Medical Hypotheses 118 (2018) 74–77

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Ketogenic diet for schizophrenia: Nutritional approach to antipsychotic T

treatment
⁎
Adam Włodarczyk , Mariusz S. Wiglusz, Wiesław Jerzy Cubała
Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland

A R T I C LE I N FO A B S T R A C T

Keywords: Schizophrenia is a mental disorder that mostly appears in the second or third decade of life with no consistent
Schizophrenia appearance. The first-line pharmacological treatment are antipsychotic drugs, which mainly act by suppressing
Ketogenic diet the activity of dopamine. Unfortunately many of schizophrenic patients suffer from persistent positive or ne-
Dietary intervention gative symptoms that cannot be fully treated with available medication. With exploration on the possible causes
GABA-ergic activity
of the disease there is evidence on dopaminergic transmission defects, there is a need to find more holistic way in
treating the disease and a diet regimen could be one of them. Ketogenic diet, which is a popular diet regimen that
consists in low-carbohydrate (about 30–50 g/day), medium-protein (up to 1 g/kg daily) and high-fat intake
(around 80% of daily calories) mainly known for its helpful role in weight-loss. The key mechanism is to gen-
erate ketosis. A state in which ketones bodies in the blood provides energy part of the body's energy comes from
ketone bodies in the blood. Possible hypothesis can be that ketogenic diet changes the ratio of GABA:glutamate
in favor of GABA, by suppressing the catabolism and increasing the synthesis of GABA as well as glutamate
metabolism, which could help to compensate the disrupted GABA levels in schizophrenic brain, leading to
possible better outcome of the disease regarding symptomatology and preventing the weight-gain regarding
some medications used and the correlating diseases responsible for weight gain.

Overview
Schizophrenia is a mental disorder that mostly appears in the
second or third decade of life and does not have a consistent appearance
but the origin of it keeps unclear [1]. The sufferer experiences changes
in his thinking and feeling, in the sensation and in the perception of his
environment [2]. Still there are many unmet needs in trying to control
the symptoms and relapses of the disease. The first-line pharmacolo-
gical treatment is antipsychotic drugs, which mainly act by suppressing
the activity of dopamine [3]. Unfortunately, many of schizophrenic
patients suffer from persistent positive or negative symptoms that
cannot be fully treated with nowadays medication [4].
With exploration on the possible causes of the disease there is evi-
dence on dopaminergic transmission defects, there is a need to find
more holistic way in treating the disease and a diet regimen could be
one of them [5]. Regarding depression, for example, consumption of
more processed foods such as fried foods, refined sugars is associated
with depression, while eating Mediterranean-style diet associated with
prevention or reduced depression intensity [6,7]. Unfortunately, there
is a low number of strong value literature on ‘schizophrenia diet’.
Studies shown that about ¾ of the schizophrenic patients are obese,
mostly preferring bad quality nutrients, fried, processed food [8]. Thus,
often literature mostly focuses on proper vitamin B, antioxidants, mi-
nerals intake with a linkage to less comorbidities and improving the
quality of life [5,9,10,11]. There are also other potential nutritional
interventions that showed validity supporting the inflammation status
in schizophrenic patients, which are gluten-free diet and probiotic
therapy showing their impact regulation of immune system [12,13]
with certain effect on life quality through bowel difficulty [14]. Inter-
estingly, there are some papers showing improvement in the outcome of
schizophrenia when increasing intake of essential polyunsaturated fatty
acids (EPUFAs), omega-3 fatty acids. Studies mainly focused on adding
only some portion (0.3–1.4 g) of fatty acids, which did not change
significantly daily fat percentage intake [5,15], nevertheless reduction
in scores for positive and negative syndrome scale (PANSS) in positive,
negative and general subscales, the Montgomery Asberg Depression
Rating Scale (MADRS), and the Global Assessment of Functioning were
observed [15]. Furthermore, American Psychiatric Association supports
the American Heart Association’s guidelines regarding fish consump-
tion, and further recommends that patients with mood, impulse control,
or psychotic disorders consume ≥1 g/d of combined long-chain omega-
3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid

⁎
Corresponding author at: Department of Psychiatry Faculty of Medicine, Medical University of Gdańsk, Dębinki St. 7 Build. 25, 80-952 Gdańsk, Poland.
E-mail address: aswlodarczyk@gmail.com (A. Włodarczyk).

https://doi.org/10.1016/j.mehy.2018.06.022
Received 28 April 2018; Accepted 19 June 2018
0306-9877/ © 2018 Elsevier Ltd. All rights reserved.
A. Włodarczyk et al.
(DHA) [16].
Ketogenic diet
This leads to a question, what if we managed to maintain a high-fat
diet and what result would we have in schizophrenic patients?
As the diet is known from 1920s, and popularized in 1970s there
were a lot of studies regarding not only weight-loss, but also effects on
animals and humans either healthy or somatically (diabetes, metabolic
syndrome, hipercholesterolaemia) [17,18], and psychiatrically ill [19].
Now we dispose of long-term studies regarding the efficacy, tolerability
and safety using ketogenic diet. Most of them indicate ketogenic diet as
a long-term safe diet for balancing glucose levels, equalizing the lipids
HDL:LDL ratio, reduction on BMI or treating refractory epilepsy [20].
However, there were also studies showing ketogenic diet treatment
promoting negative changes in lipidogram, contributing to atherogenic
risk in patients with refractory epilepsy [21,22].
There could be an answer in managing ketogenic diet, which is a
popular diet regimen that consists in low-carbohydrate (about 30–50 g/
day), medium-protein (up to 1 g/kg daily) and high-fat intake (around
80% of daily calories) mainly known for its helpful role in weight-loss.
There can be few variations of proposed dietary regimen, mostly di-
viding on classic ketogenic diet and the medium-chain triglyceride
(MCT) ketogenic diet. The latter consisting in greater MCT oil intake,
being more ketogenic than long-chain triglycerides, allows more car-
bohydrate and protein food consumption facilitating the nutritional
regimen [23]. The key mechanism is to generate ketosis. Ketosis is a
metabolic state in which ketones bodies in the blood provides energy
part of the body's energy comes from ketone bodies in the blood (in
contrary there is glycolysis in which part of the body’s energy supply
comes from glucose). Generally, ketosis occurs when the body is me-
tabolizing fat at a high rate and converting fatty acids into ketones, thus
ketogenic diets usually lead to ketosis when the liver oxidizes high
accumulation of non-esterified fatty acids into ketone bodies (3-hy-
droxybutyrate, acetoacetate and acetone). The physiological ketosis
from low-carbohydrate diets results in urine and blood ketone bodies
appearance. Concentration of the latter is around 7–8 mM and blood pH
of 7.4. The brain prefers glucose as the main energy source, though it
can metabolize ketone bodies as energy for long periods of time during
starvation and hypoglycemia [24,25]. In contrary to ketogenic diet
ketosis, metabolic acidosis which is a potentially life-threatening con-
dition that can occur due to ketoacidosis caused by diabetes mellitus,
starvation, alcohol ingestion or lactate acidosis, renal failure or inges-
tion of substances, also is represented by ketone bodies in urine and
blood but it differs in levels of those in blood and urine (lower blood pH
in ketoacidosis than in physiological ketosis) [26].
There can be found studies showing positive effects on psychiatric
diseases [5]. Bostock et al., 2017, reviewed 15 studies where psychia-
tric disorders (anxiety, depression, bipolar disorder, schizophrenia,
autism spectrum disorder, attention deficit hyperactivity disorder) were
treated with ketogenic diet. Mostly they were on animal models, only
few of them consisted humans (4 case-reports, 2 open-label studies).
Reduction in symptomathology was observed in favor of all mentioned
diseases, except autism spectrum disorder. Also indicating that patho-
genesis of schizophrenia could be related from either glucose abnormal
levels and/or mitochondrial dysfunction in which ketogenic diet could
be a proposed mechanism of action [19].
Ketosis and its effect on schizophrenia
Ketogenic diet mechanism of action is not fully understood [27], but
among other indications and proposed actions we want to focus on
brain impact of the ketogenic diet. In the epilepsy treatment it was
concluded that ketogenic diet contributes to inhibit mammalian target
of rapamycin (mTOR) pathway signaling, implicated in epileptogenesis
[28], but also it seems to potent influence on neurotransmission in the
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Medical Hypotheses 118 (2018) 74–77
mammalian brain regarding gamma-aminobutyric acid (GABA) and
glutamate levels [4]. This could be also a proposed mechanism in
schizophrenia treatment.
Among both typical and atypical antipsychotic drugs there are other
proposed ways to try to control the refractory symptoms. There is
evidence for add-on treatment of benzodiazepines to help restoring the
balance in neurotransmission defects in the schizophrenia, surprisingly
even be helpful in negative symptomatology treatment [29]. The pro-
posed mechanism, which consists post mortem discovery in which there
were found structural and functional disturbances in transmitter sys-
tems in schizophrenic, also in GABAergic receptors [30], was also de-
scribed in papers by Szarmach et al. [31] and Wlodarczyk et al. [32],
whom found evidence that allosteric modulators of GABA, e.g. benzo-
diazepines, are causing the beneficiary effect on damaged GABA re-
ceptors helping retain the equation between main inhibitory (GABA)
and excitatory (glutamate) neurotransmitters in mammalian brain,
where the continual interplay between those two is to balance the do-
pamine levels [3]. There are single reports on a ketogenic diet in
schizophrenia, but mostly they are in favor of the diet [33,34]. One of
the first reports was an original paper, dated 1966, by Dohan who
proposed the theory that schizophrenia may be cereal (mostly wheat)
related, when he found a correlation between amount of wheat eaten
and schizophrenia risk, which he measured hospital admissions to
mental institutes and wheat and rye consumption, during World War II
[33].
This can lead to a mechanism partly responsible for schizophrenia
mentioned above. There was a study by Calderon et al., [35], on ke-
togenic diet mechanism in epilepsy treatment where the rats where set
on a 15-day ketogenic diet trial, where they measured ketones in urine
(ketosis, most important factor of ketogenic diet), but also GABA, glu-
tamate levels and weight. Not only rats that where on ketogenic diet did
gain weight only by about 1.2 g, comparing to control group – 20.8 g,
but the levels of neurotransmitters changed significantly in a favor for
GABA. In probes of microdialysate the glutamate levels decreased non-
significantly between ketogenic diet (3.5 ± 0.6 μM) and control group
(5.18 ± 0.73 μM, while GABA level where much higher (47 ± 8 nM)
in rats kept in the ketogenic diet compared to control rats (26 ± 3 nM).
In addition, there was also study in which authors demonstrated keto-
genic diet normalizing pathological behaviors in an animal model of
schizophrenia [36]. The study mentioned above can seems to have a
assurance in practice, while there are two case-reports on schizoaffec-
tive disorder, in which both patient experienced significant weight loss
and, what is probably more important, recovery in positive and nega-
tive symptoms while on ketosis, with an acute exacerbation while going
off the diet [37].
Hypothesis
Possible hypothesis can be that ketogenic diet changes the ratio of
GABA:glutamate in favor of GABA, by suppressing the catabolism and
increasing the synthesis of GABA as well as glutamate metabolism.
Yudkoff et al. speculate that ketosis activates brain astrocyte metabo-
lism, resulting in increased conversion of glutamate to glutamine,
moreover to efficient removal of glutamate and efficacious conversion
of glutamine to GABA [38], which could help to compensate the dis-
rupted GABA levels examined in schizophrenic brain, leading to pos-
sible better outcome of the disease regarding symptomatology and
preventing the weight-gain regarding some medications used re-
sponsible for weight gain (olanzapine, clozapine), and the correlating
diseases (diabetes, metabolic syndrome) (Fig. 1).
Limitations
Limitations could be following the diet regimen which would limit
or exclude high-carbohydrate food consumptions like bread, rolls, rice,
potatoes, candy, bananas, sodas etc. which would stop the ketosis in the
A. Włodarczyk et al.
Fig. 1. The interplay of Dopamine, Glutamate and GABA in the human brain.
body, which could happen regarding schizophrenic patients. As studies
show, even ¾ of the patients discontinues assigned treatment [39].
There is a chance that in some patients the diet could have negative
impact on lipidogram, as mentioned before [21,22], also in rare occa-
sions the ketoacidosis can be an adverse event of maintaining low-
carbohydrate diet regimen [26].
Summary
We propose that ketogenic diet may facilitate the therapeutic re-
sponse to antipsychotics in schizophrenic subjects. A proof of concept
study of a high fat-low carbohydrate-load, “liberal ketogenic diet”
should be performed with several patients with schizophrenia who are
not responding to usual treatment in order to test the hypothesis.
Conflict of interest
No other potential conflict of interest was reported by the authors.
Authors’ Contribution
Adam Włodarczyk: Study conception and design, Acquisition of
data, Analysis and interpretation of data, Drafting of manuscript.
Mariusz S. Wiglusz: Critical revision.
Wiesław Jerzy Cubała: Drafting of manuscript, Critical revision.
Acknowledgement
This work is supported by the Medical University of Gdańsk, Poland
(Grant No. ST-02-0039/07/221).
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