Findings from a study of olanzapine, quetiapine, and risperidone in patients with Alzheimer's disease call into question the clinical value of these second-generation antipsychotic drugs and suggest that physicians should use them judiciously.
The double-blind, placebo-controlled trial of more than 400 patients demonstrated no clear benefit from treatment with the atypical antipsychotic medications in patients with psychosis, aggression, and agitation associated with Alzheimer's disease (N. Engl. J. Med. 2006;355:1525–38).
Overall, drug-related adverse events offset any advantages, said Dr. Lon S. Schneider, of the Keck School of Medicine at the University of Southern California, Los Angeles, and the other investigators of the National Institute of Mental Health's “Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer's Disease” (CATIE-AD) study group.
The 42-site trial assessed the effectiveness of olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal) in 421 patients with a broad spectrum of disease severity and behavioral problems that were severe enough to disrupt their functioning.
The patients, who were ambulatory and living at home or in an assisted-living facility, were randomized to receive one of the drugs or placebo and were followed for 36 weeks.
In a trial designed to reflect real-world clinical practice, physicians participating in the study determined their patients' starting doses and adjusted the doses or discontinued treatment as they saw necessary.
Medications were dispensed as identically-appearing small and large capsules containing lower and higher doses of the drugs.
During the study period, the physicians increased initial doses to a mean daily dose of 5.5 mg of olanzapine, 1 mg of risperidone, and 57 mg of quetiapine.
There was no significant difference between the groups in terms of the primary outcome, the length of time patients remained on the drugs before physicians decided to discontinue for any reason. The median time to discontinuation ranged from approximately 5 weeks with quetiapine to 8 weeks for olanzapine and placebo. Overall, 63% of patients were no longer receiving their medications at 12 weeks.
Nor were there significant differences between groups in terms of the number of patients with at least minimal improvement on the Clinical Global Impression of Change scale at 12 weeks.
Improvement was seen in 32% of patients on olanzapine, 29% of patients taking risperidone, 26% of patients on quetiapine, and 21% of patients assigned to placebo
Olanzapine and risperidone fared best in terms of the time to discontinuation of treatment because of “lack of efficacy,” (a median time of 22 weeks and 27 weeks, respectively).
This finding was offset, however, by increased rates of discontinuation because of “intolerability” or “adverse events” such as sedation or extrapyramidal symptoms. Treatment was stopped for these reasons in 24% of patients who received olanzapine, 18% of those on risperidone, 16% who received quetiapine, and 5% of those receiving placebo.
In an accompanying editorial, Dr. Jason Karlawish, who is with the Alzheimer's Disease Center in the University of Pennsylvania's Institute on Aging in Philadelphia, said that despite the Food and Drug Administration's warnings against the use of atypical antipsychotics in elderly patients with dementia-related psychosis, “clinicians, including me, continue to prescribe these drugs.”
Physicians “have done this without clear evidence of the nature and extent of the clinical value of antipsychotic medications–until now,” he wrote (N. Engl. J. Med. 2006;355:1604).
Dr. Karlawish noted that previous trials of treatment for behavioral problems in patients with Alzheimer's disease have assigned patients to fixed doses of drugs for fixed periods of time and have measured efficacy using measures of symptom severity, such as the Neuropsychiatric Inventory, that are not used in clinical practice.
Such study designs do not reflect clinical practice and “hence, will not likely lead to appropriate changes in clinical practice,” he said.
These new findings suggest that atypical antipsychotics may be “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 concluded.
The recent NEJM report covers phase I of the CATIE-AD study.
In a second phase of CATIE-AD, to be reported in the future, patients whose treatment was discontinued during the 36-week period of phase I could be randomly assigned to receive another one of the three atypical antipsychotic drugs. Or they might be assigned to receive the antidepressant medication citalopram (Celexa).
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