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Behavioral manifestations of Alzheimer disease (AD) are disabling and costly. In phase I of the 36-week, double-blind Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (CATIE–AD), 421 community-dwelling AD patients with delusions, hallucinations, aggression, or agitation were randomized to receive placebo or increasing doses of the atypical antipsychotic drugs, olanzapine, risperidone, or quetiapine (mean last doses, 5.5 mg/day, 1.0 mg/day, and 56.5 mg/day, respectively). Most patients required skilled caretaking and took multiple other medications for medical problems.
The groups had similar mean time to discontinuation for any reason (range, 5–8 weeks). Mean time to discontinuation due to lack of efficacy was significantly longer for olanzapine (22 weeks) and risperidone (27 weeks) than for placebo (9 weeks) and quetiapine (9 weeks). Significantly more medication recipients (range, 16%–24%) than placebo recipients (5%) discontinued treatment due to intolerance or adverse effects. Fewer than 20% of patients remained on their initially assigned drug.
The groups had similar rates of global improvement (range, 21%–32%) and similar proportions of patients with any serious adverse event. Compared with placebo, olanzapine and risperidone were associated with higher rates of parkinsonism or extrapyramidal symptoms (1% vs. 12%), olanzapine and risperidone with higher rates of confusion (5% vs. 11%–18%), and all three drugs with higher rates of sedation (5% vs. 15%–24%) and weight gain.
Schneider LS et al. Effectiveness of atypical antipsychotic drugs in patients with Azheimer's disease. N Engl J Med 2006 Oct 12; 355:1525-38.
Comment
Although atypical antipsychotics are widely prescribed for behaviorally disturbed patients with dementia, in this study they were generally no more effective than placebo, and most patients discontinued medication early on. Benefits seem confined to those few patients who can continue treatment. The expectation of a phase II in CATIE–AD may have discouraged clinicians from maintaining initial drug assignments or from increasing dosages to improve efficacy. Quetiapine is associated with sedation, which might prevent adequate dosing in elderly patients and might explain its low effectiveness. More research is needed on the efficacy of intraclass and interclass switches to alternative agents.