Two-hundred and eighty individuals with schizophrenia who have a recent history of violent acts will be randomized in this 2-arm, parallel-group, 24-week, open-label, 7-site clinical trial to examine the effects of treatment with clozapine vs antipsychotic treatment as usual (TAU) for reducing the risk of violent acts in real-world settings

This is a single-blind, open-label, randomized, active comparator (TAU) controlled clinical trial to examine the effects of clozapine vs. TAU on the risk for violent acts as measured by the MacArthur Community Violence Interview (MCVI) and to examine the effects of clozapine vs. TAU on the Excitement Factor of the PANSS. Adults age 18-65 with schizophrenia or schizoaffective disorder who have committed a violent act within 6 months and are appropriate for treatment with clozapine or TAU will receive treatment for 24 weeks which will be naturalistically administered. Participants will also participate in assessments and appropriate medical monitoring which will include blood draws, pharmacokinetic blood samples, and physical exams, etc. Cox proportional hazards survival modeling will be used to test the association between treatment group and time until first violent act after randomization (i.e., number of weeks form randomization to violent act).

Inclusion Criteria:

• Diagnostic and Statistical Manual-5 (DSM-5) diagnosis of schizophrenia or schizoaffective disorder by the Structured Clinical Interview for DSM-5 (SCID-5)
• commission of a minor or serious act of violence as measured by the MCVI in the last six months
• willing and able to provide informed consent
• medically stable in judgment of physician providing study treatment
• appropriate for treatment with either clozapine or TAU, i.e., that there is clinical equipoise between the two treatment options. Individuals who are currently medication free or on any antipsychotic, with the exception of clozapine or long-acting injectable medication with a dosing interval of more than 30 days will be eligible

Exclusion Criteria:

• An unstable of serious medical or neurological condition including a myeloproliferative disorder or condition that surprises the bone marrow
• A history of intolerance/allergy to clozapine (e.g., agranulocytosis, small bowel obstruction, or myocarditis)
• A history of intellectual impairment
• pregnant or lactating women; women who are able to become pregnant but who are not willing to sue effective methods of birth control
• Individuals who score a 3, 4, or 5 within the previous month on the suicidal ideation section of the Columbia Suicide Severity Rating Scale (CSSRS), have any suicidal behavior (not including Not Suicidal Self Injury) within the previous 3 months, or are, in the opinion of the investigator, at too high of a risk for suicide to be safety treated in a randomized trial in which they may not be treated with clozapine
• Documented intolerance to or lack of any therapeutic benefit with clozapine after a full trial

Blinded raters and a blinded adjudication committee to ensure that the outcome is valid