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Research Article
Clinical Nutrition and Metabolism
Clin Nutr Metab, 2018 doi: 10.15761/CNM.1000105 Volume 1(1): 1-5
e eects of the ketogenic diet on psychiatric
symptomatology, weight and metabolic dysfunction in
schizophrenia patients
Javier Gilbert-Jaramillo1*, Dario Vargas-Pico2, Thonny Espinosa-Mendoza2, Svenja Falk2, Kimberly Llanos-Fernández2, Jonathan
Guerrero-Haro1, Carlos Orellana-Román2, Carlos Poveda-Loor1, José Valdevila-Figueira3 and Christopher Palmer4
1ESPOL Polytechnic University, Escuela Superior Politecnica del Litoral, Faculty of Life Sciences, Campus Gustavo Galindo Km 30.5 Via Perimetral, P.O. Box
09-01-5863, Guayaquil, Ecuador, UK
2Institute of Neurosciences of Guayaquil 090514, Ecuador, UK
3Addictive Behavior Unit, Institute of Neurosciences of Guayaquil, UK
4Department of Postgraduate and Continuing Education, McLean hospital Harvard Medical School, USA
Abstract
Objective: e authors aimed to test the eect of a therapeutic ketogenic diet (KD) on the psychotic condition, body composition and metabolic dysfunction in
schizophrenic patients, as well as to report the compliance with the diet.
Method: Two Ecuadorian schizophrenic patients’ male and female (twins) aged 22, were included in a six-week controlled-blinded pilot study under the therapeutic
KD. Compliance was determined by daily urine measurements (commercially available ketone strips). Body composition was analyzed using bio-impedance (Tanita
SC-331S) and the clinical outcomes were assessed by blood, urine and electrocardiogram analysis. e psychiatry condition was evaluated by the PANSS scale and, a
two weeks follow-up after intervention was conducted to evaluate patients’ health condition.
Results: During intervention, after ~15 days of ketosis, PANSS scores decreased in both female (97 to 91) and male (82 to 75) patients. Body fat decreased from
24.5% to 19.8% and 21.7% to 16.8%, respectively. Interestingly, after the third week of the intervention, male patient’ liver enzymes were downregulated to normal
levels (AST=0-40 U/L & ALT=0-41 U/L). No other signicant clinical outcomes were observed during the study. Of relevance, both patients broke the KD in several
occasions.
Conclusions: e present research showed that a short-time ketogenic diet (KD) has positive eects in the psychiatric condition, metabolic dysfunction and body
composition of young schizophrenia patients; suggesting the need of a clinical trial to corroborate its use as a co-treatment.
*Correspondence to: Javier Gilbert-Jaramillo, Department of Physiology,
Anatomy and Genetics; University of Oxford, Oxford OX1 3QX, E-mail:
javier.gilbertjaramillo@dpag.ox.ac.uk
Key words: ketogenic diet, schizophrenia, psychiatric conditions, clinical trial, co-
trearment
Received: July 10, 2018; Accepted: July 25, 2018; Published: August 02, 2018
Introduction
Schizophrenia is a psychiatric disorder with a lifetime prevalence
of ~1 percent and it is characterized by cognitive, positive and negative
aective symptoms [1,2]. Although the etiology of schizophrenia
remains unknown, recent evidence suggests both a hyper-responsive
dopaminergic system in the associative striatum [3] and, mitochondrial
dysfunction and energy metabolism alterations [4,5].
e most commonly prescribed psychopharmacological
intervention for patients with schizophrenia are atypical antipsychotics
(AAP). All AAP currently in use, eectively block dopaminergic D2
receptors, thereby reducing or eliminating the positive symptoms of
schizophrenia [6]. However, they pose serious adverse eects, such
as disturbances of glucose and/or fatty acid metabolism and weight
gain, thus, patients treated with AAPs frequently exhibit increased
co-morbidities of obesity, hyperglycemia, type 2 diabetes mellitus and
dyslipidemia [7-9].
e high fat, low carbohydrate ketogenic diet (KD) was developed
as an eective non-pharmacological treatment for epileptic seizures in
the 1920s [10-13], and more recently is being studied in weight loss
and a variety of neurological and psychiatric disorders [14,15]. e KD
utilizes a high fat (75% of daily intake, DI), extremely low carbohydrates
(lower than 5% of DI) and moderate protein intake (below 20% of
DI) [16,17], to promote the use of fat-derived ketone bodies (KB),
i.e. acetoacetate, –hydroxybutyric acid and acetone, as a non-glucose
source of energy in the brain [18].
Furthermore, a three-week KD conducted in schizophrenia
mice (C57BL/6) not only showed signicant weight loss, but also
demonstrated signicant improvements in the positive, negative
and cognitive symptoms (measured as ataxia, social interaction,
psychomotor hyperactivity, stereotyped behavior, social withdrawal,
and spatial working memory) of the mice [19]. Comparable results
have been described in a recent case report of two patients with
schizoaective disorders, who showed considerable weight loss and
decline in positive and negative symptoms throughout a year-long,
self-prescribed KD [20]. Even though these improvements reversed
when the KD was disrupted, they could be recovered when ketosis was
Gilbert-Jaramillo J (2018) e eects of the ketogenic diet on psychiatric symptomatology, weight and metabolic dysfunction in schizophrenia patients
Volume 1(1): 2-5
Clin Nutr Metab, 2018 doi: 10.15761/CNM.1000105
regained. Similarly, a 1965 pioneer KD trial, examining its eects in
10 treatment-resistant schizophrenic patients, found that symptoms
signicantly decreased aer two weeks following a KD [21]. Although
pioneering, the study neglected to measure ketone levels and drug-
induced adverse eects on metabolic dysfunction could not be
examined, as AAPs had yet to be developed.
us, this underlying pilot study aimed to examine the compliance
and the eects of a controlled six-weeks therapeutic 3:1 ratio KD in
Ecuadorian patients with schizophrenia; a country similar to others
in South American where the typical diet consists of rice, plantain,
potatoes, fruits, pasta, meat, chicken, sh, and vegetable salads; and
carbohydrates constitute about 60% of the DI [22].
Method
Participants
Two 22-year old opposite-sex twins with schizophrenia were
recruited at the outpatient hospital unit of the Institute of Neurosciences
of Guayaquil, Ecuador to participate in a six-week therapeutic 3:1 ratio
ketogenic diet pilot study, from early December 2017. e patients’
parents were still the primary caregivers, responsible for administering
and managing disease treatment and diet.
Study inclusion criteria were set to patients with schizophrenia,
aged between 18 and 30, who have been on their concurrent atypical
antipsychotic intervention for longer than four months. Exclusion
were: pregnancy, lactose intolerance, vegans or vegetarians, patients
with established type 2 diabetes, evidence of cardiovascular disease,
osteoporosis, or kidney/hepatic problems or renal insuciencies.
e female patient was diagnosed with schizophrenia at age 14. Her
medical history showed previous pharmacological intervention with
valproic acid, lorazepam, haloperidol decanoate, levomepromazine,
thioridazine, carbamazepine and uoxetine. Her daily pharmacological
therapy consisted of clozapine (300 mg), risperidone (6 mg),
clonazepam (3 mg) and biperiden (6 mg) for the ve months prior to
the commencement of the study.
e male patient was diagnosed with schizophrenia at age 18 and
his medical history revealed previous pharmacological treatments
with risperidone, biperiden, valproic acid, uoxetine, lorazepam,
clonazepam, lamotrigine and quetiapine. In the 23 months leading
up to the study, his daily pharmacological intervention consisted of
levomepromazine (150 mg), quetiapine (100 mg), valproic acid (1000
mg), biperiden (6 mg) and risperidone (4 mg).
Both patients were maintained on their current pharmacotherapeutic
regimens for the duration of the study
Protocol
Both patients received a 3:1 ratio ketogenic diet plan, which was set
to a daily standard of 2000 kcal and mainly consisted of avocado, olive
oil, butter, eggs, cheese, meat, spinach and broccoli. About 87% of the
daily caloric intake stemmed from fat sources, with the remainder made
up of protein plus carbohydrates [23]. erefore, total net-carbohydrate
intake was calculated to be less than 15 grams per day.
Clinical baseline measurements of body composition,
blood haematological clinical chemistry, urine composition,
electrocardiogram (ECG) and the Positive and Negative Symptom
Scale (PANSS) were examined the day prior to commencing on the
dietary intervention and assessed for ketone bodies (KB; in urine),
serum bilirubin, haematic biometry and minerals (sodium, magnesium
and potassium, which were previously suggested to be aected by KD
intervention) [24-26].
All body composition measurements, blood and urine samples
were obtained at a fasted state at 7.00am, while all ECGs were recorded
at 8 am. Body composition (body fat, muscle mass, bone mass, body
weight and height) was analyzed using a bio-impedance total body
composition analyzer (Tanita SC-331S) and recorded. Both body
composition and ECG examinations were conducted and interpreted by
the same trained professional. PANSS interviews were conducted by the
same trained professional for both patients. Environmental conditions,
i.e. luminosity and noise, were kept constant. e interviewer was
blind to the patients’ compliance to their dietary protocols to avoid any
evaluation bias.
Ketosis was determined through daily measurements of urine
ketone levels at 7 a.m., as per recommendation of Urbain & Bertz [27],
with commercially available ketone strips (Healthy Wiser), as previously
measured ketonuria levels of urine clinical physiochemical analysis
correlated with the commercially available urine strips, conrming its
correct use to determine the nutritional ketotic state [28]. All estimated
KB values were interpreted and recorded by the patients’ parents,
according to the manufacturer’s instructions. Additional clinical urine
analysis of KB was conducted in weekly increments commencing aer
15 days of the start of the study. Blood tests were carried out baseline, on
day 19 and in the last day of the study. Body composition was measured
every 15 days, and the calculated BMI was tracked throughout the
study. ECG was performed at baseline and study conclusion condition.
PANSS interviews took place at baseline and aer day 15 of the study
protocol, in weekly intervals. PANSS score was not recorded during
week four of the protocol due to patient travel. 15 days post-study, when
patients had resumed their regular Ecuadorian diet, blood samples,
body composition and PANSS were measured and analyzed to evaluate
any lasting eects of the KD.
Ethical considerations
e research was approved by the Institute of Neurosciences of
Guayaquil (INC), and National ethics approval was obtained from
the Human Research Ethics Committee of the Hospital Luis Vernaza
(Guayaquil, Ecuador). Both patients and their legal caregivers, i.e.
the parents, were thoroughly briefed on all research objectives, study
conditions, protocols, potential risks and inconveniences and informed
consent was obtained from patients and parents prior to the start of the
study and assent was reconrmed every 15 days before additional blood
and urine samples were obtained.
Results
Diet compliance and Tolerability
Both patients broke the ketogenic diet on several occasions. e
female patient did not fully comply with the prescribed diet for the
rst 21 days of the study and frequently consumed sweets and fruits.
Following non-compliance during the December holiday period, she
fully complied with the ketogenic diet and remained in moderate/high
ketosis for 15 consecutive days. e male patient fully complied with
the diet for the rst three weeks of the study; achieving moderate/high
ketosis within 3 days of commencing the diet. He remained in ketosis
for 18 consecutive days. However, following a beak with the diet during
the December holiday and new year’s evening celebrations, the male
patient was unable to remain in moderate/high ketosis for longer than
~4 consecutive days. Moreover, both patients reported that adherence to
the ketogenic dietary protocol for longer than 14 days was problematic
Gilbert-Jaramillo J (2018) e eects of the ketogenic diet on psychiatric symptomatology, weight and metabolic dysfunction in schizophrenia patients
Volume 1(1): 3-5
Clin Nutr Metab, 2018 doi: 10.15761/CNM.1000105
due to the onset of severe, high sugar food cravings for fruit, sweets and
rice. e patients showed no gastrointestinal reactions, e.g. diarrhea,
vomiting and constipation in reaction to the ketogenic diet.
Female patient
At baseline, the female patient had a calculated BMI of 21.3 kg/m2
and a measured body composition of 12.5 kg of body fat (24.5 %), 37.2
kg of muscle mass and 2 kg of bone mass. Electrocardiogram (ECG),
blood and urine analyses were clinically unremarkable and the PANSS
total score at baseline was 101 (positive = 28, negative = 16, and general
psychopathology = 57). Although, the patient failed to reach ketosis by
day 15 of the study, her calculated BMI slightly decreased to 20.7 kg/ m2
and total PANSS score reduced to 97 (positive = 28, negative = 16, and
general psychopathology = 53). Body composition remained unaltered
and outcome panels of blood and urine analyses remained clinically
unremarkable.
At conclusion of the study, the female patient had remained in
moderate/high ketosis for ~15 consecutive days and presented with a
markedly decreased calculated BMI of 19.8 kg/m2, 9.5 kg of body fat
(19.8%) and 36.6 kg of muscle mass. ere were no changes in bone
mass over the course of the study. e total PANSS score decreased to
91 (positive = 26, negative = 15, and general psychopathology = 50).
ECG results showed no alteration during this time.
Lastly, 15 days aer stopping the ketogenic diet, urine ketones were
no longer detectable. Positive and negative PANSS scores increased
to baseline initial scores, while her general psychopathology score
decreased further to 48. e calculated BMI (19.9 kg/m2) and body
composition measurements of body fat (9.9 kg) and muscle mass
(36.6 kg) slightly increased. Overall, blood clinical analyses remained
clinically unremarkable.
Male patient
At baseline, the male patient had a calculated BMI of 25.1 kg/m2 and
a measured body composition of 14.4 kg of body fat (21.7 %), 49.5 kg of
muscle mass and 2.6 kg of bone mass. Blood analysis revealed elevated
liver enzymes (AST=46 U/L & ALT=63 U/L). However, all other blood,
urine and ECG examinations remained clinically unremarkable. e
patient’s PANSS total score at baseline was 82 (positive = 19, negative
= 18, and general psychopathology = 45). At ~18 consecutive days of
moderate/high ketosis, his PANSS total score decreased to 75 (positive
= 16, negative = 17, and general psychopathology = 42) and liver
enzymes downregulated (AST=29 U/L & ALT=45 U/L), while all other
analyses of blood and urine remained clinically unremarkable.
Despite episodes of diet non-compliance at three dierent
occasions, i.e. the patient consumed rened sugars, his BMI markedly
decreased to 22.9 kg/m2, and his body fat (10.2 kg, (16.8%)) and muscle
mass (48 kg) also reduced. Although his PANSS total score increased
to 78 (positive = 17, negative = 17, and general psychopathology = 44),
it still remained below baseline testing. Interestingly, liver enzymes
normalized (AST=0-40 U/L & ALT=0-41 U/L).
Overall, there were no changes in bone mass or ECG readings over
the course of the study. 15 days aer stopping the ketogenic diet, urine
ketones were no longer detectable. Positive and negative PANSS scores
increased to baseline initial scores, while his general psychopathology
decreased further to a score of 40. e patient’s calculated BMI (23.4
kg/m2) and body composition measurements of body fat (10.9 kg)
and muscle mass (51.4 kg) slightly increased, but still remained below
baseline measurements. Overall, liver enzymes were detected at normal
levels (AST=0-40 U/L & ALT=0-41 U/L, while all other blood analyses
remained clinically unremarkable.
Conclusion
A high-fat low-carbohydrate therapeutic 3:1 ratio KD diet is a
dramatic variation from the typical Ecuadorian diet. However, its
therapeutic potential for psychiatric disorders, such as schizophrenia
merits the conduct of controlled pilot studies and clinical trials [14,15].
e underlying study evaluated the 3:1 ratio KD in a six-week pilot
study in two schizophrenia patients.
Overall, both patients showed compliance diculties with the KD
protocol and did not achieve moderate/high ketosis for prolonged times
during the study. ese warrant monitoring measures to be established
for any follow-up studies. Anticipatory planning of celebratory foods as
part of the diet may avoid a break in a future patient cohort. Similarly,
sweet cravings may be counteracted in future patient cohorts by
integrating low-sugar sweet treats, made with zero-caloric sweeteners,
e.g. stevia or erythritol, into the KD protocol.
Clinical outcomes
e gradual decrease in blood urea levels in both patients, which
was independent of a ketotic state, is inconsistent with previous
studies [29], and can potentially be explained by the patients’ reduced
dietary protein intake [30]. Blood creatinine are in line with previous
observations [31] and remained unaected throughout the study. As
liver enzymes of the female patients showed no indication of liver
abnormalities, and blood urea levels of both patients increased to
baseline measurements 15 days post-KD, the KD is not suspected to
impair liver function. Interestingly, the male patient showed elevated
liver enzymes at baseline, which could be indicative of non-alcoholic
fatty liver disease (NAFLD), or toxicity from valproic acid therapy [32-
34]. While on the KD, his liver enzymes normalized, and remained
within normal limits 15 days post-diet. Recent research suggests a KD
may improve liver enzymes and reduce triglyceride levels in hepatic
tissue [35], but other research is more ambiguous [36].
Moreover, the unaltered LDL cholesterol levels are in keeping
with results by Sharman et al. (31) of a six weeks KD in healthy, albeit
normal weight subjects. However, the underlying study failed to detect
the increased HDL cholesterol in schizophrenia patients. Despite
reports that minerals (sodium, potassium, magnesium and calcium)
can decrease with a KD in epileptic patients [10,37,38]; no alteration of
minerals in blood or bone density was exhibited during the six weeks.
However, this might be attributable to the short duration of the trial,
diet breaks and/or patient age. Lastly, the invariable ECG results across
the study are in accordance with ndings obtained by Sharma and
Gulati [39].
Body composition
Body weight, and primarily body fat, decreased over the duration
of the study, which is consistent with ndings in the eld of KD on
the whole [40-42]. Bio-impedance measurements showed a decrease in
the total muscle mass; however, this was partially reconstituted aer
two weeks of stopping the KD. e decrease in the total muscle mass
could be accounted to a depletion of the skeletal muscle glycogen
store to produce lactate [42-45], in the rst stage of the ketogenic
diet. ereaer, the citric acid function can be maintained via the
deamination of aspartate and asparagine (46), whereby preventing
skeletal tissue breakdown and ensuring the maintenance of muscle
mass. us, it appears that a KD regimen resulted in no loss of lean
muscle mass [47,48].
Gilbert-Jaramillo J (2018) e eects of the ketogenic diet on psychiatric symptomatology, weight and metabolic dysfunction in schizophrenia patients
Volume 1(1): 4-5
Clin Nutr Metab, 2018 doi: 10.15761/CNM.1000105
Psychiatric symptomatology
Our ndings in the psychiatric symptomatology in both patients
emulate the results in animal models of Krauter et al. (19), showing
improved symptomatology aer ~14 consecutive days of moderate/
high ketosis. is indicates that a short-term 3:1 ratio KD is sucient
to exert an, at least short-term, psychiatric amelioration in patients
with schizophrenia. Similarly, Ari et al. [49] suggested that a ketotic
state might be the cause of the symptom amelioration by potentially
providing a non-glucose source of energy to a potential pathological
mechanism characterized by glucose impairment and altered glucose
metabolism [50-52].
ere is an overall trend of decreasing PANSS scores during
ketosis, which is consistent with two case studies previously reported
[25]. However, by comparison the PANSS scores did not decrease to
the same extent, which could potentially be accounted to the shorter
overall duration that patients remained in ketosis. Moreover, the
general symptomatology did not return to baseline scores aer the
intervention but did showed an increased trend aer breaking the diet.
Although the PANSS interviewer remained blinded throughput the
study, post-study blinding of the examiner was compromised and could
have induced potential bias into the interpretation of the nal PANSS
interview results.
Limitations of the study
More specialized analyses e.g. change in the brain glucose uptake,
to reveal the mechanism of action of the KB in the patients, was
not available. Blood ketone beta-hydroxybutyric acid could not be
measured due to inaccessibility of laboratory protocols and devices.
is was a small pilot study intended to show a proof-of-concept,
safety, effects and overall practicability of the KD in schizophrenia
patients. Given the small sample size, statistical significance could
not be determined.
Future research
A larger sample, longer study duration is needed to determine
if these results can be extrapolated to the schizophrenia patient
population and to allow for statistical analyses to be conducted. Future
blood clinical follow-up can be done at more prolonged intervals during
a 3:1 ratio KD trial in schizophrenia patients, as no significant
changes were observed during the trial. The present protocol and
the standard laboratory assessment recommendations from ‘The
Charlie Foundation for Ketogenic Therapies’ can be used as a
template [23].
Patient perspectives
Both patients suggested that compliance with the diet daily was
dicult due to the amount of olive oil that was included in the salads,
yet, when olive oil was used for making mayonnaise, due to their culture,
made the diet easy and more exciting. Also, stop eating rice, potato,
plantains and specially sweets were accused to be the most dicult part.
Both patient reported satiety aer few days of compliance with the diet
reason why they stop having dinner 1 or 2 days. With regards to the
behavioral condition, female patient showed happiness accusing that
the two girls that regularly told to hurt herself were gone. e male
patient was feeling good when he started losing fat, recovering desire to
play football at the park with his friends. Overall, patients reported an
improved emotional condition and diet acceptance, despite most of the
time the food traditions were dicult to overcome.
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