CLOZAPINE Response in Biotype-1

The CLOZAPINE study is designed as a multisite study across 5 sites and is a clinical trial, involving human participants who are prospectively assigned to an intervention. The study will utilize a stringent randomized, double-blinded, parallel group clinical trial design. B2 group will serve as psychosis control with risperidone as medication control. The study is designed to evaluate effect of clozapine on the B1 participants, and the effect that will be evaluated is a biomedical outcome. The study sample will be comprised of individuals with psychosis, including 1) schizophrenia, 2) schizoaffective disorder and 3) psychotic bipolar I disorder. The investigators plan to initially screen and recruit n=524 (from both the existing B-SNIP library and newly-identified psychosis cases, \~50% each) in order to enroll n=320 (B1 and B2) into the RCT.

The clinical hypotheses underlying this experiment are that (i) B1 individuals are uniquely responsive to the pharmacological properties of clozapine because they have low Intrinsic EEG Activity (IEA), an index of compromised cortical neuronal responsiveness. This is plausibly associated with both (ii) reduced excitatory and (iii) reduced inhibitory stimulation in cortex and that IEA will track this altered excitatory/inhibitory balance and parallel clinical antipsychotic response. Furthermore, (iv) B2 probands (based on their high IEA) will not respond to clozapine. In this study clozapine response is measured by a 'super-APD' (AntiPsychotic Drug) drug response, a response in addition to what is seen with a usual APD (e.g., risperidone). The investigators believe that the 30-35% of individuals who show a 'super-APD' clozapine response in schizophrenia in the pivotal study will be predominantly in B1, because the B1 completers will no longer be diluted by the other non-responders like B2s. Therefore, the investigators postulate that \>50% of B1 will show a unique therapeutic action of clozapine (beyond general APD action), contrasted with the usual predicted response of B1 to risperidone or of B2 to clozapine or risperidone.