Longitudinal PET Imaging of Antipsychotic Binding to the Dopamine-3 Receptor in Schizophrenia

July 15, 2026 updated by: Ragy Girgis, New York State Psychiatric Institute
This is a clinical trial in which 40 participants with schizophrenia will be randomized to 15 days of treatment with cariprazine (CAR) or brexpiprazole (BREX) in a single-blind manner. [11C]PHNO PET scans will be obtained before treatment and after 1 day and 15 days of treatment to examine the effects of antipsychotic medications on the dopamine-3 receptor (D3R). The overall objectives of the current study are to: 1) measure the acute binding of CAR/BREX to the D3R; 2) measure D3R availability for evidence of upregulation following subchronic administration of CAR/BREX in the same set of patients; 3) examine relationships between subchronic binding of CAR/BREX to, and upregulation of, the D3R vs. D2R and changes in positive symptoms, negative symptoms, and cognitive deficits. Relationships between subchronic binding of CAR/BREX and EPS will be explored.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

There is a great need for the development of new treatments for schizophrenia (SCZ). Aside from the recently approved muscarinic agonist xanomeline, all current treatments have been assumed to function by blocking dopamine-2 receptors (D2Rs). Interest in the dopamine-3 receptor (D3R) was encouraged by preclinical findings that D3R antagonists reverse cognitive impairment and improve negative symptoms. In vivo imaging of the D3R became possible with the development of [11C]-(+)-PHNO, a D3R-preferring radioligand. However, while numerous preclinical studies have demonstrated that the D3R is relevant to both the neurobiology and treatment of SCZ, in vivo studies initially and surprisingly reported that, after several weeks of administration, antipsychotic medications may not bind to the D3R and may paradoxically increase levels of the D3R. These findings were discrepant with our own findings in non-human primates and individuals with SCZ demonstrating that acute doses of antipsychotic medications bind to the D3R and D2R in ratios predicted by their in vitro binding profiles. In a later study conducted by our group, 10 days of chronic dosing of the D2R-preferring antipsychotic medication brexpiprazole (BREX) also led to increased levels of the D3R at 1mg and negligible binding at 4mg. Finally, in our study of the D3R-preferring antipsychotic medication cariprazine (CAR), there was robust binding to the D3R and D2R after both acute and subchronic dosing. These seemingly discrepant findings may be related to methodological differences, differences in the binding profiles of D2R- vs. D3R-preferring antipsychotic medications, or to homeostatic responses to chronic antipsychotic treatment (i.e., upregulation). Upregulation is a potentially critical, though underexamined, effect common to all D2R/D3R-binding antipsychotic medications, including partial agonists. It has been hypothesized to be largely responsible for differences in occupancy estimates from single and repeat dose studies and contribute to waning effects of antipsychotic medications and tardive dyskinesia. The goals of this proposal are to elucidate the contribution of D3R, compared to D2R, binding to antipsychotic action, both acutely (SA1) and subchronically (SA2), in the same patients. The relationship between occupancy, upregulation, and clinical effects (SA3, EA) will be investigated.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
100

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Individuals, any gender or sex, aged 18 to 55, inclusive at screen
  2. Capable of understanding the study procedures and able to provide informed consent
  3. Diagnosed with schizophrenia, schizoaffective, or schizophreniform disorder
  4. Negative urine toxicology
  5. Antipsychotic free (by choice and for reasons unrelated to the study), and for at least 3 weeks (4 for aripiprazole or LAIs) at the time of the baseline PET scan, inclusive of any antipsychotic-free time prior to consent. [Any patient who requires inpatient hospitalization or acute medication treatment for clinical stabilization during the medication free period will not be included in this study; any participant who in the clinical judgment of the PIs or any involved clinician is not stable or appropriate for a medication free period will not be included.]
  6. PANSS total score > 80 and < 120 (inclusive)

Exclusion Criteria:

  1. Diagnosis of substance use disorder within the previous month
  2. A history of poor or inadequate response or hypersensitivity to CAR or BREX for any reason
  3. EKG abnormality that is clinically significant including a QTc interval > 450 msec for men and > 470 msec for women,
  4. Pregnant or breast-feeding women. Women of child-bearing potential must have a negative serum β-hCG pregnancy test at Visit 1, must have been using an acceptable method of contraception for 30 days before the study (i.e., before the first PET or MRI scan, whichever comes first), and must agree to do so for the whole study and 30 days after (unless post-menopausal or surgically sterile)
  5. Any clinically significant or unstable medical/neurological illness, condition, or disorder that is anticipated to potentially compromise participant safety on study medication
  6. Any material in the body that is a contraindication for MRI procedures or participated in prior nuclear medicine procedures in the past year that exceed FDA-defined limits when combined with radiation dosimetry from PET scanning in this protocol to avoid exceeding annual dosimetry limits (metal screener repeated before MRI scan). Individuals exposed to radiation in the workplace in the previous year will be excluded.
  7. Acute risk for suicide (i.e., score of 4-5 within the previous month or 6 within the previous 3 months on the CSSRS) or violence/homicide (e.g., homicidal ideation), or history of severe violent behavior or behavioral dyscontrol while antipsychotic-free
  8. A history of treatment resistance to antipsychotics or who have a duration of illness of greater than 20 years
  9. Claustrophobia
  10. Use of nicotine products within the previous month (prior to first PET scan)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Cariprazine 1mg
Cariprazine 1mg daily for 15 days
Drug: Cariprazine
Cariprazine is an antipsychotic medication
Drug: [11C] PHNO
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study. It is experimental and used for imaging purposes.
Experimental: Cariprazine 2mg
Cariprazine 2mg daily for 15 days
Drug: Cariprazine
Cariprazine is an antipsychotic medication
Drug: [11C] PHNO
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study. It is experimental and used for imaging purposes.
Experimental: Cariprazine 3mg
Cariprazine 3mg daily for 15 days
Drug: Cariprazine
Cariprazine is an antipsychotic medication
Drug: [11C] PHNO
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study. It is experimental and used for imaging purposes.
Experimental: Cariprazine 4mg
Cariprazine 4mg daily for 15 days
Drug: Cariprazine
Cariprazine is an antipsychotic medication
Drug: [11C] PHNO
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study. It is experimental and used for imaging purposes.
Experimental: Brexpiprazole 1mg
Brexpiprazole 1mg daily for 15 days
Drug: [11C] PHNO
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study. It is experimental and used for imaging purposes.
Drug: Brexpiprazole
Brexpiprazole is an antipsychotic medication
Experimental: Brexpiprazole 2mg
Brexpiprazole 2mg daily for 15 days
Drug: [11C] PHNO
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study. It is experimental and used for imaging purposes.
Drug: Brexpiprazole
Brexpiprazole is an antipsychotic medication
Experimental: Brexpiprazole 3mg
Brexpiprazole 3mg daily for 15 days
Drug: [11C] PHNO
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study. It is experimental and used for imaging purposes.
Drug: Brexpiprazole
Brexpiprazole is an antipsychotic medication
Experimental: Brexpiprazole 4mg
Brexpiprazole 4mg daily for 15 days
Drug: [11C] PHNO
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study. It is experimental and used for imaging purposes.
Drug: Brexpiprazole
Brexpiprazole is an antipsychotic medication

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Acute D2 and D3 Receptor Occupancy
Time Frame: Day 1
Delta BPND in poscommissural putamen and midbrain
Day 1
Upregulation of D3 receptor following subchronic administration of antipsychotics
Time Frame: Day 15
The availability of D3Rs following two weeks of antipsychotic treatment will be measured.
Day 15

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Positive and Negative Syndrome Scale (PANSS) Total Positive Symptoms
Time Frame: 15 days
Correlations between changes in PANSS total positive symptoms and receptor binding will be examined.
15 days
Positive and Negative Syndrome Scale (PANSS) Total Negative Symptoms
Time Frame: 15 days
Correlations between changes in PANSS total negative symptom scores and receptor binding will be examined.
15 days
MATRICS Cognitive Deficits (Composite Score)
Time Frame: 15 days
Correlations between changes in cognitive deficits (MATRICS composite score) and receptor binding will be examined.
15 days

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Abnormal Involuntary Movement Scale (AIMS) Score
Time Frame: 15 days
Correlations between changes in extrapyramidal side effect scores (AIMS) and receptor binding will be examined.
15 days
Simpson-Angus Scale (SAS) Score
Time Frame: 15 days
Correlations between changes in extrapyramidal side effect scores (SAS) and receptor binding will be examined.
15 days
Barnes Akathisia Rating Scale (BARS) Score
Time Frame: 15 days
Correlations between changes in extrapyramidal side effect scores (BARS) and receptor binding will be examined.
15 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
New York State Psychiatric Institute

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Mental Health (NIMH)
Columbia University
Stony Brook Medicine

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 30, 2030

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 30, 2030

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 11, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 15, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 20, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 20, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 15, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NYSPI2026-31
  • 1R01MH139651-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Data will be shared via the NIH data archive.

IPD Sharing Time Frame

Data will be shared after the study has been completed, as per NIH guidelines.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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