Relapse risk after discontinuation of risperidone in Alzheimer's disease

Abstract

Background: Among patients with Alzheimer's disease who have had a response to antipsychotic medication for psychosis or agitation-aggression, the risk of a recurrence of symptoms after discontinuation of the medication has not been established.

Methods: Patients with Alzheimer's disease and psychosis or agitation-aggression received open-label treatment with risperidone for 16 weeks. Those who had a response to risperidone therapy were then randomly assigned, in a double-blind fashion, to one of three regimens: continued risperidone therapy for 32 weeks (group 1), risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2), or placebo for 32 weeks (group 3). The primary outcome was the time to relapse of psychosis or agitation.

Results: A total of 180 patients received open-label risperidone (mean dose, 0.97 mg daily). The severity of psychosis and agitation were reduced, although there was a mild increase in extrapyramidal signs; 112 patients met the criteria for response to treatment, of whom 110 underwent randomization. In the first 16 weeks after randomization, the rate of relapse was higher in the group that received placebo than in the groups that received risperidone (60% [24 of 40 patients in group 3] vs. 33% [23 of 70 in groups 1 and 2]; P=0.004; hazard ratio with placebo, 1.94; 95% confidence interval [CI], 1.09 to 3.45; P=0.02). During the next 16 weeks, the rate of relapse was higher in the group that was switched from risperidone to placebo than in the group that continued to receive risperidone (48% [13 of 27 patients in group 2] vs. 15% [2 of 13 in group 1]; P=0.02; hazard ratio, 4.88; 95% CI, 1.08 to 21.98; P=0.02). The rates of adverse events and death after randomization did not differ significantly among the groups, although comparisons were based on small numbers of patients, especially during the final 16 weeks.

Conclusions: In patients with Alzheimer's disease who had psychosis or agitation that had responded to risperidone therapy for 4 to 8 months, discontinuation of risperidone was associated with an increased risk of relapse. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00417482.).

Figure 1. Screening, Enrollment in Phase A, Randomization in Phase B, and Outcomes

A total of 12 patients discontinued the study after phase A and before randomization for reasons other than a lack of response, death, or unacceptable side effects; these other reasons included withdrawal of consent (7 patients), a move away from the study center (3), nonadherence to medication (1), and a medical illness (1). In the first 16-week period of phase B, 1 patient in group 1, 1 patient in group 2, and 2 patients in group 3 in whom a relapse was considered to be imminent (as assessed by an independent psychiatrist, who was unaware of the group assignments) were classified as having had a relapse.

Figure 2. Time from Randomization to Relapse among Patients Receiving Risperidone and Those Receiving Placebo

Panel A shows Kaplan–Meier curves for the risk of relapse during the first 16-week period of phase B (weeks 16 to 32 of the study) among the 70 patients who were randomly assigned to continue to receive risperidone (groups 1 and 2) and the 40 patients who were assigned to be withdrawn from risperidone at the end of phase A and switched to placebo (group 3). Panel B shows Kaplan–Meier curves for the risk of relapse during the second 16-week period of phase B (weeks 33 to 48 of the study) among the 13 patients who continued to receive risperidone (group 1) and the 27 patients who were switched to placebo at the end of the first 16-week period (group 2).