Biomarkers to Enhance Early Schizophrenia Treatment

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

• Aged 18 to 35.
• DSM5 diagnosis (as determined by the SCID5) of schizophrenia, schizoaffective disorder, schizophreniform disorder.
• 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.
• Preserved striatal connectivity, as determined by screening MRI scan
• Absence of the MC4R high-risk genotype, as determined by genetic testing
• Absence of the HLA-DQB1 high-risk genotype, as determined by genetic testing
• 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)
• Ability to provide informed consent

Exclusion criteria

• 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
• An abnormal EKG at screening that the investigator determines could interfere with the interpretation of the efficacy or safety measurements
• Any medical condition which requires treatment with a medication with psychotropic effects.
• 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).
• Cognitive limitations, or any other factor that would preclude potential participants providing informed consent
• Contraindications to MRI (e.g. pacemaker).
• 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
• 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)
• Prior psychosurgery
• Pregnancy (self-report)
• Seizure disorder (self-report)

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