Pilot study on Ketosis Impact on Signs and Symptoms of Schizophrenia and Bipolar Disorders

Cumulative evidence points towards a shared disease mechanism underlying
schizophrenia spectrum and bipolar disorders (SSD/BD): a dysfunction in energy
homeostasis in the brain1,2. The bioenergetic dysfunction-hypothesis provides a
comprehensive disease model for both disorders, highlighting the role of
multi-level glucose metabolism problems in the brain. Importantly, this is
hypothesized as a causative mechanism, instead of an associational one.
Therefore, therapeutically restoring energy homeostasis in SSD/BD could be of
immense clinical value. While fully glucose-dependent under normal feeding
conditions, the brain switches to metabolizing ketones derived from fatty acid
oxidation in the liver during fasting/starvation. The ketogenic diet (KD)
induces ketosis by greatly restricting carbohydrate intake. Indeed, small
recent studies suggest the KD is effective in treating core SSD/BD symptoms3-6.
However, the KD*s restrictive nature hinders its adherence and applicability.
We propose that using a well-researched ketone drink can replace the KD,
restore brain energy homeostasis, and improve SSD/BD symptoms. This
double-blind, controlled crossover pilot study aims to investigate both
clinical and mechanistic effects of exogenous ketones in SSD/BD.

The current pilot study intends to establish the effect of a single dose of dGK
on relevant (neuro-)electrophysiological (primary outcome: Pre-Pulse Inhibition
(PPI); furthermore on resting EEG, on the ERP P300, cognitive, metabolic,
inflammatory, and patient-experience outcome measures (secondary).

Aggregated n=1 design: Randomised, double-blind controlled 2-way cross-over
study.

Oral intake of nutritional drink (50 g dGK versus isocaloric carbohydrate
drink). Patients (n=24) will follow a crossover trial, and be randomised in a
double-blind fashion to either intervention first (1x50g dGK) or gold standard
first (1x50g isocaloric carbohydrate drink). After a 72-hour washout period,
patients will crossover to the other condition.

At baseline, height, weight, waist circumference will be measured, and clinical
measures taken to determine psychiatric symptom severity (Positive and Negative
Syndrome Scale; PANSS or Young Mania Rating Scale, YMRS; or Inventory of
Depressive Symptomatology - Clinician, IDS-C duration 10 to 45 minutes). On
test days, a nutritional drink will be administered (50g dGK or isocaloric
carbohydrate drink). The drinks can be considered unpalatable, which will be
counteracted by offering sparkling water after nutritional drink ingestion. The
safety of dGK is well established, and side effects are infrequent and very
mild8-12. An EEG and EMG of the eye muscle (both non-invasive) will be
administered using an electrode cap following standard operating procedures
(burden to patients consists mainly of not being able to freely move around
during EEG measurements, total duration maximum 3 hours on test days).
Cognitive tests will be administered on test days (max. 30 minutes). An iv-line
will be offered to patients (opt-out possible): single venapuncture on test
days, max. 123 ml of blood sampled. Indirect calorimetry will be done on test
days: while non-invasive the gas-exchange canopy placed over the head of
patients may by some be experienced as claustrophobic. As such, patients can
choose to opt-out of this measurement and still participate in the rest of the
study. For the 5-day trial duration, patients will wear a small, watch-sized
non-invasive biosensor measuring biomarkers in passive sweat (attached using a
skin-safe sticker; minimal to no patient burden), as well as a continuous
glucose monitor (CGM: pain-free insertion in the subcutis of upper arm without
discomfort). Patients will be asked to collect 3-5 saliva samples every day for
5 days, and to keep a diet and smoking diary, without changing their
nutritional and nicotine intake.