The Effect of Exogenous Ketones on Signs and Symptoms of Schizophrenia Spectrum and Bipolar Disorders: Study Protocol for a Triple-Blind, Randomized, Controlled Crossover Pilot Study

Abstract

Background: Inflammation, oxidative stress, and bioenergetic dysfunction are proposed underlying mechanisms of schizophrenia spectrum disorders (SSDs) and bipolar disorders (BDs), contributing to the largely untreated cognitive and negative symptoms in these conditions. Ketone bodies may offer a therapeutic option for these symptoms through their positive effects on the aforementioned mechanisms. Exogenous ketones like ketone esters (KEs) provide a means to quickly induce ketosis without dietary restrictions, though their effects on SSD and BD have not yet been investigated.

Objectives: This ongoing triple-blind, randomized controlled crossover trial investigates the effects of a single ingestion of KE on signs and symptoms of SSD and BD.

Methods: A total of 24 patients (12 SSD and 12 BD) receiving inpatient care at Amsterdam University Medical Center (UMC) will be included in the study. Patients will ingest a single dose of KE ((R)-3-hydroxybutyl-(R)-3-hydroxybutyrate deltaG Ketones (dGK) and an isocaloric carbohydrate control with a washout period of 3 days between drinks. The primary outcome is the change in prepulse inhibition of the startle reflex induced by dGK ingestion compared with control. Secondary outcomes include resting-state electroencephalography, P3B amplitude, cognitive performance, and metabolic, immune, oxidative stress, and circadian rhythm parameters. Feasibility and potential side effects will also be assessed.

Results: N/A (study protocol).

Conclusions: Our current study will offer valuable preliminary data on the effects of KE in patients with SSD and BD. It can provide the foundation for future research into the therapeutic potential of KE in alleviating symptoms and improving functional outcomes in these disorders.This trial was registered at www.clinicaltrials.gov as NCT06426134.

Keywords: bipolar disorder; exogenous ketones; ketone ester; ketosis; prepulse inhibition; schizophrenia; treatment.

FIGURE 1

Overview of measurements during study participation. Schematic overview of the 5-day study protocol. On day 1, baseline assessments include psychiatric symptom scales [Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), Inventory of Depressive Symptomatology (IDS-C)], anthropometric measures, and the application of continuous glucose monitors (CGMs) and sweat sensors. On days 2 and 5 (test days A and B), participants ingest either the ketone ester (deltaG, dGK) or an isocaloric carbohydrate control drink (iCarb). These test days include neuroelectrophysiological recordings [resting state, prepulse inhibition (PPI), and the P3b event-related potential], cognitive tests [Trail-Making Test A/B (TMT-A/B), Digit Span Test (DST), and the 15-Word Test (15 WT)], and visual analog scales (VAS). Optional procedures include intravenous blood sampling (≤8 times) and indirect calorimetry. EEG, electroencephalography; EMG, electromyography.