This study is recruiting participants who are experiencing a first episode of psychosis and who have certain genetic factors that may make them respond better to certain medications that are used to treat people with psychosis.

The study is designed to test the hypothesis that, compared with standard treatment with FL-APs (risperidone or aripiprazole), early treatment with clozapine (CLZ) will benefit patients in the first episode of psychosis (FEP) who have been designated three biomarker positive (3B+) as follows: 1) likely to have a poor response to FL-APs; 2) not at heightened risk for clozapine-induced agranulocytosis and 3) not at heightened risk for antipsychotic-induced weight gain. The study will recruit n=410 FEP across the 5 participating sites for screening on each of the 3 biomarkers (striatal connectivity in relation to risk of treatment response/resistance to conventional antipsychotics, MC4R genotype in relation to weight gain risk, and HLA-DQB1 genotype in relation to agranulocytosis risk), which involves a rs-fMRI scan (for response/non-response prediction) and a blood draw for genotyping per above (to screen for heightened risk for each of the two side effects). Those failing to meet any of the 3 biomarker criteria will receive FEP care but will not be enrolled in the study.

Inclusion Criteria:

1. Aged 18 to 35.
2. DSM5 diagnosis (as determined by the SCID5) of schizophrenia, schizoaffective disorder, schizophreniform disorder.
3. Current positive symptoms rated ≥4 (moderate) on one or more of the following BPRS positive subscale items: unusual thought content, conceptual disorganization, hallucinatory behavior, suspiciousness.
4. Preserved striatal connectivity, as determined by screening MRI scan
5. Absence of the MC4R high-risk genotype, as determined by genetic testing
6. Absence of the HLA-DQB1 high-risk genotype, as determined by genetic testing
7. In an early phase of illness as defined by having taken antipsychotic drugs for a cumulative lifetime period of 4 weeks or less (with exceptions of very low doses for other off-label indications, e.g. sleep)
8. Ability to provide informed consent

Exclusion Criteria:

1. The patient reports or medical records state a serious neurological or endocrine disorder at screening that the investigator determines could interfere with the interpretation of the efficacy or safety measurements

2. An abnormal EKG at screening that the investigator determines could interfere with the interpretation of the efficacy or safety measurements

3. Any medical condition which requires treatment with a medication with psychotropic effects.

4. Significant risk of suicidal or homicidal behavior (i.e. 'severe' risk on the Columbia Suicide Scale, a 'hostility' score of 7 on the BPRS, or an answer of 'yes' on questions 4,5 or 6 on the CDSS).

5. Cognitive limitations, or any other factor that would preclude potential participants providing informed consent

6. Contraindications to MRI (e.g. pacemaker).

7. Meeting SCID-5 substance use disorder moderate or severe for any substance, other than nicotine within 3 months of screening visit. Meeting SCID5 substance use disorder mild for any substance other than cannabis, alcohol, or nicotine for less than 3 months prior to screening visit, or a positive urine baseline drug screen with a substance other than nicotine, alcohol, or cannabis

8. Suspected DSM5 intellectual disability based upon clinical interview and psychosocial history, as well as screening with the Weschler Test for Adult Reading (IQ score <71)

9. Prior psychosurgery

10. Pregnancy (self-report)

11. Seizure disorder (self-report)

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All de-identified data will be placed in the NDA.

The data will be transferred 12 months after the study starts and then every 6 months

Access to the NDA will be controlled by the NDA following their policies and procedures.