Ketogenic Diet for Schizophrenia: Clinical Implication

Zoltán Sarnyai; Ann-Katrin Kraeuter; Christopher M. Palmer


Curr Opin Psychiatry. 2019;32(5):394-401. 

In This Article

Efficacy of Ketogenic Diet in Animal Models of Schizophrenia

Although the full spectrum of disease pathophysiology and the human-specific symptoms (delusions, hallucinations and thought disorder) cannot be captured by animal model, it is possible to utilize mechanistically driven and translationally validated animal models to study treatment efficacy.[51,52,53] Glutamate receptor (NMDA-type) antagonist psychotomimetic drugs, such as phencyclidine and ketamine, are known to produce symptoms indistinguishable from schizophrenia in humans[54] and induce a behavioural profile in rodents that captures a wide spectrum of the schizophrenia-like phenotype.[55] We utilized the NMDA-type glutamate receptor antagonist dizocilpine (MK-801) to induce hyperactivity, stereotyped behaviour, decreased sociability/social withdrawal, working memory deficit and impaired prepulse inhibition of the acoustic startle reflex in mice. Three weeks of ketogenic diet induced metabolic ketosis characterized by elevated levels of the main circulating ketone body, β-hydroxybutyrate, lower circulating blood glucose levels and temporary weight loss compared with mice in standard diet.[56] The ketogenic diet regimen resulted in a complete restoration of the normal behavioural phenotype in the MK-801-treated mice.[57] Furthermore, we demonstrated that the efficacy of the ketogenic diet is independent of the temporary calorie restriction, as its effect of the MK-801-induced prepulse inhibition deficit persisted even when the weight loss was not anymore present.[57] Converging evidence for the efficacy of ketogenic diet has been provided by the use of the DBA/2 mice that have been proposed to exhibit a variety of behavioural and metabolic features that resemble that of schizophrenia.[52,58] In a proof-of-concept study, Tregellas et al.[59] examined effects of ketogenic diet on hippocampal P20/N40 gating in DBA/2 mice, a translational endophenotype that mirrors inhibitory deficits in P50 sensory gating in schizophrenia patients. They showed that animals with the highest blood ketone levels showed the lowest P20/N40 gating ratios, indicating that ketogenic diet normalizes sensory gating deficits. This preliminary result, together with the efficacy of ketogenic diet on the MK-801-induced disruption of sensorimotor gating, measured as prepulse inhibition of startle,[57] suggests that the ketogenic diet may effectively target sensory gating deficits, which are conceptualized as fundamental in the development of hallucinatory episodes in persons with schizophrenia.

Although, further preclinical studies using animal models of different etiopathogenesis, such as the maternal immune activation-driven neurodevelopmental model, are needed to provide additional evidence for the efficacy of ketogenic diet in schizophrenia, the recent results presented here lend support for trialling ketogenic diet in patients with schizophrenia.