight loss (Palmer et al. 2019). ...
Chapter
Recently, the relationship between nutrition and mental health has gained considerable scientific interest. In this chapter, we aim to highlight and disentangle myths about diet and various psychiatric conditions that have often clouded public understanding. We systematically examine a range of popular beliefs that pertain to diet and its relationship with psychiatric conditions, including eating disorders, mood disorders, and psychosis. We then review the literature on the role of particular food types and diets in mental health. While tackling each of the above, we carefully debunk misconceptions by focusing on evidence-based research and clinical data. In pointing out fallacies, we emphasize the critical interplay between diet and mental health, with the former operating as a constituent in a more complex matrix of factors. Our review concludes with clinical recommendations that guide how best to utilize dietary nutrients in promoting mental health.
... To date, many of the studies on the KD and psychiatric conditions have focused on mechanisms of action in rodents and mice, and less so in humans (12)(13)(14)(15). Though human studies have recently been published they are predominantly case studies or initial pilot studies (6,(16)(17)(18)(19) no randomized control trials have been carried out to investigate the impact of the ketogenic diet on psychological wellbeing or depressive symptoms, though they are now underway. ...
Article
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Background Evidence suggests that a ketogenic diet (KD) may help to alleviate psychiatric symptoms, including depression and anxiety. Positive changes have been reported such as improvements in cognition, concentration, and sleep, a reduction in hunger, and an increase in well-being, energy, confidence, and resilience. This research aims to understand the impact of a non-calorie-restricted KD on depression and aspects of psychological well-being in those with varying degrees of depressive symptoms. Though there are a few studies directly exploring the experiences of those following a KD, this will be the first study to explore the narrative from a mental health and psychological well-being viewpoint. Method A sample of nine participants who had followed a non-calorie restricted KD intervention of 50 g of carbohydrates or less per day for at least 12 weeks were recruited. Participants were split into ‘healthy adults’ group who had no to low depressive symptoms and ‘depressive symptoms’ group who had mild to moderate depressive symptoms. A reflexive thematic analysis was considered suitable for this study. Findings Five core themes and 24 subthemes were created. These were, (1) Poor health prior to program; (2) Hunger and cravings-the food and mood connection; (3) Psychological well-being improvements; (4) It becomes a lifestyle; and (5) Implementation difficulties. Participants experienced mental health improvements such as increased self-esteem, confidence, motivation, and achievement. Some experienced more control in life and a greater sense of reward. Those with depressive symptoms who initially reported low self-worth and hopelessness later reported increased self-esteem and renewed meaning and purpose in life. The findings from this study reflect the previous reports that the diet implementation can be difficult initially, but soon becomes easy to follow and turns into a lifestyle. Conclusion In the literature, there are very few qualitative studies that explore the accounts and lived experiences of those following a KD. From the participants’ accounts in this study, it appears that the benefits and positive outcomes of this diet outweigh any negative side-effects experienced. This is encouraging for those who are looking for adjunctive therapies to address and improve their depressive symptoms and overall mental health.
... They continued to follow the diet, and the hallucinations and suicidal thoughts disappeared. Their mood improved significantly, and they became independent without needing specialist care or medication [117]. ...
Article
Full-text available
It is widely acknowledged that the ketogenic diet (KD) has positive physiological effects as well as therapeutic benefits, particularly in the treatment of chronic diseases. Maintaining nutritional ketosis is of utmost importance in the KD, as it provides numerous health advantages such as an enhanced lipid profile, heightened insulin sensitivity, decreased blood glucose levels, and the modulation of diverse neurotransmitters. Nevertheless, the integration of the KD with pharmacotherapeutic regimens necessitates careful consideration. Due to changes in their absorption, distribution, metabolism, or elimination, the KD can impact the pharmacokinetics of various medications, including anti-diabetic, anti-epileptic, and cardiovascular drugs. Furthermore, the KD, which is characterised by the intake of meals rich in fats, has the potential to impact the pharmacokinetics of specific medications with high lipophilicity, hence enhancing their absorption and bioavailability. However, the pharmacodynamic aspects of the KD, in conjunction with various pharmaceutical interventions, can provide either advantageous or detrimental synergistic outcomes. Therefore, it is important to consider the pharmacokinetic and pharmacodynamic interactions that may arise between the KD and various drugs. This assessment is essential not only for ensuring patients’ compliance with treatment but also for optimising the overall therapeutic outcome, particularly by mitigating adverse reactions. This highlights the significance and necessity of tailoring pharmacological and dietetic therapies in order to enhance the effectiveness and safety of this comprehensive approach to managing chronic diseases.
... Examples of the clinical application of KD in schizophrenia are recent studies [146,147] and a publication almost 60 years old [148]. ...
Article
Coordinated regulation of energy conversion processes in the brain maintains its highly productive work and efficient mental activity. Impairments of the brain energy metabolism are considered among pathogenetic factors in the schizophrenia origin, but presently it is difficult to say whether these impairments are primary and causative the development of the disease or represent consequences of certain changes in the functioning of neurotransmitter and other neurochemical systems. This review discusses the main results of the energy metabolism research in schizophrenia – at various levels and using different approaches, as well as regards some attempts of influencing the energy processes in the brain as an adjunctive therapy in schizophrenia. To date, the efficacy of these therapeutic approaches has not been proven, this may be due to the paucity of studies and the lack of preliminary identification/stratification of patient subgroups to whom the energy metabolism-targeted therapy would be the most useful. Based on the data presented, one can conclude that an analysis is necessary of relationships between the psychopathological manifestations of schizophrenia and energy metabolism deviations for further identification of those patients to whom the use of mitochondrial modulators, mitoprotection, and other approaches may represent a promising method of adjunctive therapy.
... Since the 1920s, the KD has been employed as a therapeutic approach for various neurological disorders, most notably in the management of drug-resistant refractory childhood epilepsy [92,104,105]. More recently, its potential role has been explored in the context of several neurodegenerative diseases, including AD [66] and PD [105,106], as well as in psychiatric diseases such as schizophrenia [107,108], depression [109,110] and Borderline Syndrome [111]. The success behind the use of the KD is linked to its action in common features shared by most CNS diseases, such as glucose hypometabolism, energetic deficits, imbalanced GABA and glutamate transmission, inflammation and oxidative stress [70,92]. ...
Article
Full-text available
Given the remarkable progress in global health and overall quality of life, the significant rise in life expectancy has become intertwined with the surging occurrence of neurodegenerative disorders (NDs). This emerging trend is poised to pose a substantial challenge to the fields of medicine and public health in the years ahead. In this context, Alzheimer’s disease (AD) is regarded as an ND that causes recent memory loss, motor impairment and cognitive deficits. AD is the most common cause of dementia in the elderly and its development is linked to multifactorial interactions between the environment, genetics, aging and lifestyle. The pathological hallmarks in AD are the accumulation of β-amyloid peptide (Aβ), the hyperphosphorylation of tau protein, neurotoxic events and impaired glucose metabolism. Due to pharmacological limitations and in view of the prevailing glycemic hypometabolism, the ketogenic diet (KD) emerges as a promising non-pharmacological possibility for managing AD, an approach that has already demonstrated efficacy in addressing other disorders, notably epilepsy. The KD consists of a food regimen in which carbohydrate intake is discouraged at the expense of increased lipid consumption, inducing metabolic ketosis whereby the main source of energy becomes ketone bodies instead of glucose. Thus, under these dietary conditions, neuronal death via lack of energy would be decreased, inasmuch as the metabolism of lipids is not impaired in AD. In this way, the clinical picture of patients with AD would potentially improve via the slowing down of symptoms and delaying of the progression of the disease. Hence, this review aims to explore the rationale behind utilizing the KD in AD treatment while emphasizing the metabolic interplay between the KD and the improvement of AD indicators, drawing insights from both preclinical and clinical investigations. Via a comprehensive examination of the studies detailed in this review, it is evident that the KD emerges as a promising alternative for managing AD. Moreover, its efficacy is notably enhanced when dietary composition is modified, thereby opening up innovative avenues for decreasing the progression of AD.
... Our observations in this study are consistent with several preliminary case reports and observational studies noting improvement of psychiatric symptoms in bipolar disorder and schizophrenia patients on a ketogenic diet 3,4,27,28,29,30 Metabolic Significant changes in risk factors for cardiometabolic disease were observed among the participants, 70% of whom were overweight or obese. Participants reduced their mean weight by 4.2kg, mean BMI by 5.3% and mean systolic blood pressure by 7.4 mmHg. ...
Preprint
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Background Bipolar disorder and epilepsy are treated with anti-seizure medications. Preliminary evidence indicates that a ketogenic diet (a metabolic treatment for epilepsy) may be effective in the treatment of bipolar disorder. Aims To explore the impact of a ketogenic diet on clinical outcomes, and metabolomic and brain magnetic resonance spectroscopy biomarkers. Methods Euthymic individuals with bipolar disorder (N=27) were recruited to a 6-8 week single-arm trial of a modified ketogenic diet and a range of metabolic and clinical outcome measures were assessed. Results There was a positive correlation between daily ketone levels and ecological momentary assessments of mood (p < 0.001) and energy (p < 0.001) and an inverse correlation between ketone levels and impulsivity (p < 0.001) and anxiety (p < 0.001). Mean weight fell by 4.2kg (p < 0.001), mean BMI fell by 5.3% (p < 0.001) and mean systolic blood pressure was reduced by 7.4 mmHg (p < 0.041). Brain Glx (a putative marker of treatment response to anti-seizure medication) decreased by 13.1% in the posterior cingulate cortex (PCC) (p < 0.001) and by 9.2% in the anterior cingulate cortex ACC (p = 0.02). At the dietary cessation period, one third of participants, who reported reduced mood lability, opted to remain on a ketogenic diet. Conclusion The majority of participants had improved cardiometabolic risk parameters and approximately one third experienced improvement in psychiatric symptoms. The study findings are consistent with our a priori hypothesis of ketone bodies acting as an alternative metabolic substrate under conditions of impaired insulin signalling in a subgroup of patients with bipolar disorder.
... 12 Case series have suggested benefits of a ketogenic diet in several psychiatric disorders, including bipolar disorder 13,14 and schizophrenia. 15,16 Analysis of data from online bipolar disorder forums (165 people with bipolar disorder adhering to a ketogenic diet) found that 56% reported either remission of symptoms or significant mood stabilisation. 4 Recent narrative reviews have indicated that a ketogenic diet may affect metabolic and biochemical features of bipolar disorder, including: reduction in oxidative stress; improved mitochondrial function and biogenesis; improved glutamate/GABA transmission; and reductions in intracellular sodium and calcium. 17 In this pilot study, we aimed to assess recruitment, acceptability and feasibility of the intervention and completion of relevant outcome measures. ...
Article
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Background Recent evidence from case reports suggests that a ketogenic diet may be effective for bipolar disorder. However, no clinical trials have been conducted to date. Aims To assess the recruitment and feasibility of a ketogenic diet intervention in bipolar disorder. Method Euthymic individuals with bipolar disorder were recruited to a 6–8 week trial of a modified ketogenic diet, and a range of clinical, economic and functional outcome measures were assessed. Study registration number: ISRCTN61613198. Results Of 27 recruited participants, 26 commenced and 20 completed the modified ketogenic diet for 6–8 weeks. The outcomes data-set was 95% complete for daily ketone measures, 95% complete for daily glucose measures and 95% complete for daily ecological momentary assessment of symptoms during the intervention period. Mean daily blood ketone readings were 1.3 mmol/L (s.d. = 0.77, median = 1.1) during the intervention period, and 91% of all readings indicated ketosis, suggesting a high degree of adherence to the diet. Over 91% of daily blood glucose readings were within normal range, with 9% indicating mild hypoglycaemia. Eleven minor adverse events were recorded, including fatigue, constipation, drowsiness and hunger. One serious adverse event was reported (euglycemic ketoacidosis in a participant taking SGLT2-inhibitor medication). Conclusions The recruitment and retention of euthymic individuals with bipolar disorder to a 6–8 week ketogenic diet intervention was feasible, with high completion rates for outcome measures. The majority of participants reached and maintained ketosis, and adverse events were generally mild and modifiable. A future randomised controlled trial is now warranted.
... Case series have suggested benefits of a ketogenic diet in several psychiatric disorders, including bipolar disorder (13) and schizophrenia (14). Analyses of data from online bipolar disorder forums (165 people with bipolar disorder adhering to a ketogenic diet) found that 56% reported either remission of symptoms or significant mood stabilisation (4). ...
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Background Recent evidence from case reports suggests that a ketogenic diet may be effective for bipolar disorder. To date, no clinical trials have been conducted. Aims To assess the recruitment and feasibility of a ketogenic diet intervention in bipolar disorder. Methods Euthymic individuals with bipolar disorder were recruited to a 6-8 week trial of a modified ketogenic diet and a range of clinical, economic and functional outcome measures were assessed. Results Of 27 recruited participants, 26 commenced and 20 completed the modified ketogenic diet at 6-8 weeks. The completeness of the outcomes dataset was 95% for daily ketone measures, 95% for daily glucose measures and 95% for daily Ecological Momentary Assessment of symptoms during the intervention period. Mean daily blood ketone readings were 1.3 mmol/L (SD= 0.77, Median = 1.1), and 91% of all readings indicated ketosis indicating a high degree of adherence to the diet. Over 91% of daily blood glucose readings were within normal range with 9% indicating mild hypoglycaemia. Eleven minor adverse events were recorded, including fatigue, constipation, drowsiness and hunger. One serious adverse event was reported (euglycemic ketoacidosis in a participant taking SGLT2-inhibitor medication). Conclusions The recruitment and retention of euthymic individuals with bipolar disorder to a 6-8 week ketogenic diet intervention was feasible, with high outcome measure completion rates. The majority of participants reached and maintained ketosis and adverse events were generally mild and modifiable. A future randomised controlled trial is now warranted.
... Both individuals either intentionally or accidentally interrupted KD, and their psychotic symptoms reverted immediately [106]. Two additional case studies [108] highlighted the prolonged efficiency of KD as a balanced therapy that may lead to a complete reduction of psychotic symptoms, at least in certain individuals. The first case concerned a 12 year follow-up of a 70 year old woman [106]. ...
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Background: The ketogenic diet (KD) has become widespread for the therapy of epileptic pathology in childhood and adulthood. In the last few decades, the current re-emergence of its popularity has focused on the treatment of obesity and diabetes mellitus. KD also exerts anti-inflammatory and neuroprotective properties, which could be utilized for the therapy of neurodegenerative and psychiatric disorders. Purpose: This is a thorough, scoping review that aims to summarize and scrutinize the currently available basic research performed in in vitro and in vivo settings, as well as the clinical evidence of the potential beneficial effects of KD against neurodegenerative and psychiatric diseases. This review was conducted to systematically map the research performed in this area as well as identify gaps in knowledge. Methods: We thoroughly explored the most accurate scientific web databases, e.g., PubMed, Scopus, Web of Science, and Google Scholar, to obtain the most recent in vitro and in vivo data from animal studies as well as clinical human surveys from the last twenty years, applying effective and characteristic keywords. Results: Basic research has revealed multiple molecular mechanisms through which KD can exert neuroprotective effects, such as neuroinflammation inhibition, decreased reactive oxygen species (ROS) production, decreased amyloid plaque deposition and microglial activation, protection in dopaminergic neurons, tau hyper-phosphorylation suppression, stimulating mitochondrial biogenesis, enhancing gut microbial diversity, restoration of histone acetylation, and neuron repair promotion. On the other hand, clinical evidence remains scarce. Most existing clinical studies are modest, frequently uncontrolled, and merely assess the short-term impacts of KD. Moreover, several clinical studies had large dropout rates and a considerable lack of compliance assessment, as well as an increased level of heterogeneity in the study design and methodology. Conclusions: KD can exert substantial neuroprotective effects via multiple molecular mechanisms in various neurodegenerative and psychiatric pathological states. Large, long-term, randomized, double-blind, controlled clinical trials with a prospective design are strongly recommended to delineate whether KD may attenuate or even treat neurodegenerative and psychiatric disease development, progression, and symptomatology.
... [121] Clinical studies have suggested that KDs are effective in treating schizophrenia. [122,123] In MK801-treated mice, acute 3HB attenuated spontaneous motor activity, MK801-induced motor hyperactivity, and MK801-induced prepulse inhibition. [124] 3HB offered a new treatment option for individuals with schizophrenia by 6 of 10 -WANG ET AL. ...
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3‐hydroxybutyrate (3HB), or BHB, is an anionic small molecule acid metabolite with a hydroxyl group. 3HB is the major ketone body that is distributed in the human brain and its primary energy source when glucose is absent. A better understanding of 3HB and how to adapt neuronal response mechanisms is expected to facilitate the development of new interventions to promote cognitive brain function and prevent neurodegenerative diseases. It provides important concepts for the clinical application of 3HB therapy. This review summarizes the distribution of 3HB in the brain, its properties, and its mechanism in brain and nerve regulation. We focus on 3HB biosynthesis in natural human cells and engineered bacteria via synthetic biology platforms and 3HB treatment in various brain and nerve diseases, including epilepsy, multiple sclerosis, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, depressive disorder, and schizophrenia. Ultimately, this review explores the future development trend of 3HB as a potential small‐molecule drug for brain and nerve diseases.
... When it comes to schizophrenia, the ketogenic diet can be considered to be an efficient treatment and can even reverse some of the persistent symptoms of this disease [109]. In another case study, a 33-year-old man diagnosed with MDD and schizoaffective disorder was prescribed with several medications including lamotrigine and lorazepam and then started a ketogenic diet for 3 weeks [110]. ...
Chapter
The ketogenic diet, known as a low-carbohydrate, high-protein, and high-fat diet, drastically restrains the major source of energy for the body, forcing it to burn all excess fat through a process called ketosis—the breaking down of fat into ketone bodies. First suggested as a medical treatment for children suffering from epilepsy, this diet has gained increased popularity as a rapid weight loss strategy. Over the past few years, there have been numerous studies suggesting that the ketogenic diet may provide therapeutic effects for several psychiatric conditions such as mood- and anxiety-related disorders. However, despite significant progress in research, the mechanisms underlying its therapeutic effects remain largely unexplored and are yet to be fully elucidated. This chapter provides an in-depth overview of preclinical and clinical evidence supporting the use of a ketogenic diet in the management of mood and anxiety disorders and discusses its relationship with inflammatory processes and potential mechanisms of actions for its therapeutic effects.KeywordsAnxietyBipolar disorderInflammationKetogenic dietMajor depressive disorderMood disorders Schizophrenia
... [73] Other case studies have also showed remission of psychotic symptoms in schizophrenia after patients altered their diets. [74] Other diseases associated with nutrient dysregulation and specific dietary recommendations have also been associated with symptoms indistinguishable from those associated with schizophrenia, such as Wilson's disease (a result of high levels of copper), unrecognized adult phenylketonuria, [75] pellagra, and celiac disease. [76] After following a gluten-free diet, a patient with celiac disease and classic schizophrenia experienced complete resolution of both conditions. ...
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Schizophrenia is a poorly understood mental disease, which contributes to patients with schizophrenia having few therapeutic options apart from atypical antipsychotic drugs. The first part of this review addresses the challenges regarding the low therapeutic efficacy and low adherence rate of antipsychotic drugs used to treat schizophrenia, and the second part explores biochemical imbalances (nutrient excesses or deficiencies) healthcare providers should consider as factors causing schizophrenia. This article addresses the relationships and challenges between vitamin C, niacin, zinc, copper, cobalamin, folate, and various types of diets and schizophrenia. Considering the low efficacy and adherence to pharmacological therapies, alternative treatments and nutrients could be considered as complementary or options to patients with schizophrenia.
... W studiach przypadków i dwóch badaniach klinicznych dotyczących zaburzeń ze spektrum autyzmu (ASD) wykazano zmniejszenie objawów u osób z ASD, przede wszystkim usprawnienie komunikacji społecznej [45,[51][52][53][54]. Dowiedziono także, że dieta ketogeniczna działa przeciwlękowo, co może mieć zastosowanie w leczeniu zaburzeń depresyjnych [45,55,56]. Istnieją także wczesne dowody kliniczne na skuteczność KD w chorobie afektywnej dwubiegunowej [57], w schizofrenii [58][59][60] i w zaburzeniach z napadami objadania się [61]. Niealkoholowa stłuszczeniowa choroba wątroby Niealkoholowa stłuszczeniowa choroba wątroby (NAFLD) jest główną przyczyną przewlekłej choroby wątroby, charakteryzującej się akumulacją tłuszczu w wątrobie i możliwym rozwojem zapalenia, zwłóknienia i raka. ...
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Introduction and purpose: Ketogenic diet (KD) is a form of nutrition based on usage of ketone bodies, received from transformation of consumed fats as a main source of energy. Advantages of this type of metabolism are used in treatment of various diseases. Our purpose is to sum up and present what we know about its usage, as a therapeutic tool, so far. Description of the state of knowledge: The use of ketone bodies, instead of glucose, as a main source of energy is more efficient, reduces oxidative stress and inflammation. Furthermore, it modulates gut microbiota. KD is used in the treatment of drug-resistant epilepsy in children and is proved to be useful in the treatment of type 2 diabetes. It can improve health of patients with non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases and psychiatric diseases. The usage in other areas is still under research. It is also necessary to take into consideration adverse effects of KD such as an increase in level of LDL-cholesterol and a potential lack of some macro- and microelements. Additionaly, maintaining the diet seems to be difficult, therefore, there is no enough data to fully describe its impact on human health in long-term perspective. Conclusions: The findings presented in this paper suggest that a ketogenic diet can constructively supplement the treatment of drug-resistant epilepsy in children and aid the treatment of type 2 diabetes. Regarding diseases associated with oxidative stress and inflammation, the reviewed data indicates that KD could be of use. However, KD is not recommended to be routinely ordered before further studies have substantiated and observable effect.
... Giving a ketogenic diet with a ratio of 3: 1 for 6 weeks showed that after 15 days there was an improvement in mental disorders (Gilbert-Jaramillo et al., 2018). Regular administration of the ketogenic diet has a positive impact on people with mental disorders (Palmer et al., 2019). In the study by Zang et al. (2020). ...
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Background and Objectives: Konjac glucomannan has the effect of maintaining Blood Glukosa Fasting (BGF) in the general population, but there is no research on schizophrenic patients who are susceptible to hyperglycemia. Our study aims to evaluate the effects of konjac glucomannan on blood glucose levels in schizophrenia in patients with hyperglycemia. Methods and Study Design: eight people with schizophrenia were enrolled in a 30-day pra experimental study. The subjects in the experimental group were given a capsule containing konjac glucomannan 30 minutes before each meal Results: The plasma glucose was measured at baseline and at the first of 0-day treatment end of 31-day treatment. Eight subjects completed the study. There was a substantial decrease in plasma glucose in the experimental group. Conclusions: We concluded that a diet supplemented with konjac glucomannan may prevent the deterioration of hyperglycemia in people with schizophrenia, demonstrating its potential value in the treatment of metabolic disorders in schizophrenia as a new therapeutic method herb.
... Owing to the complex metabolic state induced by the consumption of a KD, it is not simple to dissect the mechanisms responsible for its amelioration of neurodegenerative disorders. Finally, a KD appears to be beneficial in autism spectrum disorder [80], bipolar disorder [81], migraine [82], and schizophrenia [83]. However, in the literature, there is a lack of preclinical research focusing on the cellular/molecular mechanisms involved, and of randomized controlled clinical studies systematically evaluating the efficacy of KD treatments. ...
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The consumption of a high-fat, low-carbohydrate diet (ketogenic diet) has diverse effects on health and is expected to have therapeutic value in neurological disorders, metabolic syndrome, and cancer. Recent studies have shown that a ketogenic diet not only pronouncedly shifts the cellular metabolism to pseudo-starvation, but also exerts a variety of physiological functions on various organs through metabolites that act as energy substrates, signaling molecules, and epigenetic modifiers. In this review, we highlight the latest findings on the molecular mechanisms of a ketogenic diet and speculate on the significance of these functions in the context of the epigenome and microbiome. Unraveling the molecular basis of the bioactive effects of a ketogenic diet should provide solid evidence for its clinical application in a variety of diseases including cancer.
... A KD shifts energy metabolism toward β-oxidation, the mitochondrial aerobic catabolism of fatty acids into acetyl-CoA (16), which can reduce the risk of seizures in patients with epilepsy (17)(18)(19)(20)(21). In addition, KDs have shown therapeutic effects in patients with Alzheimer's disease (22) and Parkinson's disease (23), and have been proposed as a potential therapeutic intervention for psychiatric disorders such as autism spectrum disorder (24,25), major depressive disorder (26,27), schizophrenia (28,29), and bipolar disorder (30,31). However, patient adherence to KDs, particularly those that most tightly restrict carbohydrate content (32), is limited by their poor palatability. ...
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Alcohol use disorder (AUD) is a chronic, relapsing brain disorder, characterized by compulsive alcohol seeking and disrupted brain function. In individuals with AUD, abstinence from alcohol often precipitates withdrawal symptoms than can be life threatening. Here, we review evidence for nutritional ketosis as a potential means to reduce withdrawal and alcohol craving. We also review the underlying mechanisms of action of ketosis. Several findings suggest that during alcohol intoxication there is a shift from glucose to acetate metabolism that is enhanced in individuals with AUD. During withdrawal, there is a decline in acetate levels that can result in an energy deficit and could contribute to neurotoxicity. A ketogenic diet or ingestion of a ketone ester elevates ketone bodies (acetoacetate, β-hydroxybutyrate and acetone) in plasma and brain, resulting in nutritional ketosis. These effects have been shown to reduce alcohol withdrawal symptoms, alcohol craving, and alcohol consumption in both preclinical and clinical studies. Thus, nutritional ketosis may represent a unique treatment option for AUD: namely, a nutritional intervention that could be used alone or to augment the effects of medications.
... Neuroinflammation, HPA axis hyperactivity, and altered neurotransmitters (such as 5-HT) are common mechanisms for epilepsy and comorbid depression, and involved in the gut-brain axis (117,198,199). KD, a well-known treatment for epilepsy, has been shown to play a role in psychiatric disorders (200). Other than KD, antibiotics, FMT, probiotics, and prebiotics also have potential in regulating both mood and epilepsy (158,163,188,192). ...
Article
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The gut–brain axis refers to the bidirectional communication between the gut and brain, and regulates intestinal homeostasis and the central nervous system via neural networks and neuroendocrine, immune, and inflammatory pathways. The development of sequencing technology has evidenced the key regulatory role of the gut microbiota in several neurological disorders, including Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. Epilepsy is a complex disease with multiple risk factors that affect more than 50 million people worldwide; nearly 30% of patients with epilepsy cannot be controlled with drugs. Interestingly, patients with inflammatory bowel disease are more susceptible to epilepsy, and a ketogenic diet is an effective treatment for patients with intractable epilepsy. Based on these clinical facts, the role of the microbiome and the gut–brain axis in epilepsy cannot be ignored. In this review, we discuss the relationship between the gut microbiota and epilepsy, summarize the possible pathogenic mechanisms of epilepsy from the perspective of the microbiota gut–brain axis, and discuss novel therapies targeting the gut microbiota. A better understanding of the role of the microbiota in the gut–brain axis, especially the intestinal one, would help investigate the mechanism, diagnosis, prognosis evaluation, and treatment of intractable epilepsy.
... In schizophrenia, comorbidity with IBS [73], non-celiac gluten sensitivity [74], and the correlation between the amount of Lactobacillus and the severity of the symptomatology [75] also provide evidence of a possible connection to the MGB. Indeed, a reduction in the symptoms associated with the schizophrenia spectrum, such as delusions or disorganized behavior, has been associated with the use of a ketogenic diet [76], which could activate the auditory sensory gating deficit characterized in schizophrenia patients, as suggested in preclinical studies in DBA/2 mice [77]. ...
Article
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The accumulating evidence linking bacteria in the gut and neurons in the brain (the microbiota–gut–brain axis) has led to a paradigm shift in the neurosciences. Understanding the neurobiological mechanisms supporting the relevance of actions mediated by the gut microbiota for brain physiology and neuronal functioning is a key research area. In this review, we discuss the literature showing how the microbiota is emerging as a key regulator of the brain’s function and behavior, as increasing amounts of evidence on the importance of the bidirectional communication between the intestinal bacteria and the brain have accumulated. Based on recent discoveries, we suggest that the interaction between diet and the gut microbiota, which might ultimately affect the brain, represents an unprecedented stimulus for conducting new research that links food and mood. We also review the limited work in the clinical arena to date, and we propose novel approaches for deciphering the gut microbiota–brain axis and, eventually, for manipulating this relationship to boost mental wellness.
... Palmer et al. recently described two cases of schizophrenia remission patients eating a ketogenic diet, both of whom remained free of psychotic symptoms and stopped all antipsychotic medications while on the diet[214]. The ketogenic diet has also been shown capable of improving symptoms in patients with a range of other conditions such as type 2 diabetes, autism, and depression[215]. ...
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The Warburg effect refers to a metabolic state in which cells preferentially use aerobic glycolysis rather than oxidative phosphorylation to generate ATP and macromolecules. A number of chronic inflammatory conditions are characterized by host cells that adopt a sustained, pathological Warburg-like metabolism. In cancer, previously healthy cells shift into a Warburg state centered on rapid energy production and increased cell proliferation that drives tumor formation. Macrophage in atherosclerotic plaque and in sarcoidosis granuloma can also harbor a Warburg-like phenotype that promotes an inflammatory milieu. The question of why host cells in patients with cancer and other chronic inflammatory conditions adapt a pathological Warburg-like metabolism is a matter of debate. This review/hypothesis piece explores how intracellular infection can contribute to this Warburg metabolism or related pathological metabolic states. We detail molecular mechanisms by which viral, bacterial, and protozoan intracellular pathogens can induce, or contribute to, a Warburg-like metabolism in infected host cells in order to meet their own replication and nutritional needs. We also discuss how host defense towards infection may impact cellular metabolic changes. We then provide examples of how many of these same intracellular pathogens have been identified in tumors, atherosclerotic lesions, granuloma, and other tissues containing cells with a Warburg or altered metabolism. Last, we examine further trends associated with infection and host cell metabolism, including how pathogen-driven hijacking of host cell lipid metabolism can support viral, bacterial, and parasite survival and replication.
... Two studies on mouse models of schizophrenia indicate that a ketogenic diet may be an effective treatment (Kraeuter et al., 2019). In addition, two clinical studies of ketogenic diets in the treatment of human mental disorders have been successful (Palmer et al., 2019). ...
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The human body hosts enormous diversity of microbiota. Recently, the importance of microbial communities to host physiology has been recognised. Evidence is now emerging that the bidirectional communication between the central nervous system and gastrointestinal tract may affect human nerves, cognition and behaviour through the gut‐brain axis (GBA). Although the connection between enteropathy and neurological diseases has been found, it now seems intestinal microorganisms represent the direct mediator of psychopathology. The interactions between host neurological function and intestinal microbiota suggested dietary is a possible way to alleviate psychopathological and neurodegenerative diseases. This review discusses the possible effect of intestinal microbiota on the changes of nerves and emotions in human brain. Maintaining healthy diet strategies should be an important part of preventing neurological diseases and psychopathologies caused by systemic metabolic changes. We hope to provide a novel insight for the design of dietary therapies from the perspective of GBA.
... The ketone bodies acetoacetate (AcAc) and beta-hydroxybutyrate (BHB) are small molecules catabolized in the liver via fatty acid oxidation during times of starvation or metabolic stress, when carbohydrates are scarce (Achanta and Rae 2017;Newman and Verdin 2014). Metabolic shifts toward ketone body catalysis have been reported in patients with schizophrenia (Yang et al., 2013), and increasing circulating ketones, through either ketogenic diets (Sussman et al. 2015;Phelps et al. 2013;Kraeuter, van den Buuse, and Sarnyai 2019;Kraft and Westman 2009;Palmer 2017;Palmer et al. 2019;Kraeuter et al., 2015;Murphy et al., 2004;Ahn et al., 2014;Evangeliou et al., 2003;Ruskin et al., 2017;Murphy and Burnham 2006) or exogenous ketone supplementation (Ari et al., 2016;Kashiwaya et al., 2013;Brownlow et al., 2017), have demonstrated therapeutic effects in psychiatric disease in both rodents and humans. AcAc and BHB freely cross the blood-brain barrier and enter the mitochondria, where they are converted to acetyl-CoA, driving ATP synthesis (Achanta and Rae 2017;Newman and Verdin 2014). ...
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Mitochondrial metabolism is increasingly implicated in psychopathologies and mood disorders, including post-traumatic stress disorder (PTSD). We recently reported that mice exposed to a novel paradigm for the induction of PTSD-like behavior displayed reduced mitochondrial electron transport chain (mtETC) complex activity as well as decreased multi-system fatty acid oxidation (FAO) flux. Based on these results, we hypothesized that stressed and PTSD-like animals would display evidence of metabolic reprogramming in both cerebellum and plasma consistent with increased energetic demand, mitochondrial metabolic reprogramming, and increased oxidative stress. We performed targeted metabolomics in both cerebellar tissue and plasma, as well as untargeted nuclear magnetic resonance (NMR) spectroscopy in the cerebellum of 6 PTSD-like and 7 resilient male mice as well as 7 trauma-naïve controls. We identified numerous differences in amino acids and tricarboxylic acid (TCA) cycle metabolite concentrations in the cerebellum and plasma consistent with altered mitochondrial energy metabolism in trauma exposed and PTSD-like animals. Pathway analysis identified metabolic pathways with significant metabolic pathway shifts associated with trauma exposure, including the tricarboxylic acid cycle, pyruvate, and branched-chain amino acid metabolism in both cerebellar tissue and plasma. Altered glutamine and glutamate metabolism, and arginine biosynthesis was evident uniquely in cerebellar tissue, while ketone body levels were modified in plasma. Importantly, we also identified several cerebellar metabolites (e.g. choline, adenosine diphosphate, beta-alanine, taurine, and myo-inositol) that were sufficient to discriminate PTSD-like from resilient animals. This multilevel analysis provides a comprehensive understanding of local and systemic metabolite fingerprints associated with PTSD-like behavior, and subsequently altered brain bioenergetics. Notably, several transformed metabolic pathways observed in the cerebellum were also reflected in plasma, connecting central and peripheral biosignatures of PTSD-like behavior. These preliminary findings could direct further mechanistic studies and offer insights into potential metabolic interventions, either pharmacological or dietary, to improve PTSD resilience.
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Article
Purpose of review: Ketogenic diets, which have been used to treat drug-refractory paediatric epilepsy for over 100 years, are becoming increasingly popular for the treatment of other neurological conditions, including mental illnesses. We aim to explain how ketogenic diets can improve mental illness biopathology and review the recent clinical literature. Recent findings: Psychiatric conditions, such as schizophrenia, depression, bipolar disorder and binge eating disorder, are neurometabolic diseases that share several common mechanistic biopathologies. These include glucose hypometabolism, neurotransmitter imbalances, oxidative stress and inflammation. There is strong evidence that ketogenic diets can address these four fundamental diseases, and now complementary clinical evidence that ketogenic diets can improve the patients' symptoms. Summary: It is important that researchers and clinicians are made aware of the trajectory of the evidence for the implementation of ketogenic diets in mental illnesses, as such a metabolic intervention provides not only a novel form of symptomatic treatment, but one that may be able to directly address the underlying disease mechanisms and, in so doing, also treat burdensome comorbidities (see Video, Supplementary Digital Content 1, http://links.lww.com/COE/A16, which summarizes the contents of this review).
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Introduction The application of ketogenic dietary interventions to mental health treatments is increasingly acknowledged within medical and psychiatric fields, yet its exploration in clinical psychology remains limited. This article discusses the potential implications of ketogenic diets, traditionally utilized for neurological disorders, within broader mental health practices. Methods This article presents a perspective based on existing ketogenic diet research on historical use, biological mechanisms, and therapeutic benefits. It examines the potential application of these diets in mental health treatment and their relevance to clinical psychology research and practice. Results The review informs psychologists of the therapeutic benefits of ketogenic diets and introduces to the psychology literature the underlying biological mechanisms involved, such as modulation of neurotransmitters, reduction of inflammation, and stabilization of brain energy metabolism, demonstrating their potential relevance to biopsychosocial practice in clinical psychology. Conclusion By considering metabolic therapies, clinical psychologists can broaden their scope of biopsychosocial clinical psychology practice. This integration provides a care model that incorporates knowledge of the ketogenic diet as a treatment option in psychiatric care. The article emphasizes the need for further research and training for clinical psychologists to support the effective implementation of this metabolic psychiatry intervention.
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Background Schizophrenia, schizoaffective disorder, and bipolar affective disorder are debilitating psychiatric conditions characterized by a chronic pattern of emotional, behavioral, and cognitive disturbances. Shared psychopathology includes the pre-eminence of altered affective states, disorders of thoughts, and behavioral control. Additionally, those conditions share epidemiological traits, including significant cardiovascular, metabolic, infectious, and respiratory co-morbidities, resulting in reduced life expectancy of up to 25 years. Nutritional ketosis has been successfully used to treat a range of neurological disorders and preclinical data have convincingly shown potential for its use in animal models of psychotic disorders. More recent data from open clinical trials have pointed toward a dramatic reduction in psychotic, affective, and metabolic symptoms in both schizophrenia and bipolar affective disorder. Objectives to investigate the effects of nutritional ketosis via a modified ketogenic diet (MKD) over 14 weeks in stable community patients with bipolar disorder, schizoaffective disorder, or schizophrenia. Design A randomized placebo-controlled clinical trial of 100 non-hospitalized adult participants with a diagnosis of bipolar disorder, schizoaffective disorder, or schizophrenia who are capable of consenting and willing to change their diets. Intervention Dietitian-led and medically supervised ketogenic diet compared to a diet following the Australian Guide to Healthy Eating for 14 weeks. Outcomes The primary outcomes include psychiatric and cognitive measures, reported as symptom improvement and functional changes in the Positive and Negative Symptoms Scale (PANSS), Young Mania Rating Scale (YMS), Beck Depression Inventory (BDI), WHO Disability Schedule, Affect Lability Scale and the Cambridge Cognitive Battery. The secondary metabolic outcomes include changes in body weight, blood pressure, liver and kidney function tests, lipid profiles, and markers of insulin resistance. Ketone and glucose levels will be used to study the correlation between primary and secondary outcomes. Optional hair cortisol analysis will assess long-term stress and variations in fecal microbiome composition. Autonomic nervous system activity will be measured via wearable devices (OURA ring and EMBRACE wristband) in the form of skin conductance, oximetry, continuous pulse monitoring, respiratory rate, movement tracking, and sleep quality. Based on the encouraging results from established preclinical research, clinical data from other neurodevelopment disorders, and open trials in bipolar disorder and schizophrenia, we predict that the ketogenic metabolic therapy will be well tolerated and result in improved psychiatric and metabolic outcomes as well as global measures of social and community functioning. We additionally predict that a correlation may exist between the level of ketosis achieved and the metabolic, cognitive, and psychiatric outcomes in the intervention group.
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Abstract: This monograph aims to evaluate the utility of single nutraceuticals as well as whole dietary interventions in the prevention and treatment of mental disorders. There is lot of data on the possible advantages of prophylactic nutrition interventions for neurodegenerative diseases, most commonly based on polyunsaturated fatty acids (PUFA), monounsaturated fatty acids (MUFA), B vitamins. However, there is little evidence for the treatment efficacy of these nutraceuticals for neurocognitive disorders so far. Regarding patients at risk for schizophrenia or suffering from psychosis there is some evidence for efficacy of N-acetylcysteine, PUFA, or B vitamins. The use of vitamin C, E, D3 or zinc in this population is of uncertain utility. The supplementation of omega-3 PUFA, magnesium, zinc, selenium, iron or N acetylcysteine is under investigation as prevention or treatment for depression and anxiety. Next, PUFA omega-3, N-acetylcysteine, folic acid, coenzyme Q10, magnesium, or amino acids may be used in the treatment of bipolar disorder. Nonetheless, their therapeutic role in the clinical population needs to be confirmed. Recently, awareness of the influence of the gut microbiota, the central nervous system functioning, and mental health has been growing. The imbalance of gut microbes and their dysfunction has been shown to be connected with many mental disorders, e.g., schizophrenia, depression, autism spectrum disorder, or bipolar disorder. There is research data on the influence of probiotics or prebiotics for the functioning of the nervous system. Gut microbiota may also affect the metabolism of many pharmaceuticals. On the other hand, animal studies have shown the influence of pharmacotherapy on the microbiota changes. Regarding the whole dietary interventions, there is lack of consensus on the influence of vegetarian or vegan diet on mood, stress level, or quality of life. Ketogenic diet, on the contrary, may be an important part in the therapy of such diseases as binge eating disorder, autism spectrum disorder, or schizophrenia. Additionally, it was shown that elimination of gluten from the diet may have favourable effect on schizophrenia clinical picture. Moreover, Mediterranean diet, thanks to modulation of inflammatory or metabolic processes, or the positive influence on cognitive functions, may be a therapeutic option for patients with affective and psychotics disorders, among others. The same probably applies to Japanese, Nordic o any other traditional diets. To sum up, dietary interventions are modern preventive and therapeutic approaches to mental illnesses. Diet impacts the gut microbiota, modulating metabolism and functioning of the host. Particular elements of the diet, like vitamins, macro- and microelements, PUFA, influence on the metabolism of neurotransmitters, or may act as anti inflammatory, immunomodulatory and antioxidant factors. Keywords: mental disorders, mental illnesses, depression, nutrition, diet, dietary supplements, nutraceuticals, vitamins, minerals, microbiota
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The disruption of brain energy metabolism, leading to alterations in synaptic signaling, neural circuitry, and neuroplasticity, has been implicated in severe mental illnesses such as schizophrenia, bipolar disorder, and major depressive disorder. The therapeutic potential of ketogenic interventions in these disorders suggests a link between metabolic disturbances and disease pathology; however, the precise mechanisms underlying these metabolic disturbances and the therapeutic effects of metabolic ketogenic therapy remain poorly understood. In this study, we conducted an in silico analysis of transcriptomic data to investigate perturbations in metabolic pathways in the brain across severe mental illnesses via gene expression profiling. We also examined dysregulation of the same pathways in rodent or cell culture models of ketosis, comparing these expression profiles to those observed in the disease states. Our analysis revealed significant perturbations across all metabolic pathways, with the greatest perturbations in glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC) across all three disorders. Additionally, we observed some discordant gene expression patterns between disease states and ketogenic intervention studies, suggesting a potential role for ketone bodies in modulating pathogenic metabolic changes. Our findings highlight the importance of understanding metabolic dysregulation in severe mental illnesses and the potential therapeutic benefits of ketogenic interventions in restoring metabolic homeostasis. This study provides insights into the complex relationship between metabolism and neuropsychiatric disorders and lays the foundation for further experimental investigations aimed at appreciating the implications of the present transcriptomic findings as well as developing targeted therapeutic strategies.
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Background Bipolar disorder is a serious mental illness, which requires new strategies for prevention and management. Recent evidence suggests that a ketogenic diet may be an effective intervention. This research aimed to explore the feasibility and acceptability of a ketogenic diet intervention for bipolar disorder, fidelity to its behavioural components and the experiences of the participants and research clinicians involved. Methods A mixed-methods process evaluation was conducted. Semi-structured telephone interviews were carried out with 15 participants 1-2 months after completing a 6-8 week modified ketogenic diet intervention, and 4 research clinicians from the study team following the completion of data collection. Data were thematically analysed. Fidelity checklists completed by research dietitians were analysed using descriptive count and percentage statistics. Findings are reported post-hoc, following the analysis and publication of the main pilot study findings. Results Qualitative data indicated that participants had various motives for taking part in the study, including weight loss. It was important to support people’s motives while facilitating clear and realistic expectations. Despite the challenges of initiating and maintaining a ketogenic diet, including for some its disruptive effects on daily living, many participants perceived physical and psychological benefits (e.g. significant weight loss, mood stability and an enhanced ability to focus). A range of behavioural ( e.g. goal setting), social ( e.g. family and dietitians) and technological ( e.g. apps for monitoring) support mechanisms were generally considered key facilitating factors. Meanwhile, dietary preferences, concerns about the diet and its impact, the testing burden and capacity of the delivery team were perceived as barriers for some. The importance of wider contextual influences ( e.g. the cost of living and sociocultural expectations) were highlighted. Overall, descriptive analyses indicated moderate-to-good fidelity to the behaviour change components of the study. Conclusion We provide novel insight into the experiences of people living with bipolar disorder initiating and following a ketogenic diet, as well as those of research clinicians who support the intervention. Future trials may benefit from increased clinical research capacity, better-defined entry and exit routes, additional interpersonal support, and greater understanding of how social and societal factors impact participation. Trial registration Study registration number: ISRCTN6163198 (02 March 2022)
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Background and hypothesis. A growing number of studies implicate a key role for metabolic processes in psychiatric disorders. Recent studies suggest that ketogenic diet may be therapeutically effective for subgroups of people with schizophrenia (SCZ), bipolar disorder (BPD) and possibly major depressive disorder (MDD). Despite this promise, there is currently limited information regarding brain energy metabolism pathways across these disorders, limiting our understanding of how brain metabolic pathways are altered and who may benefit from ketogenic diets. We conducted gene expression profiling on the amygdala, a key region involved in in the regulation of mood and appetitive behaviors, to test the hypothesis that amygdala metabolic pathways are differentially altered between these disorders. Study Design. We used a cohort of subjects diagnosed with SCZ, BPD or MDD, and non-psychiatrically ill control subjects (n=15/group), together with our bioinformatic 3-pod analysis consisting of full transcriptome pathway analysis, targeted pathway analysis, leading-edge gene analysis and iLINCS perturbagen analysis. Study Results. We identified differential expression of metabolic pathways in each disorder. Subjects with SCZ displayed downregulation of mitochondrial respiration and nucleotide metabolism pathways. In comparison, we observed upregulation of mitochondrial respiration pathways in subjects with MDD, while subjects with BPD displayed enrichment of pathways involved in carbohydrate metabolism. Several pathways associated with brain metabolism including immune system processes and calcium ion transport were also differentially altered between diagnosis groups. Conclusion. Our findings suggest metabolic pathways are differentially altered in the amygdala in these disorders, which may impact approaches for therapeutic strategies.
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[Extract] Recent transcriptomic, proteomic and metabolomics studies suggest that abnormal glucose and energy metabolism may underlie the pathophysiology of schizophrenia (Harris et al., 2013). We hypothesized that interventions that influence energy metabolism might be therapeutically beneficial. One such intervention is the high-fat/low-carbohydrate ketogenic diet (KD) that has been effectively used in drug-resistant epilepsies (Paoli et al., 2013). To test our hypothesis we fed mice with KD for 3 weeks and induced acute NMDA receptor hypofunction by MK-801 (dizocilpine) administration to model the hypo-glutamatergic state that has been hypothesized to contribute to schizophrenia (Amann et al., 2010). We measured psychomotor hyperactivity and stereotyped behavior, social withdrawal and working memory deficits, reflecting the positive, negative and cognitive symptoms of schizophrenia, respectively (Jones et al., 2011).
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Background: The ketogenic diet (KD), being high in fat and low in carbohydrates, has been suggested to reduce seizure frequency. It is currently used mainly for children who continue to have seizures despite treatment with antiepileptic drugs. Recently, there has been interest in less restrictive KDs including the modified Atkins diet (MAD) and the use of these diets has extended into adult practice. Objectives: To review the evidence for efficacy and tolerability from randomised controlled trials regarding the effects of KD and similar diets. Search methods: We searched the Cochrane Epilepsy Group's Specialized Register (30 March 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 30 March 2015), MEDLINE (Ovid, 30 March 2015), ClinicalTrials.gov (30 March 2015) and the WHO International Clinical Trials Registry Platform (ICTRP, 30 March 2015). We imposed no language restrictions. We checked the reference lists of retrieved studies for additional reports of relevant studies. Selection criteria: Studies of KDs and similar diets for people with epilepsy. Data collection and analysis: Two review authors independently applied pre-defined criteria to extract data and assessed study quality. Main results: We identified seven randomised controlled trials that generated eight publications. All trials applied an intention-to-treat analysis with varied randomisation methods. The seven studies recruited 427 children and adolescents and no adults. We could not conduct a meta-analysis due to the heterogeneity of the studies. Reported rates of seizure freedom reached as high as 55% in a 4 : 1 KD group after three months and reported rates of seizure reduction reached as high as 85% in a 4 : 1 KD group after three months. One trial found no significant difference between the fasting-onset and gradual-onset KD for rates of seizure freedom and reported a greater rate of seizure reduction in the gradual-onset KD group. Studies assessing the efficacy of the MAD reported seizure freedom rates of up to 10% and seizure reduction rates of up to 60%. One study compared the MAD to a 4 : 1 KD, but did not report rates of seizure freedom or seizure reduction. Adverse effects were fairly consistent across different dietary interventions. The most commonly reported adverse effects were gastrointestinal syndromes. It was common that adverse effects were the reason for participants dropping out of trials. Other reasons for drop-out included lack of efficacy and non-acceptance of the diet. Although there was some evidence for greater antiepileptic efficacy for a 4 : 1 KD over lower ratios, the 4 : 1 KD was consistently associated with more adverse effects. No studies assessed the effect of dietary interventions on quality of life, or cognitive or behavioural functioning. Authors' conclusions: The randomised controlled trials discussed in this review show promising results for the use of KDs in epilepsy. However, the limited number of studies, small sample sizes and a sole paediatric population resulted in a poor overall quality of evidence. There were adverse effects within all of the studies and for all KD variations, such as short-term gastrointestinal-related disturbances, to longer-term cardiovascular complications. Attrition rates remained a problem with all KDs and across all studies, reasons for this being lack of observed efficacy and dietary tolerance. There was a lack of evidence to support the clinical use of KD in adults with epilepsy, therefore, further research would be of benefit. Other more palatable but related diets, such as the MAD ketogenic diet, may have a similar effect on seizure control as classical KD but this assumption requires more investigation. For people who have medically intractable epilepsy or people who are not suitable for surgical intervention, a KD remains a valid option; however, further research is required. © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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The high-fat ketogenic diet (KD) is a remarkably effective treatment for medically intractable epilepsy and has been part of the clinical armamentarium for nearly a century. However, the mechanisms underlying the KD's actions have remained elusive. Over the past decade, there has been phenomenal international growth of clinical centers offering metabolism-based therapies for epilepsy, and rapidly expanding research into the cellular and biochemical effects induced by the KD. At present, there are many hypotheses regarding KD action, and while each is uniquely compelling, it is becoming more apparent that the KD likely works through multiple mechanisms that target fundamental biochemical pathways linked to cellular substrates (e.g., ion channels) and mediators responsible for neuronal hyperexcitability. This is not altogether surprising given the complexity of the epileptic brain, and the many different pathophysiologic mechanisms that underlie seizure genesis and epileptogenicity. The scientific literature involving the KD strongly supports the notion that epilepsy may indeed in part represent a "metabolic disease", and that this concept could serve as a novel framework for the development of more effective anti-seizure drugs. Copyright © 2015. Published by Elsevier Ireland Ltd.
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Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high-energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders.