Pharmacologic therapy for behavioral symptoms of alzheimer's disease

ALZHEIMER’S DISEASE AND DEMENTIA

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PHARMACOLOGIC THERAPY FOR BEHAVIORAL SYMPTOMS OF ALZHEIMER’S DISEASE Pierre N. Tariot, MD, J. Michael Ryan, MD, Anton P. Porsteinsson, MD, Rebekah Loy, PhD, and Lon S. Schneider, MD

There is every reason.for geriatricians to be concerned with the behavioral signs and symptoms of Alzheimer’s disease (AD) and other dementias because they are so prevalent, so distressing to the patient, and so upsetting for caregivers. A previous cross-sectional multicenter study examining this issue in several hundred outpatients with AD found that no patient had been free of behavioral signs or symptoms in the preceding month.53More recently, a landmark population-based study of dementia found a point prevalence of psychopathology of over 60%, and asserted that the lifetime risk of psychopathology for a patient with dementia approaches These figures make it clear that caring for a person with dementia means knowing how to recognize and manage its behavioral manifestations. Behavioral signs and symptoms of dementia are quite heterogeneous and can be confusing to the uninitiated. Clinical experience and studies teach us, however, that certain symptom patterns can be expected to occur. Indeed, a recent consensus conference on the issue asserted that behavioral signs and symptoms occur commonly and can include observable motor and verbal behaviors and psychological phen~mena.’~ These signs and symptoms, summarized in Table 1, often do not meet usual criteria for major psychiatric disorders. Rather, they tend to occur in a subsyndromal Supported in part by the Alzheimer’s Disease Cooperative Study. From the Departmentsof Neurology (RL)and Psychiatry (PNT,JMR,APP, RL), University of Rochester Medical Center, Rochester, New York;and the Departmentsof Psychiatryand the Behavioral Sciences and Neurology, Keck School of Medicine and the Leonard Davis School of Gerontology,University of Southern California,Los Angeles, California (LSS) ~~~

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Table 1. SUMMARY OF LITERATURE REGARDING PSYCHOPATHOLOGYOF DEMENTIA (PERCENTAGE OF PATIENTS AFFECTED AMONG STUDIES REVIEWED) Range

Disturbed affect or mood Disturbed ideation Altered perception Hallucinations Misperceptions Agitation Global Wandering Aggression Verbal Physical Resistive or uncooperative Anxiety Withdrawn or passive behavior Vegetative behaviors Sleep Diet/appetite

Median

0-86 10-73

19 33.5

21-49 1-49

28 23

10-90 0-50

44

11-51 0-46 27-65 0-50 21-88

24 14.3

0-47 12.5-77

18

44 31.8 61 27

34

Adapfed froin Tariot P, Blazina L The psychopathology of dementia. In Moms J (ed):Handbook of Dementing Illnesses. New York, Marcel Dekker, Inc., 1993, p 461; with permission.

fashion. The figures in Table 1provide a rough estimate of the likelihood of a patient experiencing a particular sign or symptom. These features tend to vary within individuals over time and there is tremendous heterogeneity among individuals. For instance, the study of Devanand et all3found that affective symptoms tend to fluctuate considerably over months or years and psychotic symptoms somewhat less so, whereas agitation tends to emerge as the illness progresses and tends to persist once it has emerged. The main points, however, are that patterns of signs and symptoms can be predicted, and there is a significant degree of heterogeneity among and within patients. Although there is not a uniform relationship between severity of dementia, some general trends can be discerned. In mild stages, depressive and anxious symptoms are relatively common, as are social withdrawal and lack of initiative, which may be interpreted as manifestations of depression but actually might be understood better as apathy. In moderate stages of illness, irritability, delusions (frequently paranoid in nature), wandering, and agitation are most common. In advanced stages, socially inappropriate or disinhibited behavior, repetitive purposeless actions, aggression, or marked apathy can be seen?' Bear in mind, however, that these are generalizations. Agitation is the paradigm of psychopathology addressed in this article because the principles pertaining to treatment of agitation are easily applied to treatment of other behavioral signs and symptoms. In caring for a patient with dementia and agitation, we rely on a systematic approach to evaluation and management that has been articulated p r e v i o ~ s l y . ~ ~ , ~ ~ ~ The key general elements in this approach are summarized in the following

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list, which emphasizes clarificationof target symptoms, ruling out delirium or occult major psychiatric diagnoses, and creatively addressing possible social, environmental, or behavioral remedies: 1. Define target symptoms 2. Establish or revisit medical diagnoses 3. Establish or revisit neuropsychiatric diagnoses 4. Assess and reverse aggravating factors 5. Adapt to specific cognitive deficits 6. Identify relevant psychosocial factors 7. Educate caregivers 8. Use behavior management principles 9. Use psychotropic medications for specific psychiatric syndromes 10. For remaining problems, consider symptomatic pharmacotherapy Use psychobehavioral metaphor Use medication class relevant to metaphor and with empirical evidence of efficacy Start low, go slow (but go!) Avoid toxicity Use lowest effective dose Withdraw after appropriate period and observe for relapse Serial trials are sometimes needed The role of combinations is unclear Adapted from Tariot I": Treatment of agitation in dementia. J Clin Psy-

chiatry 60(suppl8):11-20,0 1999Physicians Postgraduate Press; with permission. There are excellent reviews of nonpharmacologic interventions that offer practical guidelines to caregiversand health professionals, such as decreasing escalation, simplifylng communication, taking advantage of routines, and using humor and d i s t r a ~ t i o n . 'Only ~ , ~ in emergent situations or when these nonpharmacologic interventions have failed should medications be used. SELECTING A MEDICATION

In selecting a medication, the authors begin by identifymg a target symptom pattern that is reminiscent of a behavioral syndrome that we already know to be drug-responsive. The authors have previously termed this the psychobehavioral metaphorrB a phrase that emphasizes the uncertainty of the terminology and the heterogeneity of the signs and symptoms one is dealing with. A psychotropic is then selected to match the dominant target symptoms. For instance, if the agitation is associated with delusions of theft or harm, one might select an antipsychotic. If it is associated with tearfulness, social withdrawal, or preoccupation with themes of loss or death, one might consider first an antidepressant. If it is associated with

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impulsivity, aggression, lability of mood, or excessive motor activity, one might consider first a mood stabilizer. Although this approach has not been validated by clinical studies, two major practice guidelines for treatment of agitation rest on the assumption that matching target symptoms to drug class is appropriate. One was based strictly on published data, offered by the American Psychiatric Association.2 A more recent one was based on the clinical opinion of identified experts in the field.’ The details of the methodology and conclusions can be found in these primary references, but their significance lies in the recommendation that the face-valid clinical approach advocated in this article is supported by expert opinion. Once a medication has been selected, the authors choose one for which there is reasonable evidence of efficacy, and ideally one with known and limited safety and tolerability problems. After starting treatment, the authors try to address honestly whether the medication is helping or hurting the patient, discontinuing it if it is harmful or ineffective. Although ”starting low and going slow” is a valid truism in geriatric practice, it is also important to “go.”That is, giving a prolonged trial of a dose of medication that is subtherapeutic for an individual patient is pointless and even harmful because doing so protracts that period of distressing symptoms. Sometimes serial trials are needed. Remember that no one medication or class is effective for every patient, and, except in rare cases, it is difficult to find something that achieves complete remission for a particular patient. The clinical question of relevance is whether the improvement is sufficient. Patients with the most refractory symptoms tend to be those who undergo serial trials of increasingly unconventional therapies, and who receive combination therapy. MAJOR CLASSES OF PSYCHOTROPICS

Because information regarding safety, tolerability, and efficacy is the major determinant of the selection of a specific medication for a specific patient, these issues are the focus of the rest of this article. Examples of typical starting doses and target doses are provided in Table 2 for the more commonly used medications. The authors have previously written comprehensive reviews of the available literature, with complete tables and r e f e r e n ~ e s .The ~ ~ ,thrust ~ ~ here is to focus on classic publications and the most recent data, highlighting the major points as seen at present. Bear in mind that the field is changing quickly, because new studies are emerging on a regular basis that may have the potential to alter our opinion of certain agents or classes. Because antipsychoticshave been studied most extensively, the review begins with these agents. CONVENTIONAL ANTIPSYCHOTICS

Historically, important studies of these agents converged on the overall conclusions that the effects of these agents were consistent, modest,

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Table 2. SELECTED PSYCHOPHARMACOLOGIC AGENTS ~

Drug and Class

Ant ipsychot ics Typical Haloperidol Thioridazine Atypical Clozapine Olanzapine Quetiapine Risperidone Antidepressants SSRIS Citalopram Fluoxetine Sertraline Trazodone Tricyclics Nortriptyline Desipramine Anticonviclsants Carbamazepine Valproate Anxiolytics and Sedatives Benzodiazepine A1prazo1am Lorazepam Oxazepam Non-benzcdiazepine Buspirone Zolpidem Cholinesterase Znhibitors Donepezil Rivastigmine Tacrine

~~

Suggested Starting Total Daily Dose (mgld)

Suggested Maximal Total Dally Dose (mgld)

0.5 12.5-25

2-3 50-100

6.25-12.5 2.5 25 0.5

2 5 1 00 5-10 100-200 1-2

10 10 25-50 25

20 20 100-200 150-250

10 25

50-100

50-100

300-500

250-375

750-1500

0.5 0.5 10

20-40

1-2 1-2 40-60

5

30-60 10

5 3 40

10 6-12 120-160

10

Dosing suggestions are based upon published data as well as clinicalexperience and should be viewed with caution. “Maximal” doses may be excessive for individual patients. Adnptedfronr Loy R, Tariot PN, RosenquistK Alzheimer’s disease: Behavioralmanagement. In Katz IR, Oslin D, Lawton MP (eds):Annual Review of Gerontology and Geriahics: Focus on Psychopharmacologic Interventions in Late Life. Springer Publishing Company, Inc., New York 10012,1999,p 136;and Rosenquist K, Tariot PN, Loy R: Treatments for behavioral and psychological symptoms in AIzheimer’s disease and other dementias. In Ames D, Bums A, OBrien J (eds): Dementia. Chapman and Hall, 2000; with permission.

that no single agent showed superiority, and that side-effects tended to emerge in a predictable fashion and ultimately define selection of a particular agent. Schneider et a14’published an oft-cited meta-analysis, and reported the overall result that 59% of patients treated with a conventional antipsychotic showed categorical behavioral improvement versus 41% of those receiving placebo, an 18%drug-placebo difference. This difference is referred to as the effect size (i.e., an objective measure of actual drug effect that factors in the effect of placebo). Remarkably, the figure of 18%tends to stand up across trials of most psychotropic agents conducted

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since that time, as becomes evident in this review. Placebo response rates in the Schneider et a141 meta-analysis ranged from 20% to 65%. A more recent meta-analysis was conducted by Lanctot et alu that included several modem studies and earlier studies that Schneider et a14' had excluded because of lack of methodologic rigor. The conclusions were fairly similar: the average effect size seen was 26%,with placebo response rates ranging from 19% to 50%. Both meta-analyses emphasized that side effects occurred significantly more often on drug than placebo (typically 25% more often at least, for studies of fairly short duration). These side effects included akathisia, parkinsonism, tardive dyskinesia, sedation, peripheral and central anticholinergic effects, postural hypotension, cardiac conduction defects, and falls. Long-term safety data are generally lacking. Bear in mind, however, that rates of tardive dyskinesia are at least fivefold greater in the elderly than in younger populations, meaning that practitioners should be on the lookout for later tolerability problems emerging later in therapy, including some not seen in short-term trials." The meta-analyses cited previously did not include a recent major study by Devanand et all4examining short-term use of placebo versus low doses (0.5 to 0.75 mg/d) versus higher doses (2 to 3 mg/d) of haloperidol. Response rates were 25%to 30%,25%to35%,and 55%to 60%,respectively, remarkably similar to the results of the previous meta-analyses. Moderate to severe extrapyramidal signs and symptoms were seen in subjectsreceiving 2 to 3 mg/d. This study provides the best illustration of the narrow therapeutic index of this type of agent in patients with dementia. Teri et a1% have reported negative results from a study comparing haloperidol with other approaches in an outpatient trial, reminding clinicians that results from trials can vary considerably. An important clinical issue that highlights the toxicity of conventional agents is the experience of patients with dementia with Lewy bodies, in whom marked toxicity is seen in response to conventional therapy3 Patients with extrapyramidal disorders serve as unfortunate litmus tests for the degree of risk of extrapyramidal toxicity of both older and newer antipsychotics. ATYPICAL ANTIPSYCHOTICS

Given the toxicity of the conventional agents, the field has looked o p timistically to the atypical agents in the hope that they might be especially effective, safe, and tolerable in this population.' The hope has been realized in part. Clozapine This was the earliest atypical agent released, and remains the paradigm in terms of lowest rate of motor toxicity, and arguably, greatest likelihood of success in patients with schizophrenia who are refractory to other

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therapies. There are on1 anecdotes addressing the use of this agent in patients with dementia.27,9,48 A typical starting dose tends to be 12.5 mg/d, with maintenance doses 12.5 to 50 mg/d. These anecdotes point out occasional successes, but emphasize toxicity, such as sedation, ataxia, falls, delirium, and suppression of bone marrow function. These toxicities, the need for monitoring of cell counts, and the lack of data indicating efficacy mean that most clinicians are likely to choose other agents first. The authors' practice is to reserve the use of clozapine for patients with extrapyramidal features who fail on other atypical agents.

Y

Risperidone Two large multicenter trials have been completed in nursing home patients with fairly severe dementia (Mini-Mental State Examination 6 to 7). Both studies were 3 months in duration and included patients with AD or vascular dementia who experienced agitation or psychotic features. In the first study, risperidone at doses of 0.5,1, and 2 mg/d was compared with placebo in 625 subjects.22Reasons for discontinuation included adverse events (15.4%);lack of efficacy (5%);and other causes (10.1%). Extrapyramidal features emerged in roughly one quarter of subjects at the 2 mg/d dose during this time, with good tolerability and safety otherwise. Using an a priori definition of clinical response, 33% of patients in the placebo group were rated as improved, a similar percentage of patients in the 0.5 mg/d group, 45% of those receiving 1 mg/d, and 50% of patients receiving 2 mg/d. Subscale scores indicated beneficial effects both on measures of psychosis and aggression (verbal or motor). These response rates (e.g., 12%to 17%)are in the range of those previously reported by Schneider et a14' for conventional antipsychotics, but the results suggest improved safety and tolerability of this agent compared with prior studies of conventional agents. The other large risperidone study compared placebo with flexible doses of risperidone or haloperidol (0.5 to 4 mg/d) in 344 nursing home residents with dementia accompanied by agitation or psychosis." The mean doses used were 1.2 and 1.1 mg/d, respectively. There were 18% dropouts because of adverse experiences, 15% because of lack of efficacy, and 6% for other reasons. There was no significant difference between haloperidol and risperidone on a global measure of psychopathology that was selected a priori. Secondary analyses showed an absence of effect of either active treatment relative to placebo on measures of psychosis, with a positive effect with both active treatments on measures of aggression. Incidence of extrapyramidal adverse events was 11%for patients on placebo, 15% for those on risperidone, and 22% for those on haloperidol, numbers generally consistent with prior studies. Sedation occurred more frequently on haloperidol (18.3%)and risperidone (12.2%) than placebo (4.4%). In the aggregate, these risperidone studies comprised the largest placebo-controlled, multicenter studies ever conducted of any form of

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treatment for agitation associated with dementia. A conservative interpretation of the available evidence is that the efficacy of risperidone is roughly equivalent to that of haloperidol, perhaps slightly better. The tolerability of risperidone seems to be better, with low-moderate risk of dose-related parkinsonism and sedation.

Olanzapine

At this juncture there are two published abstracts addressing the use of this agent in patients with dementia. One was a placebo-controlled parallel group study in 238 outpatients with dementia and agitation or psychosis. The primary aim of this pilot study was to address appropriate dosing and tolerability. The dose range used was 1 to 10 mg/d and the average dose at the end of the study was 2.7 mg/d; this dose was not associated with either toxicity or efficacy.40More recently, Street et a145reported results from a randomized, parallel group, multicenter study in 206 nursing home residents treated with placebo versus olanzapine in doses of 5,10, and 15 mg/d, again including patients with dementia and agitation or psychosis. Approximately 5% of the placebo group dropped out because of adverse experiences, versus 10.7%of the 5 mg/d group and 17%of the 15mg/d group. Information available as of this writing indicates that measures of agitation and psychosis improved significantly at 5 mg/d versus placebo, an effect less evident at 10 mg/d and not evident at 15 mg/d. The chief side effects observed were apparently dose-related sedation and postural instability, occurring in roughly 25%of subjects. Full details from this study are pending.

Quetiapine fumarate

The most significant evidence regarding this agent comes from a publication addressing a 1-year open-label study of flexible-dose quetiapine in older patients with psychoses of multiple origins, of whom 101 had either vascular dementia or AD.%The starting dose was 25 mg/d and the median dose was roughly 100mg/d. A total of 15%of subjects withdrew over 1year because of adverse experiences or intercurrent illnesses. Side effects were typically mild, occurring early in the course of treatment, and frequently transient. Thirty percent of subjects experience sedation, 15%developed orthostatic hypotension, and 12%experienced dizziness. The incidence of extrapyramidal signs and symptoms was low, consistent with encouraging pilot studies in patients with extrapyramidal disorders associated with dementia or p s y ~ h o s i sThe . ~ ~open trial in patients with dementia suggested encouraging behavioral effects, which led to the implementation of a more definitive multicenter placebo-controlled trial of this agent in comparison with haloperidol and placebo.

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SUMMARY OF ATYPICAL ANTIPSYCHOTICS

The available data provide a strong signal, falling short of absolute proof, that the atypical antipsychoticsas a class are very likely better tolerated than typical antipsychotics, and at least as efficacious. There seem to be modest differences within the class of atypicals in terms of clinical effectiveness, but the significance of these differences is unclear and there have been no head-to-head studies. There are limited long-term data addressing either safety or efficacy of these agents. Jeste et alZ0recently reported a cumulative incidence rate for tardive dyskinesia of 2.6% in 330 patients with dementia treated openly with risperidone (mean dose about 1 mg/d) for a median of 273 days. This figure is considerably less than that reported in older subjects treated with conventional agents,ls and is consistent with data reported in a recent prospective longitudinal study of risperidone and haloperidol in older subjects with mixed psychiatric di~0rders.l~ We are not aware of long-term data with olanzapine in patients with dementia. The available long-term data for quetiapine come from the 1-year open t i a l mentioned previously. Given the number of studies in progress, we expect that there will be a considerable amount of new data regarding all of these agents in the very near future, including data from a study initiated by the National Institute of Mental Health that will compare the effectiveness of atypical antipsychotics in patients with dementia complicated by agitation, psychosis, or both. If, as a result of such studies, better effectiveness is proved in comparison with conventional agents, it is likely that consensus guidelines will be developed rapidly that advocate routine preferential use of these agents instead of conventional agents. BENZODIAZEPINES

Most studies with benzodiazepines are older and have been reviewed previouslyz7These generally showed an average reduction in agitation with short-term therapy, although few were placebo-controlled. The study of Coccaro et aI8is probably the most rigorous of the modem studies of this type of agent, in which oxazepam, 10 to 60 mg/d, was compared with lowdose haloperidol in patients with mixed dementia diagnoses. Five percent of patients in the benzodiazepine group were reported as improved, versus 24%of those in the haloperidol group, a difference that seems large but did not reach statistical significancebecause of the small sample size. The most recent study of this class of agents compared alprazolam, 0.5 mg twice a day, with haloperidol, 0.6 mg/d, in a crossover study? The doses of both agents used in this study were probably too low to expect an effect, and none was seen. Literature reviews suggest a high rate of side effects with benzodiazepines, such as ataxia, falls, confusion, anterograde amnesia, sedation light-headedness,and tolerance and withdrawal ~ y n d r o r n e sIt. ~ is~for these reasons that we tend to reserve use of benzodiazepines for agitation associated with procedures or time-limited acute or as-needed use. Drugs with

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simpler metabolisms and relatively short half-lives, such as lorazepam, 0.5 mg 1 to 4 times daily, are selected most often; long-acting agents such as flurazepam are usually avoided. BUSPIRONE

No randomized, placebo-controlled, double-blind studies of this agent have been conducted: the only studies available are limited in scope and methodology. A single-blind, placebo-controlled study of 8 weeks in duration found improvement in measures of aggression, although only 60% of the 20 subjects completed the study.26Lawlof4 conducted a crossover study in 10 subjects comparing buspirone with trazodone, finding no relative benefit of buspirone. Cantillon et a14 compared buspirone, 15 mg, versus haloperidol, 1.3 mg/d, for 10 weeks in 26 subjects, finding no significant benefit of either drug. The medication is generally well tolerated, requires dosing twice a day, and may require several weeks to achieve maximal clinical benefit. Consensus statements’ point to its possible use most commonly in patients with mild agitation associated with anxiety or irritability, typically starting at 5 mg twice a day, increasing to a usual maximum daily dose of 40 to 60 mg/d. ANTIDEPRESSANTS

There are a number of case series and open trials suggesting benefit of trazodone in doses from 50 to 400 mg/d.39Symptoms of irritability, anxiety, restlessness, and depressed affect have been reported to improve in some cases, along with disturbed sleep. The main side effects have included sedation, orthostatic hypotension, and occasional delirium. Sultzer et a146compared trazodone at a mean dose of 220 mg/d with haloperidol at a mean dose of 2.5 mg/d in 28 patients in a 9-week crossover study. Agitation improved equally in both grou s with better tolerability in the trazodone group. More recently, Teri et a15Freported negative results for all active treatments in a multicenter outpatient study contrasting trazodone, haloperidol, placebo, and caregiver training. The available evidence is an example of clinical equipoise, with positive and negative evidence for efficacy. The Expert Consensus Guideline’ favors trazodone for sleep disturbance primarily, relegating it to second- or third-line use for mild agitation. A typical starting dose is 25 mg/d, with maximum doses usually 100 to 250 mg/d. There are mixed results in clinical trials using selective serotonin reuptake inhibitors for agitation in patients with dementia. A review of controlled studies of citalopram in patients with various dementia diagnoses was performed by Nyth and Gottfries?’ suggesting some beneficial behavioral effects. This conclusion was supported by two recent open trials of this agent.”,37Pollock et a13 also reported in abstract form that beneficial effects were seen in a controlled pilot study. Specifically, perphenazine at

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a target dose of 0.2 mg/kg/d and citalopram at 10 to 20 mg/d showed reduction in measures of agitation or psychosis in comparison with placebo during a 17-day treatment trial. No other citalopram data are yet available. Regarding other agents, no benefit has been reported for fluoxetine or fluvoxamine, and only anecdotes have been presented with respect to other serotonergic agents.27Despite the relatively limited research information about them, use of serotonergic agents is fairly widespread. This may be caused in part by familiaritywith this class of agents in treatment of depressive disorders, and basic, preclinical, and clinical evidence linking impulsivity to disordered serotonergicfunction.' The usual side effect profile of this class includes gastrointestinal symptoms; sedation or insomnia; sexual dysfunction; and less commonly, paradoxical agitation. It is important to learn results from large placebo-controlled studies to clarify further the exact role of this class of agents in treating our patients. ANTICONVULSANTS

Carbamazepine and valproate have both shown efficacy in the treatment of mania, and are the best-studied psychotropic agents in this class. The bulk of available evidence supports the conclusion that they may have antiagitation efficacy in dementia that more or less is equivalent to other effective psychotropics.Carbamaze ine has been examined in three placebocontrolled studies. Chambers et a1 performed an 8-week crossover study in 19 women with mild agitation who also received antipsychotics:this brief report was negative. Tariot et a150performed a 12-week placebo-controlled pilot crossover study in 25 patients, showing encouraging effects on agitation and not other aspects of psychopathology. A more recent confirmatory parallel group study of 6 weeks' duration in 51 patients also found a significant reduction in agitation using a mean dose of 300 mg/d.51Tolerability in these studies was generally good, with evidence of sedation and a t a ~ i a ; ~ ' , ~ ~ there was an 8%dropout because of side effects in the larger confirmatory carbamazepine study. It is likely that side effects seen in other populations, such as rashes, more serious sedation, hematologic abnormalities, hepatic dysfunction, and altered electrolytes, would be more evident with widespread use of this agent in the elderly, which may limit its use.52It has considerable potential for significant drug-drug interactions. The carbamazepine studies help provide proof-of-concept for the antiagitation efficacy of anticonvulsants. The question of whether alternative agents may be equally or more effective, or at least safer and better tolerated, remains open. Valproic acid, which is also available as a significantly better-tolerated enteric-coated derivative, divalproex sodium, has clinical effects generally similar to those achieved by carbamazepine in the treatment of mania. It is approved by the US Food and Drug Administration for treatment of acute mania associated with bipolar disorder. In the review of Rosenquist et al,39 12 case reports or case series are summarized that describe a total of 134 subjects treated with valproate. Subsequently, GoldbergI6

s

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performed an extensive chart review in 22 subjects. When the open treatment literature is viewed in the aggregate, approximately two thirds of these 156 subjects were reported to show improved agitation, with valproate doses ranging from a general low of about 500 mg/d to a general maximal dose of 1500 mg/d, with levels typically ranging from 20 to about 100 &mL. The first randomized, placebo-controlled, parallel group study of this agent, 6 weeks in length, was recently completeds in 56 nursing home residents who experienced dementia with agitation. The purpose of this study was not to prove efficacy but to establish effect size and clarify proper dosing to plan a larger definitive study, provided that a reasonable antiagitation signal was observed. The average divalproex dose achieved in this study was 826 mg/d, resulting in an average level of about 46 pg/mL. There was a 10%dropout rate because of adverse experiences. Despite the small sample size, the primary measure of agitation showed a nearly significant reduction on valproate versus placebo, supported by similar results with a clinical global impression of change. There were no changes in other behavioral measures. Tolerability was generally good: serious adverse events occurred at a rate of 10%in both the drug and placebo groups, with milder side effects occurring more often in the drug group, chiefly consisting of sedation, mild gastrointestinal distress, mild ataxia, and expected mild (but not clinically significant)decrease in platelet count (about 20,000 / mm3). A multicenter, randomized, placebo-controlled, 6-week, parallel group study of divalproex sodium has been conducted in patients with dementia and agitation who also met criteria for secondary mania.% Information is available only in abstract form. This study was designed using an aggressive dosing and titration protocol, in which a target dose of 20 mg/kg/d was achieved in 10 days. This plan resulted in unacceptable sedation in roughly 25% of the drug-treated group and a relatively high dropout rate, leading to premature discontinuation of the study. The original sample size was 172 nursing home residents, with 100 completers at the time the study was suspended. Although there was no significant drug-placebo effect on manic features, there was a significant effect of drug on agitation as measured by the Cohen-Mansfield Agitation Inventory? Sedation occurred in 36% in the drug group versus 20% of the placebo group, and mild thrombocytopenia occurred in 7% of the drug group and none of the placebo-treated patients. There were no other drugplacebo differences in adverse effects, although there was a trend toward increased likelihood of gastrointestinal distress. Nineteen percent of the active group withdrew because of adverse events versus 4%of the placebo group. Side effects reported in the package insert include those described previously plus hair loss, mild thrombocytopenia, and hepatic or pancreatic dysfunction that can rarely be fatal. These more serious events have not been reported in the elderly at this juncture, and are more likely to be seen in children requiring multiple anticonvulsants. The available evidence suggests that, if divalproex is used, it is reasonable to begin with a starting dose of about 125 mg orally twice a day increasing by 125- to 250-mg increments every 5 to 7 days, with a maximal

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dose determined by clinical response, or where there is uncertainty, a serum level of about 60 to 90 Fg/mL. The role of the new once-daily extended release formulation is not yet established in this population. There are no controlled studies of which the authors are aware of the newer anticonvulsants including lamotrogine, gabapentin, and topiramate, although there is at least one case report suggesting benefit with gabapentin plus haloperidol.38The reader is cautioned against the assumption that "all anticonvulsants are equal" in terms of efficacy or safety and tolerability. Because anticonvulsants as a class seem to be relatively welltolerated, based on years of experience in numerous clinical populations with other disorders, definitive trials showing efficacy and reasonable tolerability in dementia will very likely influence clinical practice in the future. Although beyond the scope of this article, the curious reader may wish to know that there is considerable intriguing biologic data addressing the mechanism of action of mood stabilizers suggesting in particular that lithium and valproate but not other agents may have clinically relevant neuroprotective pr0perties.2~A better understanding of these issues may differentiate among available agents and also lead to the identification of new targets for therapy. OTHER AGENTS FOR AGITATION

As eloquently summarized by Cummings," there is considerable evidence suggesting that cholinergic agents, especially cholinesterase inhibitors, may have psychotropic effects in patients with dementia. The most compelling data come from recent trials. A prospective clinical trial of metrifonate versus placebo found modest reduction in average neuropsychiatric symptoms in the drug group versus placebo g r o ~ pDe.~ velopment of this drug, however, has been abandoned because of toxicity. Tariot et a155showed reduced incidence of neuropsychiatric symptoms on drug versus placebo in outpatients who generally lacked psychopathology at baseline in a 5-month study of galantamine. Less rigorous studies of cholinergic agents suggested similar effects." It is possible that future trials data will clarify the extent to which cholinergic therapy given presymptomatically may delay or attenuate the emergence of agitation. Once behavioral symptoms are present, it seems that these agents as a class may have clinically important behavioral effects for certain symptoms, at least in some patients with dementia, that are relatively modest on average. The role of cholinergic agents for agitation specifically is likely to be fairly limited, however. Beta blockers have not been studied very extensively, with most evidence coming from older reports in patients with mixed organic brain syndromes.%Shankle et al"' have published the most recent study, reporting that some measures of aggression improved in 8 to 12 patients with dementia who received low doses of propranolol (30 to 80 mg/d). The likelihood of adverse reactions in this population, including bradycardia, hypotension, worsening of congestive heart failure, or asthma, is high.

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Because there are no placebo-controlled, randomized studies of this class of agents, it probably is relegated to rare, unconventional use. There are no definitive studies of either estrogenic or antiandro enic approaches, although there are roughly a dozen published a n e c d ~ t e sThe .~ available evidence is provocative but by no means definitive: controlled studies will be extremely helpful. Other rarely used or unconventional approaches have been summarized in previous publication^.^^,^^,

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TREATMENT OF DEPRESSIVE FEATURES IN DEMENTIA

The definition of syndromal depression in dementia is a topic of debate, because there is a wide range of depressive signs and symptoms that can occur and fluctuate spontaneously. The thoughtful clinician is urged to gauge the severity of these signs and symptoms individually and in the aggregate before deciding whether to intervene, and specifically whether to use medications. Controlled clinical trials in dementia are modest in number and quality. They have been reviewed by Devanand.12 On balance, the trials show a small or no advantage for antidepressant over placebo, leaving clinicians uncertain as to what extent efficacy should be expected. No specific class of antidepressants was shown to be superior to any others. Adverse events seen in patients with dementia are similar to those observed in other patient groups. Specific agents studied included clomipramine, imipramine, citalopram, fluvoxamine, paroxetine, and moclobemide. Consensus statements generally conclude that the use of tricyclic antidepressants should be limited to those at the lowest anticholinergic burden (i.e., nortriptyline or desipramine). In general, these consensus documents emphasize the use of SSRIs because of more favorable tolerability profiles2;endorse the usual principles, such as "start low and go slow"; and emphasize that it is important to treat for an adequate duration to properly assess efficacy. As indicated in Table 2, doses used tend to be lower than those used in other populations. Electroconvulsive therapy is generally reserved for treatment of patients with dementia who suffer clear-cut and severe syndromal depression who have not responded to other therapy or who cannot tolerate it, or are in jeopardy because of the severity of depression. SLEEP DISTURBANCESIN DEMENTIA

The key issues in this regard have been reviewed by Swearer.47Sleep disturbances seen in dementia include increased sleep onset latency, frequent awakenings, and decreased total sleep time. There is a rough relationship between severity of dementia and magnitude of these problems. There is remarkably little clinical trials information regarding treatment of insomnia in dementia, and the available literature is characterized by hazy diagnostic terminology and use of unclear outcome measures.

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Management recommendations typically include standard approaches to sleep hygiene, including reduction of stimulant medications, reduced use of caffeinated beverages, maintenance of regular sleep-wake cycle, reduction of environmental stimuli, and enhanced exercise during the day. The available literature regarding medications counsel against the use of barbiturates. Benzodiazepines are widely used, but are associated with a high risk of significant side effects, which were reviewed previously." There is an increased risk of adverse effects with benzodiazepines after chronic administration, meaning that they should be used only for short periods of time and at low doses. There are case series suggesting that the nonbenzodiazepine zolpidem helped with sleep and was associated with good tolerability." Psychiatrists frequently use antidepressants to treat insomnia, partly because of the frequent association of sleep disturbance with depressive disorders and because of the relative safety of this class of agents. Trazodone is used the most often,' although there are no clinical trials supporting this consensus view. Usual doses for this and the other agents are summarized in Table 2. SUMMARY

Clinicians attempt to treat agitation and other behavioral psychological symptoms associated with dementia as best they can. The clearest guidance regarding use of medications comes from definitive clinical trials. At this point, evidence is mounting that certain treatment approaches make sense and can be roughly rank-ordered, although none have been proved beyond a shadow of a doubt to dictate standard clinical practice. This state of affairs highlights the significance of available consensus statements to guide the practicing clinician.',* Psychotropic medication should be used only after simpler nonpharmacologic interventions have been attempted. The authors, along with the consensus statement authors, adopt an approach toward drug selection that is based on matching target symptoms to the most relevant drug class. Most of the available clinical trials data indicate that antipsychotics as a group are likely to show benefit for agitation associated with psychotic features. Evidence is also substantial that this class of agents may show efficacy or agitation or aggression even in the absence of psychosis. The evidence is quite clear that the typical antipsychotics have a high risk of side effects in the short run and especially in the long term. The newer agents seem quite promising at least in terms of tolerability relative to conventional agents; the returns are not all in yet regarding relative efficacy. The volume of studies addressing nonantipsychotic medications is less, chiefly addressing the potential role of anticonvulsants, antidepressants, and anxiolytics. By and large, evidence supports benefit of these agents at least in a substantial percentage of patients. Interestingly, available data regarding effect size across all effective agents point toward an average drug group response rate in the neighborhood of 60%,and a placebo response rate in the neighborhood of 40%. No one agent works for all patients, and

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it is not yet known whether someone who fails one agent is more or less likely to respond to another. Likewise, although combination therapy is widely used, there are remarkably few data to guide the clinician in this respect. Clinicians must assess this issue on a case-by-case basis. There is some room for hope, because a significant amount of data is on the horizon. This includes a study of divalproex%;the details of the olanzapine nursing home study originally reported in abstract form by Street et a145;the results from a multicenter trial of donepezil in the nursing home57;and details of a preliminary report of a study combining sertraline and donepezil, to name a few. These studies and others will give us a clearer sense of exactly how and when therapy should be deployed, and begin to address combination therapies. In the meantime, clinicians are obliged to deal as thoughtfully as possible with patients on a case-by-case basis, attempting first and foremost to avoid toxicity of therapies intended to help.

References 1. Alexopoulos GS, Silver JM, Kahn DA, et al: Treatment of agitation in older persons with dementia. Postgrad Med: 148,1998 2. American Psychiatric Association Work Group on Alzheimer’s Disease and Related Dementias, Rabins P, Blacker D, et al: Practice guideline for the treatment of patients with Alzheimer’s disease and other dementias of late life. Am J Psychiatry 1541-39,1997 3. Ballard C, Grace J, McKeith I, et al: Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer’s disease. Lancet 351:1032-1033,1998 4. Cantillon M, Brunswick R, Molina D, et a1 Buspirone vs. haloperidol: A double-blind trial for agitation in a nursing home population with Alzheimer’s disease. Am J Geriatr Psychiatry 4:263-267,1996 5. Chambers CA, Bain J, Rosbottom R, et al: Carbamazepine in senile dementia and overactivity: A placebo controlled double blind trial. IRCS Medical Science 10:505-506,1982 6. Christensen DB, Benfield WR: Alprazolam as an alternative to low-dose haloperidol in older, cognitively impaired nursing facility patients. J Am Geriatr SOC46:620-625,1998 7. Coccaro E F Neurotransmitter correlates of impulsive aggression in humans. Ann NY Acad Sci 794:82-89,1996 8. Coccaro EF, Kramer E, Zemishlany Z, et al: Pharmacologic treatment of noncognitive behavioral disturbances in elderly demented patients. Am J Psychiatry 1471 640-1645, 1990 9. Cohen-Mansfield J: Agitated behaviors in the elderly. 11. Preliminary results in the cognitively deteriorated. J Am Geriatr Soc W722-727,1986 10. Cummings JL: Cholinesterase inhibitors: A new class of psychotropic compounds. Am J Psychiatry 1574-16,2000 11. De Deyn PP, Rabheru K, Rasmussen A, et al: A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology, 53946955,1999 12. Devanand DP: Depression in dementia. In Qizilbash N, Schneider L, Chui H, et al: Evidence-Based Dementia: A Practical Guide to Diagnosis and Management. Oxford, Blackwell Science Ltd, in press 13. Devanand DP, Jacobs DM, Tang MX, et al: The course of psychopathologic features in mild to moderate Alzheimer disease. Arch Gen Psychiatry 54:257-’263,1997 14. Devanand DP, Marder K, Michaels K, et a 1 A randomized, placebo-controlled, dosecomparison trial of haloperidol for psychosis and disruptive behaviors in Alzheimer’s disease. Am J Psychiatry 1551512-1520,1998 15. Finkel SI, Costa, Cohen G, et al: Behavioral and psychological signs and symptoms of dementia: A consensus statement on Current knowledge and implications for research and treatment. Int Psychogeriatr 8(suppl3):497-500,1996

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16. Goldberg RJ: The use of adjunctive divalproex for neuroleptic unresponsive behavioral disturbances in nursing home residents with dementia. Ann Long-Term Care 7:6346, 1999 17. Beck C, Heacock P: Nursing interventions for patients with Alzheimer‘s disease. Nurs Clin North Am 2395124,1988 18. Jeste DV, Caligiuri MP, Paulsen JS, et al: Risk of tardive dyskinesia in older patients: A prospective longitudinal study of 266 outpatients. Arch Gen Psychiatry 52756-765, 1995 19. Jeste DV, Lacro JP, Bailey A, et al: Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr Soc 47716719,1999 20. JesteDV, Okamoto A, Napolitano J, et al: Low incidence of persistent tardive dyskinesia in elderly patients with dementia treated with risperidone. Am J Psychiatry 1571150-1155, 2000 21. Jost BC, Grossberg GT The evolution of psychiatric symptoms in Alzheimer’s disease: A natural history study. J Am Geriatr Soc 44:1078-1081,1996 22. Katz IR, Jeste DV, Mintzer JE, et al: Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: A randomized, double-blind trial. Risperidone Study Group. J Clin Psychiatry 60107-115,1999 23. Lanctot KL, Best TS,Mittmann N, et al: Efficacy and safety of neuroleptics in behavioral disorders associated with dementia. J Clin Psychiatry 59:550-561,1998 24. Lawlor BA: A pilot placebo-controlled study of trazodone and buspirone in Alzheimer’s disease. Int J Geriatr Psychiatry 95559,1994 25. Leibovici A, Tariot PN: Agitation associated with dementia: A systematic approach to treatment. Psychopharmacol Bull 24:49-53,1988 26. Levy MA, Burgio LD, Sweet R, et a1 A trial of buspirone for the control of disruptive behaviors in community-dwelling patients with dementia. Int J Geriatr Psychiatry 9:841848,1994 27. Loy R, Tariot PN, Rosenquist K Alzheimer’s disease: Behavioral management. b i Katz IR, Oslin D, Lawton MP (eds): Annual Review of Gerontology and Geriatrics: Focus on Psychopharmacologic lnterventions in Late Life. New York, Springer Publishing, 1999, pp 136-194 28. Lyketsos CG, Steinberg M, Tschanz JT, et al: Mental and behavioral disturbances in dementia: Findings from the Cache County Study on Memory in Aging. Am J Psychiatry 157708-714,2000 29. Manji HK, Moore GJ, Chen G: Lithium up-regulates the cytoprotective protein Bcl-2 in the CNS in vivo: A role for neurotrophic and neuroprotective effects in manic depressive illness. J Clin Psychiatry 6l(suppl9):82-96,2000 30. Moms JC, Cyrus PA, Orazem J, et al: Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer‘s disease. Neurology 501222-1230, 1998 31. Nyth AL, Gottfries CG: The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders: A Nordic multicentre study. B J Psychiatry 157894901,1990 32. Parsa MA, Bastani B Quetiapine ( S e q u e l ) in the treatment of psychosis in patients with Parkinson’s disease. J Neuropsychiatry Clin Neurosci 10:216-219,1998 33.Patel S, Tariot PN: Use of benzodiazepines in behaviorally disturbed patients: Risk-benefit ratio. I n Lawler BA (ed): Behavioral Complications of Alzheimer’s Disease. Washington, DC,American Psychiatric Association Press, 1995,p p 153-170 34 Pollock BG, Mulsant BH, Sweet R, et a 1 An open pilot study of citalopram for behavioral disturbances of dementia. Plasma levels and real-time observations. Am J Geriatr Psychiatry 5:70-78,1997 35 Pollock BG, Rosen J, Mulsant BH, et al: Treatment of behaviors in dementia with Citalopram. APA New Research #281.5-16,2000 36. Porsteinsson AP, Tariot PN, Erb R, et al: Placebcontrolled study of divalproex sodium for agitation in dementia. Am J Geriatr Psychiatry, in press 37. Ragneskog H,Eriksson S, Karlsson I, et al: Long-term treatment of elderly individuals with emotional disturbances: An open study with citalopram. Int Psychogeriatr 8:659668,1996

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Pierre N. Tariot, MD Monroe Community Hospital 435 East Henrietta Road Rochester, NY 14620