New findings questioning the value of second-generation antipsychotics (SGAs) for treating acute behaviors in patients with Alzheimer’s disease have raised more questions on when and how to use these agents in the elderly.
The National Institute of Mental Health-sponsored Clinical Antipsychotic Trial of Intervention Effectiveness-Alzheimer’s disease (CATIE-AD) concluded that SGAs offer no overall advantage over placebo. Although SGAs helped some trial patients, the medications were discontinued for approximately 8 in 10 patients because of intolerable side effects or ineffectiveness.
CATIE-AD’s principal investigator says the findings—published in the October 12 New England Journal of Medicine1—will guide clinicians in adjusting SGA dosages and durations for older patients with dementia.
But other psychiatrists argue that the study—led by prominent researchers and published in a prestigious medical journal—will deter clinicians from trying SGAs for older patients with dementia-related psychosis, aggression, or agitation.
Barbara Kamholz, MD
Clinical associate professor, department of psychiatry, University of Michigan Medical School; staff psychiatrist, VA Medical Center, Ann Arbor
Lon Schneider, MD
Professor of psychiatry, neurology, and gerontology, University of Southern California, Los Angeles
Sumer Verma, MD
Director, geriatric psychiatry education program, McLean Hospital, Belmont, MA
“These drugs are not FDA-approved for dementia. They may cause diabetes. They cause weight gain. They carry boxed warnings that they could increase risk of stroke and—in patients over age 85—can increase risk of dying,” says Sumer Verma, MD, director of the geriatric psychiatry education program at McLean Hospital (Belmont, MA). “Doctors already were reluctant to use SGAs, and now these researchers publish this study in one of the country’s most respected journals and make an unqualified statement to the effect that [SGAs] are no better than placebo. How many clinicians will be comfortable prescribing them?”
421 outpatients with psychosis, agitation, or aggression, or who met DSM-IV-TR criteria for Alzheimer’s-type dementia or probable Alzheimer’s disease based on history, physical examination, structural brain imaging results, and Mini-Mental State Examination scores between 5 and 26, indicating some degree of cognitive deficit. These patients:
- were ambulatory
- lived at home or in an assisted-living facility
- had delusions, hallucinations, aggression, or agitation that developed after dementia onset, disrupted functioning, and justified treatment with an antipsychotic
- showed signs and symptoms of psychosis, aggression, or agitation almost daily during the previous week or intermittently for 4 weeks.
Up to 36 weeks
Study drugs/mean dosages at endpoint
- olanzapine (5.5 mg/d)
- quetiapine (56.5 mg/d)
- risperidone (1 mg/d)
Physicians could increase dosages or prescribe a benzodiazepine or haloperidol if problem behaviors emerged.
- Time to discontinuing treatment for any reason did not differ significantly among the treatment and placebo groups.
- Median time to discontinuation because of lack of efficacy was significantly longer with olanzapine (22.1 weeks) or risperidone (26.7 weeks) than with quetiapine (9.1 weeks) or placebo (9.0 weeks).
- Rates of discontinuation because of intolerance, adverse effects, or death were 24% with olanzapine, 16% with quetiapine, 18% with risperidone, and 5% with placebo.
- Overall rates of discontinuation for any reason were 63% after 12 weeks and 82% after 36 weeks.
- Parkinsonism or extrapyramidal symptoms were more prevalent among the olanzapine and risperidone groups (12% in each) than among the quetiapine and placebo groups (2% and 1%, respectively).
- Sedation was more common with the three SGAs (15% to 24% of patients) than with placebo (5%).
- Confusion or mental status changes were more common with olanzapine (18%) and risperidone (11%) than with placebo (5%). Cognitive disturbances and psychotic symptoms were more common with olanzapine (5% and 7%, respectively) than with the other SGAs or placebo (0 to 2%).
- Body weight increased 0.4 to 1 lb/month among the SGA groups and decreased 0.9 lb/month in the placebo group.
- Rates of improvement—as measured with the Clinical Global Impression of Change scale—did not differ significantly among the treatment and placebo groups.
CATIE-AD—a double-blind, multicenter, randomized trial (Box)—followed 421 ambulatory outpatients with Alzheimer’s disease and psychosis, aggression, or agitation. Patients received the SGAs olanzapine (mean dosage, 5.5 mg/d), quetiapine (mean 56.5 mg/d), risperidone (mean 1 mg/d), or placebo. Dosages were adjusted as needed.
After 36 weeks, times to discontinuation because of lack of efficacy were longest for olanza-pine and risperidone, but these drugs also had the highest rates of discontinuation because of intolerability (24% and 18%, respectively). Quetiapine’s rate of discontinuation because of intolerability was 16%.
SGAs were stopped because of lack of efficacy or intolerable side effects—such as parkinsonism, extrapyramidal symptoms, sedation, or weight gain—in:
- 63% of treatment and placebo group patients within 12 weeks
- 82% of all patients within 36 weeks.
Lon Schneider, MD, principal investigator for CATIE-AD, acknowledged that the findings could discourage psychiatrists from prescribing SGAs for acute dementia-related behaviors, specifically in patients with Alzheimer’s disease.