Ketosis as a Treatment for Severe Mental Illness: A Critical Review of Preclinical and Clinical Data

Abstract

Abstract Purpose Ketogenic interventions, including ketogenic diets, are increasingly being explored as potential treatments for severe mental illnesses. Ketosis – the metabolic state characterised by high circulating levels of ketone bodies – is thought to be central to the beneficial effects of these diets. Hence, it is plausible that other interventions that induce ketosis may similarly improve mental health outcomes. Here, we critically appraise the evidence surrounding the use of ketosis-inducing interventions for the treatment of severe mental illness. Recent Findings Several uncontrolled trials suggest beneficial mental and metabolic health effects of ketogenic diets in depression, bipolar disorder and schizophrenia, but are limited by confounders and expectation bias. The only reported randomised controlled clinical trial so far suggested a small, greater between-group difference in antidepressive effect of a modified ketogenic diet over a phytochemical control diet in treatment-resistant depression, that did not reach statistical significance. Additionally, ketone levels did not correlate with psychiatric outcomes. Preclinical studies suggest a beneficial effect of ketogenic diets on psychiatric symptom correlates but largely did not explore ketone-outcome correlations. Exogenous ketone and oral medium-chain triglyceride supplements induce nutritional ketosis, however, they have not been tested in patients with severe mental illness. Fasting and time-restricted eating produce ketosis but it is unclear if this explains their reported mental health and metabolic effects. Summary Large, randomised controlled clinical trials are needed to examine and compare the effects of different ketogenic interventions in severe mental illness. Trials should be designed to isolate the role of ketosis, investigate the mechanistic basis of beneficial effects observed, assess dose-response relationships, examine treatment adherence in routine clinical settings, ascertain the duration of treatment effects following discontinuation, and clarify the impact of ketosis-inducing interventions on the need for psychiatric medications and standard care.