Atypical Antipsychotics in Dementia

To the Editor:

The recent review article by Keys and DeWald¹ on the use of atypical antipsychotics in dementia is disturbing. The authors breeze by the thorny issue of whether the use of antipsychotic drugs—of any kind—is appropriate in people with dementia and behavior disorders without psychosis. The issue is certainly controversial, but the data hardly support the widespread use of these drugs in those without psychosis. Indeed, their use in venues that are overseen by government agencies is highly regulated because of longstanding misuse and the harm that such misuse does to older Americans.

While the authors provide references, they fail to state that none of these trials, alone or in combination, has been adequate to convince the FDA that such use of antipsychotics is appropriate. None of the atypical antipsychotics has an indication for anything other than schizophrenia. An indication for use of an antipsychotic drug in this population is highly desirable by drug companies, and all makers have been seeking such an indication for many decades without success; they have failed because they have not been able to present adequate data demonstrating effectiveness.

Of the 38 references, six were from poster presentations. Several others are from journals not indexed in Current Contents, a strong indicator of a poor-quality journal. I do not think that this paper serves your readership well.

Sincerely,
Mark H. Beers, MD
Merck Manuals Blue Bell, PA

Reference

1. Keys MA, DeWald C. Clinical perspective on choice of atypical antipsychotics in elderly patients with dementia, Part II. Annals of Long-Term Care: Clinical Care and Aging 2005;13(3):30-38.

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Authors’ response:

Your comments, and hopefully the issues presented in our two-part article,^1,2 are timely with respect to the recent U.S. Food and Drug Administration (FDA) advisory warning regarding the off-label use of atypical antipsychotic medications for the treatment of dementia-related behavioral disorders in the elderly due to an increased risk of mortality. The warning was based on an analysis of 17 placebo-controlled, 10-week trials showing that the use of olanzapine, aripiprazole, risperidone, and quetiapine in 5106 elderly patients with dementia-related behavioral disorders was associated with an increased risk of mortality compared with placebo (4.5% vs 2.6%). Most deaths appeared to be related to cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) causes. The FDA has recommend that clinicians review the use of atypical agents in patients with dementia.³

Many of the issues you raise were addressed in Part I of the article.¹ The article was not a meta-analysis of research trials, but a broad review of studies of each of the atypical agents that are being prescribed in this population. Studies cited involving the most recent medications, aripiprazole and ziprasidone, constitute five of the six nonpublished poster presentations cited. We felt that they were reasonable to include because they represented what little data was available on these agents in this population. Indeed, it is an important point that risperidone, olanzapine, and quetiapine have been better studied and offered the clinician better safety and efficacy data to help promote clinical choice. We would go further and point out that the majority of the studies cited involving all these agents in this patient population are sponsored by the pharmaceutical industry, and may be criticized for concern of potential inherent bias.

The federal government sends two different messages to clinicians. The FDA does not recognize psychosis and behavioral symptoms of dementia as a treatment indication, largely because no pharmaceutical company, to our knowledge, has formally applied for an indication. That may change in the near future. On the other side, the Federal Nursing Home Reform Act, or OBRA ’87, developed clear guidelines and indications for the use of antipsychotic medications in nursing home settings, including indications for psychotic and behavioral symptoms associated with dementia. The study by Liperoti et al⁴ suggests increasingly more appropriate and uniform use of these medications in nursing home settings.

Finally, there is the important question of whether atypical antipsychotics are ever appropriate for persons with nonpsychotic behavioral symptoms associated with dementia. Emerging data from the [National Institutes of Mental Health] NIMH-sponsored Clinical Antipsychotic Trial of Intervention Effectiveness-Alzheimer’s Disease (CATIE-AD) study may give us better insight into this question. The longstanding clinical assumption has been that antipsychotics should be reserved for only classical psychotic symptoms of hallucinations and delusions. New data suggest that this may not necessarily be true. Consider: How common are auditory hallucinations in Alzheimer’s disease? Are visual hallucinations responsive to antipsychotics on a consistent basis? Common delusional themes such as “people are stealing from me,” “my house is not my home,” and spousal infidelity may be less responsive to antipsychotic medications than in comparative paranoia and bizarre delusions seen in schizophrenia. In contrast, verbal and physical aggressiveness associated with dementia may show relative greater response than previously thought. Over the next several months, the data from the CATIE-AD trial will be presented and hopefully will give us better answers and insight into these issues.

The bottom line is that the patients with neurodegenerative disorders displaying psychosis and behavioral symptoms are a heterogeneous and complex group of patients to manage. Are atypical antipsychotics associated with serious adverse events contributing to increased mortality and morbidity requiring careful monitoring? Of course. Are atypical antipsychotics the treatment of choice for every patient with behavioral problems associated with dementing disorders? Clearly not. These should not be viewed as broad-spectrum agents. Efficacy and tolerance will need to be more narrowly defined and considered. However, to the question, “Do atypical antipsychotics offer reasonable tolerability, safety, and efficacy to a significant number of patients, improving quality of life for both patients and caregivers?” our clinical experience is clearly yes.

For clinicians who manage these patients day to day, we feel that the burden of clinical responsibility has now fallen to us not only to explain risk, benefit, and alternatives to patients, families, and caregivers, but to solely accept adverse outcomes as well. For the immediate future, we will have to be up to the task. As the FDA asks clinicians to review current treatment of patients receiving atypical antipsychotics, we would hope that clearer guidelines would be forthcoming as to what are the meaningful and better alternatives.

Sincerely,
Michael Keys, MD, and Carol Dewald, MSN
Cincinnati, OH 

1. Keys MA, DeWald C. Clinical perspective on choice of atypical antipsychotics in elderly patients with dementia, Part I. Annals of Long-Term Care: Clinical Care and Aging 2005;13(2):26-32.

2. Keys MA, DeWald C. Clinical perspective on choice of atypical antipsychotics in elderly patients with dementia, Part II. Annals of Long-Term Care: Clinical Care and Aging 2005;13(3):30-38.

3. FDA Public Health Advisory. Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances. April 11, 2005.

4. Liperoti R, Mor V, Lapane KL, et al. The use of atypical antipsychotics in nursing homes. J Clin Psychiatry 2003;64(9):1106-1112.