This is a single site clinical trial in which 12 participants with schizophrenia will be randomized to one of three doses of treatment with Cobenfy for 5 weeks. [18F]DOPA PET scans will be obtained before and after treatment to examine the effects of Cobenfy on dopamine transmission.

The overall objective of the current study is to measure Cobenfy's ability to engage its putative target (DA transmission/synthesis capacity in the striatum and midbrain as measured by [18F]DOPA Kicer ([18F]DOPA relative uptake rate)).

Inclusion Criteria:

1. Individuals aged 18 to 50, 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. Antipsychotic free at Visit 1 (by choice and for reasons unrelated to the study), and for at least 3 weeks (4 for aripiprazole, Cobenfy or LAIs) at the time of the baseline PET scan, inclusive of any antipsychotic-free time prior to consent
5. PANSS total score > 80 and < 120
6. Willing to use qualified methods of contraception (listed in section 5.3) for the study duration (for women of childbearing potential only)
7. Stable dosing of herbal/dietary supplements for at least 6 weeks at the time of the first dose of Cobenfy and willingness to avoid products with known hepatotoxic ingredients (e.g., green tea extract, kratom, ashwagandha).

Exclusion Criteria:

1. Diagnosis of moderate or severe substance use disorder within the previous month (from first PET scan)
2. A history of poor or inadequate response to Cobenfy for any reason, hypersensitivity to Cobenfy or trospium or no justifiable reason to expect improvement on Cobenfy, or treatment with Cobenfy within 4 weeks of the first PET Scan
3. EKG abnormality that is clinically significant including a QT interval > 450 msec for men and > 470 msec for women, as corrected by the Fridericia formula (QTcF)
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 (section 5.3) for 30 days before the study, 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 illness, condition, or disorder that is anticipated to potentially compromise participant safety on study medication, including (but not necessarily limited to) the following: urinary retention, moderate or severe hepatic impairment, gastric retention, untreated narrow-angle glaucoma, hypernasality, resting heart rate >100 bpm or systolic Blood Pressure >150 mmHg, a history of orthostatic hypotension or abnormal orthostatic blood pressure (change in mean arterial pressure [1/3 systolic + 2/3 diastolic] of > 20% between supine and standing blood pressures), known human immunodeficiency virus (i.e., by history), cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, symptomatic gallstone disease, active hepatic infections, history of bladder stones, recurrent urinary tract infections, or International Prostate Symptom Score > 7 or any one item > 2 (not including the nocturia item).
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 during visit 2)
7. Participants with suicidal ideation with intent or plan (indicated by affirmative answers to items 4 or 5 of the Suicidal Ideation section of the baseline C-SSRS) in the past 1 month or suicidal behavior in the past 3 months
8. Laboratory abnormality that would compromise the well-being of the participant, including Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value > 2 times the upper limit of the laboratory normal reference range, elevated bilirubin (i.e., >2 x upper limit of normal (ULN)), or serum prostate specific antigen (PSA) >10 ng/ml (for men only).
9. A history of treatment resistance to antipsychotics
10. Use of nicotine products within the previous month (prior to first PET scan)
11. History of significant violent behavior when antipsychotic-free or currently homicidal
12. Positive toxicology screen for any substances of abuse

Data may be shared with direct and valid request.