Article

The antidepressant properties of the ketogenic diet

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Abstract

The ketogenic diet is used to treat epilepsy refractory to anticonvulsant medication. Individuals with epilepsy often have behavioral problems and deficits in attention and cognitive functioning. The ketogenic diet has been found to effect improvements in these domains. It has also been suggested that the ketogenic diet may act as a mood stabilizer. The present research used the Porsolt test, an animal model of depression, to determine whether the ketogenic diet has antidepressant properties. Porsolt test scores of rats on the ketogenic diet were compared with those of rats on a control diet. The rats on the ketogenic diet spent less time immobile, suggesting that rats on the ketogenic diet, like rats treated with antidepressants, are less likely to exhibit "behavioral despair." It is concluded that the ketogenic diet may have antidepressant properties.

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... Forty Wistar rats were on standard diet or ketogenic diet for seven days (Table 2) (Murphy et al., 2004). Ketogenic diet animals were more mobile and showed improvement in depressive-like behaviour compared to standard diet animals (Murphy et al., 2004). ...
... Forty Wistar rats were on standard diet or ketogenic diet for seven days (Table 2) (Murphy et al., 2004). Ketogenic diet animals were more mobile and showed improvement in depressive-like behaviour compared to standard diet animals (Murphy et al., 2004). ...
... Ketogenic diet has not been investigated within the context of anxiety and depression in humans. Ketogenic diet decreased anxiety-and depression-like behaviours (Huang et al., 2018;Murphy et al., 2004;Sussman et al., 2013). In the chronic unpredictable stress and lipopolysaccharides paradigm, BHB was able to alleviate all symptoms of major depressive disorder in combination with a reduction of inflammatory markers. ...
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.
... In recent years, many studies have been shown that KD has beneficial health effects and therapeutic potential for a broad range of disorders, containing central nervous system disorder and stress induced situations such as anxiety and depression disorders. In literature, there are a couple of studies that report KD leads to a decrease in anxiety and depression behaviors [37][38][39] whereas other studies report that the levels of anxiety and depression are not affected following KD therapy [40,41]. In the last years, several studies investigated effects of exercise on anxiety and depression behavior in rodent animals, however, findings are quite contradictory. ...
... In the FST, the immobility time decreased in KD-Ex mice merely when compared to control mice and also there was a slight difference in terms of the immobility time between KD-Ex, KD and Ex mice altough it wasn't significant. Murphy et al. [37] reported that the rats of KD group spent lower the immobility time than the rats of control mice. Our findings suggest that KD-Ex may have antidepressant effects. ...
... An increase of time spent in the closed arms of EPM which known as anxious behavior was moderate negative correlated with BHB level. In a conflicting report, Murphy et al. [37] demonstrated that the prensence of ketosis wasn't needed to observe a behavioral change, suggesting the therapeutic effects of KD are not just linked its potential in stimulate ketosis. The immobile duration was moderate negatively correlated with BHB levels while insulin or glucose were moderate positively correlated with depression behaviors in FST. ...
Article
The positive effects of both ketogenic diet (KD) and regular voluntary exercise on anxiety and depression behavior have been recently reported in rodent animals, but the effects of pairing a KD with exercise on depression and anxiety are unknown. In this study, we aimed to investigate the effects of combination of KD and regular voluntary exercise on anxiety and depression-like behavior in Balb/c mice. We’ve demostrated that anxiety and depression levels decreased in KD-exercised (KD-Ex) mice. β-hydroxybutyrate (BHB) levels increased while glucose, insulin levels and LDL/HDL ratio decreased in KD-Ex mice. There was a negative correlation between BHB and the time spent in the closed arms of elevated plus maze (EPM) or the time spent in periphery walls of open field test (OFT) and the immobility time in forced swim test (FST) which all of them are indicators of low depression and anxiety levels. There was a positive correlation between LDL/HDL ratio and the time spent in the closed arms of EPM or the immobility time in FST. The immobility time in FST was positively correlated with insulin while the mobility time in FST was negatively correlated with glucose. In conclusion, these results suggest that decline in anxiety and depression-like behaviors resulted from KD with regular voluntary exercise may be associated with increased BHB levels and decreased LDL/HDL ratio and insulin or glucose levels. Further research is necessary for our understanding of the mechanisms by which pairing a KD with voluntary exercise influences brain and behavior.
... Regarding MDD, the potential efficacy of KD in the treatment of mood disorders was evaluated in animal models for depression. Specifically, Murphy et al. (2004) used a model developed by Porsolt et al. (1977), which is a well-established model to evaluate the antidepressant properties of new agents/substances. The model has two steps. ...
... The rats submitted to the KD group in this study spent less time immobile than did the rats in the control diet group. This suggests that the KD may have effects that are similar to antidepressant drugs (Murphy et al., 2004). Another interesting finding of this experiment was that the presence of ketosis was not required to observe a behavioral change, suggesting that perhaps the therapeutic effects of KD are not just linked its potential in induce a ketogenic state. ...
... Although the rats from the KD group had a higher level of ketosis than the control group, this level was quite low. The authors state that this finding is in line with the literature in humans with epilepsy, indicating that seizure control and behavioral changes are not always linked, while other studies on epilepsy have shown that improvements on mental status and behavior could be found even when seizure control is not achieved (MacCracken and Scalisi, 1999;Pulsifer et al., 2001;Murphy et al., 2004). ...
Article
Despite significant advances in pharmacological and non-pharmacological treatments, mood disorders remain a significant source of mental capital loss, with high rates of treatment resistance, requiring a coordinated effort in investigation and development of efficient, tolerable and accessible novel interventions. Ketogenic diet (KD) is a low-carb diet that substantially changes the energetic matrix of the body including the brain. It has been established as an effective anticonvulsant treatment, and more recently, the role of KD for mental disorders has been explored. Ketogenic diet has profound effects in multiple targets implicated in the pathophysiology of mood disorders, including but not limited to, glutamate/GABA transmission, monoamine levels, mitochondrial function and biogenesis, neurotrophism, oxidative stress, insulin dysfunction and inflammation. Preclinical studies, case reports and case series have demonstrated antidepressant and mood stabilizing effects of KD, however, to date, no clinical trials for depression or bipolar disorder have been conducted. Because of its potential pleiotropic benefits, KD should be considered as a promising intervention in research in mood disorder therapeutics, especially in treatment resistant presentations.
... The ketogenic diet exhibited an anxiolytic effect during Open Field Testing as evidenced by increased ambulation and exploratory behavior compared to the control group (Kashiwaya et al. 2013). Murphy et al. (2004), using a sample of 40 Wistar rats, tested a ketogenic diet in reference to depressive symptoms, or "behavioral despair". The Porsolt test, a behavioral test, observes rat movement in water and is accepted as a reliable test for depressive symptoms in animals. ...
... This study found that during the Porsolt test, rats on a ketogenic diet spent less time immobile than those on a standard diet, meaning they were less likely to exhibit behavioral despair or depression. The results of the rats on a ketogenic diet were similar to rats that had previously been tested while on antidepressants (Murphy et al. 2004). ...
Article
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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.
... Metabolic and neuroendocrine disorders caused by environmental stress may affect the BHB metabolism in the brain [16]. Besides being used to treat epilepsy, BHB plays a neuroprotective role in neurodegenerative diseases and psychotic disorders [17e19], and has been demonstrated antidepressant effect in depression [20]. It is highly conceivable that BHB might act to increase the levels of BDNF (Brain derived neurotrophic factor) [21,22]. ...
... In another independent experiment, stress group and control group mice were assigned into six groups, contral groups (Con, Str), ketogenic diet groups (Con þ Ket, Str þ Ket) and exercise groups (Con þ Exe, Str þ Exe). Ketogenic diet groups mice were given ketogenic diet (purchased from SLAC Company, Shanghai, China) according to previously described [20]. Exercise groups mice were individuality housed in cage with free access to a running wheel [21]. ...
... The quality of life and mood has also been improved, which was indicated by less severity of subjective symptoms. The results of intervention studies with individuals with depression indicate a decrease in body weight is accompanied by mood changes [20,21,22]. ...
... Poprawie uległa także jakość życia, nastrój, o czym świadczy mniejsze subiektywne nasilenie objawów. Wyniki badań interwencyjnych z udziałem osób ze zdiagnozowaną depresją wskazują, że wraz ze zmniejszeniem masy ciała, obserwowana jest zmiana nastroju [20][21][22]. ...
Article
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Introduction: There has been a growing interest in the ketogenic diet (KD) due to its suggested therapeutic potential to support numerous chronic diseases. KD is characterized by high amounts of fats and a reduced amount of carbohydrates and protein intake. During following the nutrition protocol, ketones are synthesised, which are the primary source of energy. The elevated concentration of ketones in blood serum inhibits hunger, what leads to reduced body weight. Some authors suggest KD has antidepressant potential and could stabilise mood by affecting neurotransmitters homeostasis in the central nervous system. Material and methods: The aim of the study was to assess the effect of KD on body weight reduction and improvement of mood in the patients with mood disorder diagnosis. To interpret the results of nutritional intervention, the laboratory parameters and structuralised scales and questionnaires were used. Results: After following 4-week therapy, the reduction of body weight, correction of some laboratory measurements and reduction in mood symptoms were noticed. Conclusions: The ketogenic diet affects the anthropometric measurements. However, a variety of simultaneous therapeutic approaches makes impossible determination of the effect on depressive symptoms.
... Frontiers in Pharmacology | www.frontiersin.org November 2020 | Volume 11 | Article 578396 Preclinical studies, case reports, and case series have demonstrated mood stabilizing and antidepressant effects of the ketogenic diet (Murphy et al., 2004;Yankelevitch-Yahav et al., 2015;Brietzke et al., 2018;Grigolon et al., 2020). ...
... This evidence suggests that the ketogenic diet acts like antidepressant drugs in the Porsolt swim test, a behavior despair test commonly applied in experimental studies to assess depressive-like behavior in rodents. Furthermore, the handling test revealed that the reduced immobility appeared to be due to the antidepressant properties of the ketogenic diet (Murphy et al., 2004;Yankelevitch-Yahav et al., 2015). The main literature data regarding the efficacy of the ketogenic diet in animal models and in humans are synthetized in Table 1. ...
Article
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The ketogenic diet, used for over a century as an alternative therapy for the control of drug-resistant seizures in both children and adults, has recently drawn increasing interest in various neurological or psychiatric disorders other than epilepsy. In particular, there are a few preliminary studies in mood and neurodevelopmental disorders such as anxiety, depression and autism spectrum disorders. Mood disorders in comorbidity with epilepsy are commonly seen in adolescents and young adults both at the onset and during the course of the epileptic disorder. The rationale for the use of the ketogenic diet is based on the potential mood stabilizing effects through level modifications of metabolites such as dopamine and serotonin and the regulation of GABA/glutamatergic neurotransmission, mitochondrial function and oxidative stress. In this review, epilepsies with a higher risk of mood disorders in adolescents will be considered. A brief overview of the various types of ketogenic diet that can currently be offered to young patients in order to improve palatability and compliance with the diet, is also included. The efficacy and tolerability of the ketogenic diet options for the treatment of mood disorders, with or without drug therapy including mood stabilizers and antidepressant drugs, are as well discussed.
... Ketojenik diyet uygulamasının hayvan depresyon modellerinde ve tanılı depresyon hastalarında depresif bozukluk bulgularını istatistiksel olarak önemli ölçüde azalttığını, semptomlarda düzelme sağladığını, antidepresan ilaç tedavisine benzer bir etki gösterdiğini kanıtlayan çalışmalar bulunmaktadır (Bostock et al., 2017: 1-10;Cox et al., 2019Cox et al., : 1475Murphy et al., 2004;981-3). Ketojenik diyet ve depresyonla ilgili yedi randomize kontrollü çalışmanın incelendiği, konuyla ilgili en güncel derleme olan Cochrane derlemesinde sonuçların genel olarak ketojenik diyet lehine olduğu belirtilmiştir. ...
Conference Paper
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Bu araştırmanın amacı Mardin yöresinde en çok yetiştirilen Adana 99, Ceyhan 99, Segittario ve Dinç ekmeklik buğday çeşitlerinin fiziksel, teknolojik ve fiziko-kimyasal kalite özelliklerini incelemek-tir. Buğday örnekleri Tarım İşletmeleri Genel Müdürlüğü’nden temin edilmiştir. Analizlerden önce tüm buğday çeşitleri içindeki yabancı maddeler, taş, toprak, kırık ve bozuk taneler ayıklanmak suretiyle te-mizlenmiştir. Sonuçlar, ekmeklik buğday çeşitleri arasında, bin tane ağırlığı (g/g k.m), hektolitre ağırlığı (kg/hl), tane boyutu (uzunluk (mm), genişlik (mm), kalınlık (mm), eşdeğer çap (mm)), küresellik, Hun-ter renk (L *, a * ve b *) değerleri gibi fiziksel özellikler açısından önemli farklılıklar olduğu ve bu farkların istatistiksel (P≤0.05) olarak anlamlı olduğu bulunmuştur. Ayrıca kuru ağırlık (g/100 tane), yaş ağırlık (g/100 tane), su alma kapasitesi (g/tane), su alma indeksi (%), kuru hacim (ml), ıslak hacim (ml), şişme kapasitesi (ml/tane) ve şişme indeksi (%) gibi teknolojik kalite özellikleri bakımından bu çeşitler arasında istatistiksel olarak anlamlı farklar bulunmuştur (P≤0.05). Fiziko-kimyasal kalite özellikleri (nem (%), yaş glüten (%), gluten indeksi (%), Zeleny sedimantasyon (ml) ve gecikmeli sedimantasyon (ml)) bakımından da buğday çeşitleri arasında önemli farkla bulunmuş ve bu farkların istatistiksel (P≤0.05) olarak anlamlı olduğu tespit edilmiştir. Ekmeklik buğday çeşitleri arasındaki tespit edilen ka-lite karakteristiklerindeki bu farklılıklar un sanayisinde ve ekmek yapımındaki işlemler açısından önemli olabilir. Bu sektörlerdeki işletmecilere bir kılavuz olabilir.
... There is evidence that a ketogenic diet, which leads to elevated levels of BHB in the serum and brain, produces antidepressant effects 35 , as seven days on a ketogenic diet increases the levels of serum BHB and decreases immobility time in the FST 36 . In addition, adult offspring previously exposed to a prenatal ketogenic diet exhibits reductions in anxiety-like behaviors in the OFT and depressive-like behaviors in the FST. ...
Article
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Aims: Neuroinflammation is deeply related to the pathophysiology of depression. Beta-hydroxybutyrate (BHB), which is an endogenous ketone body, exerts anti-inflammatory effects, and peripheral administration of BHB induces antidepressant effects in an animal model of depression; however, it is unclear whether BHB specifically mediates these actions in the brain. Thus, we administered BHB directly into the brain in a rodent model of depression using a chronic unpredictable stress (CUS) paradigm. Methods: BHB was continuously microinjected into the prefrontal cortex (PFC) using osmotic pumps for 21 days. Behavioral testing included the forced swim test (FST) and the open field test (OFT); the levels of pro-inflammatory cytokines, such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), were quantified in the PFC, and the concentration of corticosterone in blood serum was measured. Results: BHB administration into the PFC significantly decreased immobility time in the FST, without significantly altering locomotor activity assessed in the OFT. Also, CUS significantly increased the levels of TNF-α in the PFC and decreased serum corticosterone levels; these changes were attenuated by BHB administration. These findings suggest that a small amount of BHB administered into the PFC directly produces antidepressant effects, possibly through anti-inflammatory mechanisms, and can improve hypothalamus-pituitary-adrenal axis responses. Conclusion: BHB may be a novel therapeutic candidate for the treatment of depression based on the neuro-inflammatory hypothesis, and the PFC is a region implicated in the antidepressant action of BHB.
... Beyond this, the ketogenic diet has brought about improvement in multiple neurologic diseases, though evidence for effectiveness in these other indications is limited to case reports or observational studies. Treatment of Parkinson's disease, [49][50][51] amyotrophic lateral sclerosis, 52 depression, 53,54 multiple sclerosis, 55. and autism 56,57 are among the anecdotally supported uses of the ketogenic diet. ...
Article
Dementia (major neurocognitive disorder) is an increasingly common syndrome with a significant burden on patients, caregivers, the health-care system, and the society. The prevalence of dementia will certainly continue to grow as the US population ages. Current treatments for dementia, though, are limited. One proposed nonpharmacologic approach for the delay or prevention of dementia is the use of a ketogenic diet. The ketogenic diet was originally employed to treat refractory epilepsy and has shown promise in many neurologic diseases. It has also gained recent popularity for its weight loss effects. Several preclinical studies have confirmed a benefit of ketosis on cognition and systemic inflammation. Given the renewed emphasis on neuroinflammation as a pathogenic contributor to cognitive decline, and the decreased systemic inflammation observed with the ketogenic diet, it is plausible that this diet may delay, ameliorate, or prevent progression of cognitive decline. Several small human studies have shown benefit on cognition in dementia with a ketogenic diet intervention. Future, large controlled studies are needed to confirm this benefit; however, the ketogenic diet has shown promise in regard to delay or mitigation of symptoms of cognitive decline.
... The tail suspension test is used to screen antidepressants, and if coupled with a locomoter test, can differentiate locomotor stimulant doses from antidepressant doses (Steru et al., 1985). The KD is a potential metabolic therapy for mood disorders (Brietzke et al., 2018), and rats on a KD are less likely to exhibit behavioral despair (depression) (Murphy et al., 2004). We found no significant effect of KD in WT or Fmr1 KO mice. ...
Article
The ketogenic diet is highly effective at attenuating seizures in refractory epilepsy and accumulating evidence in the literature suggests that it may be beneficial in autism. To our knowledge, no one has studied the ketogenic diet in any fragile X syndrome (FXS) model. FXS is the leading known genetic cause of autism. Herein, we tested the effects of chronic ketogenic diet treatment on seizures, body weight, ketone and glucose levels, diurnal activity levels, learning and memory, and anxiety behaviors in Fmr1KO and littermate control mice as a function of age. The ketogenic diet selectively attenuates seizures in male but not female Fmr1KO mice and differentially affects weight gain and diurnal activity levels dependent on Fmr1 genotype, sex and age.
... Novije studije upu}uju na mogu}u korist od primjene ketogene dijete u pacijenata s autizmom (66) i depresijom (67), iako mehanizam djelovanja u psihijatrijskih poreme}aja nije jasan. ...
Article
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UVOD Historijat ketogene dijete Ketogena dijeta podrazumijeva prehranu siroma{nu ugljikohidratima i bogatu mastima, koje ~ine najve}i dio kalorijske vrijednosti prehrane. Takav na~in prehrane zapravo imitira stanje gladovanja, pri ~emu metabolizam masti postaje osnovni izvor energije, potiskuju}i glukozu i ostale ugljikohidrate. Ketogena je dijeta razvijena u Mayo klinici kao terapijski tretman za kontrolu refraktorne epilepsije u djece po~etkom dvadesetih godina pro{loga stolje}a (1), u vrijeme ograni~ene dostupnosti i u~inkovitosti antiepileptika. Mogu}a korist od posta u tretmanu epilepsije opisana je jo{ u Bibliji, dok se u suvre-menoj medicinskoj literat uri sli~an pristup prvi put spominje u radovima Guelpa i Mariea iz 1911. (1). Sljede}a dva desetlje}aobiljèili su brojni izvje{taji o djelotvornosti ketogene dijete u tretmanu epilepsije. Otkri}e fenitoina 1938. bitno mijenja takav trend, a novaistràivanja i terapijska doktrina usmjereni su na fenitoin i nove antiepileptike. U usporedbi s novom farmakoterapijom, ketogena je dijeta ocijenjena kao zahtjevna, slabo podno{ljiva i skupa. Sve manja primjena, kao i veoma slaba preciznost i kontrola tretmana kona~no je krajem 90-tih godina pro{loga stolje}a rezultirala stavom mnogih lije~nika da primjena ketogene dijete vi{e nije opravdana (2). Ipak, primjena ketogene dijete u tretmanu epilepsije u djece nastavljena je u bolnici Johns Hopkins (Maryland), podjednako dob-rim rezultatima kakvi su opisivani i prethodnih desetlje}a. Ponovnoj aktualizaciji keto-gene dijete krajem 20. i po~etkom 21. stolje}a pridonio je hollywoodski producent Jim Abrahams, ~iji je sin Charlie bolovao od farmakorezistentne epilepsije. Budu}i da prim-jena mnogih antiepileptika i razli~itih terapijskih tretmana nije zaustavila konvulzivne napade, Abrahams je sina odveo u bolnicu Johns Hopkins, gdje su napadi u djeteta u potpunosti zaustavljeni ubrzo nakon uvo|enja ketogene dijete (3). Nakon takvog uspjeha, Abrahams je osnovao fondaciju (Charlie Foundation) kojapodràva i poti~e kontinuirani rad na terapijskoj primjeni ketogene dijete. Iznimna popularnost uslijedila je nakon medijske promocije i rezultirala velikim zanimanjem roditelja za takav vid lije~enja. Stoga su 1994. zapo~eli multicentri~nu studiju u sedam klini~kih centara i financirali je iz Charlie fondacije. Rezultati te studije (4), kao i rezultati primjene ketogene dijete u 150 djece u bolnici Johns Hopkins (5,6) bili su prvi objavljeni rezultati klini~kih studija o efi-kasnosti ketogene dijete, nakon ~ega je uslijedio dramati~an porast zanimanja stru~ne i znanstvene javnosti za tu temu. U usporedbi s prethodnim desetlje}ima, nakon 1996. mnogostruko je porastao broj objavljenih apstrakta i ~lanaka prikazanih Ameri~kom P R E G L E D N I R A D O V I 613
... A preclinical study found that rats on the KD exhibited fewer signs of depressive behavior. [88] ...
... The same mechanism of KDinduced KAT upregulation cannot be ruled out as a driver of the anticonvulsant effect in our patients. It has also been documented that the KD exerts antidepressant and mood-stabilizing properties [20,21]. Similarly, Lee and coworkers suggested that mice fed a high-fat diet who perform aerobic exercise exhibit a rising KYNA/3-OH-KYN ratio, which is believed to be a meaningful anti-aging indicator [22]. ...
Article
Purpose: There is growing evidence to support the role of the kynurenine pathway in the anticonvulsant efficacy of ketogenic diets (KDs) in refractory epilepsy. The aim of the present study was to measure blood levels of tryptophan (TRP) and its kynurenine derivatives and correlate them with seizure reduction after starting the KD in children with refractory epilepsy. Methods: Sixteen children (9 F/7 M; 7.1 ± 5.1 years) with refractory epilepsy were treated with the KDs. Clinical efficacy and metabolic ketosis were monitored throughout the study; blood levels of TRP, kynurenine (KYN), kynurenic acid (KYNA), and 3-OH-kynurenine (3-OH-KYN) were measured at 3, 6, and 12 months on the diet and compared to the pre-KD levels. Results: Out of 16 children, 14 attained a ≥50% reduction (responders) in seizure frequency 3 months after starting the KD. In the 14 responders, TRP levels decreased numerically (18-25%) but not significantly (P = 0.077) compared to the pre-KD control values. KYN levels decreased significantly (30-57%; P = 0.001) compared to the pre-KD control levels while KYNA levels significantly increased (38-96%; P < 0.001). KYNA/KYN ratios significantly increased (100-323%; P = 0.003) while 3-OH-KYN levels (P = 0.680) and KYN/TRP ratios (P = 0.385) remained unchanged. Higher concentrations of KYNA and lower concentrations of KYN (P < 0.05) were found in patients who attained a higher reduction in seizure frequencies on the KD. Conclusions: We report a pattern of changes in the blood level of kynurenines in patients with refractory epilepsy who started the KD. The results of this study further support the role of specific kynurenines (e.g. KYNA) in the efficacy of the KD in refractory epilepsy.
... MCT oils are proposed as an alternative. The present results are consistent with previous studies that have found evidence that lactate [74] and ketogenic diets can produce anti-depressive-like effects in rodents [79,80]. ...
Article
While investigating the effect of alternative energy substrates on extracellular brain glucose or lactate, Béland-Millar (2017) noted a reduction of physical activity after intraperitoneal administration of lactate and ketone bodies. These observations were similar to an older study that examined the impact of drinking a sodium lactate/lactic acid solution before sleep in hospitalized patients with major depression. Patients and control participants self-reported drowsiness, early sleep onset and better overall sleep after consumption. Some patients showed improved mood after several days of treatment. We re-evaluated the effects of the solution used (0.59 g/kg) as well as several smaller doses (0.47, 0.35, 0.24 and 0.12 g/kg) on blood lactate and glucose in CD-1 mice and on sleep onset associated activity reduction. Because of adverse effects with the lactate/lactic acid solution, we also examined the effects of a medium chain triglyceride (MCT) solution (10, 5, 2.5, and 1 ml/kg) on blood lactate and glucose. Oral gavage administration of lactic acid/lactate produced adverse effects particularly for the largest doses. However consumption of 10 and 5 ml/kg volumes of MCT oils significantly increased blood lactate concentration to levels comparable to Lowenbach's solution without piloerection indicative of adverse effects. To evaluate pre-sleep activity reduction produced by lactate, mice were intraperitoneally administered diluted sodium lactate (2.0 g/kg, 1.0 g/kg, 0.5 g/kg, 0.25 g/kg, or saline) for 6 days, 120 min before their sleep period and their running activity was measured. Larger lactate doses reduced pre-sleep running each day up to 60 min post injection. Smaller doses reduced running after a single treatment only. These results suggest that the modulation of blood lactate levels may be useful in treating sleep onset problems associated with depression.
... Thus, ketogenic diet-evoked effects on psychiatric diseases may result (at least partly) from beneficial metabolic effects of βHB, for example, on mitochondrial functions, neuronal activity, neurotransmitter release, and inflammatory processes (43, 50,52,86,91). Indeed, administration of a ketogenic diet not only increased the ketone body level but also was associated with improvements in anxiety disorder (75,77), bipolar disorder (120), schizophrenia (42, 70,73,74,121), depression (77,122), autism spectrum disorder (78,80,123), and ADHD (124,125) in animal models and/or humans, suggesting the beneficial effects of exogenous ketone supplement-induced ketosis on psychiatric diseases ( Figure 1B). ...
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.
... However findings are mostly limited to animal models [41]. In rats, KD increased physical activity and boosted some brain areas and this result was similar to that produced by antidepressants [48][49]. To the best of our knowledge, there are no published studies investigating KD effect on the microbiome of depressed patients. ...
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An intriguing topic that has captured the interest of many scientists is the brain-gut interaction. A growing body of literature elucidates that the microbiome residing within the gastrointestinal tract interacts with the brain and affects mental health. This is possible through the microbiome's ability to modify behavioral and cognitive brain activities through the synthesis of neuroactive molecules, vitamins, and Short Chain Fatty Acids. The microbiome dates back to early stages of life yet as we grow it continues to be affected by genetic and environmental factors. It is shown that disturbances in the microbiome homeostasis decode into different illnesses ranging from metabolic conditions to neurologic and psychiatric diseases. In depression, certain intestinal bacterial strains are found to be either depleted or augmented. The bacterial phyla correlated with depression will be reviewed in this paper, in addition to recent therapeutic implications that alleviate depression symptoms and adjust the microbiome.
... Military personnel struggling with sleep loss [59], traumatic brain injury [60], and post-traumatic stress disorder or depression [61,62] may experience mood stabilization in part due to elevated blood ketone levels [63]. There is further evidence that ketones may support recovery from brain injury [ ...
... Ketogenic diet could stabilize blood-glucose level and also reduce hunger, which might be its link with mood (Boden et al., 2005). Moreover, this diet plays a role as mood stabilizer and antidepressant (Murphy et al., 2004). ...
Article
A number of studies have examined the association between diet and mood state, but the findings have been inconclusive. Herein, we conducted a systematic review to assess the association between different diet and mood state. PubMed, Cochrane's library, Science direct, Scopus, Google scholar and ISI web of science databases were searched for all available literature until December 2017 for studies assessing the association between diet and mood state. The Newcastle-Ottawa Scale and Jadad scale for reporting randomized clinical trials were used to assess study quality. A total of 18 studies out of 2857 met our inclusion criteria and included in our systematic review. Although there are not consistent findings between studies, it seems that DASH, vegetable-based, glycemic load-based, ketogenic and Paleo diets could improve mood more than the others. Further studies are needed to assess such relationship in a longer period to draw a firm link between diet and mood.
... [48], [96][97][98] Il peut agir également comme un stabilisateur de l'humeur c'est-à-dire ayant des propriétés antidépresseurs. [99] En conclusion, le régime cétogène est une alternative thérapeutique efficace pour les enfants avec une épilepsie réfractaire, indépendamment de l'âge du patient, du sexe, de la durée de la maladie, du type d'épilepsie ou de son étiologie. [100][101][102] Le succès est en partie dû à l'implication de plusieurs professionnels de santé ; médecins, infirmières, diététiciens travaillent ensemble. ...
Thesis
L'indication de la diète cétogène chez un enfant est posée par un médecin spécialiste neurologue ou neuropédiatre, et son introduction se fait toujours en milieu spécialisé.Ce régime est utilisé chez les enfants dont les crises d'épilepsie échappent au traitement médical : on parle d'épilepsie réfractaire. En effet, malgré l'apparition des nouveaux antiépileptiques, 25 à 30% des épilepsies ne répondent pas aux médicaments. La diète cétogène est un régime thérapeutique strict dont la composition et l'apport calorique sont calculés. Il s'agit d'une alimentation riche en graisses et pauvre en sucres avec un apport en protéines suffisant pour assurer la croissance de l'enfant. Le calcul de la ration cétogène est déterminé selon des critères définis (poids, taille, besoins énergétiques). Le régime permet une réduction des crises d'épilepsie avec progressivement une diminution de la posologie et du nombre d'antiépileptiques. Il est efficace pour un large éventail d'épilepsies. Le succès de cette thérapie est dû à l'implication de plusieurs professionnels de santé (médecins, diététiciens et infirmières travaillent ensemble) et il dépend aussi de la ténacité et de l'engagement de toute la famille. Comme tout traitement, la diète cétogène présente des effets secondaires, mais la plupart des complications sont transitoires et une surveillance étroite permet de les éviter. Compte tenu de la rigidité du régime, les calories apportées par les médicaments doivent être considérées. Le calcul de la ration cétogène est alors ajusté car, si le contenu en glucides des médicaments est négligé, un retour des crises peut survenir.En collaboration avec les laboratoires pharmaceutiques, la valeur calorique totale et la valeur calorique en glucides des médicaments utilisés par les enfants ont été recherchées. Cet outil va servir aux prescripteurs, diététiciens et infirmières dans leur pratique de tous les jours.
... According to Kraft B. & Westman E. (2009) [30], the possible reasons for the effective influence of KGD on schizophrenic symptoms include metabolic consequences of gluten elimination from the diet and modulation of schizophrenic disease at the cellular level. According to Murphy P (2004) KGD also has therapeutic effect on depression -a common symptom of schizophrenia and bipolar disorder [32] The direct effect on GABA levels (the mechanism is explained above), is well-studied in patients with depression and to date are thought to be genetically related to schizophrenia and bipolar disorder [33]. Yoon et al. reported a significant reduction in GABA levels in patients with schizophrenia [34]. ...
Article
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Introduction: The ketogenic diet (KGD) is a high-fat, adequate-protein, low-carbohydrate diet. In 1920`s the diet was developed to treat difficult-to-control epilepsy in children. Nowadays its efficacy has been proven in many other diseases, such as metabolic disorders, brain tumours, autism, Rett syndrome, and in other areas, it has been actively studied. Aim: The aim of this article is to represent the historical review of the therapeutic implication of KGD, as well as to reveal the contemporary clinical trends in which it is being used. Material and Methods: A literature review of 96 scientific reports in English has been made. Results and Discussion: The KGD was developed in the early 1920s. In the period 1970-1990, the therapeutic use of the diet was discontinued, due to the breakthrough of the new anticonvulsants for epilepsy. The interest in KGD was recovered after a meeting of the “American Epilepsy Society” in 1996. The diet demonstrates anticonvulsant efficacy in epilepsy therapy. According to a survey in 2013, the incidence of seizures among half of the number of children was reduced by at least a half, and 15% of them were completely discontinued. The diet is also used in the treatment of metabolic diseases, such as GLUT 1-deficiency syndrome, reducing the incidence of seizures, improving muscle coordination and concentration. It is also effective in pyruvate dehydrogenase deficiency syndrome by replacing the major energy source - glucose with ketones. Along with these, it is also used in patients with autism (in approximately 60% of patients it improves learning ability and social skills), Rett syndrome, Alzheimer's disease, Parkinson's disease, and others. Its mechanism of action is not fully clarified, as well as its degree of effectiveness in some areas. Conclusion: The ketogenic diet is widely implemented worldwide. It comprises a tremendous therapeutic potential that has been growing considerably during the past decades.
... Although there have been no previous reports indicating that BHB produces antidepressant-like effects, there is some evidence suggesting that a ketogenic diet -which elevates levels of BHB in the brain -may be associated with antidepressant effects. For example, it has been reported that a ketogenic diet decreases the time spent immobile in the FST 33 , while another report demonstrated that adult offspring exposed to a prenatal ketogenic diet exhibited reduced susceptibility to anxiety and depression 34 . ...
Article
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Neuro-inflammation has been shown to play a critical role in the development of depression. Beta-hydroxybutyrate (BHB) is a ketone body and has recently been reported to exert anti-inflammatory effects via inhibition of NLRP3 inflammasome. Here, we investigated the potential antidepressant and anti-inflammatory effects of BHB on rats exposed to acute and chronic stress. We examined the influence of repeated BHB administration on depressive and anxiety behaviors in a rodent model of chronic unpredictable stress (CUS). Additionally, the influence of acute immobilization (IMM) stress and single BHB administration on hippocampal interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were assessed. Repeated administration of BHB attenuated CUS-induced depressive- and anxiety-related behaviors. IMM stress increased levels of IL-1β in the hippocampus, while a single pre-administration of BHB attenuated this increase. Although no effect was observed on hippocampal TNF-α levels after 1 h of IMM stress, a single BHB pre-administration reduced hippocampal TNF-α. Our previous report showed that the release of IL-1β and TNF-α caused by stress is tightly regulated by NLRP3 inflammasome. These findings demonstrate that BHB exerts antidepressant-like effects, possibly by inhibiting NLRP3-induced neuro-inflammation in the hippocampus, and that BHB may be a novel therapeutic candidate for the treatment of stress-related mood disorders.
... Second, to assess the effects of antidepressants, the time spent immobile is used as a dependent variable, and reductions are interpreted for significance (56). To examine the antidepressant properties of KD, 20 Wistar rats given the diet (4:1 lipid:non-lipid ratio) were compared to 20 fed a standard diet (39). It was found that rats on KD spent less time immobile than control rats thus providing some evidence for potential antidepressant effects of the diet. ...
Article
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Background The ketogenic diet (KD) has been used in treatment-resistant epilepsy since the 1920’s. 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. Methods Narrative review of electronic databases PubMED, PsychINFO and Scopus. Results The 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 behaviours in a rat model. In depression, KD significantly reduced depression-like behaviours in rat and mice models in two controlled studies. In bipolar disorder, one case study reported a reduction in symptomatology a second case study no improvement. In schizophrenia, an open-label study in female patients (n=10) reported reduced symptoms after two weeks of KD, a single case study reported no improvement. In a brief report, three weeks of KD in a mouse model normalized pathological behaviours. In ASD an open-label study in children (n=30) reported no significant improvement; one case study a pronounced and sustained response to KD. In ASD, in four controlled animal studies, KD significantly reduced ASD-related behaviours in mice and rats. In ADHD, in one controlled trial of KD in dogs with co-morbid epilepsy, both conditions significantly improved. Conclusions Despite 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 analogue 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.
... The intestinal microbiota may play a part impacting cognition, mood, anxiety, and depression, as well as CNS physiology. The microbial imbalance or maladaptation, also known as dysbiosis, have been suggested to correlate with various neurodegenerative disorders (Paoli et al., 2014;Jiang et al., 2017;Parashar and Udayabanu, 2017), autism (Evangeliou et al., 2003), depression (Murphy et al., 2004), multiple sclerosis (Storoni and Plant, 2015), seizure susceptibility in epilepsy (Dahlin and Prast-Nielsen, 2019), and cancer (Scheck et al., 2012;Allen et al., 2014). ...
Article
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Epilepsy is a severe neurological disorder involving 70 million people around the globe. Epilepsy-related neuropsychiatric comorbidities such as depression, which is the most common, is an additional factor that negatively impacts the living quality of epilepsy patients. There are many theories and complexities associated with both epilepsy and associated comorbidities, one of which is the gut-brain-axis influence. The gut microbiome is hypothesized to be linked with many neurological disorders; however, little conclusive evidence is available in this area. Thus, highlighting the role will create interest in researchers to conduct detailed research in comprehending the influence of gut-brain-axis in the manifestation of depressive symptoms in epilepsy. The hypothesis which is explored in this review is that the gut-brain-axis do play an important role in the genesis of epilepsy and associated depression. The correction of this dysbiosis might be beneficial in treating both epilepsy and related depression. This hypothesis is illustrated through extensive literature discussion, proposed experimental models, and its applicability in the field. There is indirect evidence which revealed some specific bacterial strains that might cause depression in epilepsy.
... This suggests that the KD has effects that are similar to antidepressant drugs in the Porsolt swim test, a behavioral despair test that is commonly used in experiments to study depressive-like behavior in rodents 69,70 . Additionally, the handling test demonstrates that the reduced immobility does not appear to be the result in irritability or reactivity 70 . This suggests that the KD could provide an antidepressant property. ...
Article
Ketogenic diet (KD) is comprised of a distinct macronutrient combination: i.e. 90% fat, 8% of protein and 2% of carbohydrates, typically characterized as a high-fat low-carbohydrate diet. KD's efficacy was largely established for treatment resistant epilepsy in children, but its mental, emotional and behavioral effects remain largely unknown. Nevertheless, the efficacious effects of KD in childhood epilepsy provide rationale for repurposing this approach for other brain-based disorders. Consequently, clinicians and researchers should be aware of the evidence regarding efficacy, as well as the benefits and risks of adopting this diet. Results from animals and humans studies provide equivocal evidence across multiple domains of psychopathology. Conceptually, KD shows promise to serve as an efficacious treatment for mental disorders.
... Medium-chain fatty acids have a high level of oxidation for obtaining energy, thus avoiding storage in adipose tissue and promoting higher energy use [53] that leads to weight loss without recovery in the long term [54]. This lipolytic effect of ketone bodies has been associated with improvements in depression [55][56][57][58]. In this line, anxiety and depressive symptomatology stand out among these types of patient [59][60][61]. ...
... KD was initially employed as an effective non-pharmacological treatment for refractory epilepsy with beneficial results (Henderson et al., 2006;Levy et al., 2012). However, in recent years, it has demonstrated to be effective in the treatment of numerous neurological disorders such as traumatic brain injury (Appelberg et al., 2009;Hu et al., 2009); neuropsychiatric disorders as schizophrenia (Kraft and Westman, 2009;Kraeuter et al., 2015), autism spectrum disorder (Ahn et al., 2014;Lee et al., 2018), depression (Murphy et al., 2004;Sussman et al., 2015), anxiety (Sussman et al., 2015;Ari et al., 2016) and bipolar disorder (Phelps et al., 2013); as well as mitochondrial dysfunctions (Kang et al., 2007;Kim et al., 2010), cancer (Seyfried et al., 2012;Cohen et al., 2018), aging (Balietti et al., 2010a,b) and obesity (Paoli, 2014;Zhang et al., 2018). ...
Article
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Ketogenic diet, a high fat and low carbohydrate diet, has been used as a non-pharmacological treatment in refractory epilepsy since 1920. In recent years it has demonstrated to be effective in the treatment of numerous neurological and non-neurological diseases. Some neurological and neuropsychiatric disorders are known to be caused by gamma-aminobutyric acid (GABA)-mediated neurotransmission dysfunction. The strength and polarity of GABA-mediated neurotransmission are determined by the intracellular chloride concentration, which in turn is regulated by cation-chloride cotransporters NKCC1 and KCC2. Currently, it is unknown if the effect of ketogenic diet is due to the modulation of these cotransporters. So, we analyzed the effect of ketogenic diet on cation-chloride cotransporters expression. We estimated the total number of NKCC1 immunoreactive (NKCC1-IR) neuronal and glial cells by stereology and determined KCC2 labeling intensity by densitometry in the molecular and granule layers as well as in the hilus of dentate gyrus of rats fed with normal or ketogenic diet for three months. The results indicate that ketogenic diet provided during three months increases KCC2 expression, but not NKCC1in the dentate gyrus of the rat. The significant increase of KCC2 expression could explain, at least in part, the beneficial effect of ketogenic diet in the diseases where the GABAergic system is altered by increasing the inhibitory efficiency.
... Metabolism is shifted towards the use of fats as the primary fuel source and liver catabolism of fatty acids is increased leading to subsequent rises in ketone bodies levels, which serve as an alternative energy supply for the brain [29]. Contrary to WD, the KD can reduce neuronal inflammation [30], decrease behavioral patterns of depression in animal models [31], ameliorate cognitive defects [32], and mitigate neuronal injury [33]. ...
Article
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Traumatic brain injury (TBI) is a global health burden and a major cause of disability and mortality. An early cascade of physical and structural damaging events starts immediately post-TBI. This primary injury event initiates a series of neuropathological molecular and biochemical secondary injury sequelae, that last much longer and involve disruption of cerebral metabolism, mitochondrial dysfunction, oxidative stress, neuroinflammation, and can lead to neuronal damage and death. Coupled to these events, recent studies have shown that lifestyle factors, including diet, constitute additional risk affecting TBI consequences and neuropathophysiological outcomes. There exists molecular cross-talk among the pathways involved in neuronal survival, neuroinflammation, and behavioral outcomes, that are shared among western diet (WD) intake and TBI pathophysiology. As such, poor dietary intake would be expected to exacerbate the secondary damage in TBI. Hence, the aim of this review is to discuss the pathophysiological consequences of WD that can lead to the exacerbation of TBI outcomes. We dissect the role of mitochondrial dysfunction, oxidative stress, neuroinflammation, and neuronal injury in this context. We show that currently available data conclude that intake of a diet saturated in fats, pre- or post-TBI, aggravates TBI, precludes recovery from brain trauma, and reduces the response to treatment.
... The relationship between ketogenic diets and ASD is of particular interest, as both are strongly associated with changes in the gut microbiome, which some studies suggest mediate the therapeutic effects of ketogenic diets [14,43]. Ketogenic diets are also well known to have anxiolytic effects and are thought to help improve MDD [44][45][46]. Further preclinical and early clinical evidence for the efficacy of ketogenic diets in BPD [47], schizophrenia [10 & ,11,48] and binge eating disorder (BED) [49 & ] also exist. ...
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).
... Some animal studies support an antidepressant-like effect of the KD in models of depression. In a rodent study using "behavioural despair" induced immobility as the outcome, rats on a KD spent less time immobile than rats on a control diet, an effect that occurred without the need for rats to be in metabolic ketosis (Murphy et al., 2004). Key mechanisms of action proposed for KD overlap with hypotheses of contributory biological processes in mood disorders and schizophrenia: modulation of BDNF expression, mitochondrial dysfunction, and systemic inflammation (Brietzke et al., 2018;Sarnyai et al., 2019). ...
Article
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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.
... Also outside of patients with LI, research in both animals and humans has shown that adopting a KD improves mood, attention, and social interactions, and also reduces depression through possible underlying mechanisms affecting brain function [105,106]. These mechanisms may include diet-induced changes in energy consumption or neurotransmitter usage (GABAergic/glutamatergic transmission and monoamine modulation) and by altering biological mediators present in mood disorders that can then reduce depression [107]. ...
Article
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Lipedema (LI) is a common yet misdiagnosed condition, often misconstrued with obesity. LI affects women almost exclusively, and its painful and life-changing symptoms have long been thought to be resistant to the lifestyle interventions such as diet and exercise. In this paper, we discuss possible mechanisms by which patients adopting a ketogenic diet (KD) can alleviate many of the unwanted clinical features of LI. This paper is also an effort to provide evidence for the hypothesis of the potency of this dietary intervention for addressing the symptoms of LI. Specifically, we examine the scientific evidence of effectiveness of adopting a KD by patients to alleviate clinical features associated with LI, including excessive and disproportionate lower body adipose tissue (AT) deposition, pain, and reduction in quality of life (QoL). We also explore several clinical features of LI currently under debate, including the potential existence and nature of edema, metabolic and hormonal dysfunction, inflammation, and fibrosis. The effectiveness of a KD on addressing clinical features of LI has been demonstrated in human studies, and shows promise as an intervention for LI. We hope this paper leads to an improved understanding of optimal nutritional management for patients with LI and stimulates future research in this area of study.
... Also outside of patients with LI, research in both animals and humans has shown that adopting a KD improves mood, attention, and social interactions, and also reduces depression through possible underlying mechanisms affecting brain function [105,106]. These mechanisms may include diet-induced changes in energy consumption or neurotransmitter usage (GABAergic/glutamatergic transmission and monoamine modulation) and by altering biological mediators present in mood disorders that can then reduce depression [107]. ...
... Ketojenik diyet uygulamasının hayvan depresyon modellerinde ve tanılı depresyon hastalarında depresif bozukluk bulgularını istatistiksel olarak önemli ölçüde azalttığını, semptomlarda düzelme sağladığını, antidepresan ilaç tedavisine benzer bir etki gösterdiğini kanıtlayan çalışmalar bulunmaktadır (Bostock et al., 2017: 1-10;Cox et al., 2019Cox et al., : 1475Murphy et al., 2004;981-3). Ketojenik diyet ve depresyonla ilgili yedi randomize kontrollü çalışmanın incelendiği, konuyla ilgili en güncel derleme olan Cochrane derlemesinde sonuçların genel olarak ketojenik diyet lehine olduğu belirtilmiştir. ...
Conference Paper
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Kefir, bir çeşit fermente probiyotik süt ürünüdür. Kardiyovasküler hastalıklar dünya çapında en önemli ölüm nedenlerinden biridir ve dislipidemi bu hastalıklar için en önemli risk faktörlerinden biridir. Bu araştırma normal ve dislipidemik özellikler gösteren bireylerde kefirin kan lipid profilini üzerine olumlu etki yapacağının düşünülmüştür. Bu etkiyi araştırmak amacıyla prospektif, öz-kontrollü 8 haftalık klinik araştırma yapılmış ve çalışma için gerekli etik kurul izni alınmıştır. Çalışmaya randomize olarak seçilen 20-55 yaş arası herhangi bir sağlık şikayeti olmayan ve kriterleri taşıyan 23 gönüllü katılmıştır. Gönüllüler ilk dört 4 haftası kefir tüketimli denek grubu olarak, son dört 4 haftası da rebaunt etkiyi görmek amaçlı kefir tüketimsiz denek grubu olarak çalışmaya dâhil edilmişlerdir. Gönüllü grubunun tükettiği 200 ml kefir yaklaşık 10,54 log cfu / ml Lactobacillus içeriğine, 10,62 log cfu / ml, Lactococcus içeriğine, 7,78log cfu / ml Bifidobacterium içeriğine sahiptir. Dört haftanın başında ve sonunda gıda tüketim kayıtları, antropometrik ölçümler ve kan örnekleri alınmış, Açlık Total kolesterol, LDL kolesterol, HDL kolesterol ve Trigliserid düzeyleri lipid metabolizma parametreleri incelenmiştir. Alınan sonuçlara göre dislipidemik bulgulara sahip 13 bireylerin 8 haftalık çalışma sonucunda serum lipid profillerindeki değişimlerine bakıldığında , istatiksel açıdan TK %5.71 düşüşle anlamlı (p<0,018), LDL-K %5,31 düşüşle anlamlı ( P<0,021) , HDL-K %8.58 düşüşle anlamlı ( p<0,035 ) ve TG %17,21 artışla (P<0,926) anlamsız olarak sonuçlar bulunmuştur. Normal bulgulara sahip 10 bireylerin 8 haftalık çalışma sonucunda serum lipid profillerindeki değişimlerine bakıldığında istatiksel açıdan TK %5.33 düşüşle anlamsız (p<0,302), LDL-K %2.67 düşüşle anlamsız ( P<0,831) , HDL-K %12.79 düşüşle anlamlı ( p<0,013 ) ve TG %12,65 artışla (P<0,122) anlamsız olarak bulunmuştur. Sonuç olarak düzenli kefir tüketiminin dislipidemik bulgulara sahip bireylerde kan lipid profillerinden Total Kolesterol ve LDL kolesterolü düşürmede kadın ve erkek bireyler üzerine etkili olduğu sonucuna varılırken, Normal bireylerde bu etki görülmemiştir.
... 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). ...
Article
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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.
... KD is a diet with a high proportion of fat intake, a moderate proportion of protein intake and a low proportion of carbohydrate intake, which is commonly used as an adjutant non-drug therapy for the treatment of epilepsy in children (67,68). Although the mechanism of KD is not fully understood, it has benefits in anti-epilepsy and in improving cognitive function and behavior. ...
Article
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Background Dravet syndrome (DS) is a refractory developmental and epileptic encephalopathy (EE) with a variety of comorbidities, including cognitive impairment, autism-like behavior, speech dysfunction, and ataxia, which can seriously affect the quality of life of patients and impose a great burden on society and their families. Currently, the pharmacological therapy is patient dependent and may work or not. Neuromodulation techniques, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), responsive neurostimulation (RNS), and chronic subthreshold cortical stimulation (CSCS), have become common adjuvant therapies for neurological diseases, but their efficacy in the treatment of DS is unknown. Methods We searched Web of Science, PubMed, and SpringerLink for all published cases related to the neuromodulation techniques of DS until January 15, 2022. The systematic review was supplemented with relevant articles from the references. The results reported by each study were summarized narratively. Results The Web of science, PubMed and SpringerLink search yielded 258 items. A total of 16 studies published between 2016 and 2021 met the final inclusion criteria. Overall, 16 articles (109 cases) were included in this study, among which fifteen (107 patients) were involved VNS, and one (2 patients) was involved DBS. After VNS implantation, seizures were reduced to ≥50% in 60 cases (56%), seizure free were found in 8 cases (7.5%). Only two DS patients received DBS treatment, and the initial outcomes of DBS implantation were unsatisfactory. The seizures significantly improved over time for both DBS patients after the addition of antiepileptic drugs. Conclusion More than half of the DS patients benefited from VNS, and VNS may be effective in the treatment of DS. However, it is important to note that VNS does not guarantee improvement of seizures, and there is a risk of infection and subsequent device failure. Although DBS is a safe and effective strategy for the treatment of refractory epilepsy, the role of DBS in DS needs further study, as the sample size was small. Thus far, there is no strong evidence for the role of DBS in DS.
... It has been recently reported that chronic treatment with a KD and MCT diet induced decreased anxiety-and depression-like behaviors in rodents. 8,9,11,12,27 Our study suggests that C10 is one of the fatty acids partially contributing to the antidepressant-like effects. ...
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Aim Capric acid (also known as decanoic acid or C10) is one of the fatty acids in the medium-chain triglycerides (MCTs) commonly found in dietary fats. Although dietary treatment with MCTs is recently of great interest for the potential therapeutic effects on neuropsychiatric disorders, the effects of oral administration of C10 on behavior remain to be examined. This study investigated acute and chronic effects of oral administration of C10 on locomotor activity and anxiety-like and depression-related behaviors in adult male C57BL/6J mice. Methods To explore the acute effects of C10 administration, mice were subjected to a series of behavioral tests in the following order: light/dark transition, open field, elevated plus maze, Porsolt forced swim, and tail suspension tests, 30 minutes after oral gavage of either vehicle or C10 solution (30 mmol/kg dose in Experiment 1; 0.1, 0.3, 1.0, 3.0 mmol/kg doses in Experiment 2). Next, to examine chronic effects of C10, mice repeatedly administered with either vehicle or C10 solution (0.3, 3.0 mmol/kg doses per day, for 21 days, in Experiment 3) were subjected to behavioral tests without oral administration immediately before each test. Results The mice administrated with the high dose of C10 (30 mmol/kg) showed lower body weights, shorter distance traveled, and more anxiety-like behavior than vehicle-treated mice, and the results reached study-wide statistical significance. The C10 administration at a lower dose of 0.3 mmol/kg had no significant effects on body weights and induced nominally significantly longer distance traveled than vehicle administration. Repeated administration of C10 at a dose of 3.0 mmol/kg for more than 21 days caused lower body weights and decreased depression-related behavior, although the behavioral differences did not reach study-wide significance. Conclusions Although these results suggest dose-dependent effects of oral administration of capric acid on locomotor activity and anxiety-like and depression-related behaviors, further study will be needed to replicate the findings and explore the underlying brain mechanisms.
... However findings are mostly limited to animal models [41]. In rats, KD increased physical activity and boosted some brain areas and this result was similar to that produced by antidepressants [48][49]. To the best of our knowledge, there are no published studies investigating KD effect on the microbiome of depressed patients. ...
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An intriguing topic that has captured the interest of many scientists is the brain-gut interaction. A growing body of literature elucidates that the microbiome residing within the gastrointestinal tract interacts with the brain and affects mental health. This is possible through the microbiome's ability to modify behavioral and cognitive brain activities through the synthesis of neuroactive molecules, vitamins, and Short Chain Fatty Acids. The microbiome dates back to early stages of life yet as we grow it continues to be affected by genetic and environmental factors. It is shown that disturbances in the microbiome homeostasis decode into different illnesses ranging from metabolic conditions to neurologic and psychiatric diseases. In depression, certain intestinal bacterial strains are found to be either depleted or augmented. The bacterial phyla correlated with depression will be reviewed in this paper, in addition to recent therapeutic implications that alleviate depression symptoms and adjust the microbiome.
... In addition, a KD could result in a change in the level of monoamine neurotransmitters such as serotonin and dopamine, 158 which are related to depression and anxiety symptoms. 159 b-Hydroxybutyrate, a ketone body, could increase the level of brain-derived neurotrophic factor, which is involved in neuronal cell survival and antiapoptosis pathways 160 (Figures 2 14,41 and 3B 78 ). Furthermore, a KD could boost the level of ATP and the activation of synaptic receptors. ...
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... [73,74] Although it is claimed that the lowcarb ketogenic diet, characterized by high fat, low carbohydrate, and low protein content, targets the opposite of mitochondrial dysfunction with the transition from aerobic energy production to glycolytic energy production in depression, not enough work has been done yet. [75,76] EPIgEnETICS As a result of various factors, the occurrence of hereditary changes in gene expression without any changes in the sequencing of DNA, also referred to as genetic code, is called epigenetics. [77] Epigenetic modifications that can be passed on to new generations and are essential for normal cell development and differentiation; DNA methylation, histone modification, chromatin folding, the regulatory effects of mRNA. ...
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In the treatment of psychiatric illnesses such as depression and anxiety, pharmacological and psychotherapy approaches, such as certain antidepressants, are also usually applied. The fact that pharmacological methods have certain side effects has prompted researchers to look at alternative treatment options for depression. Nutritional oxidative stress, which has been proven by studies that can be used in the prevention and treatment of depression, can affect cognitive functions through mechanisms such as inflammation, mitochondrial dysfunction, epigenetics, intestinal microbiota, obesity, tryptophan metabolism, the hypothalamic-pituitary-adrenal axis (HPA axis) and adult hippocampal neurogenesis (AHN). This review focuses on pathways associated with depression and nutrients, nutrients, and dietary models that can affect cognitive function. Long-term and large-cohort research is required to reveal different mechanisms and to fully understand the relationship between nutrition and depression.
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Thomas Seyfried remarked in his book [(1), page 6]: “The definition of ketogenic diet allows for considerable leeway in food choices as long as the individual has reduced blood glucose and is producing ketones.” Unfortunately, these parameters are lacking in many if not most of studies into metabolic effects of macronutrients. Meanwhile, there is a precise way to predict whether or not a diet will induce ketosis and the aim of this opinion article is to advocate a broader usage of this way. Why is this so important? Excess of carbohydrate intake typical for consumers of the Western diet may cause detrimental effects on metabolism and increase risks of the onset and progression of many neurodegenerative diseases (2–4). On the other hand, diets high in fat and low in carbohydrates decrease appetite, probabilities of food addiction and obesity, and are neuroprotective (5, 6). Carbohydrate restriction induces physiological changes which are very similar to the well documented beneficial effects of calorie restriction (7, 8). Conversely, the hallmark of high-carbohydrate diets is homeostatic inadequacy (9), an overproduction of reactive oxygen species and advanced glycation products, both of which are implicated in neuroinflammation and neurodegeneration (10–12). However, the meaning of “high” or “low” in diets' definition has been drifting away from the previously established quantitative criterion known as ketogenic ratio. ------------------------ * (references as is in the paper)
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Aims Psychosocial stress is a form of mental stress associated with human relationships that underlies the pathogenesis of mental disorders such as depression. Previous studies have suggested that intake of energy-dense foods, also known as “palatable foods,” can relieve psychosocial stress. However, it remains unclear whether the volume of palatable food affects abnormal behavior induced by psychosocial stress. In the present study, we aimed to determine whether levels of high-fat food intake significantly influence psychosocial stress using the social-defeat stress (SDS) paradigm. Main methods Mice subjected to SDS ate either a high-fat or normal chow diet for 10 days. Behavioral tests were conducted following the completion of the SDS paradigm. The hypothalamus, liver, and blood were examined post-mortem. Key findings Mice with sufficient intake of high-fat chow immediately following exposure to SDS did not exhibit social avoidance behavior, suggesting that a high-fat diet may improve social behavior. However, inadequate intake of high-fat food, which did not alter cholesterol metabolism or hypothalamic-pituitary-adrenal axis activity, was not associated with such benefits, instead increased anxiety-like behavior. Significance The results of the present study demonstrate that eating a high-fat diet may attenuate stress, but that this benefit disappears with insufficient intake of high-fat foods. The benefits of a high-fat diet under SDS may be related to cholesterol metabolism in the liver.
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The ketogenic diet (KD) is characterized by a diet ratio of 4:1 fat to non-fat energy sources. For decades KD has been successfully used to control seizures in epilepsy patients. Investigations into its mechanism of action suggest that it may have an effect on the metabolic, nervous, immune, and digestive systems. In this review, we postulate that KD may also improve depressive symptoms - for that, we highlight the similarities between depression and epilepsy, describe the extent to which body systems involved in both conditions are affected by the KD, and ultimately hypothesize how KD could improve MDD outcomes. Research into animal models and human patients have reported that KD can increase mitochondrial biogenesis and increase cellular resistance to oxidative stress both at the mitochondrial and genetic levels. Its effect on neurotransmitters alters cell-to-cell communication in the brain and may decrease hyperexcitability by increasing Gamma Aminobutyric Acid (GABA) and decreasing excitatory neurotransmitter levels. Its anti-inflammatory effects are mediated by decreasing chemo- and cytokine levels, including TNF-alpha and IL-1 levels. Finally, KD can alter gut microbiota (GM). Certain strains of microbiota predominate in major depressive disorder (MDD) when compared to healthy individuals. Recent evidence points to Bacteroidetes as a potential treatment predictor as it seems to increase in KD treatment responders for epilepsy. Each of these observations contributes to the presumed modulatory effects of KD on mood and supports its potential role as antidepressant.
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Objectives Patients with epilepsy are known to exhibit high rates of comorbid psychiatric disorders such as depression, anxiety, and other mood disorders. Little is known about the psychiatric effects of a ketogenic diet therapy (KDT) on adults with epilepsy. The objective of this study was to better understand the relationship between KDT and psychological state based on depressive and anxiety symptoms in adults with chronic epilepsy. Methods Adults at the Johns Hopkins Adult Epilepsy Diet Center on a modified Atkins diet (MAD) for at least one month were surveyed retrospectively. Adults who were diet naïve were given a baseline survey and an additional survey after 3 months or more on MAD. Surveys included validated measures of depressive and anxiety symptoms as well as their severity. Participant demographics, seizure frequency, and use of concomitant antiseizure drugs (ASDs), chronic anxiolytics (excluding as-needed benzodiazepines for seizure rescue only), and/or antidepressant drugs were extracted from electronic medical records. Results One-hundred participants aged 19–75 enrolled in the study. Sixty participants filled out a single retrospective survey. Of 40 diet naïve participants who filled out a baseline prospective survey, 19 completed a follow-up survey while on MAD and 21 participants were lost to follow-up. Longer diet duration was significantly associated with fewer anxiety and depressive symptoms, based on psychiatric measure scores, in retrospective study participants. Lower seizure frequency was also significantly associated with less anxiety symptoms in the retrospective cohort. Prospective study participants did not experience significant change in anxiety or depressive symptoms on the diet. There was a significant correlation between higher ketone level and responder rate (≥50% seizure reduction) in the prospective cohort, although no correlation between ketone level and change in psychiatric symptoms was seen. Significance Psychiatric comorbidity among patients with epilepsy is quite common and can be influenced by multiple factors such as seizure frequency, the use of various ASDs, social factors, and underlying etiology. Although ketogenic diet therapies have been in clinical use for one century, the psychiatric impacts have been insufficiently explored. This study provides preliminary evidence that KDT may have a positive impact on psychological state independent of seizure reduction or ketone body production and may be influenced by longer duration of diet therapy. These results support further investigation into specific effects and potential therapeutic benefits on various psychiatric disorders.
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Purpose of Review This paper aims to review data regarding two determinants of comorbidity between depression and obesity, i.e., the role of disturbed gut microbiome in their genesis and of diets in their treatment. Recent Findings Obesity and major depressive disorders (MDD) are highly comorbid, the “metabolic” (obese) subtype of MDD affects about one third of all individuals with MDD. There is an urgent need for better therapies strategies, which may include specific dietary measures. A diet low in carbohydrates (low-carb), effective in obesity, may be beneficial also in MDD. However, the underlying mechanisms have not yet been elucidated. Recent data suggest a key role of gut microbiota, neuroplasticity, and neuroinflammation in obesity and MDD. We will focus on the brain-derived neurotrophic factor (BDNF), and microglial fractalkine, a main modulator of neuroinflammation. Summary BDNF and fractalkine may be involved in “metabolic” depression. Future studies may uncover specific pathophysiological pathways in affected patients towards more efficient causal therapies.
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Low carbohydrate ketogenic diet (LCKD), originally used as a treatment for childhood epilepsy is currently gaining acceptance as a nutritional therapy for obesity and type 2 diabetes. In addition, this diet has a positive effect on body weight, blood glucose level, glycosylated hemoglobin, plasma lipid profile, neurological disorders and cancer. This review focus on the therapeutic effectiveness, negative effects and the rationale of using LCKD for the treatment Type 2 diabetes. It is shown that LCKD contributes to the reduction in the intake of insulin and oral antidiabetic drugs in patients with type 2 diabetes. Furthermore, the data presented in this review reveal the efficacy and cost-effectiveness of LCKD in the management of type 2 diabetes.
Research of the last two decades showed that chronic low-grade inflammation, elevated blood glucose and insulin levels may play role in the onset of a number of non-communicable diseases such as type 2 diabetes and some forms of cancer. Regular exercise and fasting can ameliorate high blood glucose and insulin levels as well as increase the concentration of plasma ketone bodies. These, in consequence, may lead to reduction of inflammation. Exercise or severe restriction of caloric intake is not always advisable for patients, in particular those suffering from cancer. The ketogenic diet (KD), characterized by high fat, moderate protein and very low carbohydrate composition can evoke a physiological state similar to that triggered by exercise or fasting. These attributes of KD prompted its possible use in treatment of a number of metabolic diseases, including several types of malignancies. Although results from clinical studies employing KD in the treatment of cancer are still limited, the results obtained from animal models are encouraging and show that KD presents a viable option as an adjunct therapy for cancer.
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The effects of zinc, the N-methyl-D-aspartate glutamate receptor inhibitor, were studied in mice and rats using the forced swim test. Zinc (ZnSO4) in a dose of 30 mg/kg and imipramine (30 mg/kg), reduced the immobility time in the forced swim test in both species. Moreover, combined treatment in this test with zinc and imipramine at their ineffective doses (1 and 5 mg/kg, respectively) induced a statistically significant effect in rats. The doses active in the forced swim test reduced (in mice) or did not affect (in rats) locomotor activity. The results obtained indicate that zinc induces an antidepressant-like effect and enhances the effect of imipramine in the forced swim test, suggesting a potential antidepressant activity of zinc in humans.
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Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (PIP) cycle, a source of two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP3). Clinical studies have reported that inositol is effective in relieving symptoms of depression. The present study examined the effects of inositol on two animal models of depression: the Porsolt forced swim test, a behaviorally based model; and the reserpine-induced immobility model, a pharmacologically based model. Chronic inositol injections (daily for 14 days) of 1.2 g/kg (but not at lower doses) reduced immobility time and increased struggle time in the Porsolt test compared with control animals. The same dose and treatment schedule also reduced complete immobility time but did not affect ambulatory activity in the reserpine test compared with controls. Chronic oral treatment with inositol (10% in food for 14 days) had effects similar to IP inositol in the Porsolt test. The effect of inositol in animal models of depression supports its possible importance as a new treatment for the disorder, and permits research on its mechanisms of action.
Chapter
Until the 20th century there were few effective treatments for epilepsy. Prayer and fasting had been advocated as therapy since at least biblical times. In the early 20th century attention turned to the fasting component and led to Wilder’s original publication in 1921 that outlined a ketogenic diet.1 On the basis of earlier studies of metabolism in diabetics, he recognized that fasting produced ketosis, which could be sustained by a diet that contained an excess of ketogenic foods (fats) rather than antiketogenic foods (proteins and carbohydrates). He and colleagues at the Mayo Clinic recommended an energyrestricted diet that provided approximately 1 g/kg per day of protein, a small amount of carbohydrates and more than 90 per cent of energy intake as fats.2.
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Immobility induced by forced swimming is well known as an animal model of depression. Using this paradigm, we have, in the present work, tested the possibility that the medicinal plant Rhazya stricta, which has previously been found to affect the monoamine oxidase inhibitory activity in rat brain, may have an antidepressant-like action. Rats were pretreated with various doses (0.025-6.4 g/kg) of the lyophilized extract of the plant leaves, or with desipramine (10, 20, and 40 mg/kg) and were subjected to the forced swimming test. The results indicated that the plant extract produced a biphasic (bell-shaped) effect on the immobility time. The lower doses (0.1, 0.2, and 0.4 g/kg) elicited a highly significant and inversely dose-dependent decrease in immobility time, and the higher doses (0.8, 1.6, and 6.4 g/kg) showed a dose-dependent decrease in immobility time. Under the same experimental conditions desipramine (20 and 40 mg/kg) produced dose-dependent significant decreases in immobility time. Following administration of R. stricta (6.4 g/kg) the immobility time recovered progressively with time, and 4 h after its administration the immobility time was about 70% of the control level (statistically insignificant). It is concluded that R. stricta extract [or component(s) thereof] may possess an antidepressant-like effect.
Article
Purpose: Fat is the major component of the ketogenic diet (KD), yet no studies have examined whether the type of fat used in the diet can be optimized to provide additional benefits. The purpose of the present experiments was to compare the efficiency of different fats in inducing ketosis and affording seizure resistance. Methods: The effects of KDs that incorporate lard, butter, medium-chain triglycerides (MCT), or flaxseed oil or a mixture of the latter three fats were examined in rats fed KD for up to 98 days. The maximal electroshock (MES) or pentylenetetrazole (PTZ) threshold tests were used to assess seizure susceptibility in two separate experiments. Results: The rank order of induced ketosis was MCT < mixture < flaxseed oil ± lard = butter < control. MES failed to reveal anticonvulsant effects, but the PTZ test indicated that up to 50% of rats fed the KD were seizure protected (p <0.05). The measures of seizure protection, seizure incidence and score, did not correlate, however, with the level of ketosis in the range of 0.7–5.2 mmol/L for β-hydroxybutyrate. In the long-term study, flaxseed oil KD maintained stable ketosis throughout 98 days, whereas ketones declined with lard and butter KD to the control level. Conclusions: Seizure protection with the versions of the KD did not improve with the higher level of ketosis. The focus of the KD improvement, therefore, is not the achievement of higher ketosis per se but rather designing a diet that provides steady ketosis, exploits advantages of certain fats for neurological development or seizure protection via a nonketogenic mechanism, and is nutritionally balanced.
Article
Use of the ketogenic diet for seizure control in children with epilepsy has seen a recent resurgence. Little cost-benefit analysis of this therapy has been published. Lack of diet standardization and method for evaluation of diet efficacy makes the decision to implement this diet therapy problematic for dietetics practitioners. In 1995, a 3-year trial ketogenic diet program was implemented; the decision on whether to continue the program depended on patient outcomes and financial implications to the institution. The program initiation process involved development of a protocol encompassing inpatient and outpatient care, patient/caregiver education materials, and a parent/caregiver satisfaction survey for evaluation of subjective responses to therapy. The program was researched and developed by registered dietitians and required approximately 55 hours of labor over a period of 5 months. Nutrition management averaged 16 hours per patient. Available cost data revealed 83% reimbursement of hospital charges and 99% reimbursement of inpatient costs. Seizure reduction and/or improved behavior occurred in 6 of 11 (55%) patients. Although program development and patient-care management was labor intensive, results have been encouraging based on reduction in seizures and behavioral improvements in patients and parent/caregiver satisfaction.
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Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.
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A MAJOR problem in the search for new antidepressant drugs is the lack of animal models which both resemble depressive illness and are selectively sensitive to clinically effective antidepressant treatments. We have been working on a new behavioural model in the rat which attempts to meet these two requirements. The method is based on the observation that a rat, when forced to swim in a situation from which there is no escape, will, after an initial period of vigorous activity, eventually cease to move altogether making only those movements necessary to keep its head above water. We think that this characteristic and readily identifiable behavioural immobility indicates a state of despair in which the rat has learned that escape is impossible and resigns itself to the experimental conditions. This hypothesis receives support from results presented below which indicate that immobility is reduced by different treatments known to be therapeutic in depression including three drugs, iprindole, mianserin and viloxazine which although clinically active1-3 show little or no `antidepressant' activity in the usual animal tests4-6.
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The ketogenic diet was developed in the 1920s as a treatment for intractable childhood seizures when few antiepileptic drugs (AEDs) were available. There are still children whose seizures are refractory even to modern therapy, but use of the ketogenic diet appears to be waning. At Johns Hopkins, we continue to believe that the diet is very effective and well accepted by patients and families. To reevaluate our opinion of the efficacy and acceptability of this form of therapy in patients cared for in the 1980s with the newer AEDs, we analyzed the records of 58 consecutive patients who had been started on the diet. Before using the diet, 80% of the patients had multiple seizure types and 88% were treated with multiple AEDs; these children were among our most intractable patients. Despite this, seizure control improved in 67% of patients with the ketogenic diet, and actuarial analysis indicated that 75% of these improved patients continued the diet for at least 18 months. Sixty-four percent had AEDs reduced, 36% became more alert, and 23% had improved behavior. The improvement in these patients with intractable seizures and the length of time that families maintained the regimen indicate that the ketogenic diet continues to have a very useful therapeutic role in selected patients and their families.
Article
Despite the continued development and release of new antiepileptic drugs (AEDs), many children have seizures that do not respond to conventional therapy or have related side effects that preclude continued use. While some of these children are surgical candidates, the majority do not qualify for surgical resection. In these children alternative therapies are often considered by desperate physicians and parents. Three of the less conventional therapies which are currently used for intractable epilepsy are: the ketogenic diet, immunoglobulins, and steroids. None of these therapies has been adequately studied and it remains unclear which patients may benefit or be harmed by these therapies. Despite the lack of scientific vigor in evaluating these therapies, the television and print media has proclaimed these therapies as miraculous, yet grossly under-utilized by an ignorant medical community. The ketogenic diet has been demonstrated to reduce seizure frequency in some patients, but has an unclear mechanism of action, while immunoglobulins have both unknown efficacy and an unknown mechanism of action. While steroids are accepted as an effective therapy for infantile spasms, their role in the treatment of the Landau-Kleffner syndrome is far less clear. Although the ketogenic diet, immunoglobulins, and steroids may have a role in the treatment of severe childhood epilepsy, all three therapies need to be critically evaluated in regard to efficacy, mechanism of action, and safety.
Article
There has been a dramatic resurgence of interest in the ketogenic diet during the past several years. For many children with difficult-to-control epilepsy, the diet presents an alternative approach to trying multiple medications. The ketogenic diet's current success rate, when properly executed, greatly exceeds that of the medications which have recently become available. Its side effects, both cognitive and allergic, appear fewer than most available medications. The ketogenic diet is also cheaper than most new anticonvulsants. Even though we now know that the diet works, we still do not know how it works. Nor do we know how most anticonvulsants work. The mechanism of action of the ketogenic diet appears to rely on a fundamental change in the brain's metabolism from that of a glucose-based energy substrate to a ketone-based substrate. This change is, in some fashion, critical to the maintenance of seizure threshold. Why should the source of the energy make a difference in seizure threshold? The change in seizure threshold appears to occur without affecting the brain's ability to carry out its normal complex functions. Could the brain's utilization of an energy substrate for seizure control be different from its utilization of energy for normal brain function? If so it should it be possible to study the metabolic differences between the two and develop a biochemistry of epilepsy, which is differentiated from the biochemistry of normal cognition and function. The ketogenic diet is successful in controlling or ameliorating a broad spectrum of seizure types and etiologies. Perhaps then, common metabolic pathways, independent of seizure type, are used in the initiation and spread of electrical seizures. Based on clinical experience and limited research data, it would appear that different seizures and different epilepsies must have metabolic pathways in common that make them susceptible to treatment with a common metabolic therapy. If we could understand how the ketogenic diet "works," how changing from a glucose substrate' to a ketone body substrate is anticonvulsant, then perhaps a medication could be developed that would simulate the biochemical effects of the ketogenic diet. Such an approach would be a major departure in the study of the neuroscience of epilepsy. The ketogenic diet offers a new paradigm to think about epilepsy and its treatment, and perhaps will stimulate new approaches to this still often devastating condition.
Article
Immobility induced by forced swimming is well known as an animal model of depression. Using this paradigm, we have, in the present work, tested the possibility that the medicinal plant Rhazya stricta, which has previously been found to affect the monoamine oxidase inhibitory activity in rat brain, may have an antidepressant-like action. Rats were pretreated with various doses (0.025-6.4 g/kg) of the lyophilized extract of the plant leaves, or with desipramine (10, 20, and 40 mg/kg) and were subjected to the forced swimming test. The results indicated that the plant extract produced a biphasic (bell-shaped) effect on the immobility time. The lower doses (0.1, 0.2, and 0.4 g/kg) elicited a highly significant and inversely dose-dependent decrease in immobility time, and the higher doses (0.8, 1.6, and 6.4 g/kg) showed a dose-dependent decrease in immobility time. Under the same experimental conditions desipramine (20 and 40 mg/kg) produced dose-dependent significant decreases in immobility time. Following administration of R. stricta (6.4 g/kg) the immobility time recovered progressively with time, and 4 h after its administration the immobility time was about 70% of the control level (statistically insignificant). It is concluded that R. stricta extract [or component(s) thereof] may possess an antidepressant-like effect.
Article
To evaluate attentional difficulties in children with complex partial seizures, we reviewed the records of 12 children with complex partial seizures with attention deficient hyperactivity disorder (CPS/ADHD); 21 children with CPS without ADHD (CPS); 22 children with ADHD; and 15 control children. Each child completed a computerized performance test (CPT), which evaluated sustained attention, inhibition of response, response time, and consistency of response. The ADHD groups also completed the CPT after a dose of methylphenidate. The results found poorest performance on the CPT by the CPS/ADHD group. Particular difficulty in attention was found for children with epilepsy regardless of the ADHD diagnosis. When methylphenidate was administered to the ADHD groups, both groups improved in performance on the CPT. Epilepsy may predispose children to attention problems that can significantly interfere with learning. Similar improvement for children with CPS/ADHD was found with methylphenidate compared with baseline as for children with ADHD but without CPS.
Article
Motor and cognitive functions in patients with partial or generalized onset of seizures were evaluated prior to the administration of antiepileptic medication. Motor function, attention and memory of 52 consecutive newly diagnosed adult patients with partial or generalized seizures were assessed with neuropsychological tests. Patients with partial onset of seizures did not differ from patients with generalized seizures in tests of motor function or attention, nor in tests of learning and memory. Compared to controls patients with epilepsy performed significantly worse on visual motor tasks, mental flexibility and in delayed visual memory. Within the patient group as a whole lower education, higher age and symptomatic epilepsy with more abnormal CT scan findings tended to associate with worse performance in tests of concentration and mental flexibility and tests of memory. These findings indicate that newly diagnosed adult patients with partial or generalized onset of seizures prior to treatment with antiepileptic medication experience some problems in visual motor tasks, mental flexibility and memory even without the numerous risk factors for cognitive deficits in epilepsy. In newly diagnosed patients with epilepsy as a whole symptomatic etiology was associated with somewhat more pronounced cognitive problems.
Article
Fat is the major component of the ketogenic diet (KD), yet no studies have examined whether the type of fat used in the diet can be optimized to provide additional benefits. The purpose of the present experiments was to compare the efficiency of different fats in inducing ketosis and affording seizure resistance. The effects of KDs that incorporate lard, butter, medium-chain triglycerides (MCT), or flaxseed oil or a mixture of the latter three fats were examined in rats fed KD for up to 98 days. The maximal electroshock (MES) or pentylenetetrazole (PTZ) threshold tests were used to assess seizure susceptibility in two separate experiments. The rank order of induced ketosis was MCT > mixture > or = flaxseed oil > or = lard = butter > or = control. MES failed to reveal anticonvulsant effects, but the PTZ test indicated that up to 50% of rats fed the KD were seizure protected (p < 0.05). The measures of seizure protection, seizure incidence and score, did not correlate, however, with the level of ketosis in the range of 0. 7-5.2 mmol/L for beta-hydroxybutyrate. In the long-term study, flaxseed oil KD maintained stable ketosis throughout 98 days, whereas ketones declined with lard and butter KD to the control level. Seizure protection with the versions of the KD did not improve with the higher level of ketosis. The focus of the KD improvement, therefore, is not the achievement of higher ketosis per se but rather designing a diet that provides steady ketosis, exploits advantages of certain fats for neurological development or seizure protection via a nonketogenic mechanism, and is nutritionally balanced.
Article
The ketogenic diet is increasingly used for the management of difficult-to-control seizures in children. Here, we describe the first prospective study of the effects of the diet on development, behavior, and parenting stress. Participants were 65 children (36 males, 29 females) with intractable seizures, ages 18 months to 14 years 6 months, enrolled in a prospective study at the Johns Hopkins Hospital, Baltimore, MD, USA, to study the diet's efficacy. Children were assessed before diet initiation and at 1-year follow-up. At follow-up, 52% (34 of 65) children remained on the diet. Mean seizure frequency decreased from 25 per day before diet initiation to less than two per day 1 year later. At follow-up, mean developmental quotient showed statistically significant improvement (p<0.05), with significant behavioral improvements in attention and social functioning. Parental stress was essentially unchanged. No baseline factor examined predicted diet adherence, and the primary reason for diet discontinuation was insufficient seizure control. These preliminary results support prior anecdotal reports of the beneficial effects of the diet on cognition and behavior.
Article
The purpose of this study was to measure quantitatively the effectiveness of the ketogenic diet (KD) in comparison to two clinically important anticonvulsant drugs (AEDs), valproic acid (VPA) and phenytoin (PHT), and to evaluate possible associated neurotoxicity. Rats were maintained on either a calorie-restricted, KD or calorie-restricted, rodent-chow diet for 3-5 weeks, after which neurobehavioral and seizure testing was completed. AEDs (either VPA or PHT) were injected acutely at the time to peak effect before neurotoxic and seizure assessment. Seizures were induced by timed infusion of pentylenetetrazole (PTZ) and maximal electroshock (MES). VPA protected from both MES- and PTZ-induced seizures, whereas the KD only elevated PTZ seizure threshold; PHT only attenuated MES-induced seizures. The KD was as effective as a high dose of VPA (i.e., 300 mg/kg) and combined treatment (i.e., KD + VPA) showed an additive increase in PTZ seizure threshold. No observed neurobehavioral deficits were associated with either diet treatment; however, drug-related side effects were noted with high doses of either VPA or PHT. These data suggest that the KD ranks among VPA and PHT as an effective treatment for seizures, without observed drug-associated neurobehavioral contraindications. In combination with AEDs, our results indicate that the KD plus VPA work synergistically to increase seizure threshold, whereas the KD plus PHT may be complementary, elevating seizure threshold (KD) and reducing seizure severity (PHT). These findings may provide insights into future directions for rational polytherapy; however, it is important to be aware that the KD has been shown to elevate VPA-induced hepatotoxicity.
Article
The ketogenic diet, originally introduced in the 1920s, has been undergoing a recent resurgence as an adjunctive treatment for refractory epilepsy, particularly in children. In this difficult-to-treat population, the diet exhibits remarkable efficacy with two-thirds showing significant reduction in seizure frequency and one-third becoming nearly seizure-free. There are several reasons to suspect that the ketogenic diet may also have utility as a mood stabilizer in bipolar illness. These include the observation that several anticonvulsant interventions may improve outcome in mood disorders. Furthermore, beneficial changes in brain-energy profile are noted in subjects on the ketogenic diet. This is important since global cerebral hypometabolism is a characteristic of the brains of depressed or manic individuals. Finally, the extracellular changes that occur in ketosis would be expected to decrease intracellular sodium concentrations, a common property of all effective mood stabilizers. Trials of the ketogenic diet in relapse prevention of bipolar mood episodes are warranted.
Article
A pilot prospective follow-up study of the role of the ketogenic diet was carried out on 30 children, aged between 4 and 10 years, with autistic behavior. The diet was applied for 6 months, with continuous administration for 4 weeks, interrupted by 2-week diet-free intervals. Seven patients could not tolerate the diet, whereas five other patients adhered to the diet for 1 to 2 months and then discontinued it. Of the remaining group who adhered to the diet, 18 of 30 children (60%), improvement was recorded in several parameters and in accordance with the Childhood Autism Rating Scale. Significant improvement (> 12 units of the Childhood Autism Rating Scale) was recorded in two patients (pre-Scale: 35.00 +/- 1.41[mean +/- SD]), average improvement (> 8-12 units) in eight patients (pre-Scale: 41.88 +/- 3.14[mean +/- SD]), and minor improvement (2-8 units) in eight patients (pre-Scale: 45.25 +/- 2.76 [mean +/- SD]). Although these data are very preliminary, there is some evidence that the ketogenic diet may be used in autistic behavior as an additional or alternative therapy.
Article
Children, adolescents, and adults with epilepsy often also show symptoms associated with attention-deficit/hyperactivity disorder (ADHD). The ketogenic diet, which is administered to children with epilepsy refractory to drug therapy, seems to improve behavior in individuals with symptoms of ADHD. The basis for this improvement is unknown, although it seems to be unrelated to seizure control. The present research was designed to investigate the effect of two ketogenic diets on the behavior of normal adult male rats. Two experiments were conducted. In experiment 1, 36 subjects were placed on one of three diets: a control diet, a 6.3:1 ketogenic diet, and a 4:1 ketogenic diet. In experiment 2, 20 subjects were placed either on a control diet or on a 4:1 ketogenic diet. The activity level of each subject was measured using an open field test. Time spent immobile, grooming, and in exploratory behavior was measured for 600 s. Subjects were tested once before initiation of the diets and once while on the diets. No significant group differences were found in activity level before initiation of the diets. After initiation of the diets, subjects in both ketogenic groups showed a significantly lower activity level than the rats on the control diet. The ketogenic diet decreases activity level in an animal model. This behavioral change may relate to the improved behavior seen when children with symptoms of ADHD are placed on the diet.
Behavioural despair in rats: A new model sensitive to antidepressant treatments
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  • Anton G Blavet
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Behavioural despair in rats
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Efficacy of the ketogenic diet for intractable seizure disorder
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Alternative epilepsy therapies
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Effects of ketogenic diet on development and behavior
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