LOS ANGELES -- Two of three atypical antipsychotic drugs were no better than placebo at quieting aggression, psychosis, and agitation in patients with Alzheimer's disease, found a multicenter trial. Overall, adverse effects of all three outweighed the benefits.
LOS ANGELES, Oct. 11 -- Two of three atypical antipsychotic drugs were no better than placebo at quieting aggression, psychosis, and agitation in patients with Alzheimer's disease, found a multicenter trial.
Overall, the adverse effects of all three outweighed the benefits, Lon S. Schneider, M.D., of the University of Southern California, and colleagues, reported in the Oct. 12 issue of the New England Journal of Medicine. In the study of more than 400 such Alzheimer's patients, a majority were taken off the drugs.
In addition, up to a quarter of the patients taking the drugs dropped out because of adverse effects, compared with only 5% of those given placebo.
The study suggests that the atypical antipsychotics Zyprexa (olanzapine), Risperdal (risperidone), and Seroquel (quetiapine) do not provide significant clinical benefits in patients with Alzheimer's, the investigators wrote.
"Antipsychotic medications have been used extensively for Alzheimer's patients without enough solid evidence of whether they are effective," said Thomas R. Insel, M.D., director of the National Institute of Mental Health, which funded the study.
"The study has vital public health implications because it provides physicians and patients with information to more accurately weigh the medications' benefits against their drawbacks, with the needs and unique reactions of their individual patients," Dr. Insel said.
Atypical antipsychotic agents have revolutionized the treatment of schizophrenia and other conditions with psychotic components, but these agents are not approved for use in older patients with dementia.
In fact, the drugs carry an FDA-mandated black-box warning stating that "elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo," noted Jason Karlawish, M.D., of the Institute on Aging at the University of Pennsylvania, in an accompanying editorial.
To determine whether the drugs could play a role in controlling the symptoms of outpatient Alzheimer's patients, Dr. Schneider and co-investigators in the Clinical Antipsychotic Trials of Intervention Effectiveness -Alzheimer's Disease (CATIE-AD) study conducted a 42-site, double-blind, placebo-controlled trial.
The 421 participants had who exhibited delusions, hallucinations, aggression, or agitation that developed after the onset of dementia and was judged to be severe enough to disrupt their function and warrant treatment with antipsychotic agents.
The patients were randomly assigned to Zyprexa at a mean dose of 5.5 mg per day, Seroquel at a mean dose of 56.5 mg per day, Risperdal at a mean dose of 1.0 mg per day, or placebo. The drug doses were adjusted as needed, and patients were followed for up to 36 weeks.
The primary study outcomes were the time from the start of treatment to discontinuation for any reason, and the number of patients with at least a minimal improvement on the Clinical Global Impression of Change scale at 12 weeks.
The authors found that there were no significant differences among the groups with regard to discontinuation of treatment for any reason. The median time for patients to be taken off Zyprexa was 8.1 weeks, compared with 5.3 weeks Seroquel, 7.4 weeks for Risperdal, and 8.0 weeks for placebo (P=0.52).
When they looked at discontinuations due to lack of efficacy, they found that patients were kept on Risperdal and Zyprexa for significantly longer than either Seroquel or placebo. The median time for discontinuation due to lack of efficacy of Risperdal was 26.7 weeks, and for Zyprexa was 22.1 weeks, compared with 9.1 weeks for Seroquel, and 9.0 weeks for placebo (P=0.002).
When the investigators focused on discontinuation of treatment due to adverse events or intolerability, they found that 24% of patients who received Zyprexa, 16% who received Seroquel, 18% who received Risperdal were taken off their respective drugs, compared with 5% of patients who received placebo. The difference was significant in favor of placebo (P=0.009).
Overall, there were no significant differences among the groups with regard to improvement on the Clinical Global Impression of Change scale, with 32% of patients assigned to Zyprexa, 26% on Seroquel, 29% on Risperdal and 21% assigned to placebo having at least a minimal degree of improvement (P=0.22).
Zyprexa was significantly better than placebo (P=0.05) on initial assessment with the Cox model but not when compared with placebo by means of a Hochberg adjustment for multiple comparisons.
"Overall, the rates of discontinuation of treatment among the four study groups ranged from 77% to 85%, the authors wrote. "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."
They concluded, "Although the atypical antipsychotic drugs were more effective than placebo, adverse effects limited their overall effectiveness, and their use may be restricted to patients who have few or no side effects and for whom benefits can be discerned. Clinicians, patients, and family members must consider both risks and benefits in order to optimize a patient's care."
In his editorial, Dr. Karlawish hailed the CATIE-AD study as "an exemplar of the clinical trial's revolutionary role in shaping therapeutics. Recent remarks by FDA officials support wider use of these kinds of adaptive designs. This trial, funded by the National Institutes of Health, is also a model for how to spend our taxes on research, particularly now that taxes also pay for prescriptions."