A clinical trial of olanzapine (Zyprexa) to determine whether early intervention can delay or prevent onset of psychosis in prodromally symptomatic patients is underway (McGlashan et al., 2003). Prevention Through Risk Identification Management and Education (PRIME) is being conducted at four sites: Yale University; the University of North Carolina at Chapel Hill; the University of Toronto; and Foothills Hospital, Calgary, Alberta, Canada.
Although a prodromal phase of psychotic illness is usually recognized in retrospect after the first psychotic break, study investigators have employed new criteria to diagnose and treat prodromal patients. Sixty study subjects were identified through responders to advertisements about mental illness development or through referrals from practitioners and health services receiving study recruitment materials on early intervention.
The PRIME study is the first randomized, double-blind, placebo-controlled trial of an atypical antipsychotic in this newly defined clinical population. The study incorporates long-term phases with and without medication to ascertain rate of psychotic-onset conversion in this population, as well as the safety and efficacy of antipsychotic intervention at this stage of illness development.
"Whereas the idea is not new, several recent developments have made early intervention research feasible, ethical and compelling," observed lead investigator Thomas McGlashan, M.D., and colleagues (McGlashan et al., 2003).
There are indications that early antipsychotic treatment administered before (Falloon, 1992; McGorry et al., in press) or soon after psychotic onset (Lieberman and Fenton, 2000) can heighten treatment response and produce better long-term outcome. Although there have not been controlled trials, treatment in the prodromal phase has appeared to exert some preventive effect (McGorry et al., in press).
The development of atypical antipsychotics has also provided opportunity for safer early intervention, in the assessment of the investigators. Although acknowledging such side effects as weight gain and somnolence, McGlashan and colleagues consider the risks of acute adverse reaction to atypical antipsychotics in the prodromal phase to be lower than that with older agents. There remains, however, the particular hazard in attempting pre-emptive, preventive medication treatment in patients who may be incorrectly diagnosed as prodromal.
"While these risks accompany any treatment study of neuroleptics in schizophrenia," McGlashan and colleagues (2003) noted, "they are magnified in prodromal intervention because such samples may contain people who are false positive prodromals who are exposed to the risks, but not necessarily the benefits of diagnosis and antipsychotic treatment."
An accurate method of identifying and rating symptoms of the prodromal syndrome was essential, then, for early intervention research to progress. The Scale of Prodromal Symptoms (SOPS) developed by McGlashan and colleagues (2001) provided a six-point scale and anchoring criteria for rating five attenuated positive symptoms, four disorganization symptoms and four general symptoms. The SOPS is distinguished from other scales of psychotic illness severity by having greater sensitivity for subpsychotic or attenuated symptoms.
The PRIME investigators embedded the SOPS rating scale into the diagnostic interview format of the Structured Interview for Prodromal Syndrome (SIPS) (Miller et al., 2002b). With this interview process, investigators could assess positive symptoms of the SOPS, employ the Global Assessment of Functioning (GAF) scale and obtain family history of mental illness. These assessments were then applied against the Criteria of Prodromal Syndromes (COPS) to classify patients into three high-risk prodromal subgroups having, respectively, genetic risk and deterioration state, attenuated positive symptom state, or brief intermittent psychotic state. These classifications have previously been reported predictive of psychosis onset within one year (Yung and McGorry, 1996).
To establish rate of psychosis development as well as treatment efficacy in this population, a final scale was developed to define onset of psychotic symptoms or "conversion" from the prodromal phase. The Presence of Psychosis Scale (POPS) marks onset by the presence of positive symptoms at the psychotic level of intensity and of sufficient frequency and duration (McGlashan et al., 2003).
The investigators have reported the SIPS to have high interrater reliability and predictive validity (Miller et al., 2002a; Miller et al., 2002b). Across study sites, patients meeting prodromal criteria experienced psychotic onset at a rate of between 36% and 54% within one year. Most patients converted within the first six months of baseline assessment. This indicated that the instruments and criteria were useful in identifying patients in the late prodromal phase of their illness: "The results support the validity of these criteria as defining prodromal states that mark high imminent risk for psychosis" (McGlashan et al., 2003).
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