Clinical Health Updates

Atypical antipsychotics minimally effective, poorly tolerated in AD

Clinical Question:
Are the newer atypical antipsychotics effective in patients with Alzheimer’s disease?

Bottom Line:
Atypical antipsychotics are minimally, if at all, effective for patients with Alzheimer’s disease (AD), and they have significant adverse effects. They should not be routinely used for the treatment of psychosis, agitation, or aggression in these patients.

Schneider LS, Tariot PN, Dagerman KS, et al, with the CATIE-AD Study Group. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006;355:1525-1538.

Study Design:
Randomized controlled trial (double-blinded)

Although atypical antipsychotics are widely used in the treatment of psychosis, agitation, and aggression in patients with AD, clinical trials to date have been of limited duration and have not adequately addressed the tolerability of the drugs. In addition, there are new concerns regarding the safety of these drugs, with recent studies* finding an increased risk of death (relative risk = 1.6 – 1.7). In this study, the authors identified 421 outpatients with probable AD, a Mini-Mental State score between 5 and 26, and delusions, hallucinations, aggression, or agitation. They were randomized in a 2:2:2:3 ratio to olanzapine (Zyprexa, 2.5 mg or 5.0 mg), quetiapine (Seroquel, 25 mg or 50 mg), risperidone (Risperdal, 0.5 mg or 1.0 mg), or placebo. Whether to use the smaller or larger dose of each drug was determined by the study physicians, who were blinded to treatment assignment. They chose an unidentified small or large pill from an envelope, then adjusted the dose on the basis of patient response. Patients were followed up for up to 3 years; the primary outcomes were the time to discontinuation of the study drug and the degree of improvement on the Clinical Global Impression of Change (CGIC) scale at week 12. Groups were balanced at the start of the study and analysis was by intention to treat. The patients’ mean Mini-Mental State score was 15, their average age was 78 years, 56% were women, and 18% were African-American.

The average final doses of each drug were olanzapine 5.5 mg, quetiapine 56 mg, and risperidone 1.0 mg. The mean time to discontinuation was between 5.3 weeks and 8.1 weeks for the 4 groups, with no significant difference between groups. The atypical antipsychotics were more likely to be discontinued because of adverse effects (16% – 24% vs 5% for placebo), while placebo was more likely to be discontinued because of lack of efficacy (70% vs 39% – 53% vs 70% for active drugs). There was no significant difference between groups regarding the response as measured by the CGIC scale at 12 weeks (21% for placebo vs 26% – 32% for active drugs). Adverse effects occurring more frequently in patients receiving an active drug included parkinsonism or extrapyramidal signs (olanzapine and risperidone), sedation and weight increase (all 3 active drugs), and confusion (olanzapine and risperidone).