Ketogenic diet reverses behavioral abnormalities in an acute NMDA receptor hypofunction model of schizophrenia

Kraeuter, Ann Katrin; Loxton, Heather; Lima, Bruna Genisa Costa; Rudd, Donna; Sarnyai, Zoltán

doi:10.1016/j.schres.2015.10.041

Cited by 54 publications

(37 citation statements)

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“…Animal models of schizophrenia fit into four induction methods including developmental, drug-induced, lesional, or genetic manipulation (62). In a recent drug-induced (MK-801, dizocilpine) animal model of schizophrenia in C57BL/6 mice, it was demonstrated that 3 weeks of KD (77.6% fat, 9.5% protein, and 4.7% crude fiber, AD fiber 4.7%) normalized pathological behaviors (41). These included psychomotor hyperactivity, stereotyped behavior, social withdrawal, and working memory deficits, which reflect the positive, negative, and cognitive symptoms of the disorder.…”

Section: Resultsmentioning

confidence: 99%

The Current Status of the Ketogenic Diet in Psychiatry

Bostock

Kirkby

Taylor³

2017

Front. Psychiatry

104

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BackgroundThe ketogenic diet (KD) has been used in treatment-resistant epilepsy since the 1920s. It has been researched in a variety of neurological conditions in both animal models and human trials. The aim of this review is to clarify the potential role of KD in psychiatry.MethodsNarrative review of electronic databases PubMED, PsychINFO, and Scopus.ResultsThe search yielded 15 studies that related the use of KD in mental disorders including anxiety, depression, bipolar disorder, schizophrenia, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD). These studies comprised nine animal models, four case studies, and two open-label studies in humans. In anxiety, exogenous ketone supplementation reduced anxiety-related behaviors in a rat model. In depression, KD significantly reduced depression-like behaviors in rat and mice models in two controlled studies. In bipolar disorder, one case study reported a reduction in symptomatology, while a second case study reported no improvement. In schizophrenia, an open-label study in female patients (n = 10) reported reduced symptoms after 2 weeks of KD, a single case study reported no improvement. In a brief report, 3 weeks of KD in a mouse model normalized pathological behaviors. In ASD, an open-label study in children (n = 30) reported no significant improvement; one case study reported a pronounced and sustained response to KD. In ASD, in four controlled animal studies, KD significantly reduced ASD-related behaviors in mice and rats. In ADHD, in one controlled trial of KD in dogs with comorbid epilepsy, both conditions significantly improved.ConclusionDespite its long history in neurology, the role of KD in mental disorders is unclear. Half of the published studies are based on animal models of mental disorders with limited generalizability to the analog conditions in humans. The review lists some major limitations including the lack of measuring ketone levels in four studies and the issue of compliance to the rigid diet in humans. Currently, there is insufficient evidence for the use of KD in mental disorders, and it is not a recommended treatment option. Future research should include long-term, prospective, randomized, placebo-controlled crossover dietary trials to examine the effect of KD in various mental disorders.

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Section: Resultsmentioning

confidence: 99%

The Current Status of the Ketogenic Diet in Psychiatry

Bostock

Kirkby

Taylor³

2017

Front. Psychiatry

104

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“…For example, there are tantalising data from animal models pointing to the potential for the ketogenic diet in animal models of psychosis (Kraeuter et al, 2015) and this could be evaluated as a possible intervention in humans. Similarly, gastrointestinal barrier dysfunction, food sensitivities, inflammation, and the metabolic syndrome are commonly seen in schizophrenia and this warrants research investigating the possible role of such factors in the genesis and progression of psychotic illnesses, and the potential of dietary interventions addressing immune dysfunction, food sensitivities and gut health in those with psychosis.…”

Section: Where To Now?mentioning

confidence: 99%

Nutritional Psychiatry: Where to Next?

2017

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The nascent field of ‘Nutritional Psychiatry’ offers much promise for addressing the large disease burden associated with mental disorders. A consistent evidence base from the observational literature confirms that the quality of individuals' diets is related to their risk for common mental disorders, such as depression. This is the case across countries and age groups. Moreover, new intervention studies implementing dietary changes suggest promise for the prevention and treatment of depression. Concurrently, data point to the utility of selected nutraceuticals as adjunctive treatments for mental disorders and as monotherapies for conditions such as ADHD. Finally, new studies focused on understanding the biological pathways that mediate the observed relationships between diet, nutrition and mental health are pointing to the immune system, oxidative biology, brain plasticity and the microbiome-gut-brain axis as key targets for nutritional interventions. On the other hand, the field is currently limited by a lack of data and methodological issues such as heterogeneity, residual confounding, measurement error, and challenges in measuring and ensuring dietary adherence in intervention studies. Key challenges for the field are to now: replicate, refine and scale up promising clinical and population level dietary strategies; identify a clear set of biological pathways and targets that mediate the identified associations; conduct scientifically rigorous nutraceutical and ‘psychobiotic’ interventions that also examine predictors of treatment response; conduct observational and experimental studies in psychosis focused on dietary and related risk factors and treatments; and continue to advocate for policy change to improve the food environment at the population level.

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“…During the last decades, application of KD has also been extended to other neurological or non‐neurological diseases, and demonstrated its beneficial effects (Koppel & Swerdlow, ). For example, KD was reported to reduce the anxiety and improve motor behavior in mice with Rett Syndrome (Mantis, Fritz, Marsh, Heinrichs, & Seyfried, ); rescue hippocampal memory defects in mice with Kabuki syndrome (Benjamin et al, ); exhibit anxiolytic and cognition‐sparing properties or improves motor performance in mouse models of Alzheimer's disease (Brownlow, Benner, D'Agostino, Gordon, & Morgan, ; Kashiwaya et al, ); improve motor performance in SOD1‐G93A transgenic mice of amyotrophic lateral sclerosis (ALS) (Zhao et al, ); delay weight loss in the R6/2 1J mouse model of Huntington's disease (Ruskin et al, ); reverse behavioral abnormalities in an acute NMDA receptor hypofunction model of schizophrenia (Kraeuter, Loxton, Lima, Rudd, & Sarnyai, ); and reverse diabetic nephropathy, which is a profound diabetic complication (Poplawski et al, ).…”

Section: Introductionmentioning

confidence: 99%

The effect of ketogenic diet on behaviors and synaptic functions of naive mice

Huang

et al. 2019

Brain and Behavior

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Introduction Beyond its application as an epilepsy therapy, the ketogenic diet (KD) has been considered a potential treatment for a variety of other neurological and metabolic disorders. However, whether KD promotes functional restoration by reducing the pathological processes underlying individual diseases or through some independent mechanisms is not clear. Methods In this study, we evaluated the effect of KD on a series of behaviors and synaptic functions of young adult naive mice. Wild‐type C57BL/6J mice at age of 2–3 months were fed with control diet or KD for three months. Body weight and caloric intake were monitored throughout the experiments. We assessed behavioral performance with seizure induction, motor coordination and activity, anxiety level, spatial learning and memory, sociability, and depression. Synaptic transmission and long‐term potentiation were also recorded. Results KD‐fed mice performed equivalent to control‐diet‐fed mice in the behavioral tests and electrophysiological assays except exhibiting slower weight gain and increased seizure threshold. Conclusions Our results contribute to the better understanding of effects of the KD on physiological behaviors and synaptic functions.

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Ketogenic diet reverses behavioral abnormalities in an acute NMDA receptor hypofunction model of schizophrenia

Cited by 54 publications

References 9 publications

The Current Status of the Ketogenic Diet in Psychiatry

The Current Status of the Ketogenic Diet in Psychiatry

Nutritional Psychiatry: Where to Next?

The effect of ketogenic diet on behaviors and synaptic functions of naive mice

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