by Jeff Ventimiglia, BSE; Amir H. Kalali, MD; Ipsit V. Vahia, MD; and Dilip V. Jeste, MD

Mr. Ventimiglia is an analyst in Clinical Strategy and Solutions, Quintiles, Inc., in Durham, North Carolina; Dr. Kalali is Vice President, Global Therapeutic Group Leader CNS, Quintiles, Inc., and Professor of Psychiatry, University of California, San Diego in San Diego, California. Drs. Vahia and Jeste are with the University of California, San Diego, in San Diego, California.

Psychiatry (Edgemont) 2010;7(11):14–17

Funding: There was no funding for the development and writing of this article. financial

Disclosures: Mr. Ventimiglia and Dr. Vahia report no conflicts of interest revelant to the content of this article; Dr. Kalali reports that he has served as an advisor to Merck, Novartis, Pfizer, and Vanda Pharmaceuticals; and Dr. Jeste reports that he has no financial relationship with any pharmaceutical companies; however, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen donate medication to his group’s NIMH-funded research grant, “Metabolic Effects of Newer Antipsychotics in Older Patients.”

Key words: Psychiatric, atypical antipsychotic, dementia, risk management, FDA warning

Abstract: In this article, the authors explore trends in intended usage of atypical antipsychotics to treat dementia following the United States Food and Drug Administration advisory safety warning issued in April 2005. Analysis suggests that physician-reported intended usage of antipsychotics to treat dementia has declined by nearly 50 percent over the past five years. When reviewing the products intended for use in the treatment of patients with dementia, atypical intended usage has declined considerably while the intended usage of anti-Alzheimer’s disease treatments has grown to replace those shares.


In April 2005, the United States Food and Drug Administration (FDA) issued an advisory warning citing an increased risk of mortality when using atypical antipsychotics to treat dementia. We investigated the intended prescribing habits of physicians for atypical antipsychotics to determine how this warning has affected use of these medications for treatment of dementia. Additionally, we sought to determine what class of drugs has experienced an increased intended-usage share to treat dementia patients.


We obtained data on class treatment from SDI/Verispan’s Prescription Drug & Diagnosis Audit (PDDA) database from January 2005 to July 2010 for patients with dementia as defined by the International Statistical Classification of Diseases and Related Health Problems, Ninth Edition (ICD-9) diagnosis codes 290 and 294. PDDA captures data on disease states and associated therapy from 3,100 office-based physicians representing 29 specialties across the United States. Intended use is determined by projected number of times a physician reports prescribing a product for the defined indication


A review of physician audit data of intended usage shows a peak in atypical antipsychotic usage in April of 2005 (Figure 1). Over the next five years, through July 2010, yearly totals of intended usage of atypical antipsychotics fell from over 700,000 to approximately 350,000; this is a decline of 50 percent. This analysis clearly shows a trend away from intended atypical antipsychotic usage since the advisory warning issued by the FDA; however, it does not indicate that physician-reported intended prescribing of atypical antipsychotics to treat dementia has ceased.

When analyzing the overall dementia marketplace, we see that over the past five years since the FDA warning share of physician-reported intended usage of antipsychotics has declined from 14 to 7 percent (Figure 2). While the share of intended usage of antipsychotics has declined, those shares have largely been replaced by anti-Alzheimer’s disease treatments. The share of intended usage of anti-Alzheimer’s disease treatments has risen from 69 to 80 percent of the market since the FDA advisory warning.

Expert Commentary
by Ipsit V. Vahia, MD, and Dilip V. Jeste, MD

Psychosis and agitation develop in as many as 60 percent of community-dwelling patients with dementia[1] and 80 percent of those in nursing homes.[2] Atypical antipsychotics are often used in this population despite a lack of FDA approval and black-box warnings. The data presented here show that, as may be expected, there has been a notable decline in the use of atypical antipsychotics in patients with dementia since the issuance of FDA black box warnings—first regarding the risk of cerebrovascular events with several atypical antipsychotics in older persons with dementia, issued in 2003–2005, and then regarding increased mortality with atypical antipsychotics as a class issued in 2005. Subsequently, the FDA black box warning regarding mortality was extended to conventional neuroleptics too.

Yet, atypical antipsychotics continue to be prescribed, albeit somewhat less frequently, largely because there are no preferable alternatives.3 There remains an absence of FDA-approved medications and a lack of evidence-based recommendations to guide the use of atypical antipsychotics or other medications for the treatment of behavioral disturbances in individuals with dementia.4 Severe and persistent psychosis, agitation, and aggression are the primary targets for off-label use of atypical antipsychotic drugs,5 and there is a need for well-designed clinical trials to assess use of different medications in this population.6 An interesting finding presented in Figure 2 is that an increase in prescriptions of anti-Alzheimer’s disease drugs appears to parallel the decline in the prescriptions of atypical antipsychotics. This may be attributable to clinicians selecting medications with better safety profiles. However, the evidence is inconclusive regarding the efficacy of cognitive enhancers in controlling psychotic or other behavioral symptoms in people with dementia.

The role of psychosocial and other nonpharmacological interventions needs to be stressed. Consensus recommendations point to these as a first-line treatment approach in many patients with agitation and aggression.6 While no psychosocial intervention has been studied in large, randomized, controlled trials, there are encouraging preliminary data supporting the use of several interventions to prevent or manage agitation, including stimulus control, problem-solving therapy, optimal cognitive stimulation, and physical activity.7 The more effective nonpharmacological interventions are individually tailored and may include a combination of approaches. Agitation and aggression often have identifiable and potentially addressable precipitants, such as pain, medical illness, boredom, loneliness, or other social/environmental stressors.4,6 In many (but not all) cases, targeting these precipitants may be a safer and more effective approach than use of medications.

In summary, the data presented here show that the medical community has heeded the black-box warnings regarding use of atypical antipsychotics in patients with dementia, yet these drugs remain in use, in the absence of evidence-based alternatives. There is a need to find safer alternative treatments and develop specific treatment guidelines. When medications are indicated, short-term off-label use for acute symptoms is preferable to long-term use of medications including atypical antipsychotics. The issues of risk-to-benefit ratio and informed consent from patients and caregivers deserve careful attention.4

1.     Lyketsos CG, Steinberg M, Tschanz JT, et al. Mental and behavioral disturbances in dementia: findings from the Cache County Study on memory in aging. Am J Psychiatry. 2000;157:708–714.
2.     Testad I, Aasland AM, Aarsland D. Prevalence and correlates of disruptive behavior in patients in Norwegian nursing homes. Int J Geriatr Psychiatry. 2007;22:916–921.
3.     Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;355:1525–1538.
4.     Jeste DV, Blazer D, Casey DE, et al. ACNP White Paper: Update on the use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology. 2008;33:957–970.
5.     Jeste DV, Finkel SI. Psychosis of Alzheimer’s disease and related dementias: diagnostic criteria for a distinct syndrome. Am J Geriatr Psychiatry. 2000;8:29–34.
6.     Salzman C, Jeste DV, Meyer RE, et al: Elderly patients with dementia-related symptoms of severe agitation and aggression: consensus statement on treatment options, clinical trials methodology, and policy. J Clin Psychiatry. 2008;69:889–898.
7.     Vernooij-Dassen M, Vasse E, Zuidema S, et al. Psychosocial interventions for dementia patients in long-term care. Int Psychogeriatr. 2010;22:1121–1128.