Antipsychotics demonstrate minimal benefit in treatment of psychosis, aggression, agitation in patients with AD

Adverse events associated with the use of atypical antipsychotic medications in the management of psychosis, aggression, and agitation in patients with Alzheimer's disease (AD) may outweigh any benefit the treatments provide, according to a double-blind, placebo-controlled study published in the New England Journal of Medicine (NEJM).

The authors stated that although atypical antipsychotics can be beneficial, side effects limited the overall effectiveness of treatment in this study. The authors also noted that physicians often quickly changed treatments when adverse effects or lack of efficacy were observed. The authors suggested limiting treatment with atypical antipsychotics to "patients who have few or no side effects and for whom benefits can be discerned."

The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) study, conducted from April 2001 to November 2004 at 42 sites (university clinics, Veterans Affairs medical centers, and private practice sites), included 421 outpatients with AD and psychosis, agitation, or aggression. The authors sought to gauge the efficacy of olanzapine, quetiapine, and risperidone compared with placebo.

Follow-up duration was 36 weeks; researchers assessed patients' weight and prolactin, glucose, cholesterol, and triglyceride levels at 12, 24, and 36 weeks. The primary outcome was the amount of time to discontinuation of the therapy for any reason; the chief secondary outcome was the number of patients demonstrating at least slight improvement on the Clinical Global Impression of Change (CGIC) scale after 12 weeks.

The overall rate of treatment termination at 12 weeks was 63%. By the end of the 36-week follow-up period, 82% of patients had stopped their original treatment. Researchers observed no significant differences among treatments regarding time to discontinuation of treatment for any reason: olanzapine median, 8.1 weeks; quetiapine median, 5.3 weeks; risperidone median, 7.4 weeks; and placebo median, 8.0 weeks. However, the risperidone and olanzapine groups demonstrated longer durations of time before discontinuation of treatment due to lack of effectiveness when compared with placebo (risperidone, 26.7 weeks; HR=0.61; P=.01; olanzapine, 22.1 weeks; HR=0.51; P<.001). For patients taking quetiapine, time until the discontinuation of therapy due to lack of efficacy (9.1 weeks) was similar to the time observed with placebo.

Discontinuation rates for adverse effects, intolerance of the drug, or death were 24% for patients taking olanzapine, 16% for patients taking quetiapine, 18% for patients taking risperidone, and 5% for patients taking placebo. Patients taking 1 of the 3 treatment drugs were much more likely to stop treatment than those taking placebo (olanzapine, HR=4.32; 95% CI, 1.84–10.12; quetiapine, HR=3.58; 95% CI, 1.44–8.91; risperidone, HR=3.62; 95% CI, 1.45–9.04).

By Week 12, the proportions of patients demonstrating a favorable response with the initial medication based on CGIC score were as follows: 32% of patients assigned to olanzapine, 26% of those assigned to quetiapine, 29% of those assigned to risperidone, and 21% of those assigned to placebo (P=.22).

The authors stated: "Although the differences among the groups may have been significant in a larger trial, our findings suggest that there is no large clinical benefit of treatment with atypical antipsychotic medications as compared with placebo."

In an accompanying editorial, Jason Karlawish, MD, commenting on the medications in the CATIE-AD trial, stated: "These drugs have a limited, but at times necessary, role in the care of patients with Alzheimer's disease. They are perhaps best prescribed in systems of care that can provide the skills and expertise needed to ensure that the risks associated with the drugs are justified by their potential benefits."

Dr Karlawish further highlighted the primary end point of the CATIE-AD study, saying it was "based on a real-world measure of clinical practice: the decision to change treatment after a reasonable time to allow titration to a therapeutic dose of the drug." He concluded by stating that the CATIE-AD study is an "exemplar of the clinical trial's revolutionary role in shaping therapeutics."

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

Karlawish J. Alzheimer's disease-clinical trials and the logic of clinical purpose[editorial]. N Engl J Med. 2006;355:1604–1606.