Otsuka America Pharmaceutical, Inc. (Otsuka) is pleased to submit the following comments for this meeting of the Advisory Council on Alzheimer's Research, Care, and Services. Otsuka appreciates HHS and ASPE's continued efforts to improve the level and quality of care for patients living with Alzheimer's disease and other forms of dementia. Like many other stakeholders, we are concerned about the use of antipsychotics in Alzheimer's patients and residents of long-term care facilities.
An estimated 5.5 million people age 65 and older in the US have Alzheimer's disease.1 In addition to cognitive decline and other neuropsychiatric symptoms, agitation is a common symptom of Alzheimer's disease that reduces health outcomes and increases costs and burden.2 As federal policymakers consider what has been achieved to date (antipsychotic usage in nursing homes reduced by 38%) and consider ways to further reduce unnecessary prescription use, Otsuka would highlight the following points:
- Federal policies should support thorough evaluation and treatment of patients with behavioral health issues living in long-term care facilities. Behavioral health issues may stem from varied sources, and should be addressed differently based on the underlying disease:
- For behavioral health issues related to underlying serious mental illness such as depression, bipolar disorder, or schizophrenia, antipsychotic medications are on-label for these uses and federal policies should not restrict appropriate access to these medications to patients for whom they are in fact appropriate.
- For behavioral health associated with Alzheimer's disease, such as agitation, non-pharmacologic interventions should be considered first to address other potential underlying causes and factors. Exceptions should be made in the case of emergent or acute episodes, or for patients currently stabilized on an antipsychotic for a previously diagnosed or co-occurring mental illness.
- Antipsychotic medications should be reasonably limited for use with dementia-related behaviors unresponsive to nonpharmacologic interventions, and within sound clinical guidelines and appropriately labelled indications for use. Although acute and/or persistent neuropsychiatric symptoms may not respond adequately to nonpharmacologic interventions alone, nonpharmacologic approaches should be evaluated for the potential to permit treatment with lower doses of antipsychotic medications.
- Federal policies should recognize and support appropriate and necessary use of antipsychotic medications for patients with neuropsychiatric symptoms.
- For antipsychotic use in long-term care facilities, policies should evaluate on-label and off-label use differently. Typical antipsychotics currently used off-label to treat agitation have significant side effects, including over-sedation.3
- Policy frameworks can and should differentiate between the use of antipsychotics for sedation or chemical restraint, both serious forms of patient abuse, and for the treatment of mental illness and dementia-related neuropsychiatric symptoms that improve patients' quality of life.
- Clinical indications and effectiveness should be reviewed periodically for all medications, including antipsychotics; however, attempts at gradual dose reduction may be inappropriate or clinically contraindicated for some patients whose behavioral symptoms are currently stabilized or who have a diagnosed serious mental illness.
Burden and impact of agitation in Alzheimer's disease
Behavioral symptoms develop in the majority of people with Alzheimer's disease and many of these symptoms are clinically diagnosed as "agitation," including restlessness, significant emotional distress, aggressive behaviors, and irritability. Symptoms of agitation place a serious burden on the people afflicted with the disease and their caregivers, significantly affecting the quality of life for all concerned. Agitation is often a determining factor in the decision to place patients in high-level residential care facilities, contributing to the roughly $259 billion cost burden of Alzheimer's disease in the U.S.4
Otsuka believes the Advisory Council should further consider the prevalence and clinical and economic burden of agitation in Alzheimer's disease when evaluating current programs and future efforts that impact people living with Alzheimer's and their caregivers. Specifically, the Council should keep in mind:
- Agitation covers a large group of behaviors occurring in patients with Alzheimer's disease, and is an excessive/inappropriate manifestation of 'normal' human emotions and behaviors. Symptoms of agitation include:
- Excessive motor activity (e.g. pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms).
- Verbal aggression (e.g. yelling, speaking in an excessively loud voice, using profanity, screaming, shouting).
- Physical aggression (e.g. grabbing, shoving, pushing, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things, and destroying property).5
- Symptoms of agitation in Alzheimer's disease are associated with significant burden and negative consequences for the patient.6,7,8,9,10,11
- Physical activity offers promise for the prevention of cognitive decline in older patients with Alzheimer's disease. A study in 437 elderly patients with a range of dementia severities shows that symptoms of agitation (as measured by the Neuropsychiatric Inventory, NPI) are associated with lower rates of participation in physical activities.12
- Symptoms of agitation, such as becoming upset easily, hoarding, and rejection of care such as bathing and dressing can interfere with the ability of a patient with Alzheimer's disease to carry out the activities of daily living.13
- Agitation and aggression commonly arise in people with Alzheimer's disease. This can be distressing for the individual and often confers risk to themselves and to others.14
- Symptoms of agitation in patients with Alzheimer's disease are associated with high burden and negative health, social and economic consequences for their caregivers.
- Fifty-nine percent of family caregivers of people with Alzheimer's and other dementias rated the emotional stress of caregiving as high or very high.15 In particular, problem behaviors (such as agitation) are consistently related to caregiver distress and depression.16,17
- Neuropsychiatric symptoms in Alzheimer's disease, including agitation, are associated with reduced employment income for caregivers.18 Data from the US report that almost 60% of US family caregivers of people with dementia are also employed; two thirds of these reported that they missed work, 8% that they turned down promotion opportunities, and up to 31% that they had given up work to attend to caregiving responsibilities.19
- Neuropsychiatric symptoms, including agitation can result in earlier placement in long-term care.20
- "...high frequency of distressing behavioural symptoms in patients with dementia can contribute to caregiver burnout, which is the most common cause of institutionalization of patients with dementia."21
- A systematic review of 80 studies found that behavioral symptoms, such as agitation, were a consistent predictor of nursing home admission in patients with dementia.22
- A 6-month study of the detailed clinical records of 3075 patients with Alzheimer's disease found that patients with symptoms of agitation were significantly more likely to be admitted to long-term care (care home, general hospital inpatient or mental health inpatient admission) during the course of the study than patients without (OR 1.97 [95% confidence interval (CI), 1.59-2.42], P<0.01).23
- Caregiver stress due to caring for an individual with behavioral symptoms (such as agitation) increases the chance that they will place the care recipient in a nursing home.24
- Behavioral symptoms present a dilemma to clinicians and care providers in a long-term care setting since disruptive or dangerous behavior requires attention and resources that are not always available.25
- Within long-term care facilities, 40-60% of Alzheimer's disease patients exhibit symptoms of agitation and aggression.26
- In a multicenter study comprising 236 patients with mild to moderate Alzheimer's disease followed over 5 years to map the natural course of illness, the percentage of patients per year experiencing agitation/wandering was 39-57%, and the percentage per year exhibiting physical aggression was 6-22%.27
- Patients diagnosed with Alzheimer's disease benefit from the development of a comprehensive treatment plan encompassing non-pharmocological and pharmacological interventions.28
- Nonpharmacological treatments for behaviors associated with Alzheimer's disease include activities such as identifying and eliminating triggers, environmental simplification, and structuring daily routines.29
- Current pharmacological treatments for agitation are associated with significant safety and tolerability trade-offs: "...as there are currently no FDA-approved pharmacological treatments for agitation in AD [Alzheimer's disease], clinicians ultimately resort to off-label use of antipsychotics, sedatives/hypnotics, anxiolytics and antidepressants in an attempt to control symptoms. Unfortunately, these treatments have limited utility given a modest efficacy that is offset by relatively poor adherence, safety and tolerability."30
- Treatment of symptoms of agitation in patients with Alzheimer's disease reduces caregiver burden and the cost of care for the patient.31
- Reducing the symptoms of agitation in a patient with Alzheimer's disease allows the caregiver to continue to manage the patient's activities of daily living at home.32
- Facilitating home care can delay the move from home to a long-term care setting, which has greater costs than home care by family. Annual residential cost per patient are: $48,000 in assisted living facilities, $89,297 in a nursing home, and $100,375 in a private room in a nursing home.33
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Otsuka appreciates the Advisory Council's consideration of our comments. We stand ready to assist with any of the issues raised in our letter. Please contact Thad Flood with any questions.
- Alzheimer's Association 2018. Facts and Figures 2018. Retrieved from https://www.alz.org/media/Documents/facts-and-figures-2018-r.pdf.
- Aigbogunet al. Treatment patterns and burden of behavioral disturbances in patients with dementia in the United States: a claims database analysis. BMC Neurology 2019; 19:33.
- American Psychiatric Association 2016, The APA Practice Guideline.
- Alzheimer's Association. 2017 Alzheimer's disease facts and figures. 2017; 13:325-373
- Cummings et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition, Int'l Psychogeriatrics (2015), 27:1, 7-17.
- Kales et al. Assessment and management of behavioral and psychological symptoms of dementia, BMJ 2015; 350:h369.
- Peters et al. Neuropsychiatric Symptoms as Predictors of Progression to Severe Alzheimer's Dementia and Death: The Cache County Dementia Progression Study, Am J Psychiatry 2015; 172:460-465.
- Scarmeas et al. Disruptive Behavior as a Predictor in Alzheimer Disease, Arch Neurol. 2007 December; 64(12): 1755-1761.
- Wilcock et al. Memantine for Agitation/Aggression and Psychosis in Moderately Severe to Severe Alzheimer's Disease: A Pooled Analysis of 3 Studies, J Clin Psychiatry 2008; 69:341-348.
- Banerjee et al. Quality of life in dementia: more than just cognition. An analysis of associations with quality of life in dementia, Neurol Neurosurg Psychiatry 2006;77:146-148.
- Arbus et al. Incidence and Predictive Factors of Depressive Symptoms in Alzheimer's Disease: The Real.FR Study, JNHA 2011; Vol. 15.
- Watts et al. (July, 2016) Neuropsychiatric Symptoms are a Barrier to Engegement in Physical Activity. Alzheimer's Association International Conference, Toronto.
- Lyketsos et al. Neuropsychiatric symptoms in Alzheimer's disease, Alzheimers Dement. 2011; 7(5): 532-539.
- Ballard et al. Agitation and aggression in people with Alzheimer's disease, Curr Opin Psychiatry 2013, 26:252-259.
- Alzheimer's Association 2015. Fact and Figures 2015. Retrieved from https://www.alz.org/media/Documents/2015FactsAndFigures.pdf.
- Pinquart et al. Associations of Stressors and Uplifts of Caregiving with Caregiver Burden and Depressive Mood: A Meta-Analysis, Journal of Gerontology: Psychological Sciences 2003, Vol. 58B, No. 2, 112-128.
- Schulz et al. Psychiatric and Physical Morbidity Effects of Dementia Caregiving: Prevalence, Correlates, and Causes, Gerontologist (1995) Vol. 35, No.6, 771-791.
- Kales et al. 2015
- Brodaty et al. Family caregivers of people with dementia, Dialogues Clin Neurosci. 2009; 11:217-228.
- Kales et al. 2015
- Blake et al. (March, 2002) Optimal Management of Psychosis & Agitation in the Elderly, Medscape. Retrieved 1/5/2017 from: http://www.medscape.org/viewarticle/429889.
- Gaugler et al. Predictors of Nursing Home Admission for Person with Dementia, Med Care 2009;47: 191-198.
- Knapp et al. Predictors of care home and hospital admissions and their costs for older people with Alzheimer's disease: findings from a large London case register, BMJ Open 2016; 6:e013591.
- Yaffe et al. Patient and Caregiver Characteristics and Nursing Home Placement in Patients with Dementia, JAMA April 2002; Vol. 287, No. 16.
- Greenblatt et al. Use of Antipsychotics for the Treatment of Behavioral Symptoms of Dementia, J Clin Pharmacology 2016, 56(9) 1048-1057.
- Gauthier et al. Management of behavioral problems in Alzheimer's disease, Int'l Psychogeriatrics (2010); 22:1, 346-372.
- Holtzer et al. Psychopathological Features in Alzheimer's Disease: Course and Relationship with Cognitive Status, JAGS 51:953-960, 2003.
- American Psychiatric Association 2016, The APA Practice Guideline on the Use of Antipsychotics to Treat Agitation or Psychosis in Patients with Dementia. Retrieved from https://psychiatryonline.org/doi/pdf/10.1176/appi.books.9780890426807.
- Gitlin et al. Managing Behavioral Symptoms in Dementia Using Nonpharmacologic Approaches: An Overview, JAMA. 2012 Nov 21; 308(19): 2020-2029.
- Antonsdottir et al. Advancements in treatment of agitation in Alzheimer's disease, Expert Opin. Pharmacother. (2015) 16(11):1649-1656.
- Hoe et al. Caring for relatives with agitation at home: A qualitative study of positive coping strategies. BJPsych Open (2017), 3(1), 34-40.
- Knapp et al. 2016.
- Gemworth Financial 2019. Cost of Care Survey 2018. Retrieved from https://www.genworth.com/aging-and-you/finances/cost-of-care.html.