International Journal of Neuropsychopharmacology (2020) 23(7): 434–439

doi:10.1093/ijnp/pyaa036
Advance Access Publication: 23 June 2020
Commentary

Commentary
Ketogenic Therapy in Serious Mental Illness:

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Emerging Evidence
Zoltán Sarnyai, Christopher M. Palmer
Laboratory of Psychiatric Neuroscience, Centre for Molecular Therapeutics, Australian Institute of Tropical
Health and Medicine (Dr Sarnyai), and College of Public Health, Medical and Veterinary Science (Dr Sarnyai),
James Cook University, Townsville, Queensland, Australia; Department of Postgraduate and Continuing
Education, McLean Hospital, Harvard Medical School, Belmont, Massachusetts (Dr Palmer).
Correspondence: Christopher M. Palmer, MD, McLean Hospital, 115 Mill Street, Belmont, MA 02478 ([email protected]).

Key Words:  Ketogenic therapy, psychosis, preclinical, case studies

We have read the recent review article on the potential appli- et  al., 2012), pharmacological inhibition of the NMDA-type glu-
cation of induced ketosis in psychiatry by Morris et al. (Morris tamate receptors by dizocilpine (MK-810) was used to induce a
et al., 2020) with great interest and shared enthusiasm. It is quite behavioral profile in rodents that captures a wide spectrum of
encouraging to see that others are recognizing the exciting po- the schizophrenia-like phenotype (Neill et al., 2014; Cadinu et al.,
tential of the ketogenic diet and other ketogenic therapies in 2018). A high-fat, very low–carbohydrate ketogenic diet was pro-
the treatment of serious mental disorders. As with all research, vided for 3 weeks, which resulted in metabolic features, such as
however, it is important to be aware of what existing evidence elevated beta-hydroxybutyrate and decreased glucose levels in
is already accumulated. This is particularly pertinent as such the plasma and decreased body weight, that correspond with
published evidence further strengthens the case for induced ke- nutritional ketosis (Kraeuter et al., 2015). The ketogenic diet pre-
tosis in psychiatry proposed as “food for thought” (Morris et al., vented the schizophrenia-like abnormal behaviors induced by
2020). In this Commentary, we aim to fill this gap by providing a acute MK-801 administration, including hyperactivity, stereo-
brief overview of the published preclinical and clinical evidence typed behavior, decreased sociability, working memory def-
that clearly supports the advancement of ketogenic therapies icit, and impaired pre-pulse inhibition of startle in male mice
in a variety of psychiatric disorders, especially in psychosis (Kraeuter et al., 2015, 2019c). Further evidence has been provided
(Figure 1). by the use of the DBA/2 mice, an inbred mouse strain, that have
The ketogenic diet is typically a high-fat, moderate-protein, been proposed to exhibit a variety of behavioral and metabolic
and very low–carbohydrate diet. Ratios of fats to protein and features that resemble those of schizophrenia (Olivier et al., 2001;
carbohydrate are sometimes prescribed, typically in a 3:1 or 4:1 Sarnyai et al., 2015). The effect of ketogenic diet was investigated
ratio. This results in 3 or 4 g of fat being consumed for every 1 g on hippocampal P20/N40 gating in DBA/2 mice, a translational
of carbohydrate or protein. Exogenous ketone supplements are endophenotype that mirrors inhibitory deficits in P50 sensory
also being studied to determine if these can mimic some of the gating in schizophrenia patients (Tregellas et al., 2015). Animals
effects of the ketogenic diet without requiring strict adherence with the highest blood ketone levels showed the lowest P20/
to the diet. N40 gating ratios, indicating that a ketogenic diet normalizes
Although preclinical animal models are unable to capture the sensory gating deficits (Tregellas et al., 2015), which are concep-
full pathophysiology and symptomatology of psychotic disorders, tualized as fundamental in the development of hallucinatory
converging evidence from pharmacological and genetic models episodes in persons with schizophrenia (Javitt and Freedman,
have provided proof-of-concept level results supporting the po- 2015). Furthermore, it was recently shown that the therapeutic
tential therapeutic utility of ketogenic diet (Table 1). Taking ad- effects of a ketogenic diet in the context of the NMDA-receptor
vantage of the leading mechanistic hypothesis of schizophrenia, hypofunction model can be generalized to female mice, and they
the NMDA receptor hypofunction (Jentsch and Roth, 1999; Coyle are similar but nonadditive to the effect of olanzapine (Kraeuter

© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://
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 Sarnyai and Palmer  |  435

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Figure 1.  Development of the use of ketogenic therapy in the treatment of schizophrenia: timeline.

Table 1.  Preclinical Studies on the Effects of KD on Animal Models of Schizophrenia

Reference (author and Schizophrenia-like

journal) Animals Model behaviors/endophenotype Findings

Kraeuter et al., 2015 C57Bl/6 mice Std and KDa (3 wk) Locomotor hyperactivity KD prevented MK-801–induced
Schizophrenia Res. (males) MK-801–induced (0.1, 0.2, Stereotyped behaviors behavioral abnormalities
and 0.4 mg/kg) Ataxia
hypo-glutamatergic Decreased sociability
state Spatial working-memory
impairment
Tregellas et al., 2015 DBA/2 mice KDb only Hippocampal P20/N40 gating Animals with highest blood ketone
Schizophrenia Res. Auditory gating deficit in in DBA/2 mice levels showed lowest P20/N40 gating
DBA/2 mice ratios
Kraeuter et al., 2019c C57Bl/6 mice Std and KDa (7 wk) Sensorimotor gating deficit KD prevented MK-801–induced
Schizophrenia Res. (males) MK-801–induced (0.25 mg/ (prepulse inhibition of sensorimotor gating deficit
kg) hypo-glutamatergic startle) (independent of decreased caloric
state intake related to KD)
Kraeuter et al., 2019b C57Bl/6 mice SD and KDa (6 mo) Sensorimotor gating deficit Long-term KD and chronic olanzapine
Schizophrenia Res. (females) Olanzapine (2 mg/kg, 8 wk) (prepulse inhibition of prevented MK-801–induced
MK-801–induced (0.25 mg/ startle) sensorimotor gating deficit in female
kg) hypo-glutamatergic mice
state No interaction between KD and
olanzapine
Kraeuter et al., 2020 C57Bl/6 mice BHB (3 wk) Sensorimotor gating deficit BHB prevented MK-801–induced
Psychopharmacology (males) MK-801–induced (0.25 mg/ (prepulse inhibition of sensorimotor gating deficit
kg) hypo-glutamatergic startle)
state

Abbreviations: BHB, beta-hydroxybutyrate; KD, ketogenic diet; Std, standard diet. 

a
Ketogenic diet composition: carbohydrates: 9.4%, protein: 9.5%, fat: 77.6%.
b
KD composition: carbohydrates: 0.6%, protein: 22.4%, fat: 77%.

et  al., 2019b) and can be mimicked by chronic administration The first suggestive clinical evidence for the potential efficacy
of the main circulating ketone body, beta-hydroxybutyrate of the ketogenic diet in psychotic disorders emerged 55  years
(Kraeuter et al., 2020). The above strong, converging evidence for ago in a small, open-label, uncontrolled trial in 10 women hos-
the efficacy of ketogenic therapies from pharmacological and pitalized with schizophrenia. The ketogenic diet was added to
genetic animal models paves the way for the introduction of this their existing treatment for 4 weeks. The researchers reported
nutritional/metabolic approach to the clinical management of a significant decrease in symptoms after 2 weeks on the diet
psychiatric disorders (Kraeuter et al., 2019a; Palmer, 2019a). (Pacheco et al., 1965).
Table 2.  Summary of Case Studies With KD in Schizophrenia

Other
Gender and psychiatric Psychiatric
Case age Primary diagnosis diagnoses Medication KD symptoms (PANSS) Metabolic features Comments

Case Male, 33 y Schizoaffective ADHD, MDD History: Coffee with MCT oil and Before KD: Before KD: Completed
#1 disorder methylphenidate, butter (“bulletproof Total = 98 146 kg certification course,
(63) amphetamine salts, coffee”), eggs, meat, fish,Positive = 27 After KD: successfully
dextroamphetamine, poultry, spinach, kale, and Negative = 25 98.9 kg participates in
bupropion, sertraline, olive oil for 3 wk; ketosisGeneral = 46 [Weight loss of 47.2 kg online college
paroxetine, buspirone, measured by urine strips After KD: after 1 y] program, has
lamotrigine, lorazepam, Total = 49 friends, began
clonazepam, Positive = 13 dating, lives
gabapentin, haloperidol, Negative = 8 independently
perphenazine, General = 28
aripiprazole, olanzapine, Symptoms worsened
quetiapine, and clozapine; within 1–2 d after
lack of symptom control breaking KD
Case Female, 31 y Schizoaffective MDD, anorexia History: Coffee, eggs, poultry, and Before KD: Weight loss of 13.6 kg Symptom control
#2 disorder nervosa sertraline, bupropion, lettuce for 4 mo Total = 107 after 4 mo on previously
(63) amphetamine salts, Positive = 24 insufficient dose of
lorazepam, lamotrigine, Negative = 29 aripiprazole
divalproex, topiramate, General = 54
436 | International Journal of Neuropsychopharmacology, 2020

risperidone, aripiprazole, After KD:

quetiapine, olanzapine, Total = 70
and clozapine; Positive = 15
23 ECT; lack of symptom Negative = 18
control General = 38
Severe paranoia and
delusion after
breaking KD but
improvement after a
3-d fast
Case Female, 22 Schizophrenia None For 5 mo before study: 3:1 ratio KD plan set to Before KD: Before KD: Blood clinical
#3 y (twin of (diagnosed at clozapine (300 mg), standard 2000 kcal/d Total = 101 BMI = 21.3 kg/m2 analysis remained
(64) case #4) age 14) risperidone (6 mg), and mainly consisted of Positive = 28 Body fat = 24.5% unremarkable after
clonazepam (3 mg), and avocado, olive Negative = 16 After KD: KD
biperiden (6 mg) oil, butter, eggs, cheese, General = 57 BMI = 19.8 kg/m2
meat, spinach, and After KD: Body fat = 19.8%
broccoli; for 15 d Total = 91
Ketosis determined by daily Positive = 26
urine analysis Negative = 15
General = 50

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Table 2.  Continued

Other
Gender and psychiatric Psychiatric
Case age Primary diagnosis diagnoses Medication KD symptoms (PANSS) Metabolic features Comments

Case #4 Male, 22 y Schizophrenia None For 23 mo before study: Same as case #3 Before KD: Before KD: Blood clinical
(64) (twin of (diagnosed at levomepromazine (150 Total = 82 BMI = 25.1 kg/m2 analysis remained
case #4) age 18) mg), quetiapine (100 mg), Positive = 19 Body fat = 21.7% unremarkable after
valproic acid (1000 Negative = 18 After KD: KD
mg), biperiden (6 mg), and General = 45 BMI = 22.9 kg/m2
risperidone (4 mg) After KD: Body fat = 16.8%
Total = 75
Positive = 16
Negative = 17
General = 42
Case #5 Female, 82 y Schizophrenia None Before start of KD in Patient-directed KD Before KD: Before KD: Regained her
(65) (same as (diagnosed at 2008: haldol-decanoate, initiated in 2008, Chronic paranoia, 150 kg independence,
in Ref. 62) age 17) risperidone, atenolol, maintains KD until today disorganized After KD: no longer need a
furosemide, trazodone, speech, and both 82 kg guardian
and sertraline visual and auditory [Weight loss of 68 kg]
[Before 2008: lithium, hallucinations,
olanzapine, ziprasidone, suicide attempts
aripiprazole, lamotrigine, After KD:
quetiapine, haloperidol, Marked reduction
perphenazine, and in psychotic
risperidone] symptoms;
stopped taking
all medication,
hallucinations
and paranoia
remitted completely,
improved mood, no
suicidal ideations
Case #6 Female, 39 y Schizophrenia MDD, anxiety, Haloperidol, clozapine, KD started in 2003 by Remained free Weight loss of 32 kg, Finished graduate
(65) (hallucinations anorexia ziprasidone, risperidone, functional medicine of psychotic anorexia exacerbated, school and works
and paranoia nervosa quetiapine, aripiprazole, practitioner for symptoms for past regained 13.6 kg, full time
started at age olanzapine, sertraline, symptoms of chronic 5 y off antipsychotic currently at normal
14; diagnosed at paroxetine, citalopram, gastrointestinal distress medications body weight
age 24) fluoxetine, duloxetine,
and venlafaxine

Abbreviations: ADHD, attention deficit hyperactivity disorder; ECT, electroconvulsive therapy; KD, ketogenic diet; MCT, medium chain triglyceride; MDD, major depressive disorder; PANSS, Positive and Negative Symptoms Scale.
Summary of case studies with ketogenic diet in schizophrenia. Reprinted with permission by Wolters Kluwer from Sarnyai et al., 2019.
Sarnyai and Palmer  |  437

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 438 | International Journal of Neuropsychopharmacology, 2020

In 2009, a 70-year-old woman with chronic schizophrenia demonstrate the efficacy as well as the safety of this proposed
since her teens was reported to have improved significantly after novel treatment approach.
starting a ketogenic diet for weight loss (Kraft and Westman,
2009). Within 8 days of starting the diet, she reported no hallu-
Acknowledgments
cinations and improved energy. After 1  year, she lost 5  kg and
remained free of hallucinations. None.
More rigorous and longer term case studies have been con-
ducted (Table 2) in different populations by one of us (C.M.P.) and
have provided encouraging results both in terms of symptom
Statement of Interest
control and safety/tolerability (Palmer, 2017, 2019b; Gilbert- None.
Jaramillo et  al., 2018), which we summarized recently (Sarnyai
et al., 2019).
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