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Ketogenic diet in the treatment of schizoaffective disorder: Two case studies

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... More recent case studies support the earlier findings (Table 1) (Palmer, 2017). Two treatment resistant subjects with schizoaffective disorder improved on ketogenic diet within weeks in hallmark symptoms of schizophrenia (Palmer, 2017). ...
... More recent case studies support the earlier findings (Table 1) (Palmer, 2017). Two treatment resistant subjects with schizoaffective disorder improved on ketogenic diet within weeks in hallmark symptoms of schizophrenia (Palmer, 2017). At follow up (male: one year, female four month), both patients significantly improved on the Positive and Negative Syndrome Scale (PANSS) (Palmer, 2017). ...
... Two treatment resistant subjects with schizoaffective disorder improved on ketogenic diet within weeks in hallmark symptoms of schizophrenia (Palmer, 2017). At follow up (male: one year, female four month), both patients significantly improved on the Positive and Negative Syndrome Scale (PANSS) (Palmer, 2017). However, when the patients were not in ketosis symptoms drastically worsened until ketosis was achieved (Palmer, 2017). ...
Article
Oxytocin (OT) has been implicated in neuroadaptive processes such as learning, memory, and social-affiliative behavior as well as in the regulation of physiological responses leading to adaptation to the changing external and internal environment. Drugs of abuse constitute a major challenge to the homeostasis of the body and behavior. Drug tolerance, dependence and addiction may involve neuroadaptive mechanisms related to learning and memory at cellular and systems levels. Considerable effort has been made toward the understanding the neurobiological mechanisms of addictive behavior. Neuropeptides OT and vasopressin (VP) might be involved in these processes based on their effects on neuroadaptation and on their neuroanatomical localization and pharmacological actions. It has been demonstrated that both OT and VP have modulatory effects on opiate and alcohol tolerance and dependence. This chapter summarize the effects of OT, and in lesser extent VP, on neuroadaptation to cocaine, a psychostimulant drug of abuse. We have shown that OT inhibits acute cocaine-induced locomotor hyperactivity, exploratory activity and stereotyped behavior in rodents. Furthermore, OT facilitated, whereas VP inhibited the development of behavioral sensitization to cocaine. In a different model, OT inhibited the development of tolerance to the stereotyped behavior-inducing effects of cocaine as well as cocaine intravenous self-administration in rats. We demonstrated that OT acts through its specific receptors in the basal forebrain and in the hippocampus. OT and VP contents in the hypothalamus and limbic structures were altered by acute and chronic cocaine administration in a dose-dependent and region-selective manner. The differential plasticity of the brain OT-ergic and VP-ergic neurotransmissions in response to cocaine may underlie the differences in the involvement of these neuropeptides in cocaine addiction. Interaction of OT with dopaminergic neurotransmission in the nucleus accumbens, a key brain structure in drug addiction, as well as OT-ergic regulation of hippocampal processes may be among the mechanisms of action through which OT modulates neuroadaptation to cocaine. A better understanding of the role of OT in neuroadaptation to cocaine may provide an insight into both the mechanisms of neuropeptide actions in the brain as well as into the neurobiology of drug addiction.
... More recent case studies support the earlier findings (Table 1) (Palmer, 2017). Two treatment resistant subjects with schizoaffective disorder improved on ketogenic diet within weeks in hallmark symptoms of schizophrenia (Palmer, 2017). ...
... More recent case studies support the earlier findings (Table 1) (Palmer, 2017). Two treatment resistant subjects with schizoaffective disorder improved on ketogenic diet within weeks in hallmark symptoms of schizophrenia (Palmer, 2017). At follow up (male: one year, female four month), both patients significantly improved on the Positive and Negative Syndrome Scale (PANSS) (Palmer, 2017). ...
... Two treatment resistant subjects with schizoaffective disorder improved on ketogenic diet within weeks in hallmark symptoms of schizophrenia (Palmer, 2017). At follow up (male: one year, female four month), both patients significantly improved on the Positive and Negative Syndrome Scale (PANSS) (Palmer, 2017). However, when the patients were not in ketosis symptoms drastically worsened until ketosis was achieved (Palmer, 2017). ...
Article
Ketogenic diet is a low carbohydrate and high fat diet that has been used for over 100 years in the management of childhood refractory epilepsy. More recently, ketogenic diet has been investigated for a number of metabolic, neurodegenerative and neurodevelopmental disorders. In this comprehensive review, we critically examine the potential therapeutic benefits of ketogenic diet and ketogenic agents on neurodegenerative and psychiatric disorders in humans and translationally valid animal models. The preclinical literature provides strong support for the efficacy of ketogenic diet in a variety of diverse animal models of neuropsychiatric disorders. However, the evidence from clinical studies, while encouraging, particularly in Alzheimer’s disease, psychotic and autism spectrum disorders, is limited to case studies and small pilot trials. Firm conclusion on the efficacy of ketogenic diet in psychiatric disorders cannot be drawn due to the lack of randomised, controlled clinical trials. The potential mechanisms of action of ketogenic therapy in these disorders with diverse pathophysiology may include energy metabolism, oxidative stress and immune/inflammatory processes. In conclusion, while ketogenic diet and ketogenic substances hold promise pre-clinically in a variety of neurodegenerative and psychiatric disorders, further studies, particularly randomised controlled clinical trials, are warranted to better understand their clinical efficacy and potential side effects.
... Through this process, ketosis (increased ketone body levels in the blood) provides energy by metabolism of ketone bodies to acetyl-CoA and synthesis of ATP for cells in the central nervous system (CNS) (43, 51,52). It has been demonstrated in animal-and/or human studies-that ketogenic diets and supplements may have metabolism-based therapeutic potential in the treatment of several diseases, such as Alzheimer's disease (53)(54)(55)(56)(57), Parkinson's disease (54,(58)(59)(60), glucose transporter type 1-deficiency syndrome (61)(62)(63), amyotrophic lateral sclerosis (60,64), cancer (44,58,65,66), epilepsy (54,67,68), schizophrenia (42, [69][70][71][72][73][74], anxiety (55,(75)(76)(77), autism spectrum disorder (78)(79)(80)(81), and depression (69,77,82). ...
... Ketogenic diets are high-fat, adequate protein and very low carbohydrate diets that may have an alleviating role on psychiatric diseases (69,73), likely through bioenergetics, ketone metabolism, and signaling, as well as their effects on, for example, neuronal activity, neurotransmitter balance, and inflammatory processes (43,52,(83)(84)(85)(86)(87)(88)(89)(90)(91). Strict patient compliance to the KD is the primary factor in achieving therapeutic ketosis, and this is often difficult or impossible in the psychiatric population (69). ...
... Based on correlation between βHB plasma levels and symptoms it was suggested that βHB may have a protective effect on executive functions in patients treated with schizophrenia (117). Other studies presented cases of patients with chronic schizoaffective disorders where the KD begin helping with mood and psychotic symptoms within 1 month or lead to remission of psychotic symptoms (73,74). It has also been suggested that plasma level of βHB is associated with severity of depression in human and that βHB-evoked antidepressant-like effects may be in relation to its inhibitory effect on NOD-like receptor pyrin domain 3 (NLRP3)-induced neuro-inflammatory processes. ...
Article
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Globally, psychiatric disorders, such as anxiety disorder, bipolar disorder, schizophrenia, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD) are becoming more prevalent. Although the exact pathological alterations are not yet clear, recent studies have demonstrated that widespread changes of very complex metabolic pathways may partially underlie the pathophysiology of many psychiatric diseases. Thus, more attention should be directed to metabolic-based therapeutic interventions in the treatment of psychiatric disorders. Emerging evidence from numerous studies suggests that administration of exogenous ketone supplements, such as ketone salts or ketone esters, generates rapid and sustained nutritional ketosis and metabolic changes, which may evoke potential therapeutic effects in cases of central nervous system (CNS) disorders, including psychiatric diseases. Therefore, the aim of this review is to summarize the current information on ketone supplementation as a potential therapeutic tool for psychiatric disorders. Ketone supplementation elevates blood levels of the ketone bodies: D-β-hydroxybutyrate (βHB), acetoacetate (AcAc), and acetone. These compounds, either directly or indirectly, beneficially affect the mitochondria, glycolysis, neurotransmitter levels, activity of free fatty acid receptor 3 (FFAR3), hydroxycarboxylic acid receptor 2 (HCAR2), and histone deacetylase, as well as functioning of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome and mitochondrial uncoupling protein (UCP) expression. The result of downstream cellular and molecular changes is a reduction in the pathophysiology associated with various psychiatric disorders. We conclude that supplement-induced nutritional ketosis leads to metabolic changes and improvements, for example, in mitochondrial function and inflammatory processes, and suggest that development of specific adjunctive ketogenic protocols for psychiatric diseases should be actively pursued.
... We recently reported in an acute N-methyl-Daspartate (NMDA) receptor hypofunction model in male mice, that a ketogenic diet exerts antipsychotic-like effects (Kraeuter et al., 2015;Kraeuter et al., 2019), suggesting that it may provide an adjunct therapy to commonly used antipsychotics. Indeed, recent clinical case studies have shown encouraging results with ketogenic diet being used as an adjunct therapy (Palmer, 2017;Gilbert-Jaramillo et al., 2018;Palmer et al., 2019;Sarnyai et al., 2019). However, in the clinical setting this dietary intervention would presumably be administered together with antipsychotic treatment over an extended period of time. ...
... Woman experience more antipsychotic-related side effects (Seeman, 2010) and, therefore, would benefit from alternative antipsychotic approaches devoid of metabolic side effects. Our present results are in line with recently published case studies in which female patients with schizophrenia benefitted from ketogenic diet (Palmer, 2017;Gilbert-Jaramillo et al., 2018;Palmer et al., 2019). However, future animal model studies will need to investigate the efficacy of the ketogenic diet in females in a wider battery of behavioural tests modelling a range of positive, negative and cognitive symptom domains of schizophrenia. ...
... Compliance remains a problem, with a recent meta-analysis reporting compliance rates of only 45% in adults (Ye et al., 2015). A study by Palmer (2017) demonstrated that ketogenic diet was effective in treating schizoeffective disorder, however compliance issues resulted in a lack of ketosis, which decreased symptom control. Thus, although ketogenic diet is effective in treating schizophrenia, potential initial side effects and compliance issues may result in discontinuation of the diet and worsened symptoms (Palmer, 2017;Gilbert-Jaramillo et al., 2018;Palmer et al., 2019;Sarnyai et al., 2019). ...
Article
We used the acute NMDA receptor hypoactivity model of schizophrenia in mice to compare the efficacy of a long-term ketogenic diet and a commonly used antipsychotic, olanzapine, and to explore the interaction between these treatments. We found that a ketogenic diet in female mice was as effective as olanzapine to diminish MK-801-induced disruption of prepulse inhibition (PPI). Furthermore, combination of the diet with olanzapine treatment resulted in a similar effect compared to either treatment alone. These results suggest that ketogenic diet can be used effectively together with antipsychotics drugs over an extended period.
... The potential of this diet as a nutritional therapeutic has been trialled in several disease areas, such as brain cancer [11], brain trauma [12], migraines [13,14], type II diabetes, as well as neurodegenerative, neurodevelopmental and psychiatric disorders [15,16]. The neurodegenerative disorders which have been tested in clinical trials using the ketogenic diet include Alzheimer's disease [16], Parkinson's disease [17,18] and multiple sclerosis [19], and the neurodevelopmental and psychiatric diseases which have been trialled include autism spectrum disorder, anxiety and depression, [20][21][22][23], attention deficit hyperactivity disorder [23,24], schizophrenia [25][26][27][28] and bipolar disorder [29,30]. ...
... Two early case studies suggested that the ketogenic diet might have clinical efficacy in the management of schizophrenia [25,26]. More importantly, two recent case reports showed that the ketogenic diet improved auditory hallucinations, mood, energy, the ability to concentrate and sociability in patients with schizoaffective disorder [27]. This and another recent study showed improvement in the Positive and Negative Syndrome Scales symptom scores following the ketogenic diet [27,28]. ...
... More importantly, two recent case reports showed that the ketogenic diet improved auditory hallucinations, mood, energy, the ability to concentrate and sociability in patients with schizoaffective disorder [27]. This and another recent study showed improvement in the Positive and Negative Syndrome Scales symptom scores following the ketogenic diet [27,28]. ...
Chapter
This chapter reviews the efficacy of the ketogenic diet in a variety of neurodegenerative, neurodevelopmental and metabolic conditions throughout different stages of life. It describes conditions affecting children, metabolic disorders in adults and disorderrs affecting the elderly. We have focused on application of the ketogenic diet in clinical studies and in preclinical models and discuss the benefits and negative aspects of the diet. Finally, we highlight the need for further research in this area with a view of discovering novel mechanistic targets of the ketogenic diet, as a means of maximising the potential benefits/risks ratio.
... Therefore, this diet could be a potential new treatment for schizophrenia. Case studies have indeed shown that the ketogenic diet is effective in treating schizoaffective disorder (Palmer 2017) and schizophrenia (Gilbert-Jaramillo et al. 2018;Palmer et al. 2019). ...
... Difficulty to maintain adequate ketone levels in the blood and side effects such as drowsiness, dehydration, abdominal pain, hunger, and lack of energy, as well as gastrointestinal disturbances such as constipation, vomiting, and diarrhoea, may lead to discontinuation of the diet (Kang et al. 2004;Neal et al. 2008). The case studies that showed that the ketogenic diet is effective in treating schizoaffective disorder also suggested that during compliance issues, symptoms worsened until ketosis was reachieved (Palmer 2017), demonstrating that a state of ketosis was vital for symptom control. Similarly in schizophrenia (Gilbert-Jaramillo et al. 2018;Palmer et al. 2019), potential initial side effects may result in discontinuation of the diet and worsening of symptoms (Palmer 2017). ...
... The case studies that showed that the ketogenic diet is effective in treating schizoaffective disorder also suggested that during compliance issues, symptoms worsened until ketosis was reachieved (Palmer 2017), demonstrating that a state of ketosis was vital for symptom control. Similarly in schizophrenia (Gilbert-Jaramillo et al. 2018;Palmer et al. 2019), potential initial side effects may result in discontinuation of the diet and worsening of symptoms (Palmer 2017). ...
Article
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RationaleImpaired cerebral glucose metabolism is a core pathological feature of schizophrenia. We recently demonstrated that a ketogenic diet, causing a shift from glycolysis to ketosis, normalized schizophrenia-like behaviours in an acute N-methyl-D-aspartate (NMDA) receptor antagonist model of the illness. Ketogenic diet produces the ketone body, β-hydroxybutyrate (BHB), which may serve as an alternative fuel source in its own right without a strict dietary regime.Objective We hypothesized that chronic administration of BHB replicates the therapeutic effects of ketogenic diet in an acute NMDA receptor hypofunction model of schizophrenia in mice.MethodsC57Bl/6 mice were either treated with acute doses of 2 mmol/kg, 10 mmol/kg, or 20 mmol/kg BHB or received daily intraperitoneal injections of 2 mmol/kg BHB or saline for 3 weeks. Behavioural testing assessed the effect of acute challenge with 0.2 mg/kg MK-801 or saline on open field behaviour, social interaction, and prepulse inhibition of startle (PPI).ResultsAcute BHB administration dose-dependently increased BHB plasma levels, whereas the 2 mmol/kg dose increased plasma glucose levels. The highest acute dose of BHB supressed spontaneous locomotor activity, MK-801-induced locomotor hyperactivity and MK-801-induced disruption of PPI. Chronic BHB treatment normalized MK-801-induced hyperlocomotion, reduction of sociability, and disruption of PPI.Conclusion In conclusion, BHB may present a novel treatment option for patients with schizophrenia by providing an alternative fuel source to normalize impaired glucose metabolism in the brain.
... Recent studies further report that this regimen has positive effects on the central nervous system (CNS) (Maalouf et al. 2009;Mattson et al. 2018). Ketogenic diets have produced beneficial effects in multiple psychiatric disorders such as autism, depression, anxiety, and schizophrenia (Evangeliou et al. 2003;Herbert and Buckley 2013;Kashiwaya et al. 2013;Mantis et al. 2009;Palmer 2017;Sussman et al. 2014;Wlodarczyk et al. 2018). There could be several reasons for the reported improvements. ...
... However, symptoms persisted until she started fasting in order to increase ketosis. After a third day of fasting, her symptoms had resolved (Palmer 2017). ...
Article
HAPS Educator, Journal of the Human Anatomy and Physiology Society, 23 (2), 446-456. https://www.hapsweb.org/page/hapsed_home The Flavor Perception Game was designed with the goals of developing an interactive and hands-on activity, providing a platform to review chemical senses of the five tastes, promoting student investment in the course material, and providing a basis for discussion on chemical senses of the five tastes. Knowledge of taste sensation is useful for nursing and exercise sciences students, as human physiology is integral to both baccalaureate curricula. The game is inexpensive, easy to incorporate into a 50-minute lecture period, and free of chocolate allergens. Student participants (N=34) tasted three candies and completed a voluntary anonymous poll regarding their detection of the presence of umami, bitter, sweet, salty and/or sour taste modalities in the different candies. During the three stages of this classroom game, a total of 214 taste selections were made, following which students discussed various aspects of taste sensation including its importance in healthcare.
... Furthermore, deficiencies in folate, vitamin C and niacin have been found to worsen schizophrenia symptoms [16] and a diet high in sugar was associated with increased prevalence of depression in schizophrenia patients [17]. The therapeutic potential of particular diets is highlighted by a limited number of case studies on ketogenic diets which resulted in a significant decrease in positive and negative symptoms in these patients [18,19]. Thus, dietary factors appear to have complex effects on the mental state of patients and may have both therapeutic-like as well as detrimental consequences. ...
... At 22 ± 2 weeks of age, male and female mice of both genotypes were randomly assigned to either HFD or control chow diet group (CHOW). Mice were exposed to the HFD (SF03-020 from Speciality Feeds, Glen Forrest, Australia: 43% digestible energy from fat, 17% from protein and 40% from carbohydrates -digestible energy is 20 mega joule per kg; total fat content: 23%, protein content: 19 ...
Article
Some diets appear to have detrimental effects on schizophrenia symptoms. Neuregulin 1 (NRG1) is a risk gene for schizophrenia and a recently developed transgenic mouse model for Nrg1 type III demonstrates a schizophrenia-relevant phenotype. The current study evaluated the behavioural response of Nrg1 type III transgenic mice to a high fat diet (HFD) to determine the potential interactive impact of diets and genetic risk factors on disease symptoms. Male and female Nrg1 III and control littermates (N = 13–24) were exposed during adulthood to either HFD or standard chow diet (CHOW) for eight weeks before being tested in behavioural domains relevant to schizophrenia. Locomotion and exploration, anxiety, social behaviours (including social preference), sensorimotor gating (i.e. prepulse inhibition, PPI), associative learning, and anhedonia were assessed. HFD increased the body weight gain of mice, suppressed locomotion, exploration, and anxiety-related behaviours in a sex-dependent manner. HFD augmented the PPI response in male mice and decreased anhedonia in a sucrose preference test. Finally, HFD had a sex-dependent impact on fear-associated memory with HFD-induced cognitive impairments being most prominent in Nrg1 transgenic females. In conclusion, HFD and mutant Nrg1 III interactively impair particular cognitive domains in a sex-specific manner. Thus, our preclinical data suggest that genetic predisposition to the schizophrenia risk gene NRG1 may modulate detrimental behavioural effects of diets. This indicates the importance to research further the role of particular diets in the context of populations at risk to develop schizophrenia.
... Recent studies further report that this regimen has positive effects on the central nervous system (CNS) (Maalouf et al. 2009;Mattson et al. 2018). Ketogenic diets have produced beneficial effects in multiple psychiatric disorders such as autism, depression, anxiety, and schizophrenia (Evangeliou et al. 2003;Herbert and Buckley 2013;Kashiwaya et al. 2013;Mantis et al. 2009;Palmer 2017;Sussman et al. 2014;Wlodarczyk et al. 2018). There could be several reasons for the reported improvements. ...
... However, symptoms persisted until she started fasting in order to increase ketosis. After a third day of fasting, her symptoms had resolved (Palmer 2017). ...
Article
Full-text available
Mitochondrial dysfunction has been linked to many psychiatric disorders. Ketogenic diets have been shown to reduce mitochondrial dysfunction and thus may be helpful to patients who suffer from these disorders. In this article, we review the effects of a ketogenic diet in patients with psychiatric disorders such as autism, depression, anxiety, and schizophrenia. Mitochondrial dysfunction, and its reversal by a ketogenic diet resulting in the relief of mental disorders, would be an excellent teaching topic on the consequences of altered cellular biology and a discussion of mitochondrial injury as one of the causes of cellular necrosis. Similarly, this information will be important in a discussion of how diet might be beneficial in the treatment of certain mental disorders.
... The literature reports case studies on two patients with schizoaffective disorder found symptoms decreased when the patients went on the KD, returned when they went off the diet, and decreased again with resumption of the KD. [150] One of these patients was a 33-year-old man who reported a dramatic decrease in auditory hallucinations and delusions, and an improved mood and higher energy level after three weeks on the KD. Maintaining the diet (with a few breaks when symptoms returned) allowed him to make other positive changes in his life as well, in that he was able to complete some online studies, move into his own apartment, and start dating. ...
... Maintaining the diet (with a few breaks when symptoms returned) allowed him to make other positive changes in his life as well, in that he was able to complete some online studies, move into his own apartment, and start dating. [150] In another case report, a 70-year-old woman experienced resolution of long-standing symptoms of schizophrenia with the use of the KD. [151] Large-scale randomized clinical trials have not been conducted for more authoritative levels of evidence. ...
... Despite little application of TRP for chronic schizophrenia, this amino possesses excellent potential to improve mood and decrease hallucinations in patients suffering from schizoaffective disorders [130][131][132][133]. In a double-blind investigation, Brewerton and Reus concluded that a combination of lithium and TRP demonstrated superior efficiency compared to lithium plus placebo in manic schizoaffective patients [134]. ...
... [127] TRP supplementation improves mood and decreases hallucinations in patients. [131] Mood disorders TRP supplementation could considerably decrease aggressive/pugnacious behavior without any impact on mood or agreeableness. [128] TRP supplementation enhances dominance, helpfulness, and affiliative responding. ...
Article
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In recent decades, neuropsychiatric disorders such as major depressive disorder, schizophrenia, bipolar, etc., have become a global health concern, causing various detrimental influences on patients. Tryptophan is an important amino acid that plays an indisputable role in several physiological processes, including neuronal function and immunity. Tryptophan’s metabolism process in the human body occurs using different pathways, including the kynurenine and serotonin pathways. Furthermore, other biologically active components, such as serotonin, melatonin, and niacin, are by-products of Tryptophan pathways. Current evidence suggests that a functional imbalance in the synthesis of Tryptophan metabolites causes the appearance of pathophysiologic mechanisms that leads to various neuropsychiatric diseases. This review summarizes the pharmacological influences of tryptophan and its metabolites on the development of neuropsychiatric disorders. In addition, tryptophan and its metabolites quantification following the neurotransmitters precursor are highlighted. Eventually, the efficiency of various biomarkers such as inflammatory, protein, electrophysiological, genetic, and proteomic biomarkers in the diagnosis/treatment of neuropsychiatric disorders was discussed to understand the biomarker application in the detection/treatment of various diseases.
... The ketogenic diet was first introduced in the 1920s for the management of medically refractory childhood epilepsy [8]. More recently, the therapeutic potential of the ketogenic diet has been trialled in a wide variety of diseases such as type II diabetes, brain cancer [12], brain trauma [13], migraine [14,15], and in neurodegenerative, neurodevelopmental and psychiatric disorders [16][17][18][19][20][21][22]. In this review, we describe the commonly used practices involving application of the ketogenic diet to aid in translatability between preclinical and clinical use. ...
... In adults, compliance rates are limited to around 45% [49]. A study by Palmer in 2017 [20] demonstrated that ketogenic diet was effective in treating schizo-affective disorder, however compliance issues resulted in a lack of ketosis and diminished symptom control. This demonstrated that a state of ketosis was vital for symptom control. ...
Chapter
Many age-related diseases are associated with metabolic abnormalities, and dietary interventions may have some benefit in alleviating symptoms or in delaying disease onset. Here, we review the commonly used best practices involved in applications of the ketogenic diet to facilitate its translation into clinical use. The findings reveal that better education of physicians is essential for applying the optimum diet and monitoring its effects in clinical practice. In addition, investigators should carefully consider potential confounding factors prior to commencing studies involving a ketogenic diet. Most importantly, current studies should improve their reporting on ketone levels as well as on the intake of both macro- and micronutrients. Finally, more detailed studies on the mechanism of action are necessary to help identify potential biomarkers for response prediction and monitoring, and to uncover new drug targets to aid the development of novel treatments.
... More rigorous and longer term case studies have been conducted (Table 2) in different populations by one of us (C.M.P.) and have provided encouraging results both in terms of symptom control and safety/tolerability (Palmer, 2017(Palmer, , 2019bGilbert-Jaramillo et al., 2018), which we summarized recently (Sarnyai et al., 2019). ...
... In the first case studies (Palmer, 2017), 2 patients with longstanding, treatment-resistant schizoaffective disorder started the ketogenic diet for weight loss. Within 2 months of starting the diet, both patients experienced significant reductions in psychotic symptoms as measured by the Positive and Negative Symptom Scale. ...
... In addition, there was also study in which authors demonstrated ketogenic diet normalizing pathological behaviors in an animal model of schizophrenia [36]. The study mentioned above can seems to have a assurance in practice, while there are two case-reports on schizoaffective disorder, in which both patient experienced significant weight loss and, what is probably more important, recovery in positive and negative symptoms while on ketosis, with an acute exacerbation while going off the diet [37]. ...
Article
Schizophrenia is a mental disorder that mostly appears in the second or third decade of life with no consistent appearance. The first-line pharmacological treatment are antipsychotic drugs, which mainly act by suppressing the activity of dopamine. Unfortunately many of schizophrenic patients suffer from persistent positive or negative symptoms that cannot be fully treated with available medication. With exploration on the possible causes of the disease there is evidence on dopaminergic transmission defects, there is a need to find more holistic way in treating the disease and a diet regimen could be one of them. Ketogenic diet, which is a popular diet regimen that consists in low-carbohydrate (about 30–50 g/day), medium-protein (up to 1 g/kg daily) and high-fat intake (around 80% of daily calories) mainly known for its helpful role in weight-loss. The key mechanism is to generate ketosis. A state in which ketones bodies in the blood provides energy part of the body's energy comes from ketone bodies in the blood. Possible hypothesis can be that ketogenic diet changes the ratio of GABA:glutamate in favor of GABA, by suppressing the catabolism and increasing the synthesis of GABA as well as glutamate metabolism, which could help to compensate the disrupted GABA levels in schizophrenic brain, leading to possible better outcome of the disease regarding symptomatology and preventing the weight-gain regarding some medications used and the correlating diseases responsible for weight gain.
... Furthermore, a three-week KD conducted in schizophrenia mice (C57BL/6) not only showed significant weight loss, but also demonstrated significant improvements in the positive, negative and cognitive symptoms (measured as ataxia, social interaction, psychomotor hyperactivity, stereotyped behavior, social withdrawal, and spatial working memory) of the mice [19]. Comparable results have been described in a recent case report of two patients with schizoaffective disorders, who showed considerable weight loss and decline in positive and negative symptoms throughout a year-long, self-prescribed KD [20]. Even though these improvements reversed when the KD was disrupted, they could be recovered when ketosis was regained. ...
... The diet results in the use of ketone bodies, Neuropsychobiology DOI: 10.1159/000493399 rather than glucose, as the fuel source for the brain. Abnormalities in glucose tolerance and insulin resistance as well as mitochondrial dysfunction and energy metabolism disturbances have all been associated with the pathogenesis of psychosis and could be potential mechanisms for this diet to exert an effect [71]. ...
Article
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Introduction: Schizophrenia spectrum disorders (SSD) represent a cluster of severe mental illnesses. Diet has been identified as a modifiable risk factor and opportunity for intervention in many physical illnesses and more recently in mental illnesses such as unipolar depression; however, no dietary guidelines exist for patients with SSD. Objective: This review sought to systematically scope the existing literature in order to identify nutritional interventions for the prevention or treatment of mental health symptoms in SSD as well as gaps and opportunities for further research. Methods: This review followed established methodological approaches for scoping reviews including an extensive a priori search strategy and duplicate screening. Because of the large volume of results, an online program (Abstrackr) was used for screening and tagging. Data were extracted based on the dietary constituents and analyzed. Results: Of 55,330 results identified by the search, 822 studies met the criteria for inclusion. Observational evidence shows a connection between the presence of psychotic disorders and poorer quality dietary patterns, higher intake of refined carbohydrates and total fat, and lower intake or levels of fibre, ω-3 and ω-6 fatty acids, vegetables, fruit, and certain vitamins and minerals (vitamin B12 and B6, folate, vitamin C, zinc, and selenium). Evidence illustrates a role of food allergy and sensitivity as well as microbiome composition and specific phytonutrients (such as L-theanine, sulforaphane, and resveratrol). Experimental studies have demonstrated benefit using healthy diet patterns and specific vitamins and minerals (vitamin B12 and B6, folate, and zinc) and amino acids (serine, lysine, glycine, and tryptophan). Discussion: Overall, these findings were consistent with many other bodies of knowledge about healthy dietary patterns. Many limitations exist related to the design of the individual studies and the ability to extrapolate the results of studies using dietary supplements to dietary interventions (food). Dietary recommendations are presented as well as recommendations for further research including more prospective observational studies and intervention studies that modify diet constituents or entire dietary patterns with statistical power to detect mental health outcomes.
... Therefore, a swift clinical translation of the use of therapeutic KD in the management of schizophrenia can be proposed. In line with this, a recent case study showed reductions in auditory hallucinations and delusions, improvement in mood, and ability to concentrate, in schizoaffective disorder in response to three weeks of KD (Palmer, 2017). However, KD is difficult to adhere to and not entirely without risk (Kosinski and Jornayvaz, 2017), therefore it should be applied with caution and under medical supervision, or alternatively, the use of exogenous ketones/ketogenic substrates (Stubbs et al., 2017;Veech et al., 2017) (such as BHB) could be considered. ...
Article
Recent transcriptomic, proteomic and metabolomics studies have highlighted an abnormal cerebral glucose and energy metabolism as one of the potential pathophysiological mechanisms of schizophrenia. This raises the possibility that a metabolically-based intervention might have therapeutic value in the management of schizophre-nia, a notion supported by our recent results that a low carbohydrate/high-fat therapeutic ketogenic diet (KD) prevented a variety of behavioural abnormalities induced by pharmacological inhibition of NMDA glutamate receptors. Here we asked if the beneficial effects of KD can be generalised to impaired prepulse inhibition of startle (PPI), a translationally validated endophenotype of schizophrenia, in a pharmacological model in mice. Furthermore , we addressed the issue of whether the effect of KD is linked to the calorie-restricted state typical of the initial phase of KD. We fed male C57BL/6 mice a KD for 7 weeks and tested PPI at 3 and 7 weeks, in the presence and absence of a significant digestible energy deficit, respectively. We used an NMDA receptor hypo-function model of schizophrenia induced by acute injection of dizocilpine (MK-801). We found that KD effectively prevented MK-801-induced PPI impairments at both 3 and 7 weeks, irrespective of the presence or absence of digestible energy deficit. Furthermore, there was a lack of correlation between PPI and body weight changes. These results support the efficacy of the therapeutic KD in a translational model of schizophrenia and furthermore provide evidence against the role of calorie restriction in its mechanism of action.
... startle response (a translationally validated endophenotype of schizophrenia) in the MK-801 NMDA hypofunction model was prevented following ketogenic diet 37 . There have also been case studies suggesting ketogenic diet may be an effective treatment for positive and negative symptoms in schizophrenia and schizoaffective disorder, as well as metabolic dysfunction 38,39 . In conclusion, accumulating evidence suggests increases in lactate could be a pathological indicator of bioenergetic defects in cognitive disorders including schizophrenia. ...
Article
Full-text available
Converging evidence suggests bioenergetic defects contribute to the pathophysiology of schizophrenia and may underlie cognitive dysfunction. The transport and metabolism of lactate energetically couples astrocytes and neurons and supports brain bioenergetics. We examined the concentration of lactate in postmortem brain (dorsolateral prefrontal cortex) in subjects with schizophrenia, in two animal models of schizophrenia, the GluN1 knockdown mouse model and mutant disrupted in schizophrenia 1 (DISC1) mouse model, as well as inducible pluripotent stem cells (iPSCs) from a schizophrenia subject with the DISC1 mutation. We found increased lactate in the dorsolateral prefrontal cortex (p = 0.043, n = 16/group) in schizophrenia, as well as in frontal cortical neurons differentiated from a subject with schizophrenia with the DISC1 mutation (p = 0.032). We also found a decrease in lactate in mice with induced expression of mutant human DISC1 specifically in astrocytes (p = 0.049). These results build upon the body of evidence supporting bioenergetic dysfunction in schizophrenia, and suggests changes in lactate are a key feature of this often devastating severe mental illness.
... Two studies of a mouse model of schizophrenia demonstrate that the ketogenic diet may be an effective treatment (Kraeuter et al., 2015;Kraeuter et al., 2018). Additionally, two case studies of the ketogenic diet in the treatment of schizoaffective disorder suggested a reduction in PANSS scores (Palmer, 2017). The following additional two cases represent unique patients from those reported in 2017 treated with the ketogenic diet for 5 and 12 years with complete remission of psychotic symptoms off of antipsychotic medications. ...
... The diet results in the use of ketone bodies, Neuropsychobiology DOI: 10.1159/000493399 rather than glucose, as the fuel source for the brain. Abnormalities in glucose tolerance and insulin resistance as well as mitochondrial dysfunction and energy metabolism disturbances have all been associated with the pathogenesis of psychosis and could be potential mechanisms for this diet to exert an effect [71]. ...
... Only one clinical study or case report of KD in schizophrenia to date had more than 2 patients: a study conducted in 1965 prior to the development of second-generation antipsychotics (reviewed by Bostock et al., 2017). Case studies of people diagnosed with schizophrenia or schizoaffective disorder trialling KD report reduction or resolution of positive symptoms, reversed when the diet is terminated or ketosis threshold is not maintained (Palmer, 2017). Gilbert-Jaramillo et al. (2018) trialled 6 weeks of the KD in a pair of twins with schizophrenia and found reductions in their Positive and Negative Symptom Scale (PANSS) scores and their BMI, despite neither patient adhering strictly to the diet due to its restrictiveness. ...
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Dietary interventions, such as calorie restriction and ketogenic diet, have been extensively studied in ageing research, including in cognitive decline. Epidemiological studies indicate beneficial effects of certain dietary regimes on mental health, including mood disorders and dementia. However, randomised-controlled trials (the gold-standard of evidence-based medicine) on calorie restriction diets and the ketogenic diet have yet to show clinically convincing effects in neuropsychiatric disorders. This review will examine the quality of studies and evidence base for the ketogenic and calorie restriction diets in common neuropsychiatric conditions, collating findings from preclinical experiments, case reports or small clinical studies, and randomised controlled clinical trials. The major cellular mechanisms that mediate the effects of these dietary interventions on brain health include neuroinflammation, neuroprotection, and neuromodulation. We will discuss the studies that have investigated the roles of these pathways and their interactions. Popularity of the ketogenic and calorie restriction diets has grown both in the public domain and in psychiatry research, allowing for informed review of the efficacy, the limitations, and the side effects of these diets in specific patient populations. In this review we will summarise the clinical evidence for these diets in neuropsychiatry and make suggestions to improve clinical translation of future research studies.
... In addition, there was also study in which authors demonstrated ketogenic diet normalizing pathological behaviors in an animal model of schizophrenia [36]. The study mentioned above can seems to have a assurance in practice, while there are two case-reports on schizoaffective disorder, in which both patient experienced significant weight loss and, what is probably more important, recovery in positive and negative symptoms while on ketosis, with an acute exacerbation while going off the diet [37]. ...
... These could be potential mechanisms for the effect of a ketogenic diet. This diet, high in fat, and low in carbohydrate, utilize ketone bodies as the fuel source for the brain, instead of glucose (118,119). A report from investigators with the Nutrition Network of the European College of Neuropsychopharmacology (ECNP) postulates that a ketogenic diet may decrease seizures in children with epilepsy (5, 120). ...
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There is a strong relationship between a healthy diet and mental well-being. Several foods and food compounds are known to modulate biomarkers and molecular mechanisms involved in the aetiogenesis of several mental disorders, and this can be useful in containing the disease progression, including its prophylaxis. This is an updated systematic review of the literature to justify the inclusion and recognition of nutrition in the management of psychiatric illnesses. Such foods and their compounds include dietary flavanols from fruits and vegetables, notable antioxidant and anti-inflammatory agents, probiotics (fermented foods) known to protect good gut bacteria, foods rich in polyunsaturated fatty acids (e.g., Omega-3), and avoiding diets high in saturated fats and refined sugars among others. While the exact mechanism(s) of mitigation of many nutritional interventions are yet to be fully understood, the evidence-based approach warrants the inclusion and co-recognition of nutrition in the management of psychiatric illnesses. For the greater public health benefit, there is a need for policy advocacy aimed at bridging the knowledge gap and encouraging the integration of nutritional intervention with contemporary therapies in clinical settings, as deficiencies of certain nutrients make therapy difficult even with appropriate medication.
... 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.
... In yet another study, a male and a female with schizo-affective disorder where given a ketogenic diet and showed an improvement in the Positive and Negative Syndrome Scale (PANSS) scores; they also lost weight. 31 These results are supported by another case study on schizophrenic individuals as well; their PANSS score lowered and they lost weight. 32 In a case report on a 70 year old female with schizophrenia, it was found that when she was allowed to eat less than 20 g/day of carbohydrates, she showed considerable improvement -no auditory or visual hallucinations, more energy, and weight loss. ...
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Schizophrenia is a severe illness that affects 24 million individuals around the globe. Individuals with schizophrenia have been known to make poor nutritional choices. In fact, they are known to consume a lot more sugar and fat, and less fruits and vegetables. In this paper, I show how diet can reduce the symptoms of schizophrenia; that is, that consumption of certain foods can lessen the symptoms of schizophrenia. Further, I create an optimal diet for individuals with schizophrenia.
... Glucose metabolism and the function of mitochondria and GaBaergic interneurons are all impaired in the cortex, basal ganglia and other brain structures in schizophrenia 34,227,305 . as in epilepsy, ketone-based interventions have been proposed as a therapy for schizophrenia 306,307 and have shown encouraging results in two clinical case reports 308 . ...
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The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.
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Purpose of review: The aim of this article is to review recent findings on the efficacy of ketogenic diet in preclinical models and in patients with schizophrenia. This review will also highlight emerging evidence for compromised glucose and energy metabolism in schizophrenia, which provides a strong rationale and a potential mechanism of action for ketogenic diet. Recent findings: Recent transcriptomic, proteomic and metabolomic evidence from postmortem prefrontal cortical samples and in-vivo NMR spectroscopy results support the hypothesis that there is a bioenergetics dysfunction characterized by abnormal glucose handling and mitochondrial dysfunctions resulting in impaired synaptic communication in the brain of people with schizophrenia. Ketogenic diet, which provides alternative fuel to glucose for bioenergetic processes in the brain, normalizes schizophrenia-like behaviours in translationally relevant pharmacological and genetic mouse models. Furthermore, recent case studies demonstrate that ketogenic diet produces improvement in psychiatric symptoms as well as metabolic dysfunctions and body composition in patients with schizophrenia. Summary: These results support that ketogenic diet may present a novel therapeutic approach through restoring brain energy metabolism in schizophrenia. Randomized controlled clinical trials are needed to further show the efficacy of ketogenic diet as a co-treatment to manage both clinical symptoms and metabolic abnormalities inherent to the disease and resulted by antipsychotic treatment.
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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.
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Over the past decade evidence from multiple research trajectories have converged to provide evidence that impaired glucose metabolism and mitochondrial dysfunction in the brain are the critical issues laying at the root of Bipolar Disorder (BD). These developments have been paralleled by increasing recognition of the systemic metabolic dysfunction accompanying mood disorders. Significant insulin resistance (IR) occurs in BD patients and this has been demonstrated to be related to illness severity independent of medication status. Preliminary evidence for a therapeutic effect of a Ketogenic Diet (KD) in BD and other neuropsychiatric conditions has recently refocused interest in the role of IR in BD pathogenesis. In this paper we review evidence of hyperinsulinemia in BD as the primary cause of mitochondrial dysfunction mediated by impairment of the PI3K/AKT/HIF1-a insulin signaling pathway. This cascade of dysfunction directly suppresses the Pyruvate Dehydrogenase Complex through HIF1-a mediated activation of Pyruvate dehydrogenase kinase 1 (PDK1) leading to the Warburg effect and mitochondrial dysfunction. We review evidence that the KD acts directly on each of these mechanisms and propose that a trial of KD in BD with a mechanistic component is needed to further investigate the role of IR in BD.
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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The gut microbiota is composed of a large number of microbes, usually regarded as commensal bacteria. It has become gradually clear that gastrointestinal microbiota affects gut pathophysiology and the central nervous system (CNS) function by modulating the signaling pathways of the microbiota-gut-brain (MGB) axis. This bidirectional MGB axis communication primarily acts through neuroendocrine, neuroimmune, and autonomic nervous systems (ANS) mechanisms. Accumulating evidence reveals that gut microbiota interacts with the host brain, and its modulation may play a critical role in the pathology of neuropsychiatric disorders. Recently, neuroscience research has established the significance of gut microbiota in the development of brain systems that are essential to stress-related behaviors, including depression and anxiety. Application of modulators of the MGB, such as psychobiotics (e.g., probiotics), prebiotics, and specific diets, may be a promising therapeutic approach for neuropsychiatric disorders. The present article primarily focuses on the relevant features of the disturbances of the MGB axis in the pathophysiology of neuropsychiatric disorders and its potential mechanisms.
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A limited number of studies suggest that poor diet choices may impact on the mental state of schizophrenia patients. Our own work found that high fat diet (HFD) reversed social recognition memory deficits in female mice mutant for the schizophrenia risk gene neuregulin 1 (i.e. Nrg1 transmembrane domain: Nrg1 TM HET). Sex effects are common in schizophrenia and adolescence is a period of increased sensitivity to environmental risk factors. Thus, we investigated whether adolescent HFD exposure modulates schizophrenia-relevant behaviours of male and female Nrg1 TM HET mice. Male and female Nrg1 TM HET and their control littermates were exposed to either HFD or a standard chow diet from late adolescence onwards. After 8 weeks, adult mice were tested for locomotion and exploration, social behaviours, sensorimotor gating (i.e. prepulse inhibition), and fear-associated learning and memory. Nrg1 TM HET mice exhibited hyper-locomotion and an anxiolytic-like phenotype across sex and Nrg1 males tended to show deficient fear-associated memory. HFD increased body weight over time in all mice, an effect less pronounced in Nrg1 female mice. The moderately suppressive effect of HFD on females’ exploration was less evident in Nrg1 mutants. Nrg1 TM HET female mice also displayed a less pronounced increase in HFD-induced cue freezing and HFD modulated the response to the cue in a complex genotype-dependent manner. In conclusion, HFD exposure starting in late adolescence has sex-specific effects on exploration and fear-associated memory, which was less pronounced in females mutant for Nrg1. This suggests that research into the role of diets in schizophrenia-relevant domains should consider genetic risk factors for the disease as schizophrenia risk genes such as Nrg1 may modulate dietary effects.
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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).
Article
Background: Schizophrenia might share intrinsic inflammatory disease pathways with type 2 diabetes. We aimed to assess whether first-episode psychosis, which could be described as developing schizophrenia, is associated with prediabetic markers, or developing diabetes, to determine whether intrinsic disease links could cause the disorders to develop in unison. We hypothesised that biochemical measures of prediabetic states would be more common in antipsychotic naive patients with first-episode psychosis than in healthy matched controls. Methods: For this systematic review and meta-analysis, using PRISMA criteria, we searched Embase, MEDLINE, PsycINFO, Web of Science, and Google Scholar for clinical studies published between database inception and Jan 6, 2016. We assessed case-control studies with biochemical assessment of prediabetic states in patients with first-episode psychosis alongside matched controls. We sought data at the summary estimate level. Several measurements were used to test for prediabetes, including fasting plasma glucose, insulin resistance (measured by the Homeostatic Model Assessment), and impaired glucose tolerance. We calculated standardised mean differences for each outcome. We used the inverse variance method, for which the weight given to each study was the inverse of the variance of the effect estimate. For dichotomous outcomes, we entered the number of events and number in each group into RevMan 5.3 and used the Mantel-Haenszel method to pool studies. Findings: We identified 1436 studies, of which 12 were included in final analysis, including 1137 participants. Pooled analyses found first-episode psychosis to be related to insulin resistance (mean difference 0·30 [95% CI 0·18 to 0·42]), impaired glucose tolerance (mean difference 1·31 [0·37 to 2·25]), and the number of patients with impaired glucose tolerance (odds ratio 5·44 [2·63 to 11·27]), but not fasting plasma glucose (mean difference 0·03 mmol/L [-0·04 to 0·09]). Interpretation: Our findings suggest a potential link between prediabetic markers, in particular impaired glucose tolerance and insulin resistance, and first-episode psychosis. However, we cannot establish causality, and the studies contributing to this review were at some risk of bias. Nevertheless, the findings might help to explain the increased prevalence of type 2 diabetes in patients with schizophrenia and could have implications for the management of patients with schizophrenia. Funding: None.
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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.
Article
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.
Article
Ketone bodies (KBs) are an important source of energy for the brain. During the neonatal period, they are also precursors for the synthesis of lipids (especially cholesterol) and amino acids. The rate of cerebral KB metabolism depends primarily on the concentration in blood; high concentrations occur during fasting and on a high-fat diet. Cerebral KB metabolism is also regulated by the permeability of the blood-brain barrier (BBB), which depends on the abundance of monocarboxylic acid transporters (MCT1). The BBB's permeability to KBs increases with fasting in humans. In rats, permeability increases during the suckling period, but human neonates have not been studied. Monocarboxylic acid transporters are also present in the plasma membranes of neurons and glia but their role in regulating KB metabolism is uncertain. Finally, the rate of cerebral KB metabolism depends on the activities of the relevant enzymes in brain. The activities vary with age in rats, but reliable results are not available for humans. Cerebral KB metabolism in humans differs from that in the rat in several respects. During fasting, for example, KBs supply more of the brain's energy in humans than in the rat. Conversely, KBs are probably used more extensively in the brain of suckling rats than in human neonates. These differences complicate the interpretation of rodent studies. Most patients with inborn errors of ketogenesis develop normally, suggesting that the only essential role for KBs is as an alternative fuel during illness or prolonged fasting. On the other hand, in HMG-CoA lyase deficiency, imaging generally shows asymptomatic white-matter abnormalities. The ability of KBs to act as an alternative fuel explains the effectiveness of the ketogenic diet in GLUT1 deficiency, but its effectiveness in epilepsy remains unexplained.