The Role of Ketogenic Metabolic Therapy on the Brain in Serious Mental Illness: A Review

Abstract

In search of interventions targeting brain dysfunction and underlying cognitive impairment in schizophrenia, we look at the brain and beyond to the potential role of dysfunctional systemic metabolism on neural network instability and insulin resistance in serious mental illness. We note that disrupted insulin and cerebral glucose metabolism are seen even in medication-naïve first-episode schizophrenia, suggesting that people with schizophrenia are at risk for Type 2 diabetes and cardiovascular disease, resulting in a shortened life span. Although glucose is the brain's default fuel, ketones are a more efficient fuel for the brain. We highlight evidence that a ketogenic diet can improve both the metabolic and neural stability profiles. Specifically, a ketogenic diet improves mitochondrial metabolism, neurotransmitter function, oxidative stress/inflammation, while also increasing neural network stability and cognitive function. To reverse the neurodegenerative process, increasing the brain's access to ketone bodies may be needed. We describe evidence that metabolic, neuroprotective, and neurochemical benefits of a ketogenic diet potentially provide symptomatic relief to people with schizophrenia while also improving their cardiovascular or metabolic health. We review evidence for KD side effects and note that although high in fat it improves various cardiovascular and metabolic risk markers in overweight/obese individuals. We conclude by calling for controlled clinical trials to confirm or refute the findings from anecdotal and case reports to address the potential beneficial effects of the ketogenic diet in people with serious mental illness.

Keywords: bipolar disorder; functional connectivity; insulin resistance; metabolic psychiatry; metabolism; neural network stability; psychotic symptoms; schizophrenia.

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Figures

Figure 1.

A depiction of the biochemistry of ketogenesis in the liver and brain. Prolonged glucose restriction leads to an increased glucagon to insulin ratio, which leads to release of free fatty acids into the bloodstream. Free fatty acids are taken up into liver mitochondria where they are used to produce acetyl coenzyme A (Acetyl-CoA). These molecules then enter ketogenesis through the formation of ketone bodies. Acetyl-CoA is converted into acetoacetate, which then allows for reversible reduction to beta hydroxybutyrate (BHB), as well as acetone. These ketone bodies then exit the liver and enter peripheral tissues and the brain, which is facilitated by monocarboxylic acid transporters. When in situ, BHB can be converted back into acetoacetate, serving as an eventual source of acetyl-CoA to release energy via the tricarboxylic acid cycle. Abbreviations: Acetyl-CoA, acetyl coenzyme A; BHB, beta- hydroxybutyrate; CAT, carnitine acylcarnitine translocase; CO2, carbon dioxide; FAs, fatty acids; MCT, monocarboxylic acid transporter; TCA, tricarboxylic acid.

Figure 2.

A diagram depicting a basic mechanistic model of the ketogenic diet and its potential benefits. Neurobiological and physiological mechanisms of the ketogenic diet are shown in rectangular boxes, with corresponding effects in circles. The flow chart depicts at a high level possible mechanisms of ketogenic diet on cognition and mental health functioning. Abbreviations: IS, insulin sensitivity, ROS, reactive oxygen species.