Among patients with Alzheimer’s disease whose symptoms of psychosis or agitation had decreased while they were receiving risperidone, the time to a relapse was shorter among those who discontinued risperidone and received placebo during the first 16 weeks after randomization than among those who continued to receive risperidone, and the risk of relapse was nearly double (60% vs. 33%). These findings were corroborated in the second 16-week period after randomization. Therefore, among patients who had a sustained response to risperidone for 4 to 8 months, subsequent discontinuation was associated with an increased risk of relapse for at least another 4 months.
Although discontinuation of risperidone resulted in an increased risk of relapse, risperidone was not highly effective in achieving and maintaining a reduction in symptoms of psychosis and agitation in patients with Alzheimer’s disease. Among patients who had had a response in phase A and continued to receive risperidone in phase B, a large proportion had a relapse or dropped out. The rates of discontinuation of risperidone treatment for any reason were 38% in the total cohort during phase A, 68% in group 1 during the 32 weeks of phase B, and 29% in group 2 during the 16 weeks in phase B in which they received risperidone. In contrast, the rate of discontinuation of initial risperidone treatment for any reason during an average of 7.4 weeks in the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (CATIE-AD) study was 77%.14
In trials of both short-term discontinuation27
and long-term discontinuation23
involving several antipsychotic drugs, increased baseline psychopathologic symptoms were associated with worsening condition when the patients discontinued the drug and were switched to placebo. However, in the current study, neither increased NPI scores at baseline or randomization nor the presence of psychosis at baseline or randomization predicted a relapse after discontinuation of risperidone and the switch to placebo in phase B.
During 4 months of initial open-label risperidone treatment, somatic side effects diminished, body weight did not change substantially, and extrapyramidal signs increased to some degree. In phase B, somatic side effects did not differ significantly between patients who continued to receive risperidone and those who were switched to placebo — even between patients who received risperidone for the entire 32-week period (group 1) and those who received placebo for the entire 32-week period (group 3), a finding that may be attributable to the low doses of risperidone used.23
In CATIE-AD, risperidone was not associated with weight gain or with the metabolic syndrome to the same extent as were olanzapine and quetiapine.15
In our study, progression of disease may underlie the small but significant decline in MMSE scores during the open-label treatment period (phase A), and the ADAS-cognitive score did not change significantly during this period. The change in MMSE scores did not differ significantly between patients who received risperidone and those who received placebo for the entire 8-month period after randomization. There is limited evidence that short-term exposure to antipsychotic drugs may worsen cognition,23,35
but long-term deleterious effects on cognition have not been established. Antipsychotic drugs with strong anticholinergic effects, such as olanzapine and clozapine, theoretically may worsen cognition, but data from patients with dementia are limited.36–39
The ADAD trial had some limitations. The sample size was inadequate to evaluate between-group differences in serious adverse events and mortality. Comparisons of adverse events in phase B were limited by the small sample and the truncated observation period for side effects in the case of patients who had an early relapse. The identification of predictors of relapse after discontinuation of risperidone treatment was limited by the small sample.
U.S. federal regulations for nursing homes strongly urge discontinuation of antipsychotic drugs after 3 to 6 months of treatment.20
Evidence from controlled trials in support of this long-standing regulation is very limited. Our findings suggest that patients with psychosis or agitation–aggression who have a sustained response to antipsychotic treatment for 4 to 8 months have a significantly increased risk of relapse for at least 4 months after discontinuation, and this finding should be weighed against the risk of adverse effects with continued antipsychotic treatment. Additional long-term, controlled trials of antipsychotic treatment and prospective, controlled trials of discontinuation of treatment among patients who have had a response to antipsychotic drugs are needed to inform current regulations that govern clinical practice.