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The Current Status of the Ketogenic Diet in Psychiatry


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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.
Content may be subject to copyright.
March 2017 | Volume 8 | Article 431
published: 20 March 2017
doi: 10.3389/fpsyt.2017.00043
Frontiers in Psychiatry |
Edited by:
Roumen Kirov,
Bulgarian Academy of Sciences,
Reviewed by:
Christian Benedict,
Uppsala University, Sweden
Jong Min Rho,
University of Calgary, Canada
Kamila C. Grokoski,
Universidade Federal do Rio Grande
do Sul, Brazil
Emmanuelle C. S. Bostock
Specialty section:
This article was submitted to
a section of the journal
Frontiers in Psychiatry
Received: 02February2017
Accepted: 02March2017
Published: 20March2017
BostockECS, KirkbyKC and
TaylorBVM (2017) The Current
Status of the Ketogenic Diet in
Front. Psychiatry 8:43.
doi: 10.3389/fpsyt.2017.00043
The Current Status of the Ketogenic
Diet in Psychiatry
Emmanuelle C. S. Bostock1*, Kenneth C. Kirkby2 and Bruce V. M. Taylor3
1 Psychology, School of Medicine, University of Tasmania, Hobart, TAS, Australia, 2 Psychiatry, School of Medicine, University
of Tasmania, Hobart, TAS, Australia, 3 Menzies Institute for Medical Research, Tasmania, Hobart, TAS, Australia
Background: 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.
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 decit 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 signicantly reduced depression-like behaviors in rat and mice models in
two controlled studies. In bipolar disorder, one case study reported a reduction in symp-
tomatology, 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 signicant improvement; one case study reported a pronounced
and sustained response to KD. In ASD, in four controlled animal studies, KD signicantly
reduced ASD-related behaviors in mice and rats. In ADHD, in one controlled trial of KD
in dogs with comorbid epilepsy, both conditions signicantly improved.
Conclusion: 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 insufcient 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.
Keywords: ketogenic diet, psychiatry, mental disorders, ketones, epilepsy
Bostock et al. KD in Psychiatry
Frontiers in Psychiatry | March 2017 | Volume 8 | Article 43
e ketogenic diet (KD) has a long-standing place in neurology
and has been used for treatment-resistant epilepsy since the 1920s
(1). KD consists of a rigidly controlled high-fat, low-protein, and
low-carbohydrate diet usually with a 4:1 lipid:non-lipid ratio (fat
to protein and carbohydrate ratio) (2). Woodyatt noted that in a
normal person in a state of starvation or eating a diet contain-
ing low carbohydrate and a high percentage of fat, the ketones
acetone, acetoacetate, and beta-hydroxybutyric acid increase (3),
and the absence of glucose serves as alternative fuels for the body.
KD has been proven an eective treatment in dicult-to-control
seizures with its use primarily in children with epilepsy (4, 5),
particularly those with epileptic encephalopathies whereby epi-
leptic activity may contribute to severe neurological and cognitive
impairments (6). e nding that KD is benecial for epilepsy
was supported by a systematic review (7), meta-analysis (8), and
a Cochrane review (9). KD and related diets have been proven
useful in pharmacoresistant childhood epilepsy (10).
e mechanism by which KD acts is not clearly understood.
However, among the many hypotheses advanced, elevation of
brain acetone may account for the ecacy of the diet in epilepsy
as it has proven anticonvulsant eects (11). In a variation of the
diet, the medium-chain triglyceride (MCT) KD increases plasma
levels of decanoic acid, which in vivo has been shown to be
anticonvulsant; although the precise mechanism remains unclear
(12). In young and adult rats, KD increases concentrations of
kynurenic acid (KYNA) in the hippocampus and striatum but
not the cortex (13). Elevated levels of KYNA in the cerebrospinal
uid have been demonstrated in patients with schizophrenia
(14) and bipolar disorder (15). Pharmacological manipulation
of kynurenines is a potential treatment strategy for psychiatric
disorders (16).
Currently, there are no international protocols guiding the
implementation of the diet, rather dietary recommendations are
based on individual treating physician’s advice. Consequently,
there exists a need for more standardized protocols for manage-
ment recommendations for clinical and research use (17). In 2006,
a group of 26 pediatric epileptologists and dieticians was convened
to create a consensus statement regarding the clinical management
of KD. ey specied the following absolute contraindications to
commencing KD “carnitine deciency (primary), carnitine pal-
mitoyltransferase (CPT) I or II deciency, carnitine translocase
deciency, beta-oxidation deciencies including medium-chain
acyl dehydrogenase deciency (MCAD), long-chain acyl dehy-
drogenase deciency (LCAD), short-chain acyl dehydrogenase
deciency (SCAD), long-chain 3-hydroxyacl-CoA deciency,
medium-chain 3-hydroxyacl-CoA deciency, pyruvate carboxy-
lase deciency and porphyria. Relative contraindications of KD
include the following: inability to maintain adequate nutrition,
surgical focus identied by neuroimaging and video EEG
monitoring, and parent or caregiver non-compliance” (18). e
possible risks of KD must be weighted against its potential value
for seizure control or its other benets (19).
Ketogenic diet has been assessed in a variety of neurological
conditions other than epilepsy in both animal models and human
trials. In an animal model of amyotrophic lateral sclerosis,
SOD1-G93A transgenic mice were fed KD. It was shown that
KD led to signicant alterations in the clinical manifestation
of the disease, specically a higher motor neuron count in the
lumbar spinal cord and preserved motor function (20). KD has
also been trialed in rats following controlled cortical impact
injury, a model for brain trauma, showing that the diet improves
both cognitive and motor functioning (21). In an animal model
of multiple sclerosis, the eects of KD on memory impairments
and inammation expressed by experimental autoimmune
encephalomyelitis were examined. In mice, it was demonstrated
that brain inammation was associated with impaired spatial
learning and memory function, and the administration of KD
exerted protective eects against these. e proposed mode of
action was through attenuation of the immune response and
increased oxidative stress observed in the mice (22).
In humans, KD has been trialed in a number of neurological
conditions. In a randomized, double-blind, placebo-controlled,
parallel group study in Alzheimer’s disease, an oral ketogenic
compound AC-1202 was tested on 152 patients. Regular medi-
cations were continued throughout the study. Daily dosing of
AC-1202 signicantly elevated the levels of beta-hydroxybutyrate
2h aer administration. Aer 45 and 90days, patients treated
with AC-1202 had signicant improvements on the ADAS-Cog
scale (23). In a small study of seven patients with Parkinson’s
disease, ve adhered to KD for 28 days (24). Scores on the
Unied Parkinson’s Disease Rating Scale improved in all ve
as did symptoms such as resting tremor, freezing, balance, gait,
mood, and energy levels. ese results should be interpreted with
caution due to the small sample size, subjective ratings, and the
lack of a control group to exclude a placebo eect. e modied
Atkins diet (a high-fat, low-carbohydrate diet), which creates a
ketotic state was trialed in adolescent patients with chronic daily
headaches (25). Due to diculties adhering to the diet, the study
was terminated prematurely. ree participants reported an
improvement in headache severity and quality of life; however,
they still required pharmacotherapy to manage their condition.
In a comprehensive review of KD in diverse neurological condi-
tions, Stafstrom and Rho concluded that there are rich opportuni-
ties for further investigation of KD in both the laboratory and
clinical practice (26).
e therapeutic advantage of KD has been replicated in animal
models of neurological illnesses, and the purported underlying
mechanisms include those which improve mitochondrial func-
tion (27). Molecular, biochemical, and physiological studies
tend to support the assumption that cellular energy status is a
determinant for multiple disorders (28). Aberrant energy pro-
duction has been associated with cancer (29), heart failure (30),
aging (31), and neurological conditions such as epilepsy (32) and
Alzheimer’s disease (33). e precise pathways by which energy
disruption is related to these and other disorders are unknown.
ere are also strong indications of metabolic pathways involv-
ing energy production in the pathophysiology of some mental
disorders including bipolar disorder, depression, schizophrenia
(34) autism spectrum disorder (ASD) (35), and potentially atten-
tion decit hyperactivity disorder (ADHD) (36). ere is also a
recognized comorbidity between epilepsy and mental disorders
(37), which might indicate some commonality of mechanisms.
Bostock et al. KD in Psychiatry
Frontiers in Psychiatry | March 2017 | Volume 8 | Article 43
Given the degree of interest in KD and neurological condi-
tions, the aim of this narrative review is to examine the eect of
the diet in mental disorders. e literature searched in anxiety,
depression, bipolar disorder, schizophrenia, ASD, and ADHD.
A comprehensive search of the electronic databases PubMed,
PsychINFO, and Scopus for peer-reviewed articles published in
English was conducted in the last week of November 2016 and
updated in January 2017. Search terms were “bipolar disorder”
“manic depress*” “depress*” “schizophren*” “autism” “ASD”
“attention decit hyperactivity disorder” “ADHD” “obsessive
compulsive disorder” “OCD” “anxiety” “anxi*” “psychiatry”
“mental disorder*” (group 1) AND “ketogenic diet” “ketosis
“ketogenesis” “ketone bodies” “high fat low carbohydrate” “diet”
“acetone” “acetoacetic acid” “beta-hydroxybutyric acid” “acetyl-
coA” “ketonemia” “ketonuria” “fatty acid metabolism” “hyper-
ketonemia” “fasting” “nutritional ketosis” “acidotic” (group 2).
ese terms were combined as follows: group 1 AND group 2. In
addition, a hand-search of the reference lists of published articles
was also conducted, and articles were assessed for their suitabil-
ity in the review. An initial search was conducted using all the
search terms listed above, and abstracts were reviewed by author
Emmanuelle C. S. Bostock. Full text publications were retrieved
for those that addressed the subject matter.
e results are discussed by mental disorders examining animal
and human studies including case reports and studies of patient
groups. e search yielded 15 studies that examined KD in men-
tal disorders, specically anxiety, depression, bipolar disorder,
schizophrenia, autism, and, ADHD. ese studies included nine
animal models, and in humans four case studies and two uncon-
trolled trials. A summary of results by animal models and human
studies are presented in Tables1 and 2, respectively.
Anxiety is a common mental disorder aecting 18.1% of the
population in the United States (52). In humans, functional
magnetic resonance imaging indicates that anxiety is associated
with activation in the ventromedial prefrontal cortex and hip-
pocampal regions of the brain (53). Symptoms of anxiety and
disorders are more frequent in patients with epilepsy with one
recent study reporting a lifetime incidence of 22.8% as opposed
to 11.2% in people without epilepsy (54).
In a recent animal model study of anxiety in male rats, two
methods of administration of exogenous ketone supplement were
applied (38). In the chronic administration condition, 48 male
Sprague-Dawley (SPD) rats were fed for 83days with either a
standard diet (n=9) or standard diet plus one of four ketone
supplementation conditions. In the sub-chronic intragastric
gavage bolus condition, 39 SPD rats were fed with standard diet
and gavaged daily with water (control, n=11) or 1 of 3 levels
of ketone supplementation for 7 days; this was repeated with
32 Wistar Albino Glaxo/Rijswijk rats receiving a half-dose of
supplementation. In both modes of supplementation, beta-
hydroxybutyrate was signicantly elevated indicating ketosis. All
treatment conditions resulted in reduced anxiety as assessed by
behavior on the elevated plus maze. e dependent variables of
less entries and time spent in closed arms, more entries and time
spent in open arms, more distance traveled in open arms, and
delayed entry to closed arm were used as an analog of anxiety
in humans. e authors hypothesized that the mode of action
was through the glutamatergic and/or GABAergic and purinergic
In a recent review, a number of studies suggested that depression
is associated with an increased risk of epilepsy (55). e eec-
tiveness of conventional antidepressant therapies is frequently
examined in animals. In rodents, to test current levels of depres-
sion, a methodology known as the Porsolt forced swim test is
oen employed (56) and has been used in testing the eectiveness
of new antidepressant drugs (57). In the two-part swim test,
animals are rst placed in a container from which they cannot
escape. When they then stop trying and immobility ensues, a state
of behavioral despair is shown. Second, to assess the eects of
antidepressants, the time spent immobile is used as a dependent
variable, and reductions are interpreted for signicance (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 eects of the diet. e diet duration was
7days, and levels of beta-hydroxybutyrate were measured.
Brain morphology and behavior of CD-1 mice exposed
to KD (4:1 lipid:non-lipid ratio) for 30days inutero and fed a
standard diet in postnatal life were examined (40). Adult mice
that were fed the diet inutero showed reduced susceptibility to
anxiety and depression and exhibited elevated physical activity
when compared with control mice fed a standard diet inutero.
Morphological dierences included cerebellar volumetric
enlargement by 4.8%, a hypothalamic reduction by 1.39%, and
a corpus callosum reduction by 4.77%, as computed relative to
total brain volume.
While animal models pave the way for future research in
humans, the conclusions that may be made are limited. e
mechanism by which KD acts in animal models of depression
is unknown; however, in children with epilepsy, KD resulted
in signicant alterations in levels of serotonin and dopamine
neurotransmitters (58), both of which are implicated in anxiety
and depression. To the best of our knowledge, there are no studies
examining the eects of KD in depressed humans.
Bipolar Disorder
A diagnosis of bipolar disorder type I requires an episode of
mania, which consists of “a distinct period of abnormally and
persistently elevated, expansive or irritable mood, lasting at least
1 week (or any duration if hospitalization is necessary)” (59).
A diagnosis of bipolar disorder type II requires at least one episode
of hypomania. In a study of nutrition and exercise behavior, when
compared to patients with schizophrenia or healthy controls, it
TABLE 2 | Summary of ndings in human studies.
Reference Condition Subjects (n) Mode of administration of diet Duration of
Ketone* Result
(46) BD Human women
Ratio not mentioned in rst but in
second (70% fat, 22% protein, and
8% carbohydrate)
2 and 3years Mood stabilization
(47) BD Human woman
4:1 lipid:non-lipid ratio 1month No urinary
No clinical improvement
(48) SZ Human women
Not listed 2weeks Not listed Statistically signicant decrease in symptomatology
(49) SZ Human woman
Not listed 12months Not listed No recurrence of auditory or visual hallucinations
(50) ASD Human children
30% MCT, 30% fresh cream, 11%
saturated fat, 19% carbohydrate,
and 10% protein
(intervals of
4weeks with 2
diet-free weeks)
40% non-compliance. Two children showed
signicant improvements on Childhood Autism
Rating Scale, while the rest showed mild-to-
moderate improvements
(51) ASD Human child (1) 1.5:1 lipid:non-lipid ratio Several years Score on the Childhood Autism Rating Scale
decreased from 49 to 17 (severe autism to
DEP, depression; BD, bipolar disorder; SZ, schizophrenia; *, ketone levels reported; MCT, medium-chain triglyceride; ASD, autism spectrum disorder.
TABLE 1 | Summary of ndings in animal models.
Reference Condition Subjects (n) Mode of administration of
Duration of
Ketone* Result
(38) ANX Sprague-
Dawley (48) and
Wistar Albino
rats (32)
Exogenous ketone supplement 83 or 7days
via oral
Reduced ANX-related behavior
(39) DEP Wistar rats (20) 4:1 lipid:non-lipid ratio 7days Some evidence for potential antidepressant properties
(40) DEP CD-1 mice (20) 4:1 lipid:non-lipid ratio inutero
and SD in postnatal life
30days Those fed KD inutero showed reduced susceptibility to ANX
and depression and increased hyperactivity
(41) SZ C57Bl/6 mice
77.6% fat, 9.5% protein, and
4.7% crude ber, AD ber
3weeks Normalized pathological behaviors including psychomotor
hyperactivity, stereotyped behavior, social withdrawal, and
working memory decits
(42) ASD Swiss mice (16) (Lard 690g/kg, sunower oil
5g/kg, protein 250g/kg, ber
10g/kg, ash 5g/kg)
In utero
exposure to
KD (70days)
Statistically signicant social decits and stereotypies that are
common behaviors in those with ASD
(43) ASD Wistar rats (6) 6:1 lipid:non-lipid ratio 10–14days KD had a signicant effect and was able to modify complex
social behaviors in valproic acid and control rats
(44) ASD BTBR mice (?) 6.3:1 lipid:non-lipid ratio 14days Temporal cortex and hippocampus brain regions showed
improvements on autistic decits associated with myelin
formation and white matter development
(45) ASD EL mice (?) 3.0:1 or 6.6:1 lipid:non-lipid
3–4weeks Social novelty test—females fed higher KD ratio exhibited
signicant preference to the new mouse. Self-grooming
signicantly decreased in males
(36) ADHD Dogs (21) 10% moisture, 28% protein,
15% fat, 6% ash, 2% crude
ber, and MCT oil
6months Signicant improvement in ADHD-related behaviors
ANX, anxiety; DEP, depression; BD, bipolar disorder; SZ, schizophrenia; *, ketone levels reported; ?, unknown sample size; MCT, medium-chain triglyceride; ASD, autism spectrum
disorder; ADHD, attention decit hyperactivity disorder; KD, ketogenic diet.
Bostock et al. KD in Psychiatry
Frontiers in Psychiatry | March 2017 | Volume 8 | Article 43
Bostock et al. KD in Psychiatry
Frontiers in Psychiatry | March 2017 | Volume 8 | Article 43
was found that patients with bipolar disorder were more likely to
report risk factors for poor nutrition including diculty obtain-
ing or cooking food (60). Treatments for bipolar disorder typically
include an antipsychotic and a mood stabilizer, and many patients
are treated with adjunct anticonvulsants.
In a case study of two women with bipolar disorder type
II, the patients maintained ketosis for an extended period of 2
and 3years, respectively. e women reported subjective mood
stabilization, which exceeded that of medication as well as an
overall improvement in their condition that they related to ketosis
(measured in the urine). Both women tolerated the diet well with
few or no side eects reported (46). e ratio of KD was not
mentioned in the rst case, but in the second it was estimated to
be around 70% fat, 22% protein, and 8% carbohydrates.
In a separate case study, a woman with treatment-resistant
bipolar disorder was placed on KD (4:1 lipid:non-lipid ratio) and
showed no clinical improvement (47). It should be noted that no
urinary ketones were detected, the type of bipolar disorder was
not listed (type I or type II), and treatment duration limited to
ese studies illustrate that careful attention should be paid
to the intricacies of the diet (such as measuring ketones and
calculating macronutrient ratios) to fully examine its ecacy
in bipolar disorder, as well as the need for larger well-designed
placebo-controlled studies in this area. e mechanism by
which KD may be eective in bipolar disorder is based on the
hypothesis that acidosis achieved through ketosis reduces intra-
cellular sodium and calcium, both of which are elevated in the
disorder (47). Mood stabilizers reduce intracellular sodium in
an activity-dependent manner within the context of KD; this is
hypothesized as being achieved through the acidication of the
blood (46).
Schizophrenia is associated with high levels of morbidity. e
precise pathophysiology of the disorder is unknown, and current
pharmacological treatment options are limited (61). Animal
models of schizophrenia t into four induction methods includ-
ing developmental, drug-induced, lesional, or genetic manipula-
tion (62). In a recent drug-induced (MK-801, dizocilpine) animal
model of schizophrenia in C57BL/6 mice, it was demonstrated
that 3weeks of KD (77.6% fat, 9.5% protein, and 4.7% crude ber,
AD ber 4.7%) normalized pathological behaviors (41). ese
included psychomotor hyperactivity, stereotyped behavior, social
withdrawal, and working memory decits, which reect the posi-
tive, negative, and cognitive symptoms of the disorder. Weight
loss was an observed side eect. Elevated levels of the ketone
beta-hydroxybutyrate and decreased glucose levels indicated that
metabolic adaptation had occurred.
In a 1965 study, the eect of KD was tested in 10 female
patients with schizophrenia. All participants were reported to
have a poor prognosis and were not treatment responsive at the
time. Concurrent therapies remained throughout the duration
of the diet including pharmacotherapy and electroconvulsive
therapy. e Beckomberga Rating Scale was administered to
patients three times during the diet period (2days, 2weeks, and
1week aer discontinuation), there was a statistically signicant
decrease in symptomatology aer 2weeks of established KD
(48). is was, however, a small, poorly controlled study, and in
addition, the lipid:non-lipid ratios were not detailed, and it was
not stated whether ketone levels were measured throughout the
study. A further consideration is that the study was conducted
in 1965 before the advent of atypical antipsychotics and their
metabolic side eects.
In a case study of a 70-year-old overweight woman with a diag-
nosis of schizophrenia, KD was initiated by her treating physician
(49). e patient remained on KD for 12months and reportedly
had no recurrences of auditory or visual hallucinations, and
the patient lost weight. e patient reported eating mainly lean
proteins and low-carbohydrate vegetables (the lipid:non-lipid
ratio was not listed), ketosis was not conrmed and perhaps not
established due to the lack of dietary fats listed; therefore, this case
report is of indeterminate value.
Some studies suggest that abnormal glucose and energy
metabolism may underlie the pathophysiology of schizophrenia,
which may provide some potential pointers into the hypothesized
mode of action of KD in the disorder (63, 64). Others have noted
that abnormal glucose metabolism may occur secondary to antip-
sychotic medications alongside signicant treatment side eects
such as weight gain, hyperglycemia, and diabetes (65). e high
metabolic risk associated with schizophrenia is due to genetic and
environmental factors (66).
Autism Spectrum Disorder
Features of patients with ASD include compromised social inter-
action and communication (67). It is estimated that between 5
and 40% of patients with autism will develop epilepsy (68), and
while most patients will respond to pharmacotherapy, in one
study, 34% of 170 patients had medically refractory epilepsy (69).
e precise pathogenesis of ASD remains unknown, but genetic
and environmental factors have been known to contribute to its
onset. One such factor is exposure to valproic acid (VPA) inutero,
which is associated with a 12% incidence of ASD in children (70)
and is used as an animal model of induction of ASD (42).
Using the animal model of autism induced by prenatal expo-
sure to VPA in mice, the eects of KD were examined. Pregnant
Swiss mice received a single intraperitoneal injection of 600mg/
kg of VPA (n=26) or saline (n=18) on gestational day 11. At day
21, 16 VPA treated and 16 control mice were used. Half of each
group was fed KD (lard 690g/kg, sunower oil 5g/kg, protein
250g/kg, ber 10g/kg, ash 5g/kg), while the other received a
standard diet. Ketone levels were not measured. Aer 70days
on KD, a statistically signicant result was found in mice with
VPA in behaviors such as social decits and stereotypies that are
common behaviors in those with ASD (42). It is also believed that
mitochondrial dysfunction may play a role in the onset of ASD
(35). Ahn etal. (43) aimed to determine if KD could reverse the
social decits and mitochondrial dysfunction seen in a prenatal
VPA animal model of autism using Wistar rats. On postnatal day
21, rats were placed on either KD (6:1 lipid:non-lipid ratio) or
standard diet for 10–14days. Beta-hydroxybutyrate was meas-
ured. KD had a signicant eect and was able to modify complex
social behaviors in VPA and control rats and mitochondrial
respiration (43).
Bostock et al. KD in Psychiatry
Frontiers in Psychiatry | March 2017 | Volume 8 | Article 43
Another animal model of autism using the inbred BTBR
mouse strain that exhibits three core features of autism, includ-
ing reduced sociability, communication, and increased repetitive
behavior, was studied (71). In another study, 33 genes were
dierentially expressed in the temporal cortex and 48 in the
hippocampus suggesting decits in the stress response and in
neuronal signaling and communication in BTBR mice. Aer
14days on KD (6.3:1 lipid:non-lipid ratio), both brain regions
showed improvements on autistic decits associated with myelin
formation and white matter development (44). One study has
found that in BTBR mice, KD reduces total gut microbial and
compositional remodeling of the mouse microbiome providing a
potential explanation as to its ecacy in this model (72).
In an animal model with behavioral characteristics of ASD
and comorbid epilepsy in male and female EL mice, the eect of
KD was assessed (45). Testing occurred at 8–9weeks postpartum
following 3–4weeks of dietary treatment. Animals were fed either
a standard diet or one of two KDs (3.0:1 or 6.6:1 lipid:non-lipid
ratio). KD raised ketones in all groups, but the higher fat ratio
deepened ketosis. Both KDs signicantly increased sociabil-
ity, time spent in the chamber with another mouse, in females
and males. Social novelty, preference for a newly introduced
mouse was higher in females fed the higher KD ratio. e test of
repetitive behavior (self-grooming) was signicantly decreased
in males but was non-signicant in females. is study provides
some intriguing results regarding the eects of sex and KD in a
mouse model of ASD and idiopathic epilepsy.
e role of KD in ASD has been examined in a pilot study
of 30 children (50). e diet (30% of energy as MCT oil, 30%
fresh cream, 11% as saturated fat, 19% carbohydrates, and 10% as
protein) was administered for 6months with intervals of 4weeks
with 2 diet-free weeks. Of the total sample, 40% did not comply
or did not tolerate the diet. Urinary ketones were measured. In the
remaining sample, two children showed signicant improvements
on the Childhood Autism Rating Scale, while the rest showed
mild-to-moderate improvements. As observed in patients with
epilepsy, aer the termination of KD the benets persisted, which
raise intriguing questions regarding the eects of plasticity.
In a case study of a child with autism and epilepsy, following
standard treatment non-response, the individual was placed
on KD (1.5:1 lipid:non-lipid ratio) with adjunct anticonvulsant
therapy (51). e patient was in ketosis. Aer initiation of the
diet several benets ensued including the resolution of morbid
obesity and the improvement of cognitive and behavioral features
of the disorder. Aer several years on the diet, the patient’s score
on the Childhood Autism Rating Scale decreased from 49 to 17,
a change from a rating of severe autism to non-autistic, and IQ
increased by 70 points. Fourteen months following the initiation
of the diet the patient was also seizure free.
e suggested mechanisms of action of KD in ASD include
that it may reduce pain sensitivity through the reduction
of glucose and may have anti-inammatory properties as it
reduces swelling and plasma extravasation (42). In a systematic
review of KD in ASD it was concluded that the limited number
of reports of improvements aer treatment with the diet is not
sucient to attest to the practicability of KD as a treatment for
the disorder (73).
Attention Decit Hyperactivity Disorder
Attention decit hyperactivity disorder is characterized by a
lack of behavioral inhibition and by neuropsychological decits
in four areas, including working memory, self-regulation of
aect–motivation–arousal, internalization of speech, and behav-
ioral analysis and synthesis (74). ADHD is the most commonly
occurring mental disorder in children and adolescents with
epilepsy occurring in 16 (29.1%) of 78 patients (75). Children
with ADHD have a high frequency of epileptiform discharges as
observed by EEG (76). In a prospective study of children with
epilepsy (n=34) on KD it was found that aer 1year on the diet
there was a statistically signicant improvement of attention and
social functioning (77).
ere is little evidence examining ADHD and KD, but a
6-month prospective, randomized, double-blinded, placebo-
controlled, crossover dietary trial compared the eects of
KD (10% moisture, 28% protein, 15% fat, 6% ash, 2% crude
ber, and MCT oil) or a standard diet on behavior in 21 dogs
with comorbid ADHD and idiopathic epilepsy (36). It was
hypothesized that there were three specic behaviors related to
ADHD in dogs including excitability, chasing, and trainability.
ADHD in dogs is manifested as inattention and excitability/
impulsivity, which have been likened to the disorder in humans
(78). When compared with the standard diet, KD resulted in
a signicant improvement in ADHD-related behaviors. Serum
beta-hydroxybutyrate was measured. e mechanisms of behav-
ioral improvements during KD remain unknown. e authors
postulated that alterations of energy metabolism in the brain
may contribute to behavioral changes. Research into humans
with ADHD and KD is lacking.
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 dysfunc-
tion has been identied as an important substrate (34). is is
congruent with ndings in neurological conditions, Stafstrom
and Rho concluding that energy metabolism changes induced
by KD in neurological conditions suggest a nal common
pathway implicating mitochondrial function (26). KD may also
inuence 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.
Bostock et al. KD in Psychiatry
Frontiers in Psychiatry | March 2017 | Volume 8 | Article 43
One other possible mediator of the benecial eects of KD in
mental disorders is the eect on sleep. In a study of 18 children
with treatment-resistant epilepsy, aer 3months of KD sleep was
reported to be enhanced with a pattern of signicant reduction in
total night sleep, preservation of slow-wave sleep, increased rapid
eye movement (REM) sleep, and decrease in sleep stage 2 (79).
e mechanisms by which KD aects sleep is unclear (80), and
more studies are necessary to conrm reports that certain dietary
patterns and foods improve sleep (81).
Sleep problems and mental disorders are codependent condi-
tions 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 signicantly 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
rst 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 awaken-
ings, lower sleep eciency, 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). e specic
eects 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 eect.
In epilepsy, KD acts dierently 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). e questions
posed by the literature indicate that the mechanism of action
is still unknown, and there may be many potential pathways
involved. e mechanism of action appears dierent from AED
and therefore probably psychiatric drugs also, which opens
potential avenues for treatment in a manner that may supplement
conventional pharmacological treatment approaches. e exact
mechanism of action of KD is unclear, and for detailed discussion,
see Rogawski etal. (91). us, present knowledge indicates that
KD exerts its eects on seizure control by mechanisms dierent
from conventional AED and therefore, in psychiatry, this may
also be the case although as yet unproven.
ere are a number of reasons why the eectiveness of KD
in mental disorders remains unproven. In addition to the low
number of human studies, the quality of the studies has some
signicant limitations. Sample sizes are small, there is no control
for placebo eects, and the establishment of ketosis is generally
lacking with no conrmatory measurement of ketones in three
human studies. ere are also signicant limitations associated
with the diet itself including the detailed regimen, unpalatable
food choices, side eects, and duration of diet required. ere 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 unexam-
ined in human studies. Ten adult patients with epilepsy followed
KD monotherapy, and it was concluded that it may be feasible,
well tolerated, and an eective long-term alternative (94).
To comply with KD, patients who may be acutely unwell are
required to measure food portions to ensure that the macronutri-
ent targets associated with the diet are met, and they may nd
it dicult to adhere to such a demanding diet (47). is is par-
ticularly 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 antip-
sychotic 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 conse-
quences 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 aer initiation (98). is included presacral and
periorbital edema, developmental impairment, and unwanted
weight loss in an infant, renal tubular acidosis, viral gastroen-
teritis, 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 denition, KD is conrmed by the production of ketones
measured in the blood or urine. In the reviewed literature cover-
ing 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 dierent (see Tables 1
and 2). In a study that compared the ecacy 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 evi-
dence 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
Bostock et al. KD in Psychiatry
Frontiers in Psychiatry | March 2017 | Volume 8 | Article 43
mechanisms associated with the complex behaviors that mimic
mental disorders in animals (101).
Another diculty posed to practitioners is that there are cur-
rently no international protocols guiding the administration of
the diet; this is something that may be established from future
research into KD. ere 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 uorodeoxy-
glucose. To observe the neural correlates of KD, a combination
of electrophysiological measures including EEG and magne-
toencephalogram 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 pharma-
cotherapy options might play alongside or as a substitute for KD.
While these animal studies are placing research into KD on a
rm footing and identifying some promising leads, on balance
the evidence in humans is insucient to form an opinion as to the
ecacy or lack thereof of this intervention in the mental disorders
reported. Further basic research to clarify the specics of dietary
manipulation or supplementation required to produce optimum
ketosis in specic models is an obvious intermediate step toward
studying the eectiveness of the diet in human mental disorders
using conventional phases of research including open-label stud-
ies and randomized controlled trials.
EB derived the concept of the article from which she received
supervision and expert advice in the area of psychiatry from KK
and neurology from BT.
EB’s research is supported by an Australian Postgraduate Award
and the Goddard Sapin-Jaloustre Trust.
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Conict of Interest Statement: e authors declare that the research was con-
ducted in the absence of any commercial or nancial relationships that could be
construed as a potential conict of interest.
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... The ketogenic diet, commonly known as the "keto diet," is one of the many low-carbohydrate regimes, consisting specifically of a high fat intake of up to 55-60% of total daily calories [1]. It is usually composed of a 4:1 ratio of lipid/ non-lipid [2]. This form of diet was first proposed by American physician Russell Wilder as a therapeutic agent to treat epilepsy in children [1]. ...
... There are converging lines of evidence showing that a ketogenic diet shows beneficial effects in the treatment of mood disorders in humans similar to that observed with traditional medications [2,[103][104][105]. A study conducted by Campbell and Campbell [106] with bipolar disorder patients showed that the majority of patients (~85%) following a ketogenic diet reported a positive effect on mood stabilization. ...
... Altogether, these findings indicate that a state of ketosis is necessary for the positive effect and impact of the ketogenic diet on bipolar disorder. Taking this concept another step forward, ketosis is postulated to decrease the level of sodium and calcium intracellularly therefore acting as a mood stabilizer [2,103,107,108]. ...
The ketogenic diet, known as a low-carbohydrate, high-protein, and high-fat diet, drastically restrains the major source of energy for the body, forcing it to burn all excess fat through a process called ketosis—the breaking down of fat into ketone bodies. First suggested as a medical treatment for children suffering from epilepsy, this diet has gained increased popularity as a rapid weight loss strategy. Over the past few years, there have been numerous studies suggesting that the ketogenic diet may provide therapeutic effects for several psychiatric conditions such as mood- and anxiety-related disorders. However, despite significant progress in research, the mechanisms underlying its therapeutic effects remain largely unexplored and are yet to be fully elucidated. This chapter provides an in-depth overview of preclinical and clinical evidence supporting the use of a ketogenic diet in the management of mood and anxiety disorders and discusses its relationship with inflammatory processes and potential mechanisms of actions for its therapeutic effects.KeywordsAnxietyBipolar disorderInflammationKetogenic dietMajor depressive disorderMood disorders Schizophrenia
... One review found that out of 300 participants across an open forum, 101 participants reported the aforementioned symptoms of "keto-flu, " particularly in the first 4 weeks following the onset of the KD. Almost half of those reported flu-like symptoms; 24.8% reported headaches, and 17.8% suffered from fatigue (Bostock et al., 2017). Given the self-reported nature of their study, a major limitation is the lack of reporting of ketone levels and likelihood that many people were not following well-formulated KDs. ...
... While this is a research area of growing interest, limited clinical studies so far have been conducted with this patient population. Emerging areas with clinical interest and mechanistic plausibility for KD as a therapeutic intervention include anxiety, depression, bipolar disorder, schizophrenia, autism spectrum disorder and attention hyperactivity disorder [reviewed in Bostock et al. (2017) and Kovács et al. (2019)]. ...
... We hypothesized that augmentation of ketosis by twice daily ingestion of a KS would facilitate the transition during the ketoadaptation weight loss phase, similarly to what was reported using an MCT-supplemented KD (D C. Harvey et al., 2018). Commonly reported "keto-flu" symptoms include headaches, fatigue, brain fog, decreased energy among others, peaking in the first few days and lasting up to 4 weeks (Bostock et al., 2017). A key physiological event associated with keto flu symptoms is the initial mineral imbalance that occurs during the keto adaptation phase, which is driven by the natriuretic and diuretic effects of very low-carbohydrate ketogenic diets. ...
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Background Ketogenic diets are a commonly used weight loss method, but little is known how variations in sodium content and ketones influence cognition and mood during the early keto-adaptation period.Objectives To investigate the effects of an exogenous ketone salt (KS) as part of a hypocaloric KD on mood and cognitive outcomes in overweight and obese adults. A secondary objective was to evaluate changes in biochemical markers associated with inflammatory and cognitive responses.Materials and methodsAdults who were overweight or obese participated in a 6-week controlled-feeding intervention comparing hypocaloric diets (∼75% of energy expenditure). KD groups received twice daily ketone salt (KD + KS; n = 12) or a flavor-matched placebo, free of minerals (KD + PL; n = 13). A separate group of age and BMI matched adults were later assigned to an isoenergetic low-fat diet (LFD; n = 12) as comparison to KD. Mood was assessed by shortened Profile of Mood States and Visual Analog Mood Scale surveys. Cognitive function was determined by the Automated Neuropsychological Assessment Metrics mental test battery.ResultsBoth KD groups achieved nutritional ketosis. Fasting serum glucose decreased in both KD groups, whereas glucose was unaffected in the LFD. Insulin decreased at week 2 and remained lower in all groups. At week 2, depression scores in the KD + PL group were higher compared to KD + KS. Performance in the math processing and go/no-go cognitive tests were lower for KD + PL and LFD participants, respectively, compared to KD + KS. Serum leptin levels decreased for all groups throughout the study but were higher for KD + KS group at week 6. Serum TNF-α steadily increased for LFD participants, reaching significance at week 6.Conclusion During a short-term hypocaloric diet, no indication of a consistent decline in mood or cognitive function were seen in participants following either KD, despite KD + PL being relatively low in sodium. WK2 scores of “anger” and “depression” were higher in the LFD and KD + PL groups, suggesting that KS may attenuate negative mood parameters during the early intervention stages.
... Examples of nutritional modifications considered to be potentially useful in supporting the treatment of affective disorders are the ketogenic [65,66], Mediterranean [67] and fasting Ramadan [68] diets. All of them require further clinical trials due to conflicting results [69][70][71]. IF in the treatment of affective disorders is measured as safe, as long as it is not practiced excessively often or for too many days in a row. However, the acceptable duration of following the diet has not been determined. ...
... Based on the performed review, it can be concluded that the followed nutritional interventions seem to be a potentially beneficial and safe additional therapy in supporting the treatment of mood disorders [2,8]. Inconsistent results and a small number of conducted clinical trials confirm that more studies are needed to fully recognize the validity of the implementation of fasting into clinical practice as a therapeutic form [69][70][71]. The small amount of work on the side effects of fasting suggests that more research is needed to reach the point where the benefits of fasting will optimally outweigh any potential harm to health. It should be emphasised that among the patients with mental illnesses, somatic diseases often coexist [86]. ...
... Przykładami modyfikacji żywienia uważanymi za potencjalnie korzystne we wspomaganiu leczenia chorób afektywnych są dieta ketogenna [65,66], śródziemnomorska [67] czy post Ramadan [68]. Z powodu heterogennych rezultatów interwencji, wszystkie z nich wymagają dalszych badań [69][70][71]. IF jako element wspomagający w terapii chorób afektywnych jest bezpieczny, o ile nie jest praktykowany nadmiernie często lub przez zbyt wiele dni z rzędu. Niemniej nie ustalono dopuszczalnego czasu, w którym stosowanie diety można uznać za bezpieczne. ...
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Introduction: Fasting is defined as a period of voluntary abstinence from eating food for religious, therapeutic or political reasons, which is associated with a reduction in the supply of sources (kilocalories) to the body. There are different types of fasting, including short, long or intermittent fasting. It has been shown that the use of different types of fasting can influence the occurrence of mood disorders. The aim of this review was to search for the relationship between the use of fasting and mood disorders and its potential use as a therapeutic method. Material and method: The available literature was reviewed by searching the PubMed and Google Scholar databases using the following keywords: fasting, intermittent fasting, mood disorders, depression, Ramadan, for studies listed from database inception to November 2021. Results: A review of the collected scientific articles indicates that the dietary restrictions, including both daily restriction of caloric consumption and the use of intermittent fasting (IF), has potentially numerous health benefits in the co-treatment of mental diseases. However, due to conflicting results, further clinical trials in mentally ill people should be conducted. It is worth remembering that among patients with mental illnesses there are somatically ill. IF in these people may require additional nutritional modifications or discontinuation of therapy. Conclusions: Dietary restriction and fasting are promising methods in co-therapy of mood disorders treatment. However, implementing therapy needs earlier individual evaluation of their benefits and risk, the same as patient’s feasibility of implementing this type of intervention.
... KD is a term for a low-carbohydrate and adequate protein diet [181]. Recent studies have demonstrated a role for KD in the compositional remodeling of GM, thereby promoting its protective effects in various CNS disorders, including AD [182,183]. When sugar is in short supply, ketone bodies, which are used as alternative energy substrates for glucose in many organs, including the brain, are produced to break down and oxidize fat [184]. ...
... To do so, more research is needed. It can easily lead to school dropouts and a lack of plant foods rich in vitamins and other antioxidant compounds [182]. ...
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Gut microbiota (GM), the microorganisms in the gastrointestinal tract, contribute to the regulation of brain homeostasis through bidirectional communication between the gut and the brain. GM disturbance has been discovered to be related to various neurological disorders, including Alzheimer’s disease (AD). Recently, the microbiota-gut-brain axis (MGBA) has emerged as an enticing subject not only to understand AD pathology but also to provide novel therapeutic strategies for AD. In this review, the general concept of the MGBA and its impacts on the development and progression of AD are described. Then, diverse experimental approaches for studying the roles of GM in AD pathogenesis are presented. Finally, the MGBA-based therapeutic strategies for AD are discussed. This review provides concise guidance for those who wish to obtain a conceptual and methodological understanding of the GM and AD relationship with an emphasis on its practical application.
... Therefore, the brain with SZ may be metabolically prepared to respond to a KD. Further studies of KD in animal models have yielded favorable results [32,81,82], however, clinical evidence in human subjects is limited to case reports and small pilot studies [83][84][85]. A case report by Palmer [85] reported on two instances of SZ patients who experienced a drastic improvement in symptoms after adopting a KD. ...
... To reverse this neurodegenerative process, increasing neurons' access to ketone bodies may be critical. Numerous clinical reviews have called for further research to confirm anecdotal and case findings [5,6,81,82], as early evidence of positive effects of the KD on schizophrenic and bipolar symptoms warrant further investigation and require confirmation through controlled clinical trials. ...
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In search of interventions targeting brain dysfunction and underlying cognitive impairment in schizophrenia, we look at the brain and beyond to the potential role of dysfunctional systemic metabolism on neural network instability and insulin resistance in serious mental illness. We note that disrupted insulin and cerebral glucose metabolism are seen even in medication-naïve first-episode schizophrenia, suggesting that people with schizophrenia are at risk for Type 2 diabetes and cardiovascular disease, resulting in a shortened life span. Although glucose is the brain's default fuel, ketones are a more efficient fuel for the brain. We highlight evidence that a ketogenic diet can improve both the metabolic and neural stability profiles. Specifically, a ketogenic diet improves mitochondrial metabolism, neurotransmitter function, oxidative stress/inflammation, while also increasing neural network stability and cognitive function. To reverse the neurodegenerative process, increasing the brain's access to ketone bodies may be needed. We describe evidence that metabolic, neuroprotective, and neurochemical benefits of a ketogenic diet potentially provide symptomatic relief to people with schizophrenia while also improving their cardiovascular or metabolic health. We review evidence for KD side effects and note that although high in fat it improves various cardiovascular and metabolic risk markers in overweight/obese individuals. We conclude by calling for controlled clinical trials to confirm or refute the findings from anecdotal and case reports to address the potential beneficial effects of the ketogenic diet in people with serious mental illness.
... Ketogenic diet (KD) is a high-fat, low carbohydrate, low protein diet which has been safely used for the treatment of patients with refractory epilepsy for almost a century (Peterman, 1924), and has been investigated in animal and human models of psychiatric disorders only until recently (Bostock, 2017, El-Mallakh, 2001, where beneficial effects at molecular and cellular levels include improvement of neuronal plasticity, stabilization of brain microglia (Huang, 2018), reduction of neurotransmitters and improvement of brain hypometabolism, stimulation of neurogenesis (Yadav, 2013), and inhibition of neuro-inflammatory processes (Yamanashi, 2017). Studies in rats suggest that KD has antidepressant effects (Murphy, 2004) and reduces susceptibility to depression (Sussman, 2015), moreover, humans examples exist showing effectiveness of this intervention, with a case study of a patient with type 2 diabetes mellitus (Cox, 2019) that reduced her depressive symptoms by consuming the diet for 12 weeks and two human trials further demonstrating that those who consumed KD had fewer depressive symptoms as compared to a low-fat diet (McClernon, 2007& Yancy, 2009. ...
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Introduction: Major depressive disorder (MDD) is a disease with a high economic burden across the world, mainly secondary to a decrease in work performance and pill burden. Ketogenic diet is a type of non-pharmacological intervention that is employed in the treatment of refractory epilepsy and has shown promise for the treatment of other psychiatric disorders, including depression. Up to the date, there is a limited number of investigations regarding this topic, making the knowledge very scarce; therefore, our study will assess the clinical efficacy of ketogenic diet, particularly Modified Atkins Diet, as compared to control diet in adults with diagnostic of MDD on standard treatment without resolution of symptoms as a difference in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline at the third month follow-up visit. Methods: This is a phase II, multicenter, randomized, controlled, open-label, parallel-group, superiority trial with blinded endpoints. Sample size was calculated as 132 participants (66 participants per arm) to maintain a power of 80% and a two-sided significance level of 0.05. The primary endpoint is the improvement in MDD symptomatology measured by MADRS scale at 3 months from baseline. Discussion: There is evidence to support the notion that ketogenic diet improves patients' symptoms by increasing levels of several molecules resulting in a decrease of neuroinflammation and an increase of neurogenesis, improving mood disorders. We hypothesize that a ketogenic diet will improve depressive symptoms in patients with moderate to severe depression when compared to patients on a control diet.
... Despite the favourable effects of KD in improving cognitive and social skills in epilepsy and autism spectrum disorder patients, further studies are needed to mention about its effect on cognitive functions.46 Its effects in isolated mental disorder or behavioural disorder have not been elucidated yet.47 In the present study, seizure in two patients significantly decreased with KD therapy. ...
Objective Prader-Willi Syndrome (PWS) is the most common genetic cause of obesity. Prevention and management of obesity, which represents the main cause of morbidity and mortality in these patients, is essential. Ketogenic diet (KD) is used in the treatment of various disorders, however knowledge on its effect in PWS is lacking. The present study assesses the characteristics of patients with PWS who were on ketogenic diet. Patients This is a retrospective, cross-sectional descriptive study investigating the subjects with PWS, who had received KD for at least 6 months. Results Ten patients with PWS [median age 52.5 (47-77) months] complied with KD. The median treatment period was 16.5 [11-52] months. Of the daily calorie, 75-85% were from fat, and 15-25% from protein+carbohydrate. The baseline body weight SD score prior to diet therapy was 2.10 [-1.11-4.11], whereas it was 0.05 [-0.92-1.2] at final evaluation (p=0.007). The baseline median BMI SD score prior to diet therapy was 3.05 [-0.21-3.72], whereas it was 0.41 [-0.87-1.57] at final evaluation (p=0.002). The height SD score remained unchanged. Mild hypercholesterolemia was the most common biochemical abnormality during treatment with KD. Conclusion Our results indicate that KD might have a favorable effect on weight management in PWS. This article is protected by copyright. All rights reserved.
... It has been reported that the hydraulic efficiency of the heart is 28% greater via the metabolism of ketone bodies compared with a heart that metabolizes glucose alone [74], explaining the adaptative route for energy supply. Unfortunately, after TRT, IR patients showed clinical symptoms related to ketonuria, similar to those shown by individuals following a ketogenic diet, the so-called "keto flu" [75], with psychiatric problems [76]. This must be taken into account before the administration of TRT to IR hypogonadal patients. ...
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Male hypogonadism is a disorder characterized by low levels of the hormone testosterone and patients may also have insulin sensitivity (IS) or insulin resistance (IR), such that they show different clinical complications and different metabolic pathways. In this review, we compare metabonomic differences observed between these two groups before and after testosterone therapy (TRT) in order to obtain information on whether the two hormones testosterone and insulin are synergistic or antagonistic. IS hypogonadism uses glucose as the main biofuel, while IR activates gluconeogenesis by the degradation of branched-chain amino acids. The Krebs (TCA) cycle is active in IS but connected with glutaminolysis, while in IR the TCA cycle stops at citrate, which is used for lipogenesis. In both cases, the utilization of fatty acids for energy (β-oxidation) is hampered by lower amounts of acetylcarnitine, although it is favored by the absence of insulin in IR. Increased free fatty acids (FFAs) are free in the blood in IS, while they are partially incorporated in triglycerides in IR. Thus, upon TRT, the utilization of glucose is increased more in IS than in IR, revealing that in IR there is a switch from preferential glucose oxidation to lipid oxidation. However, in both cases, a high production of lactate and acetyl-CoA is the final result, with these levels being much higher in IR. Lactate is used in IS in the glucose–lactate cycle between the liver and muscle to produce energy, while in IR lactate and acetyl-CoA are biotransformed into ketone bodies, resulting in ketonuria. In conclusion, the restoration of testosterone values in hypogonadism gives better results in IS than in IR patients: in IS, TRT restores most of the metabolic pathways, while in IR TRT impairs insulin, and when insulin is inactive TRT activates an ancestral molecular mechanism to produce energy. This evidence supports the hypothesis that, over time, hypogonadism switches from IS to IR, and in the latter case most of the insulin-related metabolisms are not reactivated, at least within 60 days of TRT. However, testosterone therapy in both IS and IR might be of benefit given supplementation with metabolites that are not completely restored upon TRT, in order to help restore physiological metabolisms. This review underlines the importance of using a systems biology approach to shed light on the molecular mechanisms of related biochemical pathways involving insulin and testosterone.
... Of particular interest, the new symptoms are similar to those recorded in patients fed a ketogenic diet, known as the so-called 'keto flu' [50]. Patients most notably present with psychiatric problems [51]. Thus, when implementing testosterone therapy, one must take into account whether the patient is or is not insulin-resistant. ...
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Hypogonadic subjects with insulin resistance (IR) showed different metabonomic profiles compared to normo-insulinemic subjects (IS). Testosterone replacement therapy (TRT) may have a different impact on the metabolisms of those with the presence or absence of insulin resistance. We evaluated the changes in the metabolism of IR hypogonadic patients before and after 60 days of TRT. The metabonomic plasma profiles from 20 IR hypogonadal patients were recorded using ultra-high-performance liquid chromatography (UHPLC) and high-resolution mass spectrometry (HRMS). Plasma metabolites, before and after 60 days of TRT, were compared. In hypogonadic patients, carnosine, which is important for improving performance during exercise, increased. Conversely, proline and lysine-amino acids involved in the synthesis of collagen-reduced. Triglycerides decreased and fatty acids (FFAs) increased in the blood as a consequence of reduced FFA β-oxidation. Glycolysis slightly improved, while the Krebs cycle was not activated. Gluconeogenesis (which is the main energy source for hypogonadal IR before TRT) stopped after treatment. As a consequence, lactate and acetyl CoA increased significantly. Both lactate and acetyl CoA were metabolized into ketone bodies which increased greatly, also due to leucine/isoleucine degradation. Ketone bodies were derived predominantly from acetyl CoA because the reaction of acetyl CoA into ketone bodies is catalyzed by mtHMGCoA synthase. This enzyme is inhibited by insulin, which is absent in IR patients but overexpressed following testosterone administration. Ketosis is an alternative route for energy supply and provides the same metabolic effects as insulin but at the metabolic or primitive control level, which bypasses the complex signaling pathway of insulin. After treatment, the hypogonadic patients showed clinical symptoms related to ketonuria. They presented similarly to those following a ketogenic diet, the so-called 'keto flu'. This must be taken into account before the administration of TRT to hypogonadic patients.
... The biological plausibility that KDs may be of therapeutic benefit in major depression, bipolar illness, and schizophrenia is strongly supported by the scientific literature (18,(41)(42)(43)(44). ...
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Background and hypothesis: The robust evidence base supporting the therapeutic benefit of ketogenic diets in epilepsy and other neurological conditions suggests this same metabolic approach may also benefit psychiatric conditions. Study design: In this retrospective analysis of clinical care, 31 adults with severe, persistent mental illness (major depressive disorder, bipolar disorder, and schizoaffective disorder) whose symptoms were poorly controlled despite intensive psychiatric management were admitted to a psychiatric hospital and placed on a ketogenic diet restricted to a maximum of 20 grams of carbohydrate per day as an adjunct to conventional inpatient care. The duration of the intervention ranged from 6 to 248 days. Study results: Three patients were unable to adhere to the diet for >14 days and were excluded from the final analysis. Among included participants, means and standard deviations (SDs) improved for the Hamilton Depression Rating Scale scores from 25.4 (6.3) to 7.7 (4.2), P < 0.001 and the Montgomery-Åsberg Depression Rating Scale from 29.6 (7.8) to 10.1 (6.5), P < 0.001. Among the 10 patients with schizoaffective illness, mean (SD) of the Positive and Negative Syndrome Scale (PANSS) scores improved from 91.4 (15.3) to 49.3 (6.9), P < 0.001. Significant improvements were also observed in metabolic health measures including weight, blood pressure, blood glucose, and triglycerides. Conclusions: The administration of a ketogenic diet in this semi-controlled setting to patients with treatment-refractory mental illness was feasible, well-tolerated, and associated with significant and substantial improvements in depression and psychosis symptoms and multiple markers of metabolic health.
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Nutritional ketosis has been proven effective for seizure disorders and other neurological disorders. The focus of this study was to determine the effects of ketone supplementation on anxiety-related behavior in Sprague-Dawley (SPD) and Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. We tested exogenous ketone supplements added to food and fed chronically for 83 days in SPD rats and administered sub-chronically for 7 days in both rat models by daily intragastric gavage bolus followed by assessment of anxiety measures on elevated plus maze (EPM). The groups included standard diet (SD) or SD + ketone supplementation. Low-dose ketone ester (LKE; 1,3-butanediol-acetoacetate diester, ~10 g/kg/day, LKE), high dose ketone ester (HKE; ~25 g/kg/day, HKE), beta-hydroxybutyrate-mineral salt (βHB-S; ~25 g/kg/day, KS) and βHB-S + medium chain triglyceride (MCT; ~25 g/kg/day, KSMCT) were used as ketone supplementation for chronic administration. To extend our results, exogenous ketone supplements were also tested sub-chronically on SPD rats (KE, KS and KSMCT; 5 g/kg/day) and on WAG/Rij rats (KE, KS and KSMCT; 2.5 g/kg/day). At the end of treatments behavioral data collection was conducted manually by a blinded observer and with a video-tracking system, after which blood βHB and glucose levels were measured. Ketone supplementation reduced anxiety on EPM as measured by less entries to closed arms (sub-chronic KE and KS: SPD rats and KSMCT: WAG/Rij rats), more time spent in open arms (sub-chronic KE: SPD and KSMCT: WAG/Rij rats; chronic KSMCT: SPD rats), more distance traveled in open arms (chronic KS and KSMCT: SPD rats) and by delayed latency to entrance to closed arms (chronic KSMCT: SPD rats), when compared to control. Our data indicates that chronic and sub-chronic ketone supplementation not only elevated blood βHB levels in both animal models, but reduced anxiety-related behavior. We conclude that ketone supplementation may represent a promising anxiolytic strategy through a novel means of inducing nutritional ketosis.
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The core symptoms of autism spectrum disorder are poorly treated with current medications. Symptoms of autism spectrum disorder are frequently comorbid with a diagnosis of epilepsy and vice versa. Medically-supervised ketogenic diets are remarkably effective nonpharmacological treatments for epilepsy, even in drug-refractory cases. There is accumulating evidence for beneficial effects of ketogenic diets against core symptoms of autism spectrum disorders in animal models and limited reports of benefits in patients. This study tests the behavioral effects of ketogenic diet feeding in the EL mouse, a model with behavioral characteristics of autism spectrum disorder and comorbid epilepsy. Male and female EL mice were fed control diet or one of two ketogenic diet formulas ad libitum starting at 5weeks of age. Beginning at 8weeks of age, diet protocols continued and performance of each group on tests of sociability and repetitive behavior was assessed. A ketogenic diet improved behavioral characteristics of autism spectrum disorder, and results depended on sex and type of test; ketogenic diet never worsened relevant behaviors. Ketogenic diet feeding improved multiple measures of sociability and reduced repetitive behavior in female mice; effects in males were more limited. Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior. Taken together these results add to the growing number of studies suggesting that ketogenic and related diets may provide significant relief from the core symptoms of autism spectrum disorder, and suggest that in some cases there may be increased efficacy in females.
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Ten adults were treated with ketogenic diet monotherapy for epilepsy. Four patients were naïve to antiseizure drugs(ASD) and six previously tried and stopped ASDs. Of four treatment-naïve participants, two(50%) were free from disabling seizures on Modified Atkins Diet(MAD) monotherapy for > one year. Two(50%) stopped. Four of six patients(67%) who had previously tried ASDs became seizure-free on diet monotherapy and two experienced > 50% seizure reduction. Side effects included amenorrhea, weight loss, osteoporosis, and hyperlipidemia. Diet monotherapy may be feasible, well-tolerated, and effective for adults with epilepsy who refuse pharmacotherapy and those for whom lifelong diet therapy is recommended.
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There is much emerging information surrounding the impact of sleep duration and quality on food choice and consumption in both children and adults. However, less attention has been paid to the effects of dietary patterns and specific foods on nighttime sleep. Early studies have shown that certain dietary patterns may affect not only daytime alertness but also nighttime sleep. In this review, we surveyed the literature to describe the role of food consumption on sleep. Research has focused on the effects of mixed meal patterns, such as high-carbohydrate plus low fat or low-carbohydrate diets, over the short term on sleep. Such studies highlight a potential effect of macronutrient intakes on sleep variables, particularly alterations in slow wave sleep and rapid eye movement sleep with changes in carbohydrate and fat intakes. Other studies instead examined the intake of specific foods, consumed at a fixed time relative to sleep, on sleep architecture and quality. Those foods, specifically milk, fatty fish, tart cherry juice, and kiwifruit, are reviewed here. Studies provide some evidence for a role of certain dietary patterns and foods in the promotion of high-quality sleep, but more studies are necessary to confirm those preliminary findings.
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Background Gastrointestinal dysfunction and gut microbial composition disturbances have been widely reported in autism spectrum disorder (ASD). This study examines whether gut microbiome disturbances are present in the BTBRT + tf/j (BTBR) mouse model of ASD and if the ketogenic diet, a diet previously shown to elicit therapeutic benefit in this mouse model, is capable of altering the profile. FindingsJuvenile male C57BL/6 (B6) and BTBR mice were fed a standard chow (CH, 13 % kcal fat) or ketogenic diet (KD, 75 % kcal fat) for 10–14 days. Following diets, fecal and cecal samples were collected for analysis. Main findings are as follows: (1) gut microbiota compositions of cecal and fecal samples were altered in BTBR compared to control mice, indicating that this model may be of utility in understanding gut-brain interactions in ASD; (2) KD consumption caused an anti-microbial-like effect by significantly decreasing total host bacterial abundance in cecal and fecal matter; (3) specific to BTBR animals, the KD counteracted the common ASD phenotype of a low Firmicutes to Bacteroidetes ratio in both sample types; and (4) the KD reversed elevated Akkermansia muciniphila content in the cecal and fecal matter of BTBR animals. Conclusions Results indicate that consumption of a KD likely triggers reductions in total gut microbial counts and compositional remodeling in the BTBR mouse. These findings may explain, in part, the ability of a KD to mitigate some of the neurological symptoms associated with ASD in an animal model.
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
Purpose of review: To review some aspects of the relationship between epilepsy and depression that have recently received increasing attention and may become major research topics in the near future. Recent findings: Epidemiological studies show that depression and suicide are, in some cases, premorbid symptoms preceding the onset of the epilepsy. Suicide is also three times more frequent in epilepsy than in the general population. Reliable screening instruments for depression and suicidality in patients with epilepsy are now available but data from real life clinical settings are needed to develop shared clinical pathways between neurology and psychiatry. Data in children with epilepsy are still limited although it is well known that, outside epilepsy, almost 50% of adult patients with mood and anxiety disorders have a previous history during childhood. Despite increasing attention to the problem, the additional stigma associated with mental health problems still represents one of the major barriers to prompt diagnosis and treatment. Summary: New studies will focus on the development of shared clinical pathways between neurology and psychiatry for mood disorders and suicide prevention. New global campaigns on the double stigma will support this process in areas where psychiatric comorbidities are still underdiagnosed and undertreated.
Background: Many centers still admit children for several days to start the ketogenic diet. The exact incidence of adverse effects during the admission and their potential later impact on seizure reduction has not been widely studied. Methods: We performed a retrospective study of children with intractable epilepsy electively admitted for ketogenic diet initiation at our institution from 2011 to 2016. Charts were reviewed for adverse effects during the admission period and then examined for seizure reduction and compliance at three months. A rating scale (1 to 4) was created for severity of any adverse events. Results: A total of 158 children were included, with the mean age 4.6 years. Potentially attributable adverse effects occurred in 126 (80%) children, most commonly emesis, food refusal, and hypoglycemia. Seventy-three (46%) children received some form of intervention by the medical team, most commonly the administration of juice (24%). Younger age was correlated with an increased likelihood of moderate to severe adverse effects during admission, often repeated hypoglycemia (3.6 versus 4.9 years, P = 0.04). Fasting was more likely to result in lethargy and a single blood glucose in the 30 to 40 mg/dL range, but it was not correlated with emesis, repeated hypoglycemia, or higher adverse effect scores. There was no statistically significant correlation between the severity of adverse effects and the three-month seizure reduction. Conclusions: Mild easily treated adverse effects occurred in most children admitted for the ketogenic diet. Younger children were at greater risk for significant difficulties and should be monitored closely. Because fasting led to more lethargy and hypoglycemia, it may be prudent to avoid this in younger children.
Background: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder characterized by hallmark behavioral features. The spectrum of disorders that fall within the ASD umbrella encompass a distinct but overlapping symptom complex that likely results from an array of molecular and genetic aberrations rather than a single genetic mutation. The ketogenic diet (KD) is a high-fat low-carbohydrate anti-seizure and neuroprotective diet that has demonstrated efficacy in the treatment of ASD-like behaviors in animal and human studies. Methods: We investigated changes in mRNA and gene expression in the BTBR mouse model of ASD that may contribute to the behavioral phenotype. In addition, we sought to examine changes in gene expression following KD treatment in BTBR mice. Results: Despite significant behavioral abnormalities, expression changes in BTBR mice did not differ substantially from controls; only 33 genes were differentially expressed in the temporal cortex, and 48 in the hippocampus. Examination of these differentially expressed genes suggested deficits in the stress response and in neuronal signaling/communication. After treatment with the KD, both brain regions demonstrated improvements in ASD deficits associated with myelin formation and white matter development. Conclusions: Although our study supports many of the previously known impairments associated with ASD, such as excessive myelin formation and impaired GABAergic transmission, the RNAseq data and pathway analysis utilized here identified new therapeutic targets for analysis, such as Vitamin D pathways and cAMP signaling. Autism Res 2017, 10: 456-471. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.