Relapse Risk after Discontinuation of Risperidone in Alzheimer’s Disease

D.P. Devanand, M.D., Jacobo Mintzer, M.D., M.B.A., Susan K. Schultz, M.D., Howard F. Andrews, Ph.D., David L. Sultzer, M.D., Danilo de la Pena, M.D., Sanjay Gupta, M.D., Sylvia Colon, M.D., Corbett Schimming, M.D., Gregory H. Pelton, M.D., and Bruce Levin, Ph.D.

N Engl J Med 2012; 367:1497-1507 October 18, 2012 DOI: 10.1056/NEJMoa1114058

Relapse Risk after Discontinuation of Risperidone in Alzheimer’s Disease

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.)

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