- Email: [email protected]
Antipsychotics and Dementia: Where Do We Go From Here?
Letters to the Editor / JAMDA 14 (2013) 306e308 3. Cohen-Mansfield J, Jensen B. Assessment and treatment approaches for behavioral disturbances associated with dementia in the nursing home: Selfreports of physicians’ practices. J Am Med Dir Assoc 2008;9:406e413. 4. Shorr RI, Fought RL, Ray WA. Changes in antipsychotic drug use in nursing homes during implementation of the OBRA-87 regulations. JAMA 1994;271:358e363. 5. Mitka M. CMS seeks to reduce antipsychotic use in nursing home residents with dementia. JAMA 2012;308:119e121. 6. Lindsley CW. The top prescription drugs of 2011 in the United States: Antipsychotics and antidepressants once again lead CNS therapeutics. ACS Chem Neurosci 2012;3:630e631. 7. Cohen CA, Gold DP, Shulman KI, et al. Factors determining the decision to institutionalize dementing individuals: A prospective study. Gerontologist 1993;33:714e720. 8. Franco KN, Messinger-Rapport B. Pharmacological treatment of neuropsychiatric symptoms of dementia: A review of the evidence. J Am Med Dir Assoc 2006;7:201e202. 9. Volicer L. Antipsychotics do not have to be used “off label” in dementia. J Am Med Dir Assoc 2012;13:495e496. 10. Seitz DP, Adunuri N, Gill SS, et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev 2011;(2):CD008191. 11. Siddique H, Hyan LS, Weiner MF. Effect of a serotonin reuptake inhibitor on irritability, apathy, and psychotic symptoms in patients with Alzheimer’s disease. J Clin Psychiatry 2009;70:915e918. 12. Bergh S, Selbæk G, Engedal K. Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): Double blind, randomised, parallel group, placebo controlled trial. BMJ 2012;344:e1566. 13. Fitzgerald SP, Bean NG. An analysis of the interactions between individual comorbidities and their treatmentsedimplications for guidelines and polypharmacy. J Am Med Dir Assoc 2010;11:475e484. 14. Liperoti R, Gambassi G, Lapane KL, et al. Conventional and atypical antipsychotics and the risk of hospitalization for ventricular arrhythmias or cardiac arrest. Arch Intern Med 2005;165:696e701. 15. Malhotra AK, Zhang JP, Lencz T. Pharmacogenetics in psychiatry: Translating research into clinical practice. Mol Psychiatry 2012;17:760e769. 16. Cohen-Mansfield J, Thein K, Marx MS, Dakheel-Ali M. What are the barriers to performing nonpharmacological interventions for behavioral symptoms in the nursing home? J Am Med Dir Assoc 2012;13:400e405. 17. Landi F, Liperoti R, Bernabei R. Postacute rehabilitation in cognitively impaired patients: Comprehensive assessment and tailored interventions. J Am Med Dir Assoc 2011;12:395e397. 18. Morley JE. Antipsychotics and dementia: A time for restraint. J Am Med Dir Assoc 2012;13:761e763. 19. Nakanishi M, Hattori K, Nakashima T, Sawamura K. Priority for elderly persons with behavioral and psychological symptoms of dementia on waiting lists for placement in nursing homes in Japan: Do nursing homes change priorities based on their own guidelines? J Am Med Dir Assoc 2012;13:794e799. 20. Locca JF, Büla CJ, Zumbach S, Bugnon O. Pharmacological treatment of behavioral and psychological symptoms of dementia (BPSD) in nursing homes: Development of practice recommendations in a Swiss canton. J Am Med Dir Assoc 2008;9:439e448.
Rosa Liperoti, MD, MPH Francesco Landi, MD, PhD Department of Geriatrics Catholic University of the Sacred Heart Rome, Italy http://dx.doi.org/10.1016/j.jamda.2013.01.006
Antipsychotics and Dementia: Where Do We Go From Here? To the Editor: In recent editions of the Journal of the American Medical Directors Association (JAMDA), Drs Morley1 and Volicer2 have brought to the readership a strong plea to cease or drastically reduce using antipsychotic medications for the treatment of neuropsychiatric symptoms in dementia. True to the audience of JAMDA, much of this treatment occurs in long term care facilities. Both writers, calling on complementary but different evidence bases and logic, suggest
307
primarily antidepressants as a replacement for antipsychotic medications. Morley1 also provides an algorithm that includes, at different decision points, exercise, a quiet room (Namaste therapy), and a stimulating room (Snoezalen therapy), given the needs of the patient. Volicer2 focuses on the use of antidepressants as first-line therapy, perhaps augmented by antipsychotic therapy if the antidepressant is not effective. The concern about overuse of antipsychotic medications, especially for patients with dementia in long term care facilities, is, of course, not new.3 Current and past approaches to reduce antipsychotic therapy in dementia fall into 3 broad categories: (1) alternative medications to antipsychotic medications; (2) education about the medications ranging from “soft sell” to emphatic warnings about the dangers of antipsychotic medications; and (3) alternative nonpharmacologic therapies. Each approach can be effective, yet each approach also is fraught with challenges. Drs Morley1 and Volicer2 advocate primarily the first approach, to provide an alternative medication. The challenge in managing neuropsychiatric behaviors in dementia with medications is that the effectiveness of these medications (including antipsychotic medications) is modest at best and possibly equivocal or detrimental. The very plethora of medications that are used, ranging from antipsychotics through antidepressants and antianxiety agents to even medications for treating the dementia itself (such as donepezil) suggests we are far from finding an effective pharmacological approach to controlling these neuropsychiatric symptoms. The second approach is educational. For example, in one study, investigators used a simple educational approach, a study of the efficacy of a physician-to-physician visit in the service of reducing antipsychotic drug prescribing for nursing home patients.4 Frequent antipsychotic drug prescribers were visited by a trained physician counselor who stressed known drug risks for elderly patients and suggested techniques for reducing antipsychotic drug use. Although well received, the visits did not reduce antipsychotic drug prescribing. In contrast, an “educational intervention,” which has proven effective, is to emphatically warn the clinician of dangerous side effects deriving from their use. The effectiveness of this approach has been demonstrated by the black box warning implemented by the Food and Drug Administration, first in 2005 to cover the newgeneration antipsychotics and updated in 2008 to include oldgeneration antipsychotics as well.4 The warning reads as follows: “Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.” This warning is found in the package insert for antipsychotic medications to this day. Following the black box warning, antipsychotic prescription to patients with dementia did drop significantly.5 In a study of Department of Veterans Affairs (VA) patients nationally beginning in 1999, 17.7% of patients with dementia were using atypical or conventional antipsychotics, yet use was declining gradually. Following the black box warning, decline continued with a significant difference between the early and black box warning periods. Use of new-generation antipsychotics as a group increased during the no-warning period (the hope being at the time that these medications had few significant side effects), yet declined during the early-warning period and declined more sharply during the black box warning period.6 The challenge to the effectiveness of the black box warning is that, in and of itself, it provides no guidance for alternatives, which may lead to a wide range of other medications being used based on little empirical evidence. In other words,
308
Letters to the Editor / JAMDA 14 (2013) 306e308
the clinician chooses from a large but not that appetizing menu of agents, yet feels a need to feed the patient something, given the disruptive behavior of the demented patient. The third approach is to provide an alternative nonpharmacologic intervention, an effort that has been ongoing for decades. In an illustrative study from more than 3 decades ago, investigators developed and tested a comprehensive program to reduce antipsychotic use through education of physicians, nurses, and other nursing home staff.7 The primary elements of the program were instruction in use of behavioral techniques to manage behavior problems and encouragement of a trial of gradual antipsychotic withdrawal. A nonrandomized controlled trial, the program was implemented (beginning in August 1990) in 2 rural Tennessee community nursing homes with elevated antipsychotic use; 2 other comparable homes were selected as concurrent controls. Staff in the intervention group received in-depth instruction on managing behaviors for which antipsychotic medications are usually prescribed. Days of antipsychotic use decreased by 72% in the education homes versus 13% in the control homes. Days of physical restraint use decreased 36% in the education homes versus 5% in the control homes (P < .001). Behavior problem frequency did not increase in either group, even among the 48% of baseline antipsychotic users in the education homes who had antipsychotic drug regimens. The challenge to these nonpharmacologic approaches is that the number of therapies empirically tested has been small, yet the number of approaches is myriad. This is well illustrated in a recent meta-analysis. The authors reviewed the effectiveness of community-based nonpharmacological interventions for neuropsychiatric symptoms for dementia delivered through family caregivers.8 From more than 1000 studies culled from a comprehensive literature review, only 23 met criteria for inclusion based on randomized design. Nonpharmacological interventions were effective in reducing behavioral and psychological symptoms, with an overall effect size of 0.34 (P < .01), as well as in ameliorating caregiver reactions to these behaviors, with an overall effect size of 0.15 (P ¼ .006). Yet the range of approaches to intervention across these 23 selected studies is so broad that no generalization is possible regarding the critical elements of an effective intervention. In addition, even those approaches backed by some evidence base are expensive to implement. The financial constraints placed on long term care usually preclude the addition of such approaches except in demonstration projects because the nonpharmacological intervention is considered an “add on” to existing therapies. The paradox is that if a nonpharmacological intervention were effective and if it meaningfully reduced the use of antipsychotic medications, a net cost savings may be possible.
Where do we go from here? It seems that academic physicians almost always call for “a well-designed clinical trial” when current evidence does not provide a clear approach to management of a problem. Yet that is exactly what we do need, with a twist. Given the scope of the problem, we need a large multiarmed effectiveness (not efficacy) trial that considers the joint use of medications other than antipsychotics, coupled with behavioral interventions for the neuropsychiatric symptoms of dementia. The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial design may serve as a model (although that trial focused specifically on medications).9 This real-world trial provides a guideline for setting up a real-world testing of interventions that can be both combined and sequenced (much as Dr Morley’s algorithm directs). We need a real-world trial set in long term care facilities that mirrors the setting in which antipsychotic medications are most likely to be used for treating the neuropsychiatric symptoms of dementia.
References 1. Morley JE. Antipsychotics and dementia: A time for restraint? J Am Med Dir Assoc 2012;13:761e763. 2. Volicer L. Antipsychotics do not have to be used "off label" in dementia. J Am Med Dir Assoc 2012;13:495e496. 3. Ray WA, Federspiel CF, Schaffner WA. A study of antipsychotic drug use in nursing homes: Epidemiologic evidence suggesting misuse. J Public Health 1980;70:485e491. 4. Ray WA, Blazer DG 2nd, Schaffner W, Federspiel CF. Reducing antipsychotic drug prescribing for nursing home patients: A controlled trial of the effect of an educational visit. Am J Public Health 1987;77:1448e1450. 5. US Department of Health and Human Services, Public Health Advisory. Deaths with antipsychotics in elderly patients with behavioral disturbances. http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116912. htm. Accessed December 16, 2012. 6. Kales HC, Zivin K, Kim HM, et al. Trends in antipsychotic use in dementia 1999e2007. Arch Gen Psychiatry 2011;68:190e197. 7. Ray WA, Taylor JA, Meador KG, et al. Reducing antipsychotic drug use in nursing homes. A controlled trial of provider education. Arch Intern Med 1993;153: 713e721. 8. Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry 2012;169: 946e953. 9. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry 2006;163:1905e1917.
Dan G. Blazer, MD, PhD Department of Psychiatry and Behavioral Sciences Duke University Medical Center Durham, NC http://dx.doi.org/10.1016/j.jamda.2013.01.007
Rosa Liperoti, MD, MPH Francesco Landi, MD, PhD Department of Geriatrics Catholic University of the Sacred Heart Rome, Italy http://dx.doi.org/10.1016/j.jamda.2013.01.006
Antipsychotics and Dementia: Where Do We Go From Here? To the Editor: In recent editions of the Journal of the American Medical Directors Association (JAMDA), Drs Morley1 and Volicer2 have brought to the readership a strong plea to cease or drastically reduce using antipsychotic medications for the treatment of neuropsychiatric symptoms in dementia. True to the audience of JAMDA, much of this treatment occurs in long term care facilities. Both writers, calling on complementary but different evidence bases and logic, suggest
307
primarily antidepressants as a replacement for antipsychotic medications. Morley1 also provides an algorithm that includes, at different decision points, exercise, a quiet room (Namaste therapy), and a stimulating room (Snoezalen therapy), given the needs of the patient. Volicer2 focuses on the use of antidepressants as first-line therapy, perhaps augmented by antipsychotic therapy if the antidepressant is not effective. The concern about overuse of antipsychotic medications, especially for patients with dementia in long term care facilities, is, of course, not new.3 Current and past approaches to reduce antipsychotic therapy in dementia fall into 3 broad categories: (1) alternative medications to antipsychotic medications; (2) education about the medications ranging from “soft sell” to emphatic warnings about the dangers of antipsychotic medications; and (3) alternative nonpharmacologic therapies. Each approach can be effective, yet each approach also is fraught with challenges. Drs Morley1 and Volicer2 advocate primarily the first approach, to provide an alternative medication. The challenge in managing neuropsychiatric behaviors in dementia with medications is that the effectiveness of these medications (including antipsychotic medications) is modest at best and possibly equivocal or detrimental. The very plethora of medications that are used, ranging from antipsychotics through antidepressants and antianxiety agents to even medications for treating the dementia itself (such as donepezil) suggests we are far from finding an effective pharmacological approach to controlling these neuropsychiatric symptoms. The second approach is educational. For example, in one study, investigators used a simple educational approach, a study of the efficacy of a physician-to-physician visit in the service of reducing antipsychotic drug prescribing for nursing home patients.4 Frequent antipsychotic drug prescribers were visited by a trained physician counselor who stressed known drug risks for elderly patients and suggested techniques for reducing antipsychotic drug use. Although well received, the visits did not reduce antipsychotic drug prescribing. In contrast, an “educational intervention,” which has proven effective, is to emphatically warn the clinician of dangerous side effects deriving from their use. The effectiveness of this approach has been demonstrated by the black box warning implemented by the Food and Drug Administration, first in 2005 to cover the newgeneration antipsychotics and updated in 2008 to include oldgeneration antipsychotics as well.4 The warning reads as follows: “Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.” This warning is found in the package insert for antipsychotic medications to this day. Following the black box warning, antipsychotic prescription to patients with dementia did drop significantly.5 In a study of Department of Veterans Affairs (VA) patients nationally beginning in 1999, 17.7% of patients with dementia were using atypical or conventional antipsychotics, yet use was declining gradually. Following the black box warning, decline continued with a significant difference between the early and black box warning periods. Use of new-generation antipsychotics as a group increased during the no-warning period (the hope being at the time that these medications had few significant side effects), yet declined during the early-warning period and declined more sharply during the black box warning period.6 The challenge to the effectiveness of the black box warning is that, in and of itself, it provides no guidance for alternatives, which may lead to a wide range of other medications being used based on little empirical evidence. In other words,
308
Letters to the Editor / JAMDA 14 (2013) 306e308
the clinician chooses from a large but not that appetizing menu of agents, yet feels a need to feed the patient something, given the disruptive behavior of the demented patient. The third approach is to provide an alternative nonpharmacologic intervention, an effort that has been ongoing for decades. In an illustrative study from more than 3 decades ago, investigators developed and tested a comprehensive program to reduce antipsychotic use through education of physicians, nurses, and other nursing home staff.7 The primary elements of the program were instruction in use of behavioral techniques to manage behavior problems and encouragement of a trial of gradual antipsychotic withdrawal. A nonrandomized controlled trial, the program was implemented (beginning in August 1990) in 2 rural Tennessee community nursing homes with elevated antipsychotic use; 2 other comparable homes were selected as concurrent controls. Staff in the intervention group received in-depth instruction on managing behaviors for which antipsychotic medications are usually prescribed. Days of antipsychotic use decreased by 72% in the education homes versus 13% in the control homes. Days of physical restraint use decreased 36% in the education homes versus 5% in the control homes (P < .001). Behavior problem frequency did not increase in either group, even among the 48% of baseline antipsychotic users in the education homes who had antipsychotic drug regimens. The challenge to these nonpharmacologic approaches is that the number of therapies empirically tested has been small, yet the number of approaches is myriad. This is well illustrated in a recent meta-analysis. The authors reviewed the effectiveness of community-based nonpharmacological interventions for neuropsychiatric symptoms for dementia delivered through family caregivers.8 From more than 1000 studies culled from a comprehensive literature review, only 23 met criteria for inclusion based on randomized design. Nonpharmacological interventions were effective in reducing behavioral and psychological symptoms, with an overall effect size of 0.34 (P < .01), as well as in ameliorating caregiver reactions to these behaviors, with an overall effect size of 0.15 (P ¼ .006). Yet the range of approaches to intervention across these 23 selected studies is so broad that no generalization is possible regarding the critical elements of an effective intervention. In addition, even those approaches backed by some evidence base are expensive to implement. The financial constraints placed on long term care usually preclude the addition of such approaches except in demonstration projects because the nonpharmacological intervention is considered an “add on” to existing therapies. The paradox is that if a nonpharmacological intervention were effective and if it meaningfully reduced the use of antipsychotic medications, a net cost savings may be possible.
Where do we go from here? It seems that academic physicians almost always call for “a well-designed clinical trial” when current evidence does not provide a clear approach to management of a problem. Yet that is exactly what we do need, with a twist. Given the scope of the problem, we need a large multiarmed effectiveness (not efficacy) trial that considers the joint use of medications other than antipsychotics, coupled with behavioral interventions for the neuropsychiatric symptoms of dementia. The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial design may serve as a model (although that trial focused specifically on medications).9 This real-world trial provides a guideline for setting up a real-world testing of interventions that can be both combined and sequenced (much as Dr Morley’s algorithm directs). We need a real-world trial set in long term care facilities that mirrors the setting in which antipsychotic medications are most likely to be used for treating the neuropsychiatric symptoms of dementia.
References 1. Morley JE. Antipsychotics and dementia: A time for restraint? J Am Med Dir Assoc 2012;13:761e763. 2. Volicer L. Antipsychotics do not have to be used "off label" in dementia. J Am Med Dir Assoc 2012;13:495e496. 3. Ray WA, Federspiel CF, Schaffner WA. A study of antipsychotic drug use in nursing homes: Epidemiologic evidence suggesting misuse. J Public Health 1980;70:485e491. 4. Ray WA, Blazer DG 2nd, Schaffner W, Federspiel CF. Reducing antipsychotic drug prescribing for nursing home patients: A controlled trial of the effect of an educational visit. Am J Public Health 1987;77:1448e1450. 5. US Department of Health and Human Services, Public Health Advisory. Deaths with antipsychotics in elderly patients with behavioral disturbances. http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116912. htm. Accessed December 16, 2012. 6. Kales HC, Zivin K, Kim HM, et al. Trends in antipsychotic use in dementia 1999e2007. Arch Gen Psychiatry 2011;68:190e197. 7. Ray WA, Taylor JA, Meador KG, et al. Reducing antipsychotic drug use in nursing homes. A controlled trial of provider education. Arch Intern Med 1993;153: 713e721. 8. Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry 2012;169: 946e953. 9. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry 2006;163:1905e1917.
Dan G. Blazer, MD, PhD Department of Psychiatry and Behavioral Sciences Duke University Medical Center Durham, NC http://dx.doi.org/10.1016/j.jamda.2013.01.007