## Protocol Section
### Identification Module
**NCT ID:** NCT06426134

**Acronym:** KISSeS

**Brief Title:** Ketosis Impact on Signs & Symptoms of Schizophrenia and Bipolar disorderS

**Official Title:** Pilot Study on Ketosis Impact on Signs and Symptoms of Schizophrenia and Bipolar Disorders

#### Organization Study ID Info
**ID:** NL83836.018.23
#### Organization
**Class:** OTHER
**Full Name:** Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
### Status Module
#### Completion Date
**Date:** 2025-12

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-31

**Type:** ESTIMATED

**Last Update Submit Date:** 2024-05-30

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2025-07

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-07

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-23
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-08
**Study First Submit QC Date:** 2024-05-17
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** Parnassia Groep

**Class:** OTHER

**Name:** The University of Texas at Dallas

**Class:** OTHER

**Name:** University of Alberta

**Class:** UNKNOWN

**Name:** EnLiSense

#### Lead Sponsor

**Class:** OTHER

**Name:** Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

#### Responsible Party

**Investigator Affiliation:** Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

**Investigator Full Name:** Karin Huizer

**Investigator Title:** Principal Investigator; MD, PhD

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** The goal of this clinical trial is to learn if a ketone drink can improve signs and symptoms of patients with a schizophrenia-spectrum disorder (SSD), or a bipolar-spectrum disorder (BD).

The main questions it aims to answer are:

Does a ketone drink improve information processing in patients with SSD/BD?

Other questions it aims to answer are:

Does a ketone drink improve cognitive functioning in patients with SSD/BD? Does a ketone drink improve metabolism and inflammation in patients with SSD/BD?

Research will compare the effects of the ketone drink with that of an isocaloric carbohydrate drink in the same patients ('cross-over').

Participants will:

1. drink a ketone drink and (after a wash-out period) an isocaloric control drink; after each drink:

   * EEG to determine information-processing parameters (PPI and P300)
   * cognitive tests
   * visual analog scale of mood, energy levels, ability to focus
   * indirect calorimetry to determine use of energy substrate
   * blood draws
2. for 5 consecutive days:

   * wear a continuous glucose monitor (CGM)
   * wear a non-invasive passive sweat biomarker sensor (EnLiSense device)
   * register a diet and nicotine diary
   * saliva sampling (max. 4x/day, only on both intervention days)

### Conditions Module

**Conditions:**

- Schizophrenia and Related Disorders

- Psychosis

- Bipolar and Related Disorders

- Manic Episode

- Depressive Episode

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** CROSSOVER

##### Masking Info

**Masking:** TRIPLE

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 24

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 1x50 g dGK ketone drink

**Intervention Names:**

- Dietary Supplement: (R)-3-hydroxybutyl (R)-3-hydroxybutyrate)

**Label:** dGK

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** 1x isocaloric carbohydrate control drink

**Intervention Names:**

- Other: Maltodextrin, Fructose, Pectin, Sodium alginate, Sodium chloride

**Label:** isocaloric carb control

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- dGK

**Description:** 1x50g ingestion of pure dGK

**Name:** (R)-3-hydroxybutyl (R)-3-hydroxybutyrate)

**Other Names:**

- delta G Ketones (dGK)

**Type:** DIETARY_SUPPLEMENT

#### Intervention 2

**Arm Group Labels:**

- isocaloric carb control

**Description:** Isocaloric carbohydrate control (active control)

**Name:** Maltodextrin, Fructose, Pectin, Sodium alginate, Sodium chloride

**Other Names:**

- Maurten Drink Mix 160

**Type:** OTHER

### Outcomes Module

#### Primary Outcomes

**Description:** PPI: an event-related potential (ERP) representing information processing (known to be disrupted in schizophrenia and bipolar disorder).

The PPI task is an auditory paradigm featuring a total of 10 trials split evenly into two conditions: prepulse (PP) and non-prepulse (NP) in blocks. Startle pulses are 100dB at 40 ms, which is shown to provide significant startle visible in EEG126. Prepulse stimuli are 70 dB and 50 ms in duration, presented 50ms prior to the startle pulse. There is a 12 to 18 (avg: 15 s) interstimulus interval. All stimuli are white-noise blips. A calibrated apparatus is used to present the stimuli. Total estimated time is 20 min.

**Measure:** Prepulse Inhibition (PPI) - change dGK vs isocaloric control

**Time Frame:** measured 45 minutes (Tmax) after ingestion of intervention 1 (dGK) and 45 minuts after ingestion of intervention 2 (isocaloric carb control)

#### Secondary Outcomes

**Description:** The P300 task consists of 160 stimuli in the oddball paradigm and requires the subjects to press a button on detection of the rare target (32/160). The common nontarget stimuli are 500 Hz, 100 ms duration. The rare target stimuli are 700 Hz. Both are 100 ms duration at 80 dB with variable interstimulus interval of 1.2 to 1.5 s. Preceded by 10 practice trials. This task has minimal burden and requires about 10 minutes.

**Measure:** P300 Event Related Potential (change dGK vs isocaloric control)

**Time Frame:** measured 65-75 minutes after ingestion of intervention 1 (dGK) and 75 minutes after ingestion of intervention 2 (isocaloric carb control); NB: directly after PPI.

**Description:** 15WT is a measure of verbal/episodic memory. The 15WT consists of 15 words, which have to be learned during three trials. After every trial the respondent is asked to recall as many words as possible. After a distraction period of 20 minutes, the respondent is asked to name the words they have learned before, again.

Immediate recall after 1 test: maximum 15 words (minimum 0) Immediate recall after 3 test: maximum 45 words (minimum 0).

Retention score after 20 minutes:

1. percentage of correctly remembered words in the delayed recall-trial, relative to the number of words correctly remembered in the third immediate recall-trial
2. percentage of correctly remembered words in the delayed recall-trial, relative to the maximum score in the immediate recall-trials

Higher 15WT scores indicate better verbal/episodic memory, lower scores the opposite.

**Measure:** Cognitive test: 15 Word Test (15WT) - change dGK vs isocaloric control

**Time Frame:** measured 75-85 minutes after ingestion of intervention 1 (dGK) and 75 minutes after ingestion of intervention 2 (isocaloric carb control); NB: directly after P300.

**Description:** TMT-A is a measure of (visual) attention. TMT-A outcome is the duration of time required to finalize test (including the time needed for the correction of errors prompted by the examiner), with a maximum of 5 minutes.

The average TMT-A score in healthy adults is 29 seconds; a deficient score is greater than 78 seconds.

Higher scores on TMT-A indicate worse (visual) attention.

**Measure:** Cognitive test: Trail Making Test A (TMT-A) - change dGK vs isocaloric control

**Time Frame:** measured 75-85 minutes after ingestion of intervention 1 (dGK) and 75 minutes after ingestion of intervention 2 (isocaloric carb control); NB: directly after P300.

**Description:** TMT-B is a measure of (frontal) executive functioning. TMT-B outcome is the duration of time required to finalize test (including the time needed for the correction of errors prompted by the examiner), with a maximum of 5 minutes.

Average TMT-B score is 75 seconds; a deficient score is greater than 273 seconds.

Higher scores on TMT-B indicate worse (frontal) executive functioning.

**Measure:** Cognitive test: Trail-Making Test B (TMT-B) - (change dGK vs isocaloric control)

**Time Frame:** measured 75-85 minutes after ingestion of intervention 1 (dGK) and 75 minutes after ingestion of intervention 2 (isocaloric carb control); NB: directly after TMT-A.

**Description:** DST is a measure for working memory. DST outcome is the maximum number of sequential digits correctly reproduced. In average healthy adults, the digit span is around 7 +/- 2. Minimum score is 0, maximum score is 9.

Lower DST score indicate worse working memory.

**Measure:** Cognitive test: Digit Span Test (DST) (change dGK vs isocaloric control)

**Time Frame:** measured 75-85 minutes after ingestion of intervention 1 (dGK) and 75 minutes after ingestion of intervention 2 (isocaloric carb control); NB: directly after TMT-B.

**Description:** visual analog scale (VAS) is used with a scale of 0 to 10 to measure patient-experiences effects of the interventions on their mood (0=extremely depression, 10 = extremely happy/euforic), energy level (0=completely exhauster, 10= extremely energetic) and ability to focus (0=completely unable to focus, 10=perfect focus).

**Measure:** Patient experience outcome on Mood, energy level, focus (change dGK vs isocaloric control)

**Time Frame:** measured circa 120 minutes after ingestion of intervention 1 (dGK) and circa 120 minutes after ingestion of intervention 2 (isocaloric carb control)

**Description:** sequential blood sampling through intravenous line: concentration (pg/ml) of inflammatory biomarkers relevant for immune function:

* IL-1b
* IL-6
* IL-8
* IL-10
* TNF-a
* IFN-g
* hsCRP

Comparison between dGK and isocaloric control at the same time points (see below).

**Measure:** Immune function: blood markers (change dGK vs isocaloric control)

**Time Frame:** first blood sample before ingestion (dGK or isocaloric control) (T0), then every 20 minutes in first hour after ingestion; afterwards every 30 minutes (max. 3 hours)

**Description:** RNA expression analysis (immune panel nCounter, Nanostring) in whole blood: comparison dGK vs isocaloric control only at T0 plus 90 minutes.

**Measure:** Immune function: blood RNA markers (change dGK vs isocaloric control)

**Time Frame:** first blood sample before ingestion (dGK or isocaloric control) (T0), next at T0+90 minutes

**Description:** continuous measurement of IL-6 (pg/ml) in passive sweat (EnLiSense device)

**Measure:** Immune function: passive sweat IL-6 (change dGK vs isocaloric control)

**Time Frame:** Full 5 days of the study

**Description:** continuous measurement of TNF-a (pg/ml)in passive sweat (EnLiSense device)

**Measure:** Immune function: passive sweat TNF-a (change dGK vs isocaloric control)

**Time Frame:** Full 5 days of study

**Description:** Resting energy expenditure (REE) is measured by gaseous exchange (indirect calorimetry). Oxygen consumption and CO2 production are measured during 20 minutes using a ventilated hood system (Q-NRG, Cosmed). Subjects lie flat on their backs and breathe into a canopy for 20 minutes. REE and Respiratory Quotient (RQ) are calculated with these measurements. The RQ represents the ratio of CO2 exhaled to the amount of 02 consumed by the individual and represents whole body substrate oxidation (glucose, fat and protein oxidation).

**Measure:** Metabolic function: Indirect Calorimetry (change dGK vs isocaloric control)

**Time Frame:** circa 90-120 minutes after ingestion of intervention 1 (dGK) and intervention 2 (isocaloric control); directly after finalizing cognitive tests.

**Description:** Sequential blood sampling through intravenous line, to determine the plasma and serum concentrations of:

* Glucose
* Ketones
* acylcarnitine profile
* growth hormone (GH)
* superoxide dismutase (SOD)
* gluthione S-transferase (GST)
* soluble intercellular adhesion molecule 1 (sICAM1)

Comparison between dGK and isocaloric control at the same time points (see below).

**Measure:** Metabolic function: blood biomarkers - change dGK vs isocaloric control

**Time Frame:** first blood sample before ingestion (both dGK and isocaloric control) (T0), then every 20 minutes in first hour after ingestion; afterwards every 30 minutes (max. 3 hours)

**Description:** continuous glucose monitor (CGM; Abbott Libre Sense); continuous concentration in mM.

**Measure:** Metabolic function: continuous glucose monitor (CGM) - change dGK vs isocaloric control

**Time Frame:** Full 5 days of the study.

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Patients with a first-episode psychosis (underlying schizophrenia-spectrum disorder), or patients with a (hypo)manic or depressive episode (underlying bipolar disorder)
* Age \>= 18 years old
* Receiving standard care (including antipsychotic and mood stabilizing medication)
* Mentally competent to give informed consent:

Exclusion Criteria:

* Substance use as cause of psychosis or (hypo)mania
* Substance use (other than nicotine) in the week prior to study onset
* Intellectual disability
* Diabetes mellitus (type 1 or type 2)
* Metabolic disease impacting ketone metabolism (NB: these are rare disorders diagnosed during childhood)
* Liver disease
* Kidney disease
* Cardiovascular disease
* Pregnancy
* Breastfeeding

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** k.huizer@parnassiagroep.nl

**Name:** Karin Huizer, MD/PhD

**Phone:** +31683048776

**Role:** CONTACT

**Contact 2:**

**Email:** n.beveren@parnassiagroep.nl

**Name:** Nico Beveren, van, MD/PhD

**Role:** CONTACT

#### Overall Officials

**Official 1:**

**Affiliation:** Parnassia Groep

**Name:** Karin Huizer, MD/PhD

**Role:** PRINCIPAL_INVESTIGATOR

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000019967

- Term: Schizophrenia Spectrum and Other Psychotic Disorders

- ID: D000001523

- Term: Mental Disorders

- ID: D000019964

- Term: Mood Disorders

- ID: D000019954

- Term: Neurobehavioral Manifestations

- ID: D000009461

- Term: Neurologic Manifestations

- ID: D000009422

- Term: Nervous System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BXM

- Name: Behaviors and Mental Disorders

- Abbrev: All

- Name: All Conditions

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

### Condition Browse Module - Browse Leaves

- ID: M4815

- Name: Mental Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M4996

- Name: Bipolar Disorder

- Relevance: HIGH

- As Found: Bipolar Disorder

- ID: M15376

- Name: Schizophrenia

- Relevance: HIGH

- As Found: Schizophrenia

- ID: M2598

- Name: Mania

- Relevance: HIGH

- As Found: Manic Episodes

- ID: M226

- Name: Bipolar and Related Disorders

- Relevance: HIGH

- As Found: Bipolar and Related Disorders

- ID: M14473

- Name: Psychotic Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M10687

- Name: Ketosis

- Relevance: LOW

- As Found: Unknown

- ID: M21838

- Name: Schizophrenia Spectrum and Other Psychotic Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M21835

- Name: Mood Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M21826

- Name: Neurobehavioral Manifestations

- Relevance: LOW

- As Found: Unknown

- ID: M12404

- Name: Neurologic Manifestations

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000087122

- Term: Mania

- ID: D000012559

- Term: Schizophrenia

- ID: D000001714

- Term: Bipolar Disorder

- ID: D000068105

- Term: Bipolar and Related Disorders

### Misc Info Module

- Version Holder: 2024-05-31
