Investigating the Muscarinic System in Schizophrenia Using Positron Emission Tomography

The Muscarinic Hypothesis of Schizophrenia: an [11C]MK-6884 PET Study Study Protocol

Within the schizophrenia population, there are individuals that respond to first-line antipsychotic treatments while others do not. The availability of muscarinic M4 subtype receptors (M4R) may play a role as to whether a person with schizophrenia is responsive to first-line antipsychotics or not. The goal of this observational study is to compare the availability of M4R in antipsychotic-free patients with schizophrenia and matched healthy controls. In addition, M4R availability in schizophrenia patients will be examined in relation to response to first line antipsychotics and clinical and cognitive measures. This study may help better understand antipsychotic resistance in schizophrenia and lead to the development of new treatment options, particularly for cognitive deficits and negative symptoms.

Study Overview

• Status: Active, not recruiting
• Conditions: Schizophrenia; Schizophreniform Disorders
• Intervention / Treatment: Radiation: PET Scan

Detailed Description

This study is composed of two participant groups. 1) Antipsychotic-free patients with schizophrenia and 2) healthy matched controls. The healthy controls will be matched as closely as possible for age, sex, cannabis, and nicotine consumption to the patient group. All participants will undergo a positron emission tomography (PET) scan to measure the M4R binding with [11C]MK-6884 and examine its relationship with clinical and cognitive measures.

Participants who meet the inclusion and exclusion criteria at screening visit (visit 1) will be enrolled into the study. All participants will undergo a PET scan with the novel tracer [11C]MK-6884 to examine its binding with M4R. The third visit will consist of a MRI scan and cognitive assessments. Participants with schizophrenia will have visit four, which occurs 6 weeks after the first antipsychotic trial, initiated by their treating physician. If the treating physician starts a second antipsychotic trial, then a visit five occurs 6 weeks after the second trial. Both visits four and five involve clinical and cognitive assessments.

• Study Type: Observational
• Enrollment (Estimated): 58

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T1R8
      • Centre for Addiction and Mental Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Antipsychotic-free patients with schizophrenia or schizophreniform disorder and healthy controls

Description

Inclusion Criteria:

Criteria for both Patients with Schizophrenia and Healthy Controls:

1. Age of 18 years and older
2. Willing to consent to study procedures

Criteria for Patients with Schizophrenia:

1. Inpatients or outpatients ≥18 years of age.
2. DSM-V diagnosis of schizophrenia or schizophreniform disorder confirmed using SCID-5.
3. Capable of consenting to participate in the research study (MacCAT).
4. No exposure to long-acting antipsychotics in the past 6 months and oral antipsychotic-free for at least 2-weeks
5. Deemed suitable to receive first-line antipsychotic treatment as standard of care by the treating physician.

Criteria for Healthy Controls:

1. Absence of history of psychiatric illness using the SCID-5
2. Do not have any first-degree family members with a primary psychotic disorder.
3. Are willing to attend appointments reliably.
4. Are capable of providing consent

Exclusion Criteria:

Participants will be excluded if they meet ANY of the criteria listed below:

1. DSM-V diagnosis of schizoaffective disorder or psychosis not otherwise specified.
2. Unstable medical illness or any concomitant major medical or neurological illness, including a history of seizures and traumatic head injury resulting in a loss of consciousness > 30 minutes that required medical attention.
3. Acute suicidal and/or homicidal ideation.
4. DSM-V substance use disorder (except caffeine and nicotine) within one month prior to study entry.
5. Positive urine drug screen for drugs of abuse at the screening visit (excluding cannabis and/or benzodiazepines).
6. Reporting the chronic use of medication with muscarinic mechanism of action.
7. Pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or any other conditions that would preclude the MRI scan
8. Pregnancy (Note: Females up to age 65 must have negative urine pregnancy test at screening), or breastfeeding.
9. If participation in the study would expose participants to more than the annual radiation dose limit (20 mSv) for human subjects participating in research studies, or if the potential participant already underwent a number of PET scans that, including the PET scans under this protocol, will bring the total to more than 8 PET scans /lifetime. For example, participants known to have already been exposed to radiation through X-rays, CT-scans, or other nuclear medicine procedures during the last year may have already surpassed, or will surpass via study participation, the annual radiation dose limit and thus be excluded.
10. Clinically significant claustrophobia
11. Size of head, neck, and body being unable to fit MRI or PET scanners (e.g. body weight of 350 pounds).
12. Blood or coagulation disorders, or taking anticoagulant medication (not antiplatelet).

Patients with Schizophrenia will also be excluded if they meet ANY of the criteria listed below:

1. Refusal to give consent to investigator to communicate with treating physician for entire duration of the study.
2. Previous clozapine treatment.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with Schizophrenia; Antipsychotic-free patients with schizophrenia or schizophreniform disorder	Radiation: PET Scan; PET scan using the novel [11C]MK-6884 tracer to measure M4R during the antipsychotic-free state
Healthy Controls; Healthy controls matched for age, sex, cannabis, and nicotine consumption to the 29 patients	Radiation: PET Scan; PET scan using the novel [11C]MK-6884 tracer to measure M4R during the antipsychotic-free state

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
M4 receptor expression	Regional [11C]MK-6884 uptake will be quantified as volume of distribution (VT) and binding potential relative to non-displaceable compartment (BPND), as defined by consensus nomenclature for in vivo imaging of reversibly binding radioligands. Ichise's multilinear analysis (MA1) method will be employed to quantify VT, using arterial blood sampling. The simplified reference tissue model (SRTM) will be used to estimate BPND, using the cerebellum as a reference region.	At baseline
Clinical Data Statistical Analysis	Exploratory correlations will be performed between clinical symptoms and whole brain VT within the patient group.	At baseline and 6 week Follow-up after antipsychotic trial

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Statistical Analysis of Cognitive Data	Correlations will be analyzed between memory performance and dorsal striatal VT within the patient group and healthy control group, respectively. Exploratory correlations will be performed between all other cognitive measures and whole brain VT within each group, separately.	At baseline and 6 week Follow-up after antipsychotic trial (only for patient group)
Statistical Analysis of Psychopathological Personality Traits in Health Control Group	Correlations will be performed between trait impulsivity and ventral striatal VT within the healthy control group. Exploratory correlations will be performed between all other personality trait measures and whole brain VT	At baseline

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Investigators: Principal Investigator: Ariel Graff, MD, PhD, Centre for Addiction and Mental Health

Publications and helpful links

Helpful Links

• Description The Centre for Addiction and Mental Health (CAMH) is the leading mental health and addictions research facility in Canada, and one of the largest in the world.

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2024
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: February 15, 2024
• First Submitted That Met QC Criteria: February 22, 2024
• First Posted (Actual): February 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 28, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Magnetic resonance imaging; Positron emission tomography; Antipsychotic-free
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Psychotic Disorders
• Other Study ID Numbers: 050/2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No