Discontinuation of Risperidone and Risk of Relapse in Alzheimer’s Disease

Patients with Alzheimer’s disease (AD) often exhibit symptoms of psychosis or agitation. These symptoms are associated with patient distress, and increased caregiver burden, cognitive decline, risk of institutionalization, and healthcare costs.

Antipsychotic agents have shown superiority over placebo for patients with dementia and symptoms of psychosis and agitation-aggression; however, those agents are associated with only low-to-moderate efficacy. Side effects of antipsychotic agents include sedation, extrapyramidal signs, tardive dyskinesia, weight gain, and metabolic syndrome. In addition, short-term trials showing mortality in patients with dementia treated with antipsychotic agents led the FDA to issue a Black Box warning for those medications. Antipsychotic drugs are often discontinued in patients with dementia due to adverse effects and recommendations for early discontinuation.

Researchers recently conducted the ADAD (Antipsychotic Discontinuation in Alzheimer’s Disease) trial, a multicenter study in which patients with psychosis or agitation-aggression initially received open-label risperidone treatment. Risperidone was selected because its efficacy had been demonstrated in a large sample and there was an absence of serious side effects at low doses.

Patients who had a response to risperidone were then randomly assigned to continued risperidone therapy or to discontinuation of risperidone and a switch to placebo at specified time points. The risk of relapse was then compared among the groups. The researchers reported study results in the New England Journal of Medicine [2012;367(16):1497-1507].

Following an initial period of 16 weeks when study participants received treatment with risperidone, those who had a response to therapy were assigned to 1 of 3 study groups: those who received continued risperidone therapy for 32 weeks (group 1, those who received risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2), and those who received placebo for 32 weeks (group 3). The primary study outcome was time to relapse of psychosis or agitation.

Initially 180 patients received open-label risperidone at a mean dose of 0.97 mg daily. Of those, 112 met the criteria for a response; 110 underwent randomization. In the first 16-week period following randomization, those in group 3, compared with groups 1 and 2, had an increased risk of relapse (hazard ratio [HR] with placebo, 1.94; 95% confidence interval [CI], 1.09-3.45; P=.02). Twenty-four of the 40 patients in group 3 had a relapse, compared with 23 of 70 in groups 1 and 2 (P=.004).

For the second 16-week period, group 2 had an increased risk of relapse compared with group 1 (HR with placebo, 4.88; 95% CI, 1.08-21.98; P=.02). In group 2, 13 of 27 patients had a relapse, compared with 2 of 13 in group 1 (P=.02).

There were no significant differences in the rates of adverse events and death following randomization among the 3 groups. The researchers noted that the comparisons of adverse events were based on small numbers of patients, particularly during the final 16 weeks.

In conclusion, the researchers stated, “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.”