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

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.

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)