112. Effects of Ziprasidone Versus Placebo in Patients at Clinical High Risk for Psychosis

Background: Treatment guidelines for the clinical high risk (CHR) syndrome for psychosis currently recommend psychotherapies such as cognitive behavior therapy and focused family therapy as first line treatment. Antipsychotic medications are generally discouraged for routine use, partly because of concern for adverse effects and partly due to a paucity of efficacy data, although some guidelines recommend them for more severe cases. The current study evaluated the safety and efficacy of ziprasidone in delaying or preventing conversion to psychosis among individuals meeting CHR syndrome criteria. Methods: Eligible subjects were treatment-seeking individuals 16 to 40 years old who met diagnostic criteria for CHR according to the Structured Interview for Psychosis-risk Syndromes. Exclusions were (1) use of antipsychotic medication in the previous 3 months, (2) initiation or increase in dosage of an antidepressant within 6 weeks, or (3) medical contraindications to taking ziprasidone (QTcF≥450 msec at screening or baseline, history of arrhythmia or QTc prolongation or syncope, family history of QTc prolongation, current receipt of medication known to prolong QTc, or K+, Mg++, or Ca++ below the normal range). Randomized subjects received ziprasidone 20–160 mg/d vs matching placebo for 24 weeks in two divided doses with meals. In addition, each subject was offered a Supportive Interpersonal Therapy session at each visit. Target enrollment was 80. Analyses were conducted in SPSS 21. Results: Six sites randomized 51 subjects, 27 to placebo, and 24 to ziprasidone. One ziprasidone case was never dispensed medication and was removed from analysis. Two conversions were identified in the placebo group and one in the active group; Cox regression showed no significant effect. Mixed regression on the SOPS positive symptom subscale with slope and intercept each modeled as random effects revealed a significant difference favoring ziprasidone (F = 6.64, df = 1.21, P = .017, slope difference −0.19 points per week, 95% CI −0.35 to −0.04). Two patients met QTcF criteria for safety withdrawal; both were assigned to placebo. Maximum QTcF across follow-up (placebo mean 407 msec, ziprasidone mean 403 msec) did not differ significantly. Mixed regression on weight measurements revealed no significant treatment effect (F = 0.22, df = 1.37, P = 0.645, slope difference −0.05 pounds per week, 95% CI −0.29 to 0.18). Conclusion: The primary outcome was not met, in part because the study did not meet its enrollment target and was consequently underpowered. The significant drug effect on attenuated positive symptoms provides some evidence for efficacy of ziprasidone in CHR syndrome. Together with the lack of QTc prolongation or significant weight gain in this study, the current evidence of efficacy supports consideration of ziprasidone when an antipsychotic is selected for clinical use in CHR syndrome.