Comment on the U.S. Food and Drug Administration’s (FDA) Advisory on Off-Label Use of Atypical Antipsychotics in the Elderly

Comment Date: July 13, 2005

These comments are based on published data available at this time. The AAGP reserves the right to edit these comments should new data be published.

Background
Psychiatric symptoms, which almost universally accompany dementia especially in the late stages, cause inordinate suffering. They degrade the quality of life of patients with dementia and their caregivers and are associated with excess morbidity and mortality. Nonetheless, compared with investments made to develop pharmacotherapy for cognitive symptoms, systematic efforts to improve the use of medications to treat non-cognitive behavioral symptoms (NCBS) such as agitation and psychosis, have been modest. In consequence, there is a very sparse base of evidence regarding the efficacy and safety of many medications commonly used to treat these symptoms. In this context, the American Association for Geriatric Psychiatry (AAGP) commends the efforts of some manufacturers to conduct controlled pharmacotherapy trials in patients suffering from dementia-related, non-cognitive behavioral symptoms.

FDA Action
On April 12, 2005, the U.S. Food and Drug Administration (FDA) issued a public health advisory to notify healthcare providers, patients, and caregivers of a newly identified concern associated with the off-label use of atypical antipsychotic medications for the treatment of dementia-related behavioral disorders in the elderly. This advisory, based on an FDA analysis of data from 17 placebo-controlled trials of aripiprazole, olanzapine⁴, quetiapine, and risperidone^1,2,3, in 5,106 elderly patients with dementia-related behavioral disorders, found these antipsychotic medications to be associated with a 1.6 to 1.7-fold increase in mortality rate when antipsychotic-treated patients were compared to placebo-treated patients during these acute trials. To our knowledge, only four of the 17 trials on which the FDA based this advisory warning have been published (3 with risperidone^1,2,3, and 1 with olanzapine⁴). Although no placebo-controlled trials of ziprasidone or clozapine were conducted, it is reasonable to view the increased mortality as a class effect and that older typical antipsychotic medications may present equal or greater mortality risks. In this regard, it is worth noting that there has also been evidence published recently from an extensive Centers for Medicare and Medicaid (CMS) database that atypical antipsychotic medications, compared to older antipsychotics, do not appear to be associated with an increased risk of ventricular arrhythmias or cardiac arrest⁵.

Although atypical antipsychotic medications are approved by the FDA only for the treatment of schizophrenia or mania, healthcare providers have relied heavily upon them for pharmacologic treatment of NCBS seen in elderly patients with dementia. Several studies, summarized in a Cochrane Review and in a recent systematic review published in the Journal of the American Medical Association (JAMA)⁶ cite the clinically modest, but significant reductions in NCBS demonstrated among elderly subjects treated with risperidone or olanzapine. To date, while some efficacy has been noted in published placebo-controlled trials conducted with non-antipsychotic medications such as carbamazepine, citalopram, donepezil, galantamine, or memantine, the data is even more limited than that of the atypical antipsychotics.

AAGP’s Comments
It is AAGP’s opinion that the available evidence of short-term trials conducted in nursing home patients suggests that risperidone and olanzapine may be beneficial for some of the non-cognitive symptoms accompanying dementia. Nevertheless, the decision to use any medication in this fragile population must be made on the basis of individual circumstances. In the face of even more limited data for alternative pharmacotherapy, AAGP does not believe that the use of atypical antipsychotic medications for treatment of psychiatric symptoms in dementia should be suspended on the basis of the FDA advisory. Clinicians might first consider nonpharmacologic methods and should carefully assess and reassess the individual benefit of using any medication to treat NCBS against the potential risks.

For the present, it is prudent when using atypical antipsychotic medications for any patient, and particularly when using them for an off-label indication, to include in the informed consent process a mention of the possible association of treatment with increased mortality among patients with dementia, in addition to the other potential adverse effects, such as cerebrovascular events or metabolic syndrome.

The AAGP also continues to call for escalated research to evaluate and improve treatment options for these symptoms in patients suffering from dementia.

Note: The information contained in this document should not be used to establish an exclusive course of treatment and should not substitute for the independent judgment of the physician.

References:
1 Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: A randomized, double-blind trial. J Clin Psychiatry. 1999 Feb;60(2):107-15.

2 De Deyn PP, Rabheru K, Rasmussen A, Bocksberger JP. Dautzenberg PL. Eriksson S. Lawlor BA. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology. 1999 Sep 22;53(5):946-55.

3 Brodaty H, Ames D, Snowdon J, Woodward M, Kirwan J, Clarnette R, Lee E, Lyons B, Grossman F. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry. 2003 Feb;64(2):134-43.

4. Street JS, Clark WS, Gannon KS, Cummings JL, Bymaster FP, Tamura RN, Mitan SJ, Kadam DL, Sanger TM, Feldman PD, Tollefson GD, Breier A. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group. Archives Gen Psychiatry. 2000 Oct;57(10):968-76.

5. Liperoti R, Gambassi G, Lapane KL, Chiang C, Pedone C, Mor V, Bernabei R. Conventional and atypical antipsychotics and the risk of hospitalization for ventricular arrhythmias or cardiac arrest. Arch of Intern Med. 2005 Mar 28;165(6):696-701.

6. Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA. 2005 Feb 2;293(5):596-608.

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