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.