The Current Status of the Ketogenic Diet in Psychiatry

Abstract

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 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.

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 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.

Full text

March 2017 | Volume 8 | Article 431
REVIEW
published: 20 March 2017
doi: 10.3389/fpsyt.2017.00043
Frontiers in Psychiatry | www.frontiersin.org
Edited by:
Roumen Kirov,
Bulgarian Academy of Sciences,
Bulgaria
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
*Correspondence:
Emmanuelle C. S. Bostock
ebostock@utas.edu.au
Specialty section:
This article was submitted to
Psychopathology,
a section of the journal
Frontiers in Psychiatry
Received: 02February2017
Accepted: 02March2017
Published: 20March2017
Citation:
BostockECS, KirkbyKC and
TaylorBVM (2017) The Current
Status of the Ketogenic Diet in
Psychiatry.
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

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INTRODUCTION
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.

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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.
METHOD
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.
RESULTS
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
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
systems.
Depression
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
diet
Ketone* Result
(46) BD Human women
(2)
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
(1)
4:1 lipid:non-lipid ratio 1month No urinary
ketones
detected
No clinical improvement
(48) SZ Human women
(10)
Not listed 2weeks Not listed Statistically signicant decrease in symptomatology
(49) SZ Human woman
(1)
Not listed 12months Not listed No recurrence of auditory or visual hallucinations
(50) ASD Human children
(30)
30% MCT, 30% fresh cream, 11%
saturated fat, 19% carbohydrate,
and 10% protein
6months
(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
non-autistic)
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
diet
Duration of
diet
Ketone* Result
(38) ANX Sprague-
Dawley (48) and
Wistar Albino
Glaxo/Rijswijk
rats (32)
Exogenous ketone supplement 83 or 7days
via oral
gavage
✓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
4.7%
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
ratio
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.
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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
1month.
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
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).

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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.
DISCUSSION
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.

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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

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Frontiers in Psychiatry | www.frontiersin.org 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.
AUTHOR CONTRIBUTIONS
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.
FUNDING
EB’s research is supported by an Australian Postgraduate Award
and the Goddard Sapin-Jaloustre Trust.
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