Antipsychotics appeared to increase the risk of death in patients with Alzheimer's disease, especially if taken for more than 12 months, in a randomized controlled trial.
Nursing home patients with Alzheimer's who continued taking the drugs for 1 year were 7% more likely to die than were those who discontinued them, and the mortality difference escalated over the 4-year study. By the end of the trial, just 26% of those taking the drugs were still alive, compared with 53% of those taking a placebo, Dr. Clive Ballard of King's College, London, and his associates wrote in the Lancet (doi:10.1016/S1474–4422[08]70295–3
The authors did support a limited use of the drugs, particularly in patients with severe dementia-related aggression, geriatrician Karl Steinberg noted in an interview. But the risks must be carefully considered.
“The authors make it clear that in some clinical situations, the benefits of treatment seem to outweigh the risks, but it's important to obtain informed consent when we choose to utilize them,” said Dr. Steinberg, who is in a group practice in Oceanside, Calif.
The findings seem to support the Omnibus Budget Reconciliation Act of 1987, which mandated gradual dose reductions of antipsychotics in nursing home residents, he added. “We need to keep in mind that the patients for whom we prescribe these medications are suffering from significant dementia and already nearing the end of life, where quality of life should be a major concern.”
The trial comprised 165 nursing home residents with Alzheimer's disease (mean age 89 years). At baseline, all patients were taking an antipsychotic medication. Most (93%) were taking either risperidone or haloperidol; other agents included thioridazine, chlorpromazine, and trifluoperazine.
Patients were randomized to either continue treatment (83) or discontinue treatment by taking a placebo. Because 37 patients did not start treatment, 64 were left in each treatment group. The 12-, 24-, 36-, and 42-month survival rates were analyzed among those who began taking their study medication, regardless of whether they stopped at any time during the study.
After 12 months, those on placebo were 7% more likely to survive than were those on an active agent (70% vs. 77%); the difference was statistically significant. The disparity grew as the trial continued. At 24 months, the cumulative survival rate was 71% in the placebo group vs. 46% in the active group; at 36 months, the rate was 59% vs. 30%; and at 42 months, it was 53% vs. 26%.
Death certificates were available for 78%. More deaths of a probable vascular nature occurred in the placebo group; there was no indication that antipsychotics contribute to cerebrovascular deaths. The reasons why the biggest difference in mortality occurred after the first 12 months of the trial are unclear, the researchers wrote.
They noted that up to 60% of nursing home residents with dementia in Europe and North America receive antipsychotic medication, despite studies suggesting that the risks outweigh any possible benefit.
“There is clear evidence of a significant increase in adverse events, including parkinsonism, sedation, oedema, chest infections, accelerated cognitive decline, and cerebrovascular events in patients with Alzheimer's treated with antipsychotics,” they noted. Alternative treatments include psychological management, memantine, and antidepressants, which “might be safer and effective for some neuropsychiatric symptoms.”
The results confirm other evidence of a link between the drugs and increased morbidity and mortality in dementia patients, Alzheimer's researcher Marwan Sabbagh said in an interview. “This risk was the impetus for the black box warning issued by the FDA for risk associated with antipsychotic use specifically in dementia,” said Dr. Sabbagh, director of clinical research at the Sun Health Research Institute, Sun City, Ariz.
“What makes this more compelling is that it is not simply an observational study. Rather, this is objective evidence in a randomized, placebo-controlled study that [Alzheimer's disease] subjects taking antipsychotics had demonstrable increases in mortality,” Dr. Sabbagh said. “This should compel practitioners to employ additional caution when administering this class of medication to demented individuals.”
The study was funded by the U.K. Alzheimer's Research Trust. Dr. Ballard noted financial relationships with many companies that manufacture antipsychotics and Alzheimer's medications.