Preventing overuse of antipsychotic drugs in nursing home care

Transcription

1 Balanced information for better care Preventing overuse of antipsychotic drugs in nursing home care Safer alternatives

2 Preventing overuse of antipsychotic drugs in nursing home care Safer alternatives Principal Consultants: Eran Metzger, M.D., David Osser, M.D. Series Editors: Jerry Avorn, M.D., Niteesh K. Choudhry, M.D., Ph.D., Michael Fischer, M.D., M.S., Eimir Hurley, BSc (Pharm), MBiostat. Medical Writer: Stephen Braun The Independent Drug Information Service (IDIS) is supported by the Massachusetts Department of Public Health and the PACE Program of the Department of Aging of the Commonwealth of Pennsylvania. This material is provided by the Alosa Foundation, a nonprofit organization, which is not affiliated with any pharmaceutical company. None of the authors accepts any personal compensation from any pharmaceutical company. These are general recommendations only; specific clinical decisions should be made by the treating physician based on an individual patient s clinical condition. For more information, visit

3 ii Preventing overuse of antipsychotic drugs in nursing home care

4 Alosa Foundation Preventing overuse of antipsychotic drugs in nursing home care: Safer alternatives Activity overview: The primary goal of the educational program is to help nursing home clinicians better manage the behavioral and psychological symptoms of dementia and reduce the reliance on antipsychotic medications in this population. The program synthesizes the clinical literature on the risk-benefit relationship of antipsychotic medication use in the elderly, most notably the elevated risk of mortality. It also presents practical advice on non pharmacological approaches, and identifying the reversible clinical, psychological and environmental triggers of behavioral problems in patients with dementia. In addition to providing this evidence report, the education program uses an innovative approach, academic detailing, one-on-one educational sessions with specially trained outreach educators (pharmacists, nurses, physicians) who present the educational material interactively. Reference cards for clinicians and education materials for family members are also provided. Key messages of the module: 1. Antipsychotic medications are often overused in older patients in nursing homes, and they increase risk of death and can cause substantial side effects. 2. In managing behavioral and psychological symptoms in patients with dementia, begin by ruling out any reversible clinical, psychological, or environmental triggers. 3. Identify specific target behaviors and set realistic treatment goals. 4. Initiate non drug interventions first in most patients, and continue these even if drug treatment is required. 5. If an antipsychotic medication must be used to manage a specific, identified, dangerous behavior not responding to non-drug approaches, do so cautiously. 6. Regularly re-assess and re-evaluate the need for ongoing antipsychotic medication use; discontinue if the targeted behavior is not improving. 7. Screen for specific side effects at baseline and at regular intervals. Disclosures: This material is provided by the Alosa Foundation, a nonprofit organization which is not affiliated with any pharmaceutical company. No commercial support has been received for this activity. None of the planners/authors have any financial relationships to disclose. The Independent Drug Information Service (IDIS) is supported by the Massachusetts Department of Public Health and the PACE Program of the Department of Aging of the Commonwealth of Pennsylvania. Preventing overuse of antipsychotic drugs in nursing home care iii

5 Faculty and Planners: Jerry Avorn, M.D. is a Professor of Medicine at Harvard Medical School and Chief of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital. An internist, he has worked as a primary care physician and geriatrician and has been studying drug use and its outcomes for over 30 years. Dr. Avorn has no relevant financial relationships to disclose. Niteesh K. Choudhry, M.D., Ph.D. is an Associate Professor of Medicine at Harvard Medical School and a hospitalist at Brigham and Women's Hospital. His research focuses on the use of medications to treat common chronic conditions. Dr. Choudhry has no relevant financial relationships to disclose. Michael Fischer, M.D., M.S. is an Associate Professor of Medicine at Harvard Medical School and a primary care internist who studies cost effective drug use in outpatient practices. Dr. Fischer has no relevant financial relationships to disclose. Eran Metzger, M.D. is an Assistant Professor in Psychiatry at Harvard Medical School and Director of Psychiatry, Hebrew SeniorLife. Dr. Metzger has no relevant financial relationships to disclose. David Osser, M.D. is an Associate Professor of Psychiatry at Harvard Medical School and a psychiatrist at the VA Boston Healthcare System. Dr. Osser has no relevant financial relationships to disclose. Eimir Hurley, BSc (Pharm), MBiostat is the Program Director at the Alosa Foundation. Her interest lies in the design, implementation and evaluation of programs to improve prescribing. Ms. Hurley has no relevant financial relationships to disclose. Stephen R. Braun, B.A. is a medical writer based in Amherst, MA. Mr. Braun has no relevant financial relationships to disclose. iv Preventing overuse of antipsychotic drugs in nursing home care

6 Table of Contents Introduction... 1 Overview of antipsychotic medications... 3 Antipsychotic drug risks and side effects... 3 Mortality... 3 Stroke... 5 Major APM side effects in elderly patients... 5 Strategies for managing behavioral and psychological symptoms of dementia (BPSD).. 11 BPSD overview Acute vs. non acute BPSD Non pharmacologic management strategies Pharmacologic management of BPSD: general principles Antipsychotic Medications Other pharmacological treatment options Medications with insufficient evidence to support use in patients with BPSD Antipsychotic medications in the management of acute BPSD Is it delirium? Non pharmacologic management Pharmacologic management APMs as augmentation for major depressive disorder APMs for psychotic depression Conclusions Appendix 1: Key characteristics of 2nd generation APMs Appendix 2: Black box warning concerning mortality risk of antipsychotic drugs Appendix 3: Massachusetts guidance on the use of APMs in long term care facilities References Preventing overuse of antipsychotic drugs in nursing home care v

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8 Introduction Residents of nursing homes, especially those with cognitive impairment, may sometimes present a range of symptoms 1,2 including yelling, physical aggression, apathy, hostility, sexual disinhibition, defiance, wandering, psychotic symptoms (hallucinations or delusions), emotional lability, and paranoid behavior. 3,4 The term behavioral and psychological symptoms of dementia (BPSD) is often used to describe these symptoms, although they may occur in patients without dementia as well. BPSD are common. Up to 90% of patients with dementia have such symptoms at some stage during their illness. 1,2,4-6 The prevalence of some component of BPSD in community dwelling patients with dementia is estimated at 60 88%. 7,8 Historically, a range of medications have been prescribed to help manage real or perceived behavior problems in elderly patients, including antidepressants, benzodiazepines, and antipsychotic medications (APMs). Since at least the 1980s, however, the widespread use of APMs to manage behavior problems in nursing homes has been questioned. The clinical literature demonstrates clearly that APMs offer minimal benefits as chronic treatment for behavioral problems in nursing home residents, and that they have welldocumented risks including cardiac events, pneumonia, stroke, and death as well as metabolic derangements including hyperglycemia and elevated cholesterol. In contrast, non-drug strategies can often effectively address many behavioral issues with far fewer risks than medications. In specific clinical circumstances, APMs may have a limited role, but such instances are far less common than would be justified by the current high level of use in this setting. Figure 1: In a meta-analysis of 15 randomized trials, patients given an atypical antipsychotic drug had higher rates of deaths than patients given placebo 9 4.0% 3.5% 3.0% Death rate 2.5% 2.0% 1.5% 1.0% 0.5% Placebo 54 % relative increase in mortality Atypical antipsychotic 0.0% These results are based on a meta-analysis of clinical trials of aripiprazole, olanzapine, quetiapine, and ripseridone. Other studies, which led to the FDA black box warning, found a 60-70% increased risk of death. Following a 1986 Institute of Medicine report citing the overuse of both APMs and physical restraints in nursing homes, new regulations were added to the federal Nursing Home Reform Act of 1987, aimed at curbing the use of physical or chemical restraints imposed for purposes of discipline or convenience. 10 Preventing overuse of antipsychotic drugs in nursing home care 1

9 However, despite this and other federal and state initiatives, APMs continue to be widely used in nursing homes. A 2009 study found that antipsychotic medications were being administered to 33% of elderly nursing home residents with dementia. 11 In one nationwide study of APM use in nursing homes, 83% of use was for off-label conditions, and 88% for conditions that were the subject of an FDA black box warning of increased risk of death in patients taking APMs. 12 None of these widely-used drugs has an FDA-approved indication for the management of behavioral symptoms in elderly patients with dementia. Figure 2: APMs are often prescribed for nursing home patients with dementia who have no indication for their use 13 40% Use not indicated 23% Proportion of patients with non-aggressive behavioral problems who are prescribed an antipsychotic drug Proportion of patients with no behavioral problems who are prescribed an antipsychotic drug More recently, the Centers for Medicare & Medicaid Services (CMS) found that more than 1 in 5 nursing home residents were prescribed antipsychotic medications in the first quarter of 2013, despite the absence of a diagnosis that would warrant such use. 14 A number of programs have sought to address this problem at all levels of government and in both the public and private sectors, and have begun to produce some changes. In 2012, CMS launched the Partnership to Improve Dementia Care, which brought together nursing home leaders, clinicians, pharmacists, drug makers and patients with the goal of reducing the overuse of APMs in nursing homes. In 2013, CMS reported a 9% reduction in the number of nursing home residents receiving one of these drugs between 2011 and These and other efforts, such as those being made by the Massachusetts Senior Care Foundation, are important in light of the increasing numbers of people in long-term care facilities. With the aging of the population especially the baby-boomer generation the need for such care in the U.S. is expected to rise from 13 million people in 2000 to 27 million in About 54% of elderly nursing home residents are diagnosed with dementia, 16 which makes behavioral symptoms such as aggression, delusions, or hallucinations more likely. 11 In addition, about a quarter of newly admitted nursing home residents have a psychiatric diagnosis (other than dementia) such as schizophrenia, bipolar disorder, depression, or anxiety. 17 These conditions can also lead to problematic behavior, and may co exist with dementia. 2 Preventing overuse of antipsychotic drugs in nursing home care

10 This evidence document reviews the evidence base for the use of APMs in nursing home residents and provides information about non-drug strategies that can be used to reduce the incidence and severity of disruptive or dangerous behaviors in these vulnerable patients. BOTTOM LINE: Antipsychotic medications continue to be widely used in older patients in nursing homes despite: (a) their lack of an approved indication for such use; (b) minimal evidence that they are effective for chronic use in such settings; and (c) their well established adverse effects and increased risk of death. Overview of antipsychotic medications The first APMs were introduced to the U.S. market in the early 1950 s. These first-generation drugs were used primarily to treat major psychiatric conditions such as schizophrenia. The second-generation APMs, known as atypical antipsychotics, were introduced in the mid 1990 s, starting with clozapine in 1989, then risperidone in 1994 and others in later years (see Appendix 1 for a complete list of secondgeneration APMs available as of early 2014). Although APMs are FD-approved specifically for the treatment of major psychiatric disorders such as schizophrenia and bipolar disorder, for which they are quite effective, they have been widely used (and illegally promoted) for off-label for conditions including anxiety, insomnia, chronic pain, and behavioral symptoms in elderly patients with cognitive impairment. 11,18 All APMs share the common characteristic of binding to dopamine 2 (D 2 ) receptors in several areas of the brain, with the affinity of such binding related to the potency of the drug. 19 The drugs also differ in their binding affinity to non dopamine neurotransmitter receptors. Antipsychotic drug risks and side effects Antipsychotic medications pose a range of potential risks and side effects, some life threatening. For psychotic disorders such as schizophrenia or bipolar disorder, the benefits of these drugs may outweigh their risks. But for other conditions, such as behavioral management in dementia, or uncomplicated depression, the risks of these drugs generally outweigh their potential benefits. Mortality The risk of death is higher among patients who use an APM versus those who do not, with death caused primarily by cardiac events or stroke. 9 Evidence comes from several studies, most of which were conducted with nursing home residents. 20 A large meta analysis of randomized trials found a 54% increase in the risk of death in patients who were on APMs for even a relatively short time (i.e., 8 12 weeks). 9 The risk varied somewhat by drug. This study calculated a Number Needed to Harm of 100 with a very broad 95% CI from 53 to If the low efficacy of APMs are included in the calculation, the authors estimate that for every 9 25 patients who derive some symptomatic improvement from antipsychotics, one will die. 9 Preventing overuse of antipsychotic drugs in nursing home care 3

11 A study of 75,445 new users of APMs in nursing homes found that mortality risk increased with higher doses and seems to be highest for haloperidol and lowest for quetiapine. 21 This trend was also found in a study of a large cohort of outpatient Veterans Affairs patients with dementia, which found that the risk of death was higher with haloperidol, and somewhat lower with quetiapine but the doses of quetiapine were low and, at those doses, ineffective. In another study, risk of sudden cardiac death among those on an APM was twice that for non users (RaR * 2.0; 95% CI: ), with no significant difference in risk between first and second generation agents. 22 The risk of mortality for all agents was highest in the first 30 to 120 days of use. 23 Results from a randomized controlled clinical trial of APM withdrawal also supports the contention that APMs are associated with increased mortality. The 2009 Dementia Antipsychotic Withdrawal Trial (DART AD) followed a group of 128 nursing home residents who were on an APM. Sixty-four residents were randomized to continue with their APM, while 64 were randomized to a placebo. After 24 months, patients who continued with an APM had significantly lower survival rates compared to those on placebo: 46% vs. 71%, a difference that widened further after 36 months (30% vs. 59%). 24 Figure 3: Survival of patients continuing on an antipsychotic medication compared with those on placebo 24 APMs can also cause prolongation of the QT interval, which can predispose to a potentially fatal ventricular arrhythmia, torsades de pointes. Since QT interval varies with heart rate, various formulae or computerized algorithms are used to produce a corrected QT (QTc) interval. QTc is prolonged if it is 450 ms in men or 460 ms in women. 25 Second generation APMs can induce QTc prolongation, most significantly with quetiapine and ziprasidone and least with aripiprazole; the risk with haloperidol is increased for intravenous or intramuscular administration. 26 Patients started on an APM should have an initial EKG; for those with a * Rate Ratio 4 Preventing overuse of antipsychotic drugs in nursing home care

12 baseline prolonged QTc who require an APM, consider an agent with minimal QTc prolongation. The risk of QTc prolongation in patients prescribed an APM is increased if they are also taking one or more of a long list of medications, many of which are commonly used in older patients. These include citalopram, amiodarone, and quinolone antibiotics. 19 A list of drugs that can prolong the QTc interval is available at Bradycardia, common in many older patients, increases the risk of torsades. BOTTOM LINE: The use of APMs in patients with dementia significantly increases the risk of death, a fact reflected in a black box warning for all APMs. This risk is highest in the first days of use, but persists indefinitely thereafter. It is estimated that one patient will die from antipsychotic use for every 9 25 patients who derive some symptomatic improvement from such medication. Prolongation of the cardiac QTc interval occurs more often with quetiapine and ziprasidone, and least with aripiprazole. Baseline EKG monitoring is warranted with these agents, and avoidance of other QTc prolonging agents is prudent with all APMs. Stroke Data on the risk of stroke with APMs have been conflicting. Two large cohort studies of patients with dementia comparing users of APMs with non users of APMs found no increased risk of stroke, 27,28 while a self controlled case series from a research database found the risk of stroke was 1.7 times higher during exposed times (i.e., when a patient was on an APM) compared to unexposed times. 29 Stroke risk may be higher with first generation APMs compared to second generation APMs. 30 Major APM side effects in elderly patients Even when used for their labeled indications, APMs have a narrow therapeutic window, which can increase the risk of side effects. The focus in this section is on second generation APMs because they are more commonly prescribed in the nursing home setting. (Note: although clozapine is considered a second generation APM, it is currently on a restricted distribution program in the U.S., due to the risk of agranulocytosis; as a result, it is rarely used off label for the types of behavioral symptoms seen in nursing homes.) Side effect profiles of different APMs differ by their affinity for non dopamine neuronal receptors, including acetylcholine, alpha 1, histamine, cardiac, and serotonin receptors. The table below briefly outlines side effects associated with blocking of these other receptors. Preventing overuse of antipsychotic drugs in nursing home care 5

13 Table 1: Typical side effects associated with blocking of non dopamine neuronal receptors Receptor type Muscarinic acetylcholine receptors Alpha 1 adrenergic receptors Histamine receptors Serotonin receptors Side effect profile Anti-cholinergic effects: Dry mouth and skin Blurry vision Tachycardia Sedation Constipation Urinary retention Angle closure glaucoma Orthostatic hypotension Reflex tachycardia Miosis Nasal congestion Sedation Hypotension Appetite stimulation Headache Agitation Nausea Diarrhea In general, first generation APMs are more likely to produce extrapyramidal side effects (EPS), which mimic Parkinson disease. Second generation agents are more likely to produce weight gain and metabolic side effects, including an increased risk of diabetes. Major APM side effect/adverse event profiles are summarized in Table 2. 6 Preventing overuse of antipsychotic drugs in nursing home care

14 Table 2: APMs with highest rates of specific side effects Metabolic effects Weight gain olanzapine (Zyprexa) +++ quetiapine (Seroquel) ++ risperidone (Risperdal) ++ paliperidone (Invega) ++ iloperidone (Fanapt) ++ Diabetes, hyperglycemia olanzapine +++ quetiapine ++ Neurologic effects Extrapyramidal symptoms haloperidol (Haldol) +++ phenothiazines +++ Sedation olanzapine ++ quetiapine ++ lurasidone (Latuda) ++ Cardiovascular effects QTc prolongation quetiapine ++ ziprasidone (Geodon) ++ iloperidone ++ Orthostatic hypotension paliperidone ++ quetiapine ++ risperidone = high incidence or severity, ++ = moderate incidence or severity. This is not an exhaustive list and represents the drugs most likely to cause the particular adverse effect. More detailed information on the side effect profile of each drug can be found in the evidence document accompanying this brochure. Weight gain/metabolic syndrome Weight gain and derangement in glucose and lipid metabolism occur with most of the newer APMs, but vary by specific drug. Impairment in glucose metabolism can progress to frank Type 2 diabetes. Most weight gain occurs during the first 3 months of treatment. 31 In non-elderly patients, metabolic and weight effects have been most notable for olanzapine and quetiapine, and least notable for risperidone and aripiprazole, although even aripiprazole produced a 10 lb. weight gain after three months in a younger population. 31 Patterns of insulin resistance were also similar, and highest for olanzapine. These metabolic effects are independent of weight gain; olanzapine induces insulin resistance even after a single dose. 32 These drugs also raise triglycerides and serum cholesterol levels. A large randomized trial (CATIE) in patients with schizophrenia (n=1493) found similar trends in weight gain and metabolic side effects among all of the agents studied, with the most unfavorable metabolic effects seen with olanzapine and quetiapine (Figure 4). 33 Preventing overuse of antipsychotic drugs in nursing home care 7

15 Figure 4: Mean change in cholesterol, triglycerides, and blood sugar by agent 33 Based on these trials and others, the American Diabetes Association and American Psychiatric Association endorse the following screening protocol for all patients being initiated on a second generation antipsychotic medication Table 3). 8 Preventing overuse of antipsychotic drugs in nursing home care

16 Table 3: Guidelines for screening patients on antipsychotic medications 34,35 BOTTOM LINE: Parkinsonian side effects are most prominent with first generation APMs; second generation APMs can still cause Parkinsonian signs and symptoms, as well as potentially irreversible tardive dyskinesia, but do so at a lower rate than first-generation drugs. The newer APMs can cause weight gain and metabolic side effects. Side effects vary significantly by agent. The risk of diabetes and lipid derangements is highest with olanzapine and quetiapine, is intermediate for risperidone and aripiprazole, and is minimal for ziprasidone. Weight gain is most significant with olanzapine and quetiapine. All patients taking any APM should be regularly screened for weight gain and increases in blood sugar or lipid levels. Preventing overuse of antipsychotic drugs in nursing home care 9

17 Extrapyramidal symptoms (EPS) Extrapyramidal symptoms include involuntary muscle movements, Parkinsonian symptoms, and late appearing, tardive dyskinesia (TD). All APMs may cause these motor syndromes, although, in general, they are less likely to occur with the second generation than the first generation agents, and all appear to be dose related, making it imperative to use the lowest possible dose of the drug. Tardive dyskinesia may be irreversible even after the drug is stopped. Its prevalence in patients on first generation antipsychotic drugs is ~20%, with an annual incidence of: 3 5% for first generation agents 36,37 <1% for second generation agents 38 A 9 month study of patients 45 years old being treated for schizophrenia or dementia with psychotic symptoms/agitation demonstrated a 5% cumulative incidence of TD in patients prescribed risperidone vs. a 32% incidence in those treated with haloperidol. 39 TD usually occurs after long term exposure (i.e., 3 6 months), and is more likely to occur with the following risk factors: 19,40 Older age Female gender Diabetes Higher dose and duration of drug Patients with early-appearing EPS (especially Parkinsonism) Acute EPS (such as dystonia) can be managed with anticholinergic agents (e.g. diphenhydramine or benztropine), though these can cause their own side effects, especially in the elderly. Otherwise, EPS onset can be reduced by avoiding first generation agents, and using the lowest dose possible for the shortest treatment course. Patients should be screened for EPS at every visit, including asking if they have noticed any symptoms, and by observing the patient while sitting still, focusing on the face, arms, and legs. The Abnormal Involuntary Movement Scale (AIMS) is a widely accepted assessment of signs of TD. 41 The AIMS should be administered before initiating antipsychotic treatment and at least semi annually thereafter. If possible, show patients and caregivers videos of motor symptoms, so they know what to look for between clinic visits. BOTTOM LINE: Parkinsonian symptoms and potentially irreversible tardive dyskinesia occur more commonly with first generation APMs, but can also occur with second generation drugs; the risks increase with higher dose and longer duration. Patients should be screened for EPS at every assessment. Neuroleptic malignant syndrome (NMS): NMS is an acute and potentially fatal syndrome characterized by fever, rigidity, dysautonomia, and mental status changes. It is more common with use of first generation agents, but can occur with any APM. The estimated prevalence is between 0.02% and 1.4% of elderly patients taking neuroleptics, with males twice as likely as females to develop NMS. 42 Symptoms typically develop within the first 2 weeks of taking the medication, after rapid dose increases, after switching agents, or after intravenous administration; the risk increases with dose Preventing overuse of antipsychotic drugs in nursing home care

18 In a large case series, most patients developed mental status changes first, followed by rigidity, hyperthermia, and then autonomic dysfunction. 44 Treatment consists of stopping the drug, and administering supportive treatment in a hospital, including anti-pyretics and fluids. The use of the muscle relaxant dantrolene and the dopamine agonist bromocriptine have been discussed in the literature, but their efficacy in NMS is not supported by strong evidence. 42 Most cases resolve with supportive care within 1 2 weeks. Resumption of APMs should be avoided, but if required, should be initiated after two weeks without NMS symptoms with a low-potency agent at a lowdose, with careful monitoring for symptom recurrence. 45 Bottom line: NMS is a rare but potentially fatal complication associated with APMs, particularly first generation agents. Symptoms typically include mental status changes, rigidity, hyperthermia, and autonomic dysfunction. Immediately stop the antipsychotic medication and administer supportive care in an acute care setting. Strategies for managing behavioral and psychological symptoms of dementia (BPSD) The term BPSD describes a wide variety of behavioral problems in older patients, whether or not they actually have been diagnosed with dementia, although BPSD are four times more common in patients with dementia than older adults without dementia. 5 The prevalence of BPSD is greater in nursing homes than in community settings. 2 The management strategies discussed in this document may be effective whether or not dementia is present. BPSD overview BPSD can range from the merely annoying to those that endanger the patient and/or others. Apathy, depression, and aggression are the most common features, followed (in descending order) by sleep disturbance, anxiety, delusions, and hallucinations. 1,46,47 The symptoms with the greatest potential for harm are aggression, psychosis, and mood disorders. 1,5 (Note: the term agitation, while occasionally used to describe some of these symptoms, is non specific and is rarely helpful in creating a treatment plan.) This entire set of symptoms is often used as a single primary outcome measure in clinical trials. As a result, the efficacy of therapies for specific symptoms can be difficult to determine. 5 Some BPSD symptoms fluctuate over the course of dementia, while others are more persistent. 1,4,48,49 A study of patients with mild Alzheimer disease found that wandering and purposeless/inappropriate activities persisted or increased in severity over 2 years in about 85% of patients who had these symptoms at baseline, while paranoid ideation persisted in approximately 66% of patients. 47 Hallucinations and depressive symptoms were the least persistent symptoms: less than half of the patients with depressive symptoms still had the symptoms one year later. Depressive symptoms often occur in the early stages of dementia. As dementia progresses, other behavioral and psychological symptoms may predominate. Preventing overuse of antipsychotic drugs in nursing home care 11

19 Acute vs. non-acute BPSD Management of BPSD should be based on the characteristics and severity of the symptoms. Therefore, it is helpful to differentiate between two broad classes of BPSD: acute and non-acute. People with acute BPSD are in severe distress, pose an imminent danger to themselves or others, or have severely disruptive or dangerous behaviors. People with non-acute BPSD do not have symptoms that rise to this level of an emergency situation, though their symptoms may be inconvenient, may disrupt their functioning, or otherwise may erode quality of life. Non-acute BPSD calls for a different clinical and behavioral approach than acute BPSD, using a different range of therapeutic options, or options tried in a different order (Figure 5). APMs may sometimes be needed for management of crises caused by acute BPSD, but are seldom appropriate for the ongoing management of non-acute BPSD. Figure 5: Algorithm for managing behavior problems in older patients Identify the problem behavior to be addressed. Record intensity, frequency, and consequences. Rule out reversible causes Initiate non-drug approaches REASSESS REGULARLY REASSESS REGULARLY Y Are the symptoms: severely disruptive? dangerous? distressing? N Acute BPSD (rare) Drug therapy may be required for: physical agression violent behavior hallucinations or delusions that are distressing to the patient self-harm Non-acute BPSD (common) Drug therapy rarely required Focus on non-drug interventions. Avoid APMs if possible. SSRIs may have a limited role: avoid fluoxetine (Prozac), citalopram (Celexa), paroxetine (Paxil). consider sertraline (Zoloft), escitalopram (Lexapro). 12 Preventing overuse of antipsychotic drugs in nursing home care

20 When a patient presents with BPSD, the first course of action should be to perform a comprehensive assessment of the symptom(s), considering the "ABCs": Antecedents: What are the triggers for the behavior(s)? Behavior: Which behavior, or behaviors, are appropriate targets for intervention? Consequences: What are the consequences of the behavior(s) for the patient and others? If a patient with acute BPSD is in severe distress or poses a danger to themselves or others, both pharmacologic and non-pharmacologic strategies may have to be employed (see section on pharmacologic strategies below). For patients with non-acute BPSD, a more measured approach can be taken, with input solicited from family, caregivers, and nurses. Understanding the antecedents and specific behaviors a patient may be experiencing may reveal simple and effective interventions. Complex management strategies and interventions may not be required. The assessment of a new onset behavioral symptom in an older patient with cognitive impairment must start with an assessment of potentially reversible causes of the behavior (Figure 6). Figure 6: Clinical, psychological, and environmental causes of BPSD are often reversible Examples: CLINICAL CONDITIONS DRUG- INDUCED Examples: PSYCHOLOGICAL ENVIRONMENTAL Preventing overuse of antipsychotic drugs in nursing home care 13

21 Identifying a potentially reversible trigger can be challenging if the patient's cognitive impairment is severe. Family and caregivers may be able to help by providing insight into the patient s routine and normal level of functioning. Of course, treatment of a reversible medical problem will be more effective than deploying either non pharmacologic or pharmacologic interventions. Adverse drug effects are one of the most common reversible conditions in geriatric medicine. Many medications routinely used by older adults can cause or worsen behavioral and psychological problems. For example, anticholinergic agents increase the risk of visual hallucinations, agitation, irritability, delirium, and aggressiveness. Psychotropics, such as benzodiazepines, can impair cognition, be disinhibiting, and may contribute to falls. Identifying possible drug related triggers for BPSD presents an opportunity to effect a cure by stopping the offending drug or lowering the dose. This has led to the recommendation that any new symptom in an older patient should be considered a possible drug side effect until proven otherwise. 50 Non-pharmacologic management strategies Non-drug management of BPSD can produce equivalent outcomes, in a much shorter time, and at less overall risk and cost, than pharmacologic therapies. 51,52 The evidence base supporting the efficacy of non pharmacological interventions is broad (see Table 6), although some studies of non-drug interventions are relatively small, un-controlled, or non-randomized. In part this may reflect the relative lack of research funding for non-pharmacologic vs. pharmacologic interventions, but, in addition, many of the methodologies used in drug testing (e.g., blinding and random assignment) are not possible in studies that test the efficacy of non-drug interventions. Many trials also use combinations of specific strategies, which can make it difficult to assess the quality of evidence for individual non-pharmacological interventions. Effect sizes in studies of non-pharmacologic interventions tend to be modest, although the same is true for effect sizes generally found in studies of the efficacy of APMs. For example, a meta analysis of 13 non-pharmacologic interventions for BPSD by Brodaty et al., found a pooled estimate effect size of 0.15 (95% CI: ; p=0.006). 52 This compares with a net effect size of 0.13 from a 2007 meta-analysis of studies comparing atypical APMs to placebo by Yury and Fisher, and an effect size of 0.18 in a 2006 meta-analysis of APMs in the treatment of BPSD by Schneider et al. 53,54 Non-pharmacological interventions can target patients themselves, or those who care for them. Both types of interventions have been found to be effective in reducing the incidence of BPSD and/or reducing caregiver burden (see Table 6). A good resource for nursing home staff training on non-pharmacologic techniques is the OASIS program, developed by Susan Wehry and the Vermont Local Area Network of Excellence (and being used by the Massachusetts Senior Care Foundation, which seeks to reduce off label use of antipsychotics. See for more information.) Interventions that target nursing home residents generally fall into 3 broad categories: 1. Unmet needs interventions assume that BPSD may sometimes represent a form of communication about an underlying need, such as for stimulation (e.g., repetitive speech or calling out, for auditory stimulation). Symptoms may also be a response to inadequately treated pain, or isolation. 2. Learning and behavioral interventions address the possibility that BPSD may be the product of unintentional reinforcement (e.g., a patient with dementia learns that he or she can get attention by screaming). 14 Preventing overuse of antipsychotic drugs in nursing home care

22 3. Environmental vulnerability and reduced stress threshold interventions assume a mismatch between the person s environment and their abilities to cope with the situation (e.g., a resident becomes agitated by too much noise). Behaviors likely to respond to non-pharmacological interventions include: aggression, disruption, shadowing, depression, and repetitive behaviors. Non-pharmacologic interventions should be matched to the specific needs and capabilities of the patient, and they can be used concurrently with any medications that might be employed. 55,56,57 Optimizing the management of the cognitive symptoms of dementia may help reduce the incidence of BPSD. For example, using adequate anticoagulation may prevent transient ischemic attacks/microstrokes in cases of vascular dementia, as evidence suggests an association between transient ischemic attacks and cognitive impairment. 58 Preventing overuse of antipsychotic drugs in nursing home care 15

23 Table 4: Evidence supporting non-pharmacological strategies for BPSD Interventions supported by large, randomized or controlled clinical trials Staff training/education programs Avoidance of unnecessary psychoactive medications Skills training in managing patients with dementia Activity planning and environmental redesign Enhancing support for caregivers Avorn J, et al. A randomized trial of a program to reduce the use of psychoactive drugs in nursing homes. New England Journal of Medicine 1992;327(3): Brodaty H, Arasaratnam C. Meta analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry. 2012;169: Fossey J, et al. Effect of enhanced psychosocial care on antipsychotic use in nursing home residents with severe dementia: cluster randomised trial. British Medical Journal 2006;332(7544): Meador K, et al. Predictors of antipsychotic withdrawal or dose reduction in a randomized controlled trial of provider education. Journal of the American Geriatrics Society 1997;45(2): McCallion P, et al. An evaluation of a family visit education program. J Am Geriatr Soc. 1999;47: Schmidt I, et al. The impact of regular multidisciplinary team interventions on psychotropic prescribing in Swedish nursing homes. Journal of the American Geriatrics Society. 1998;46(1): Teri L, et al. Training community consultants to help family members improve dementia care: a randomized controlled trial. Gerontologist. 2005;45: Potentially helpful interventions supported by evidence from small, uncontrolled, or case control studies Environmental modifications Support normal sleep/wake cycles Structure activities to reduce boredom Reduce unnecessary stimulation Create home-like environment Snowden M, et al. Assessment and treatment of nursing home residents with depression or behavioral symptoms associated with dementia: a review of the literature. J Am Geriatr Soc Sep;51(9): O'Connor DW, et al. Psychosocial treatments of behavior symptoms in dementia: a systematic review of reports meeting quality standards. Int Psychogeriatr Apr:21(2): Music therapy Bright light therapy Aromatherapy Behavior modification Withdrawing attention for BPSD Rewards for prosocial behaviors Behavioral redirection Provision/optimization of hearing aids Ueda T, et al. Effects of music therapy on behavioral and psychological symptoms of dementia: a systematic review and meta analysis. Ageing Research Reviews 2013; 12(2): Lovell BB, et al. Effect of bright light treatment on agitated behavior in institutionalized elderly subjects. Psychiatry Res. 1995; 57:7 12. Fung JK, et al. A systematic review of the use of aromatherapy in treatment of behavioral problems in dementia. Geriatr Gerontolo Int. 2012;12: Heard K, Watson TS. Reducing wandering by persons with dementia using differential reinforcement. J Appl Behav Anal. 1999;32: Teri L, et al. Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA. 2003;290: Palmer CV, et al. Reduction in caregiver identified problem behaviors in patients with Alzheimer disease post hearing aid fitting. J Speech Lang Hear Res. 1999;42: Preventing overuse of antipsychotic drugs in nursing home care

24 Management of physiological factors A number of common, though often-overlooked, physiological factors may play a primary or contributing role in BPSD, and these should be explored whenever possible before pharmacological interventions are attempted: 59 Urinary tract infections Pain Constipation Nocturia Hunger or thirst Dehydration Hyponatremia Hyper or Hypothyroidism Hypercalcemia B12 or folic acid deficiency Dietary and eating-related issues should be carefully assessed. An inability to chew properly or swallow easily can increase agitation, hence a patient s dental integrity, use of dentures, and swallowing ability should be considered. If a patient s appetite or cycle of hunger/satiety is not synchronized with the timing of meals provided by an institution, consider options to individualize the availability of food and/or food choice. Difficulty preparing or eating meals, confusion about mealtimes, apathy, agitation, and paranoid ideation about food and fluids may all contribute to weight loss, which is common in patients with dementia. Avoidance of alcohol and caffeine can promote good sleep hygiene and may help stabilize mood. 60 Environmental strategies Behavioral and psychological symptoms are often predictable responses to a wide range of factors that make life uncomfortable, frightening, worrisome, irritating, or boring for people with dementia. Paying close attention to such environmental factors, and eliminating or correcting them, should be the first priority for caregivers. 3 This requires patience, diligence, and a willingness to see the world through the eyes and other senses of the person whose behaviors are difficult. Because sensory deficits are common in older adults, and because vision and hearing deficits, in particular, can increase fearfulness, anxiety, and agitation, any patient displaying non-acute BPSD should be assessed for these deficits, and, if present, they should be corrected promptly with glasses, improved lighting, magnifying devices, hearing aids, or other techniques. Other environmental factors that can worsen BPSD include: temperature (too hot or too cold), noise (in or outside the room or dwelling unit), lighting (too much, too little, or quality), unfamiliarity (new people, new furniture, new surroundings), disrupted routines, needing assistance but not knowing how to ask, being uncomfortable from sitting or lying in one position for too long, or inability to communicate easily because of language difficulties. In one key intervention study, the potential effectiveness of non-pharmacologic interventions for nursing home residents was demonstrated in a 2012 randomized, placebo controlled clinical trial. 61 Agitated nursing home residents with advanced dementia from 9 nursing homes in 5 locations in Maryland were randomized into an intervention group (n=89) or a placebo group (n=36). A set of individualized non pharmacologic interventions, Treatment Routes for Exploring Agitation (TREA), was used with the intervention group for 2 weeks, and observations of agitation and affect were recorded. Relative to the Preventing overuse of antipsychotic drugs in nursing home care 17

25 control group, patients receiving the TREA interventions (e.g., social contact, reading, music, physical activity) showed significant declines in physical agitation (change in agitation score from 6.02 at baseline to 1.12 in treatment group, versus 4.74 at baseline to 5.08 in placebo group, p<0.001), and verbal agitation (change from 2.74 at baseline to 0.96 in treatment group, versus 2.41 to 2.84 in placebo group, p=0.004) and modest increases in pleasure (p<0.001) and interest (p<0.05). The authors conclude that putting these kinds of non pharmacologic interventions into practice is sorely needed although they note that this may require structural changes such as dedicating staff time to observing each agitated resident, determining unmet needs, obtaining appropriate intervention materials, conducting the individualized interventions, and evaluating results to determine efficacy. Management of psychological factors Patients with BPSD may benefit from psychological interventions such as individual, family, or group psychotherapy, depending on their level of cognitive functioning. Such interventions may help patients understand or express their feelings, correct or address cognitive errors or maladaptive thinking patterns, and develop practical steps for changing behaviors or responses to different situations. BOTTOM LINE: First-line approaches for the management of non-acute BPSD should focus on identifying any reversible environmental, psychological, or physiological factors that might be causing or contributing to symptoms. Pursue non-drug strategies before pharmacologic treatments are initiated. Pharmacologic management of BPSD: General principles The evidence base for drug treatment of BPSD is generally modest, and no medications are FDA approved for these indications. 60,62,63 Medication use in this setting has evolved over the years without guidance from large, randomized controlled studies, and in anecdotal ways involving off label uses of many classes of medications including antipsychotics, anticonvulsants, antidepressants, anxiolytics, cholinesterase inhibitors, and NMDA modulators. APMs, while of potential utility in patients with acute BPSD, should be avoided in patients with non-acute BPSD until other reasonable medications (see below) have been tried, because of the minimal efficacy of these agents for the symptoms typical of non acute BPSD and their relatively high risk of side effects, including death. If BPSD are not disruptive, dangerous, or distressing to the patient or caregiver (i.e., the patient has non acute BPSD) then the medications reviewed in this section are usually not warranted. Reserve drug intervention for the situations listed below, using it simultaneously with behavioral treatments and only if potentially reversible or remediable causes have been ruled out: physically aggressive or violent behavior that poses a danger to the patient or others hallucinations or delusions that are distressing to the patient, lead to dangerous behavior, or significantly impair normal functioning If a medication must be used, identify one or more specific target symptoms to address, to provide a benchmark to assess medication effectiveness on re-evaluation. Pharmacologic interventions are generally not warranted to address behaviors such as: wandering unsociability 18 Preventing overuse of antipsychotic drugs in nursing home care

26 poor self care restlessness nervousness fidgeting hoarding sexual disinhibition sundowning (increased confusion and restlessness in early evening) shadowing impaired memory uncooperativeness without aggressive behavior inattention or indifference to surroundings Given that many older adults are prescribed multiple medications and the inherent difficulty of determining efficacy if multiple medications are used to address a given condition, any therapeutic trial of a medication for BPSD should be completed with a single medication. If the single medication works poorly in addressing the target symptom(s) after an adequate trial, the medication should be discontinued and an alternative medication should be initiated. Assess suboptimal responses to determine whether the partial effect was due to non-specific causes or other changes in clinical status; do not automatically assume that the medication should be continued and/or another medication added for additional effect. Before any medication is administered, inform patients (as feasible), family members, and/or caregivers of the possible risks of pharmacotherapy. 64,65 Psychotropic medications traditionally used for BPSD may cause a variety of serious adverse effects including falls, fractures, delirium, and over-sedation. Elderly patients are particularly vulnerable to injury from psychotropic medications because of slower metabolic clearance, increased CNS receptor sensitivity, and reduced physiologic reserve. Plan on lower starting and target doses in older people to reduce the likelihood of these adverse events. A reduced initial dose for elderly patients is endorsed by the FDA, which mandates that drug manufacturers state a recommended geriatric dose for all medications that have been evaluated in a significant number of patients older than 65 years. Unfortunately, drug trials often under represent older patients especially those who are over 80 or frail so the evidence base for such recommendations is frequently inadequate. Initiate any medication for non-acute BPSD at the lowest possible dose, with slow titration upwards if needed to the lowest effective dose, and monitor patients closely for both adverse effects and drug drug interactions. If a medication is successful in addressing a specific target symptom, reassess the patient after 3 6 months, since BPSD symptoms are inherently unstable and subject to remission on their own. Rarely should psychoactive medication be continued indefinitely; attempt dose reduction and withdrawal regularly. 60 Antipsychotic medications No APMs are approved in the U.S. for BPSD, despite at least 17 large randomized trials, most of them unpublished, that sought evidence of effectiveness for this indication. 65 Meta analysis of these studies has indicated limited efficacy and significant potential for harm from the side effects or adverse effects noted earlier. 66 (The evidence of these risks has primarily emerged from studies conducted in patients with non acute BPSD). Thus, although APMs may help control the acute symptoms of BPSD in certain patients, they must always be used carefully and with informed consent. (In Massachusetts, this requires Preventing overuse of antipsychotic drugs in nursing home care 19