In addition to cognitive decline, patients with

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1 PHARMACOLOGIC TREATMENT OF BEHAVIORAL AND NEUROPSYCHIATRIC SYMPTOMS Jeanne Jackson-Siegal, MD * ABSTRACT The frequency and severity of neuropsychiatric and behavioral symptoms in Alzheimer s disease (AD) typically reach a peak by the middle or moderate stage of the disease. By this point, language and memory abilities are also significantly impaired, limiting the patients ability to adequately express any discomforts or concerns and compelling them to communicate their thoughts and distress in the only way they can through behaviors. There are often multiple concurrent causes of distressed behavior; identifying them requires a methodical approach. Assessment should include environmental, medical, and psychiatric evaluations, which can be considered together to form a list of working diagnoses. Nonpharmacologic interventions should be implemented whenever possible, even when pharmacologic treatment may be considered the primary intervention. Although many medications can temporarily calm a patient, they can place the patient at unnecessary risk of adverse events if underlying conditions remain untreated. Pharmacologic treatment of behavioral symptoms is warranted when the acuity of the symptom compels the need for immediate relief or when a medical or psychiatric condition has been identified that requires medical management. This article discusses common presentations of distress in dementia patients and information on many of the medications frequently used for treatment (ie, the cholinesterase *Assistant Clinical Professor of Psychiatry, Yale University School of Medicine, Medical Director, Alzheimer s Resource Center, New Haven, Connecticut. Address correspondence to: Jeanne Jackson-Siegal, MD, Assistant Clinical Professor of Psychiatry, Yale University School of Medicine, Medical Director, Alzheimer s Resource Center, 1261 S. Main Street, Southington, CT E- mail: jjgeropsychmd@yahoo.com. inhibitors, mood stabilizers, antipsychotics, antidepressants, and anxiolytics). To optimally care for our residents, it is essential for all members of the healthcare team to contribute to our understanding and identification of the various causes of distress. Beyond aiding the patient in achieving a better quality of life, we also avoid inappropriate or dangerous drug choices in this fragile population. (Adv Stud Pharm. 2005;2(5): ) In addition to cognitive decline, patients with Alzheimer s disease (AD) and other dementing illnesses exhibit numerous neuropsychiatric and behavioral symptoms, the frequency and severity of which typically peak in the middle or moderate stage of the disease (Figure 1). Neuropsychiatric symptoms may be a direct result of brain pathology (eg, perseveration) or the behavior may stem from any number of causes beyond neuronal deterioration. As dementia progresses, expressive language abilities also deteriorate, thus limiting the patients ability to express themselves effectively in words. For someone with dementia, communication may only be possible through behavior. The range of observed behavioral symptoms is extremely variable and includes anxiety, physical or verbal aggression, depression, impulsivity, hyperactivity, restlessness, withdrawal, delusions, hallucinations, and psychosis. These behaviors increase caregivers stress, risk the safety of the patient or others, and increase the risk of overmedication, institutionalization, and restraints. Fully delineating the root causes thought to contribute to a particular behavior is essential for optimal treatment and helps the staff understand and tolerate the behaviors as we begin the Advanced Studies in Pharmacy 175

2 Figure 1.The Stages of Alzheimer s Disease Stage Symptoms Mild Moderate Severe Memory loss Language problems Mood and personality changes Diminished judgment Withdrawal from activities Need for memory aids daily Some help needed with IADLs Behavioral, personality changes Unable to learn or recall new info Long-term memory affected Wandering, paranoia, aggression, Require assistance with all IADLs Unstable gait Incontinence Motor disturbances Bedridden Dysphagia Mute Poor/no ADLs LTC placement common ADLs = activities of daily living; IADLs = instrumental activities of daily living; LTC = long-term care. treatment process. For example, poor motivation is not seen as a problem when the cause is anemia. The interdisciplinary team is important because observations and insights into the driving forces for particular behaviors can come from many sources. By talking to our long-term care (LTC) staff about illnesses and syndromes rather than simply focusing on symptom management, we can more accurately develop working diagnoses and thus treat the root causes of behavioral distress. Delivering optimum treatment is critical for many reasons. DEFINING THE TREATMENT GOALS Relieving the distress observed in a demented resident and monitoring the treatment benefits over time requires precise language. In this article, terms such as problem behavior, difficult behavior, or agitation are intentionally avoided because they lack specificity and suggest that the problem lies in the resident. Behavioral distress is a person s reaction to the entire situation; behaviors are not a distinct illness. The term behavior does not necessarily involve any pathology, but simply represents the patients actions or reactions in response to internal or external stimuli. The first step to assessing distressed behavior is to precisely define the target symptoms, including frequency and severity. It is helpful to document any relevant antecedents and consequences to discover any aggravating factors that may be triggering the behavior. Table 1 offers suggestions for specific descriptors of distressed behaviors. 1,2 Posting this list at nursing stations can help staff use more clarifying language in their documentation. Carefully defining the target symptoms yields important information on another critical piece of good care the development of working diagnoses thought to be responsible for the presence of the symptoms. A validated monitoring tool, such as the Cohen-Mansfield Agitation Inventory (Figure 2) or the Neuropsychiatric Inventory Nursing Home Version, can establish a baseline and evaluate the treatment benefits over time. 3-7 The propensity to use the word agitation should be actively discouraged. This general term can make it nearly impossible to evaluate clinical effectiveness in patient care. Even careful clinical trials for the treatment of agitation are difficult to interpret. Compounding problems in the research include a mixture of the severity and type of dementia, vague inclusion criteria for exactly what agitation looks like. The high placebo response rate indicates that interventions, such as environmental changes, more one-to-one time, increased awareness of small medical problems, are occurring and are quite effective, regardless of the medication intervention chosen. Table 1. Examples of Specific Descriptors for Symptoms of Distress Physical* Verbal* Passive Hitting Threats Silence Pacing Accusations Poor oral intake Kicking Name-calling Withdrawal Biting Obscenities Refusing medications Pushing Complaining Listlessness Spitting Attention-seeking Hand wringing Scratching Screaming Blank stare When describing behaviors, it is helpful to be as specific as possible. The term agitation is not helpful in developing a working diagnosis or monitoring treatment effectively. Use of the general term distressed and avoidance of the term agitation is useful in that our differential diagnosis remains broad, encompassing possible etiologies from the environmental, medical, or psychiatric domains. *Data from Cohen-Mansfield. 1 Data from Tariot et al Vol. 2, No. 5 October 2005

3 Figure 2. Sample of the Cohen-Mansfield Agitation Inventory Please read each agitated behavior, and circle how often (from 1 7) each was manifested by the resident during the past 2 weeks: Less than Once or Several Once or Several Several once twice times twice times times Never a week a week a week a day a day an hour 1. Pace, aimless wandering Inappropriate dress or disrobing Spitting (include at meals) Cursing or verbal aggression Constant unwarranted request for attention or help Repetitive sentences or questions Hitting (including self) Kicking Grabbing onto people Pushing Users are advised to refer to the Instruction Manual for the Cohen-Mansfield Agitation Inventory before using the scale. Cohen-Mansfield J, Marx M, Rosenthal A. A description of agitation in a nursing home. J Gerontol. 1989;44:M77-M84. 7 Cohen-Mansfield, All rights reserved. example, if the main behavioral symptom is anxiety, the first 6 categories need to be evaluated to determine if there is another reason for the apparent anxiety symptom before considering an anxiety disorder diagnosis or simply treating with a benzodiazepine to unnecessarily sedate the patient. If a confusing and chaotic environment is thought to be contributing to the anxiety, relatively benign interventions such as increased structure, less stimulation, or increased one-to-one time are much more suitable than a medication. This should be followed by consideration of an acetylcholinesterase inhibitor and/or memantine, along with a medication review for inappropriate medications as we consider optimally managing their dementing illness. Next, evaluate for a potential delirium followed by consideration of any medical conditions that may be contributing to the anxiety presentation. As each diagnostic category is considered, frequently more than 1 area is found to be relevant and helpful in their treatment care plan. COMPREHENSIVE ASSESSMENT Residents with dementia often present with myriad symptoms, many of which do not fit into one precise diagnostic category, as they are the result of multifactorial etiologies. By identifying and treating multiple illness processes that are responsive to interventions, we decrease the overall burden on the patient. A comprehensive assessment of behavioral symptoms in dementia should include psychiatric, medical, and environmental evaluations (Figure 3). Using a hierarchical 8-part assessment paradigm, as outlined in Table 2, to look for root causes greatly increases our likelihood of finding multiple exacerbating factors contributing to distress. This paradigm offers a methodical approach to the evaluation process and in determining concomitant diagnoses. It is important to note that the sequence of the paradigm is critical to discovering all concomitant potential etiologies. For Figure 3. Comprehensive Approach to Assessing Distressed Behavior Medical Evaluation Yes Treat ID Target Symptoms Evaluate Environment & Improve Interventions Symptom Relief Psychiatric Evaluation Treat Yes Advanced Studies in Pharmacy 177

4 Table 2. Hierarchical Paradigm for Comprehensive Behavioral Assessment in Dementia 1. Environment/stressors 2. Dementia 3. Delirium 4. Medical problems 5. Psychotic disorder 6. Affective disorder 7. Anxiety disorder 8. Personality disorder The process of developing working diagnoses is complicated by the fact that behavioral symptoms and syndromes often overlap, as shown in Figure 4. A single symptom, such as verbal abuse, can have several different psychiatric or medical causes, in addition to possible environmental causes. We have made great strides in pharmacological approaches to disturbances of affect, behavior, and cognition, but the primary impediment to delivering optimum care still remains accurate diagnoses. When multiple working diagnoses are developed to explain the distress, the nonpharmacologic and pharmacologic interventions most effective for the diagnoses can be chosen. By identifying multiple areas for symptom relief, the resident is better able to tolerate stressors that are more permanent or unavoidable. Additionally, nonpharmacologic interventions are more likely to be effective when we understand the underlying causes of the distress. ENVIRONMENT On the assessment paradigm, environment is listed first. This is to remind us that anyone can be affected by environmental stressors, and optimum treatment of many illnesses may require changes in our approach, activities, or expectations depending on limitations and supports in the environment. Rather than view patients as appropriate for pharmacologic or nonpharmacologic interventions, consider nonpharmacologic interventions for every patient in distress and, additionally, treat any illness or severe symptom with appropriate medications. A full discussion of nonpharmacologic approaches will be included in Part 3 of this series. In this part of the series, the focus is on pharmacologic strategies. PHARMACOLOGIC TREATMENT FOR BEHAVIORAL SYMPTOMS Pharmacologic treatment of behavior symptoms should be considered when a medical or psychiatric diagnosis is identified and treatment is the normal standard of care (eg, arthritis, dementia, or major depression), the behavior generates significant safety concerns, or a diagnosis is not yet established and the distress is significant but not sufficiently responsive to nonpharmacologic interventions alone. The most commonly used psychotropic drugs for behavioral symptoms in AD are cholinesterase inhibitors, memantine, mood stabilizers, antipsychotics, antidepressants, and benzodiazepines. Whenever possible, the goal is to relieve behavioral symptoms by treating the cause without producing undue side effects or functional loss, or exacerbating underlying cognitive impairment. 8 This article addresses pharmacotherapeutic options for each of the various illness categories, as noted in the paradigm. DEMENTIA As cognition helps us to understand and cope with the world around us, maximizing this basic function is helpful in all residents with dementing illnesses, regardless of the presence of distressed behavior. Except in rare instances, improvements in cognitive processing can generally be assumed to benefit someone with cognitive impairment, thus cognitive enhancers should be considered whenever possible and any pharmacologic agent that impedes cognition Figure 4. The Symptoms and Syndromes of Alzheimer s Disease Overlap Frontal Lobe Impairment Impulsivity Hyperactivity Agitation Anxiety Disorder Restlessness Irritability Verbal Abuse Aggression Psychotic Disorder Figure courtesy of Jeanne Jackson-Siegal, MD. Worry Physical Sx Anxiety Physical Aggression Withdrawal Delusions Hallucinations Dysphoria Vegetative Sx Major Depression 178 Vol. 2, No. 5 October 2005

5 should be removed. This is a particularly important role for the consultant pharmacist who may note, for example, a high anticholinergic burden or concomitant use of medications that may exacerbate confusion. Cholinesterase inhibitors and memantine have shown a small but consistent benefit in addressing neuropsychiatric symptoms Although the US Food and Drug Administration (FDA) has approved these drugs only for dementia caused by AD, ongoing studies are evaluating the benefits of cholinesterase inhibitors and memantine in other types of dementia. The consultant pharmacist should educate LTC staff about the benefits of maximum-dose cholinesterase inhibitors and their long-term benefits, even in severe dementia. Importantly, when memantine is added to the medication regimen, the cholinesterase inhibitor should never be stopped at the same time. Deterioration in cognition and function is well known to occur after discontinuing cholinesterase inhibitors and may inappropriately be attributed to the starting of memantine. As some patients respond to memantine with increased verbalizations, staff or family may become more aware of the patients internal distress. Although this can be uncomfortable, it can be illuminating to consider a change in nonpharmacological approach or whether there is a previously unappreciated depression before immediately viewing this as a negative side effect of memantine. For this phenomenon or any side effects seen with memantine, it is worth decreasing the dose rather than completely stopping the memantine, as many symptoms can improve at a lower dose. This is particularly important if the resident has a reduced creatinine clearance. Minimum effective dose has not been fully investigated for memantine, although currently there are trials under way in nursing home patients using memantine 10 mg nightly at bedtime only. The most recent studies indicate that the greatest benefits come from treatment with a cholinesterase inhibitor (donepezil was used in the Table 3. Recommended Dosing, Administration, and Adverse Effects of FDA-Approved Drugs for AD Minimum Maximum Most Frequent Agent Usual Dose Therapeutic Dose Dose Administration Adverse Effects* Donepezil 5 mg/day; increase 5 mg/day 10 mg/day Every day; in the evening, Nausea, diarrhea, insomnia, to 10 mg/day after with or without food vomiting, muscle cramps, 4 6 weeks fatigue, and anorexia Rivastigmine 1.5 mg twice daily 3 mg twice daily 6 mg twice daily Twice daily; take with food Nausea, vomiting, loss of (3 mg/day); increase to (6 mg/day) (12 mg/day) AM and PM appetite, dyspepsia, asthenia, 3, 4, 5, and 6 mg twice daily and weight loss at 2- to 4-week intervals Galantamine Reminyl: use divided doses 16 mg/day 24 mg/day Twice daily ; take with Nausea and vomiting Razadyne: use every day food AM or PM dosing; begin at 8 mg/day; increasing at 3- to 4- week intervals to 16 mg/day and then 24 mg/day Memantine 5 mg/day; increase to 10 Unknown 20 mg/day Can be taken with or Confusion, dizziness, mg/day (5 mg twice daily), without food headache, and constipation 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice daily); minimum recommended interval between dose increases is 1 week *Based on clinical studies. Twice-daily dosing is only with Reminyl. Once-daily extended-release formulation of galantamine (Razadyne) has been approved by the FDA and is available in pharmacies in AD = Alzheimer s disease; FDA = US Food and Drug Administration. Data from Donepezil US prescribing information 14 ; Galantamine US prescribing information 15 ; Memantine US prescribing information 16 ; Rivastigmine US prescribing information. 17 Advanced Studies in Pharmacy 179

6 Table 4. Adverse Events from the Memantine Plus Donepezil Study Placebo + Memantine + Donepezil Donepezil Adverse Events (n = 201), % (n = 202), % Agitation Confusion Fall Influenza-like symptoms Dizziness Headache Accidental injury Upper respiratory infection Urinary tract infection Urinary incontinence Peripheral edema Diarrhea Fecal incontinence Adverse events shown here are the adverse events reported in at least 5% of either treatment group. Adapted with permission from Tariot et al. JAMA. 2004;291: study) and memantine simultaneously. 10 Doses and side effects of cholinesterase inhibitors and memantine are listed in Tables 3 and 4. 10,14-17 It is important to consider the diagnosis of dementia with Lewy bodies in the differential diagnosis of behavioral symptoms. Briefly, important diagnostic criteria include fluctuating cognition, well-formed visual hallucinations, and mild parkinsonism. This diagnosis is crucial to identify because patients with this type of dementia are extremely sensitive to antipsychotics, and provisional data suggest that the hallucinations may respond to acetylcholinesterase inhibitors. 18 Another important consideration in the dementia component of behavioral assessment is frontal lobe impairment. Frontal lobe dysfunction can occur in numerous types of dementia, such as AD, vascular dementia, multiple sclerosis, alcoholic dementia, and frontotemporal dementia. One of the primary functions of the frontal lobe is to inhibit an immediate response to thoughts or stimuli, thus allowing for reasoning and decision making before an action is rendered. Symptoms of dysfunction include poor impulse control, mood lability, perseveration, disinhibition, verbal or physical aggression, and sexually inappropriate behaviors. It is important to identify these symptoms, as they can be dangerous and especially upsetting to caregivers. Note that frontal dysfunction does not produce psychotic symptoms but generally represents poor impulse control. The thoughts or impulses are not particularly abnormal, although verbalization or acting on the impulse would be inhibited in normal adult brain function. (Because frontal lobe development and myelinization is not complete until a person reaches their early 20s, good impulse control is not achieved until adulthood.) When a resident has frontal lobe impairment, nonpharmacologic interventions can be extremely valuable. Medications are appropriate and useful when nonpharmacologic interventions fail to control the behavior alone or when the individual s behavior poses a risk of danger to the resident or other residents and staff in the facility. Historically, treatment with antipsychotics or benzodiazepines was the most common intervention. Over the past years, the use of mood stabilizers has increased, relying on some of the benefits seen in treatment with these medications for bipolar mania. The similarity in symptoms between frontal lobe dysfunction and mania prompted Tariot to generate the term psycho-behavioral metaphor. 19 The manic-like presentation of agitation was investigated using carbamazepine or valproate in several studies, although definitive results remain lacking. Large-scale clinical trials using extremely specific inclusion and exclusion criteria (perhaps positron emission tomography scanning would be more reliable than symptoms alone) will be needed before we can determine the true efficacy of various drug treatments in frontal dysfunction syndrome. The most frequently used mood stabilizers include valproate and carbamazepine, although formal studies of these drugs for this treatment are limited Valproate has been studied in this population in placebo-controlled trials with modest efficacy. Carbamazepine is less often used because of a more problematic side-effect profile (bone marrow suppression, liver toxicity, ataxia, and numerous drug-drug interactions). A recent review of the literature by Sink et al indicates no effect of valproate and conflicting results with carbamazepine. 13 The most frequent adverse events with valproate are thrombocytopenia and somnolence, in addition to weight gain, hair loss, tremor, and hepatotoxicity. 24 Consideration of sodium valproate versus valproic acid is frequently important when small doses (125 mg), sprinkles, or the extended-release formulation would be of benefit. Sodium valproate has fewer gas- 180 Vol. 2, No. 5 October 2005

7 trointestinal side effects, which can be critically important for tolerance in the LTC population. The initial dose of valproate for use in frontal impairment should be 125 mg to 250 mg twice daily, increasing by 125 mg to 250 mg every 5 days. The usual range for maximal dose is 500 mg to 1250 mg/day, although a good clinical response can be seen even at low serum levels. 24 Monitoring liver function tests and platelet count every 3 months is reasonable if the baseline and initial posttreatment values are normal. As other anticonvulsants are coming onto the market, they are being tried for frontal lobe dysfunction, although clinical trial data remain sparse. Currently, there are no large head-to-head, placebo-controlled trials with the newer-generation anticonvulsants. Treatment with those atypical antipsychotics shown to have efficacy in treating mania may also prove to be an effective treatment option. Bipolar mania and frontal lobe dysfunction share many symptoms, although specific data on the correlation remain very sparse. As is often the case in geriatric psychiatry when treating symptoms of great distress, clinical trial data lag behind the clinical practical approaches being used. DELIRIUM The sudden development or change in behavioral symptoms should automatically prompt a clinician to consider delirium in someone with dementia. As a general rule, the presentation of a dementing illness does not change remarkably over a few hours or days. Although the cause of a sudden change may be another type of event, such as cerebrovascular accident or seizure, the typical cause is delirium a medical problem external to the brain that impairs brain function. In LTC, the most common etiologies for delirium are urinary tract infections, pneumonia, and medication reactions. The major differences between a dementia and a delirium are that delirium has an acute (hours to days) or subacute (days to weeks) onset, rapid changes in mental status, fluctuating alertness or level of consciousness, and new-onset or worsening psychotic symptoms. Over the years, delirium has been called a variety of names, including acute confusional state, acute brain syndrome, metabolic encephalopathy, toxic psychosis, and acute brain failure. To best maintain a good standard of care for a patient with delirium, it is helpful to avoid these less conventional expressions. The term delirium is well understood and prompts the vigilance and investigation needed for appropriate medical care. The Confusion Assessment Method is a very simple and useful (but vastly underutilized) instrument for screening for delirium. 25 A diagnosis of delirium should always include a search for the cause. In some cases, the delirium is a result of compounding factors, such as multiple anticholinergic medications; these cases highlight situations in which the expertise of the consultant pharmacist can be particularly helpful. When multiple pharmacologic side effects are the cause of the delirium, the presentation may have subacute, rather than an acute, onset and thus can be more difficult to recognize. As noted earlier in this article, the reason for a delirium is often a serious medical issue, thus it is critical to identify and treat the cause. For residents admitted to the hospital with delirium, mortality rates are 10% to 26%. For those patients who develop delirium during hospitalization, the mortality rate ranges from 22% to 76%, with a high rate of death during the months following discharge. 26 By knowing and treating the cause of the delirium, we can better predict the expected duration of the new or increased psychotic symptoms. An extremely important role for the consulting pharmacist is to monitor the length of time antipsychotics are continued when they were initiated for a delirium. This is particularly important when a resident is readmitted after a hospitalization for delirium and returns to the facility. Often the staff remembers that the resident was displaying many concerning behaviors before the hospitalization for delirium. In the weeks after the treatment of the cause of the delirium, the psychotic symptoms are expected to subside. During this time the antipsychotic is maintained and the resident returns to the facility. The facility providers may hesitate to remove the antipsychotic with the concern of causing a return of the symptoms. The unfortunate result is that the resident may be exposed to antipsychotics far longer than needed to treat delirium-induced psychosis. This situation is exacerbated by the misperception that the federal guidelines are treatment guidelines. Federal Omnibus Budget Reconciliation Act (OBRA) regulations (discussed later in this article) mandate a dose reduction of antipsychotics in this situation within 6 months, far longer than the few days to weeks that are clinically indicated. MEDICAL CONDITIONS AND ILLNESSES Although one may assume that medical problems are well handled by the primary care physician, in dementia care, problems can easily be missed. The most common reason is that the residents are unable to give details Advanced Studies in Pharmacy 181

8 about their history or current symptoms because of aphasia (word-finding difficulty) or poor recall caused by their dementia. A consultant pharmacist should review the past medical history and current diagnoses with the current medication list to consider if a condition, such as arthritis or gastroesophageal reflux disease (GERD), is untreated. When an etiology for distress cannot be determined, it is helpful to have the nursing staff ask the family if there is a history of headaches, GERD, migraines, sinus problems, or pain. For example, if a resident becomes distressed in the dining room, is the cause the noise, dislike of the food, or a response to reflux or ulcer pain? Because chronic pain rarely induces any facial grimacing or eyebrow furrowing in anyone, and demented residents are unable to use a pain analog scale, chronic pain is easily underappreciated. We know that chronic pain from conditions, such as osteoarthritis, remains grossly undertreated in nursing homes. Consider how the only evidence indicating pain from contractures, skin breakdown, or muscle injury may be the distressed behavior. PRN (as needed) medications are notoriously underused if the resident is unable to state that they are in pain. Generally, the availability of PRN acetaminophen for pain has no value in treatment of chronic pain in dementia. An empiric pain medication trial of routine acetaminophen or a nonsteroidal anti-inflammatory drug for 2 to 3 weeks can be surprisingly effective in reducing the distressing behavior and illuminating its cause pain. As typical pain scales are not helpful in revealing efficacy, improvements can be monitored through such measures as oral intake, ambulation, and cooperation with personal care, sleep, and mood. Even conditions that are being treated may still contribute to the resident s behavioral symptoms. For example, when constipation does not respond to magnesium hydroxide, an uncomfortable and frightening suppository or enema may be required. For a person with dementia, this per rectal intervention may well increase their anxiety, as they may not understand what is being done or why. Consultant pharmacists can advocate for a change in bowel care policy, thus if ever a per rectal intervention (suppository/enema) is required, increased bowel medications by mouth, prune juice or increased fluids, and increased ambulation if possible are seriously considered and implemented. Other common but insufficiently treated medical conditions are deafness, visual impairment, and sleeping difficulties. Hearing impairment often increases paranoia when a person tries to imagine what is being said (this also occurs in the nondemented). Likely, this process is worsened if cognition is limited. Although the staff surely attempts to keep hearing aids in good working order, placement of a hearing aid with a dead battery actually worsens hearing impairment because of the physical blockade. Consultant pharmacists can encourage staff to verify functioning hearing aids by placing a hand near the hearing aid to hear the device squeak, in addition to encourage ophthalmologic assessment and treatment for cataracts. Reviewing sleep patterns is also important, as sleep deprivation worsens many symptoms. Sometimes it is the noisy resident who needs treatment rather than the roommate with insomnia. Typically, the cause of insomnia can range from pain to noise to depression. Use of the newer nonbenzodiazepine hypnotic agents, such as zolpidem, eszopiclone, or zaleplon, are helpful for elders, as they do not carry the side-effect profile or tolerance issues seen with benzodiazepines. Another good option is low-dose trazodone 25 mg to 50 mg nightly at bedtime, although it is prudent to get orthostatic blood pressures for the first few days or with dosage adjustments. If there is a drop of more than 20 points in systolic blood pressure on standing, the clinician may want to reconsider the options to decrease the fall risk caused by dizziness. Poor oral intake is also a common problem in dementia and is often attributed to declining cognition. It may be because of a dental problem. Dry socket, abscess, and fractured teeth may go unrecognized and untreated. Dentists may have difficulty visualizing problems and cannot obtain X rays unless the resident is medicated to allow cooperation for a full examination. However, dental hygiene is often poor, thus cooperation during oral hygiene can be difficult. PSYCHOSIS Psychosis in dementia patients can result from very different etiologies. Psychotic symptoms may be driven by a chronic psychotic mental disorder, the dementia process, delirium, medications and medication withdrawal, and psychotic depression or mania. Psychosis is defined as the presence of auditory or visual hallucinations (hearing or seeing things that others are not able to) or delusions (having false beliefs). Importantly, psychosis is a symptom, not a final diagnosis. It is critical to determine the etiology of psychotic symptoms, thus the underlying cause can be treated and, when antipsychotic medication is necessary, the drugs can be titrated to the appropriate dosage range and discontinued when no 182 Vol. 2, No. 5 October 2005

9 longer clinically warranted. Before I examine the assessment and treatment options for psychosis, I first review the relevant regulations in the LTC setting. REGULATIONS REGARDING THE USE OF ANTIPSYCHOTIC DRUGS IN NURSING HOMES The OBRA of 1987 created federal standards for nursing home care and outlined specific criteria that must be fulfilled before antipsychotic medication can be administered to a resident in an LTC facility. The OBRA regulation delineated under F Tag 329 focuses on unnecessary medications. These medications are defined as those used in excessive dose (including duplicate therapy), for excessive duration, without adequate monitoring, without adequate indications, or in the presence of adverse consequences that indicate the dose should be reduced or discontinued. For residents with cognitive impairment, antipsychotic drugs should not be used in excess of the listed daily doses (Table 5) unless documentation is provided to show why higher doses are necessary for maintenance or improvement in the resident s functional or behavioral status. The regulations specific to F Tag 330 state that for those residents with organic mental syndrome (now termed dementia, delirium, amnestic, or other cognitive disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), antipsychotic drugs can only be used in residents who exhibit symptoms that impair functioning, cause danger to themselves or other people, and/or interfere with the provision of care. The diagnosis must be one of those listed and documentation of symptoms is required; antipsychotic drugs are considered to be unnecessary if they are initiated in the absence of this documentation. This documentation needs to be quantitative and objective and indicate that the behavior is persistent and requires intervention; the behavior is determined to be permanent or transitory; the behavior has been evaluated for possible social, situational, or environmental causes or other preventable reasons; medical causes are excluded; and the behaviors are part of organic mental syndromes. These syndromes are defined by specific behaviors that have been quantified and present a danger to the patient or other people, including staff. The behaviors can include biting, kicking, extreme fear, yelling continuously, continuous crying out, screaming, or pacing. The last 3 symptoms qualify if they cause functional impairment or actually interfere with the staff s ability to provide care. It is important for the healthcare team to realize that antipsychotic drugs are not (or rarely) allowed per the OBRA guidelines if the following symptoms are the only criteria: wandering, poor self-care, anxiety/restlessness, impaired memory, uncomplicated depression, unsociability, fidgeting, nervousness, uncooperativeness, or agitation without any danger to the resident or other people. The OBRA regulatory requirement under F Tag 331 states that, regarding the use of antipsychotic drugs and based on a comprehensive assessment, the facility must assure that residents with organic mental syndromes who are treated with antipsychotic drugs receive gradual dose reductions and behavioral interventions, unless clinically contraindicated (as outlined Table 5. Appropriate Antipsychotic Agents and Typical Dose Ranges in Residents with Dementia or Delirium Dose Generic Brand (oral/injectable) Aripiprazole Abilify mg Clozapine Clozaril mg Olanzapine Zyprexa mg Quetiapine Seroquel mg Risperidone Risperdal mg Ziprasidone Geodon mg Conventional antipsychotic agents are strongly not recommended for elderly patients, thus they are not included here. Table 6. OBRA Guidelines on Contraindications for Dose Reduction of Antipsychotic Drugs Gradual dose reduction every 6 months unless clinically contraindicated by: The patient has 1 of 10 approved conditions If the diagnosis is an organic mental syndrome and: 2 previous attempts have been made in the past year to establish that the dose is reduced to the lowest level to control symptoms The doctor provides justification, including diagnosis, symptoms, differential diagnosis, consideration of medical causes, and risk/benefit analysis OBRA = Omnibus Budget Reconciliation Act. Advanced Studies in Pharmacy 183

10 in Table 6), in an effort to discontinue these drugs. Gradual dose reduction consists of tapering the resident s daily dose to discover if the resident s symptoms can be controlled by a lower dose or to determine if the dose can be eliminated altogether. It is helpful to remember that the OBRA guidelines never were intended to constitute best practice for dementia care. Written 2 decades ago, the primary focus was to prevent neglect, overmedication, and unnecessary use of restraints. The guidelines emphasized a symptombased approach for determining if a particular drug class was appropriate (ie, biting allows the use of an antipsychotic drug). Although symptom-based treatment is common, it is not ideal for the treatment of behavioral distress, as the focus is simply on masking the symptom. As our understanding of dementia-related behaviors has increased, so has our ability to provide optimal care. We have learned that except for urgent situations, best practice requires a working diagnosis and treating accordingly. A diagnostic approach is certainly in compliance with the old regulations, but it offers a significant advance in the efficacy and the avoidance of unnecessary side effects from the treatment offered. This approach is no different than the treatment of most medical disorders. For example, shortness of breath would have certain treatment interventions that are appropriate for short-term urgent treatment (oxygen) and a completely different set of treatment interventions (inhalers for asthma and furosemide for congestive heart failure) that become defined as a result of the evaluation process. As the clinician works through the assessment paradigm hierarchy to determine (or eliminate) the multiple possible causes of behavioral symptoms, each working diagnosis becomes re-evaluated in context to the other aspects of the clinical situation. As noted earlier in this article, it is ideal when the cause is identified before a medication is started. However, there are times when the acuity of the behavioral symptoms requires treatment before the etiologies are identified. In these situations, the determination of the diagnoses must become a longerrange goal and treatment must be initiated immediately. Another update in our thinking beyond the OBRA regulations has to do with medication reduction. When a working diagnosis is developed, a much clearer understanding is provided of how long an antipsychotic drug or any other medication being considered would be needed before a dose reduction may be clinically indicated. Many of the conditions for which antipsychotic drugs are initially given are temporary, such as delirium, dementiarelated psychosis, and brief reactive psychosis. These conditions do not usually require long-term treatment, and typically the dose can be safely lowered over time while maintaining good symptom control. When psychotic symptoms are thought to be a result of the dementia process, a dose reduction is often successful after 4 to 6 months. This makes sense if we recognize that as the dementing illness continues to progress, symptoms would be expected to change over time. For the treatment of psychotic major depression, typically the addition of an antipsychotic drug is beneficial and needed for 2 to 4 months before a dose reduction is indicated. Chronic psychotic disorders, such as schizophrenia, are well established to require lifelong treatment. Delirium-induced psychotic symptoms typically require a few days to weeks, depending on the cause, the efficacy of the treatment, and the brain vulnerability to delirium. Certainly it is reasonable to tailor the expected duration of treatment to the presumed underlying diagnosis. If then a dose reduction were not successful, a re-evaluation of the presumed diagnosis would be indicated. The OBRA regulations do allow PRN and duplicative therapy with antipsychotic drugs, although they mandate the same level of documentation as the category of excessive dose. If PRN antipsychotic drugs are used in place of routine dosing, all relevant documentation to avoid the F Tag 329 regarding unnecessary medication is still required. Clinically, the use of PRN antipsychotic drugs can help to establish the lowest effective dose, in addition to provide treatment in the event of a catastrophic reaction. Although a single antipsychotic agent is usually sufficient to control symptoms, there can be clinical situations in which a second antipsychotic is helpful. For example, a resident may not tolerate an efficacious dose of a single agent. As each antipsychotic drug has a unique side-effect profile but generally equal efficacy, some residents may achieve better symptom control with a reduced side-effect burden by combining 2 different antipsychotic drugs. In any situation, when a second agent is used, the rationale for this approach must be delineated in the medical record. CHOOSING AN ANTIPSYCHOTIC DRUG The specific dose and antipsychotic drug chosen is based on several factors including, but not limited to, resident-specific characteristics, laboratory values, comorbid symptoms and illnesses, and medicationspecific factors (Table 7). The therapeutic effects noted in ongoing monitoring should also impact the dose 184 Vol. 2, No. 5 October 2005

11 Table 7. Factors That Affect Choice of Antipsychotic Agent for Dementia Patients Resident-Specific Goal of treatment Compliance Age of the resident Length of treatment expected Other medications being administered Tolerance to the common side effects Specific condition being treated and related standards of practice Severity of symptoms Past history of exposure and tolerance/efficacy Laboratory Values Fasting glucose Fasting lipids HbA 1c Comorbid Symptoms Affective symptoms (eg, mania and depression) Weight (over or under) Psychomotor abnormalities Urinary urgency Urinary retention Edema Gait instability HbA 1c = glycosylated hemoglobin. Comorbid Illnesses Current tardive dyskinesia Parkinsonian symptoms caused by: Parkinson s disease Dementia with Lewy bodies Drug-induced parkinsonism Orthostatic hypotension Diabetes Hyperlipidemia Cognitive impairment Cardiovascular disease Conduction abnormalities Hypertension Tobacco dependence Other comorbid illnesses Osteoporosis Medication-Related Side-effect data specific to the condition being treated Side-effect data specific to elders Formulations available Flexibility of dosing Half-life Cost Manufacturer s recommendation prescribed and the duration of treatment. Generally, advanced age or a dementing illness requires lower doses than the doses used to provide treatment to a younger person, those with intact cognition, or for a chronic psychotic disorder such as schizophrenia. Antipsychotic drugs are not effective in all dementia patients. Studies of conventional antipsychotic drugs indicate that only 33% of patients show improvement in agitation or psychosis, at the expense of significant potential side effects, such as akathisia (motor restlessness and inability to sit still), parkinsonism, tardive dyskinesia (rhythmical involuntary movements of the tongue, face, and mouth or jaw), sedation, peripheral and central anticholinergic effects (which can counteract the benefits of cholinesterase inhibitors for cognitive function), postural hypotension, and cardiac conduction defects. 27 Newer antipsychotic drugs (termed atypical ) offer improved side-effect profiles, but their effectiveness in treating patients with dementia is still being questioned. Tariot et al reviewed the data for risperidone, olanzapine, quetiapine, and aripiprazole in studies in patients with AD. 8 The overall conclusion is that atypical antipsychotic drugs are effective treatment for agitation in dementia, with a less clear impact on psychosis (Table 8). 8,28-37 Tolerability varies substantially among the different agents and should be considered when developing a treatment plan. The most frequent adverse events seen with risperidone were somnolence, falls, injury, extrapyramidal disorder, urinary tract infection, and peripheral edema With olanzapine, the most common adverse events were accidental injury, somnolence, pain, and abnormal gait For quetiapine, the adverse events were somnolence, dizziness, agitation, and postural hypotension, all of which were transient and resolved over time With aripiprazole, the limited study data show common adverse events, such as urinary tract infection, accidental injury, somnolence, bronchitis, and extrapyramidal syndrome-related events. 37 Importantly, none of these drugs are currently FDA approved for treatment of dementia with psychosis. A more recent review by Sink et al shows that only olanzapine and risperidone offer convincing evidence of efficacy, but the product labeling warning of cerebrovascular events must be balanced against any benefit in symptoms. 13 The FDA issued a public health advisory in April 2005 concerning the use of atypical antipsychotic medications in elderly patients with behavioral disturbances, which stated that there is an increased mortality in elderly patients with dementia who are receiving atypical antipsychotic drugs. 38 The FDA will probably include older antipsychotic medications in a similar warning because limited data also suggest an increase. Large-scale, head-to-head studies of antipsychotic drugs for neuropsychiatric and behavioral symptoms in AD are lacking. One randomized, double-blind, placebo-controlled study compared quetiapine versus rivastigmine for agitation and cognitive decline in institutionalized patients with dementia (n = 93). 39 The results showed that neither quetiapine nor rivastigmine were effective in the treatment of agitation, and quetiapine was associated with significantly greater cognitive decline than rivastigmine. 39 The National Institute of Mental Health is conducting the Clinical Antipsychotic Advanced Studies in Pharmacy 185

12 Table 8. Summary of Studies of Atypical Antipsychotic Drugs in Elderly Patients with Dementia Drug Patients, n Study Duration Design Active Treatments Results Risperidone 625* 12 weeks DB, PC; nursing home residents Risperidone 0.5, 1, Dose-related response in BEHAVE-AD, with psychosis and/or or 2 mg/d significant for 1 and 2 mg only agitation associated with AD, VaD, or both weeks DB; nursing home residents with Flexible dose No difference in response by AD, VaD, or both, complicated mg/d risperidone or BEHAVE-AD between 3 treatment by psychosis or agitation haloperidol groups; response rates: 47% placebo, 54% risperidone, 63% haloperidol; CMAI (secondary outcome) scores showed significant improvement with risperidone versus placebo weeks PC; nursing home residents Flexible dose risperi- Significant reduction in aggressive with AD, VaD, or both done up to 2 mg/d behavior for risperidone versus placebo baseline to endpoint in CMAI total aggression score; similar improvement for CMAI total nonaggression subscale and for the BEHAVE-AD total and psychotic symptoms subscale; at endpoint, significantly greater improvement with risperidone compared to placebo in CGI-S and CGI-C scores Olanzapine 238 PC; outpatients with dementia Flexible dose No benefit with olanzapine therapy, complicated by agitation or perhaps because of suboptimal psychosis dosing; mean dose at study end = 2.7 mg/day weeks DB, PC; nursing home residents Olanzapine 5, 10, or Proportion of patient responders with AD exhibiting psychosis 15 mg/d; placebo ( 50% decline in NPI/NH core total or agitation scores) significantly greater with 5- and 10-mg dose versus placebo; significant improvement in sum of aggression and agitation, hallucination, and delusion items of NPI/NH with 5- to 10-mg dose versus placebo weeks DB, PC; patients with AD and 1, 2.5, 5, or 7.5 mg/d Significant improvement from baseline in delusions or hallucinations NPI/NH total scores in all 5 treatment groups, but no pairwise differences; significant improvement with CGI-C scores with 7.5 mg olanzapine versus placebo (LOCF analysis) or 2.5 mg (endpoint analysis) Quetiapine 184 # 52 weeks OL; patients with various psychotic mg/day Designed to explore dosing, titration, disorders (mostly dementia) safety, and tolerability; highest daily doses on last full day of study were mg (except for 1 patient requiring 800 mg); significant improvements in mean change from baseline of BPRS and CGI-severity scores 78** 52 weeks OL; patients with AD (subset mg/d; median Significant improvements in several of previous study) dose: 100 mg/d BPRS subscores; mean of hostility, suspiciousness, and uncooperativeness; hostility item; hostility cluster (mean of anxiety, tension, hostility, suspiciousness, uncooperativeness, and excitement) (continued on page 187) 186 Vol. 2, No. 5 October 2005