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"Science knows no country, because knowledge belongs to humanity, and is the torch which illuminates the world." - Louis Pasteur


Wednesday, May 3, 2017

Ketogenic diet and its effects in mental disorders

Abstract (as presented by the authors of the scientific work):

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

Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Discussion (as presented by the authors of the scientific work):

"In neurology, KD is an established treatment option for treatment-resistant epilepsy with evidence from a range of studies including controlled trials. By contrast, KD research in humans with mental disorders, though extending over a 50-year period, has received little attention with few studies other than case reports, small sample size open studies, and no controlled trials. Animal studies have been more systematic, investigating mechanisms as well as outcomes on putative disease analogs in rodents and canines, the latter including randomized controlled trials of KD.

With respect to mechanisms, the pathophysiology of the mental disorders covered in this review is not clearly understood, though impaired metabolism due to mitochondrial dysfunction has been identified as an important substrate (34). This is congruent with findings in neurological conditions, Stafstrom and Rho concluding that energy metabolism changes induced by KD in neurological conditions suggest a final common pathway implicating mitochondrial function (26). KD may also influence neuronal plasticity by modifying neural circuits and cellular properties to normalize function (26). Mitochondrial dysfunction may be relevant in some mental disorders including schizophrenia, ASD, and ADHD, whereas the improvements seen in anxiety, depression, and bipolar disorder may be related to alterations of neurotransmitters.

One other possible mediator of the beneficial effects of KD in mental disorders is the effect on sleep. In a study of 18 children with treatment-resistant epilepsy, after 3 months of KD sleep was reported to be enhanced with a pattern of significant reduction in total night sleep, preservation of slow-wave sleep, increased rapid eye movement (REM) sleep, and decrease in sleep stage 2 (79). The mechanisms by which KD affects sleep is unclear (80), and more studies are necessary to confirm reports that certain dietary patterns and foods improve sleep (81).

Sleep problems and mental disorders are codependent conditions that exacerbate each other and lead to impaired quality of life and increased disability (82). Impairments of sleep are a widespread feature of mental disorders. Anxious patients have been found to have significantly less sleep period time, total sleep time, percentage stage REM and percent stage 4 sleep, shorter latency to stage REM, and greater percent stage 1 sleep than healthy controls (83). REM sleep abnormalities including shortening of REM latency, lengthening of the duration of the first REM period, and heightening of REM density are found in patients with depression (84). In patients with inter-episode bipolar disorder, shorter sleep onset latency and increased REM density has been observed (85). A decrease of REM sleep latency in schizophrenia has been described (86). Individuals with ASD have prolonged sleep latency, more frequent nocturnal awakenings, lower sleep efficiency, increased duration of NREM stage 1 sleep, and decreased deeper stages of NREM sleep (87). In ADHD, disturbed sleep architecture has been described including shorter REM latencies, reduced REM sleep, and increased delta sleep percentage (88). It should also be noted that sleep deprivation can precipitate mania in bipolar disorder and seizures in epilepsy (89) and can be used as a treatment for depression (90). The specific effects of KD on these mental disorder-related sleep symptoms has not been studied in detail, but interactions are likely and may be possible mediators of a therapeutic effect.

In epilepsy, KD acts differently to antiepileptic drugs (AED) in seizure prevention. While AED act directly on ion channels and synaptic processes, KD acts through intermediary metabolic pathways (91). Chang et al. showed that an MCT (palm oil and coconut oil) diet, a variation of KD, reduces seizures in children via inhibition on AMPA receptors (12, 92, 93). The questions posed by the literature indicate that the mechanism of action is still unknown, and there may be many potential pathways involved. The mechanism of action appears different from AED and therefore probably psychiatric drugs also, which opens potential avenues for treatment in a manner that may supplement conventional pharmacological treatment approaches. The exact mechanism of action of KD is unclear, and for detailed discussion, see Rogawski et al. (91). Thus, present knowledge indicates that KD exerts its effects on seizure control by mechanisms different from conventional AED and therefore, in psychiatry, this may also be the case although as yet unproven.

There are a number of reasons why the effectiveness of KD in mental disorders remains unproven. In addition to the low number of human studies, the quality of the studies has some significant limitations. Sample sizes are small, there is no control for placebo effects, and the establishment of ketosis is generally lacking with no confirmatory measurement of ketones in three human studies. There are also significant limitations associated with the diet itself including the detailed regimen, unpalatable food choices, side effects, and duration of diet required. There are also no enforced standards as to what constitutes KD in humans with variable lipid:non-lipid ratios reported. KD monotherapy is used in animal models of mental disorders but remains unexamined in human studies. Ten adult patients with epilepsy followed KD monotherapy, and it was concluded that it may be feasible, well tolerated, and an effective long-term alternative (94).

To comply with KD, patients who may be acutely unwell are required to measure food portions to ensure that the macronutrient targets associated with the diet are met, and they may find it difficult to adhere to such a demanding diet (47). This is particularly so for patients with mental disorders where symptoms such as impulsivity in mania, apathy, and reduced appetite in depression, food cravings, and binge eating associated with antipsychotic medications may variously interfere with compliance with KD (95). A mitigating factor to the outcomes in children with epilepsy may be that the diet is typically administered in a hospital setting initially and subsequently, by caregivers.

El-Mallakh and Paskitti have outlined the adverse consequences of KD including constipation, menstrual irregularities, elevated serum cholesterol and triglycerides, hypoproteinemia, hemolytic anemia, elevated liver enzymes, and gall stones (96). Kidney stones have been noted to occur in 1 of 20 children on the diet (97). In a period of almost 2 years, prospective monitoring of 52 children with pediatric epilepsy was conducted. Ten percent of children experienced serious adverse events associated with the diet 1 month after initiation (98). This included presacral and periorbital edema, developmental impairment, and unwanted weight loss in an infant, renal tubular acidosis, viral gastroenteritis, abnormal liver function, and thrombocytopenia. It should be noted that all patients were being treated with concomitant VPA. It was reported in a retrospective study of 158 children with intractable epilepsy that, in 80% emesis, food refusal and hypoglycemia occurred (99).

By definition, KD is confirmed by the production of ketones measured in the blood or urine. In the reviewed literature covering KD in mental disorders, four studies did not report ketone levels, which severely limit comparability across studies and the ability to invoke any consistent mechanism. One study compared whether measuring serum beta-hydroxybutyrate or urinary ketones was superior to monitor KD (100). In humans, it was found that beta-hydroxybutyrate correlated more strongly with a reduction in seizures than urinary ketones; therefore, future studies should measure ketones in the blood. Another issue is that the lipid:non-lipid ratios used were different (see Tables Tables11 and and2).2). In a study that compared the efficacy and tolerability of the 3:1 versus the 4:1 lipid:non-lipid ratios, the latter was shown to have a higher seizure-free outcome (2).

One issue when interpreting the results is the levels of evidence in the evidence-based hierarchy. Animal models of mental disorders are considered valuable preclinical tools to investigate the neurobiological basis of a disorder (62). While this may be true, they are nonetheless subject to a number of limitations. One such limitation is the issue of validity, and their use is based on the assumption that humans and animals share basic neurobiological mechanisms associated with the complex behaviors that mimic mental disorders in animals (101).

Another difficulty posed to practitioners is that there are currently no international protocols guiding the administration of the diet; this is something that may be established from future research into KD. There was only one case study that detailed what the participant, diagnosed with schizophrenia, ate, and it was not established whether this individual was in ketosis. In the various studies in humans, outcomes were assessed following dietary durations that varied from 7 days to 2 years.

Further research into the neural correlates of KD is needed to help explain the mechanisms by which it acts. Some suggestions regarding methodologies, provided by Fusar-Poli are elaborated below. Changes in glucose metabolism seen in KD could be examined using positron emission tomography fluorodeoxyglucose. To observe the neural correlates of KD, a combination of electrophysiological measures including EEG and magnetoencephalogram and fMRI/PET to combine the high temporal resolution of the former with the high spatial resolution of the latter may be used (102).

In the neurological literature, a single study, in Alzheimer’s disease, used a synthesized ketogenic compound AC-1202 rather than a KD. AC-1202 is an MCT composed of glycerine and caprylic acid (23). It is not yet clear what role ketogenic pharmacotherapy options might play alongside or as a substitute for KD.

While these animal studies are placing research into KD on a firm footing and identifying some promising leads, on balance the evidence in humans is insufficient to form an opinion as to the efficacy or lack thereof of this intervention in the mental disorders reported. Further basic research to clarify the specifics of dietary manipulation or supplementation required to produce optimum ketosis in specific models is an obvious intermediate step toward studying the effectiveness of the diet in human mental disorders using conventional phases of research including open-label studies and randomized controlled trials."

Full-text access of the referenced scientific work:

Bostock EC, Kirkby KC, Taylor BV. The Current Status of the Ketogenic Diet in
Psychiatry. Front Psychiatry. 2017 Mar 20;8:43. doi: 10.3389/fpsyt.2017.00043.
eCollection 2017. Review. PubMed PMID: 28373848; PubMed Central PMCID:


Prof. Atanas G. Atanasov (Dr. habil., PhD)

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