Metabolic Improvements with a Ketogenic Diet Correlate with Symptom Improvement in Psychosis: A Randomized Controlled Trial

Abstract

Background and Hypothesis: Psychiatric medications contribute to high rates of metabolic dysfunction in psychotic disorders. Ketogenic diets reduce metabolic syndrome, have anticonvulsant effects in epilepsy, and may improve symptoms of schizophrenia and bipolar disorder. We report the first randomized controlled trial to assess effects of ketogenic diets on metabolism, psychiatric symptoms, and cognition in people with schizophrenia-spectrum and bipolar-1 disorders. Study Methods: Participants were randomized to a ketogenic diet (KETO; n = 28) or diet-as-usual (DAU; n = 30) for 1 month. Partway through the trial, a KETO extension was offered to both groups, resulting in a sub-group who completed the diet for 4 months (n = 25). We assessed changes in metabolic health, clinical symptoms, and cognition after 1 month (KETO versus DAU) and after 4 months (KETO versus baseline). Study Results: KETO participants’ daily ketone levels surpassed the standard ketosis threshold. Relative to DAU, KETO participants showed reductions in weight (Padj <  .001), hemoglobin A1c (Padj = .05), and insulin resistance (Padj = .05). Clinical symptoms (positive, negative, depression) and cognitive performance improved after 4 months on the KETO (all P-values < .001). Increased blood ketone levels in KETO participants correlated with improvements in pre-diabetic markers and depressive symptoms (all P-values < .001). Reduced weight following the KETO was unrelated to metabolic and symptom improvements. Conclusions: We demonstrate feasibility of administering a KETO in outpatients with schizophrenia and bipolar-1 disorder. Participants showed improvement in metabolic health, cognitive performance, and clinical symptoms. Improvement in depressive symptoms was associated with ketosis rather than weight loss, implicating ketosis as the therapeutic mechanism.