Clinical Trials During the Prodromal Stage of Schizophrenia

To the Editor: With criteria that reflect an “ultra high risk” for developing a psychotic disorder, the risk of converting to psychosis is from 30% to 60% over 1 year (1, 2). To our knowledge, the first published trial on the subject (1) randomly assigned 59 ultra-high-risk subjects to 6 months of active treatment (risperidone plus cognitive behavior therapy) or needs-based intervention. A second study, conducted by McGlashan and colleagues from Yale and collaborating sites from North Carolina, Toronto, and Calgary (2), used a randomized, double-blind, placebo-controlled design with 60 prodromal subjects to compare the efficacy of a low-dose antipsychotic with placebo in preventing or delaying the onset of psychosis (2).

We present recruitment and decision data from the Calgary site. During a 24-month recruitment period, 95 individuals were identified as potentially eligible for the study. Based on study entry criteria, 38% (N=36) were eligible; 86% of the eligible persons refused to enter the trial. Of those eligible, 39% who were troubled by their symptoms wanted active treatment as soon as possible and were offered treatment in our Early Psychosis Program; 47% of the eligible subjects were concerned, often felt debilitated by their symptoms, but did not want to take medication. This group either consented to enter a 1-year observational study offering education, support, and monthly assessments or attended a session to receive education about their symptoms. All had immediate access to a clinician should they experience an increase in symptoms in the near future. The remaining 14% consented to enter the medication trial. An assessment of presenting symptoms with the Scale of Prodromal Symptoms (2) demonstrated that those who wanted treatment and those who entered the trial had significantly higher scores on both the positive and negative symptom scales of the Scale of Prodromal Symptoms (p<0.05) than those who did not want active treatment.

Clinical trials examining the impact of antipsychotic medication on preventing or delaying schizophrenia psychoses likely recruit a small proportion of eligible individuals. The fact that those who enter such a trial have greater symptoms than those who refused to participate in the trial demonstrates that putatively prodromal individuals who enter medication trials are sick individuals with significant impairment who may potentially be on the cusp of conversion. The majority of eligible subjects who have less marked symptoms prefer to be involved to some degree in a range of educational and psychological interventions.