The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis I. Study rationale and design

The first double-blind placebo-controlled clinical trial of an atypical neuroleptic medication is being conducted in symptomatic treatment-seeking patients meeting new diagnostic criteria for a putative prodromal syndrome. This identifies them as being at high risk for developing psychosis in the near future. The study aims include prevention of psychosis onset and disability, as well as palliation of ongoing symptomatology. This report presents the study rationale and design. Recent studies will be reviewed that have advanced our knowledge about the early course of schizophrenia and our ability to predict onset prospectively, advances that have rendered prodromal intervention research feasible and ethical. The study design has many novel features. It tests for prevention versus delay in psychosis onset, as well as for efficacy and safety in a newly defined clinical population. This has required the development of innovative clinical research assessment instruments and a new operational definition of psychosis onset. The integration of these novel elements into an otherwise typical clinical trial design is detailed. The companion report will address sample recruitment and the clinical phenomenology at baseline of this putative "prodromal" entity.