Can neural network instability in schizophrenia be improved with a very low carbohydrate ketogenic diet?

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Wide ranging cognitive deficits are major drivers of functional decline and poor outcomes in people with schizophrenia (SZ). Antipsychotic medications do not target pathophysiological mechanisms thought to underlie these deficits. In the search for interventions targeting underlying cognitive impairment in schizophrenia, we look comprehensively beyond just the brain and to the potential role of dysfunctional systemic metabolism. Disrupted insulin and glucose metabolism are seen in medication-naïve first-episode SZ, suggesting that SZ itself, and not just the medications used to treat it, is associated with risk of Type 2 diabetes, cardiovascular morbidity and mortality, and more generally, accelerated aging. Even young people with SZ have increased risk of metabolic disease and cognitive deficits. Sadly, their life span is shortened by 15–20 years. Although the human brain is 2% of the body’s volume, it consumes over 20% of its energy, and accordingly, the brain is particularly vulnerable to the dysregulation of glucose metabolism seen in SZ. While glucose is considered to be the brain’s default fuel, ketones provide 27% more free energy and are a major source of energy for the brain. Ketones prevent or improve various age-associated diseases, and a ketogenic diet (70% fat, 20% protein, 10% carbohydrates) has been posited as an anti-aging and dementia antidote. The premise of the work is based on recent evidence that ketogenic diets improve dynamic neural network instability, related to cognitive deficits, aging, and Type 2 diabetes. The rigor of the work rests on findings of (1) poor glucose homeostasis in SZ, (2) neural network instability in SZ, and (3) direct effects of ketosis on network instability. Unknown is whether ketogenic diets can improve network instability in people with SZ. We propose a mechanistic, prospective, clinical pilot study of a 4-week ketogenic diet on neural network instability in overweight/obese SZ, at risk for insulin resistance. Seventy SZ (40-65 years old) will be randomized to a ketogenic diet (n=35) or diet-as-usual (n=35). Resting state 7Tesla fMRI scans will be acquired before and after the 4-week diets. Cognitive data at baseline will be used to determine if its relationship with network instability, seen in neurotypicals, is also seen in SZ. We will compare network stability following the two diets and consider the role of metabolic and inflammatory mechanisms in improvement of neural network instability. This work brings together cardiovascular metabolism and psychiatry to address two problems experienced by people with schizophrenia: (1) neural network instability associated with cognitive deficits, and (2) insulin resistance associated with morbidity and mortality. A controlled ketogenic diet has never been tried in people with SZ, who suffer from both cognitive deficits and insulin resistance. At the end of this 2-year project, we will know if deficient glucose metabolism, at least partially mediated by primary or secondary insulin-resistance, contributes to network instability in schizophrenia, a pathophysiological mechanism underlying accelerated aging and cognitive impairment in the disorder.