Chapter 57. Treatment of Agitation and Aggression in the Elderly

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Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff.

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Chapter 57. Treatment of Agitation and Aggression in the Elderly

TREATMENT OF AGITATION AND AGGRESSION IN THE ELDERLY:

INTRODUCTION

Severe agitation—restlessness, wandering, or screaming—may accompany late-life psychosis or

dementia, with particularly high prevalence rates in nursing homes. Aggression and assaultiveness

may also occur as a consequence of the delusions or hallucinations of late-life psychosis from

dementia, depression, or a combination of these factors. Behavioral and psychiatric symptoms

develop in as many as 60% of community-dwelling dementia patients (Lyketsos et al. 2000; Ryu et

1. 2005; Tractenberg et al. 2003; Wragg and Jeste 1988). The lifetime risk of behavioral

complications of dementia approaches 100% (Lyketsos et al. 2000). Rates of physical aggression

range from 11% to 46% among community-dwelling dementia patients and from 31% to 42%

among patients in institutional settings (Billig et al. 1991; Brodaty et al. 2003; Cohen-Mansfield et

1. 1995; Peabody et al. 1987; Wragg and Jeste 1988; Zimmer et al. 1984). The etiology of agitation

and aggression in late-life psychosis or dementia is unknown, although environmental and

biological factors, such as drug toxicity, medical illness, pain, frustration, loneliness, reduced

sensory input, new surroundings, diminished nutritional status, and altered central nervous system

(CNS) function, alone or in combination, may play important roles (Mintzer and Brawman-Mintzer

1996).

In recent years, researchers and clinicians have begun to categorize disruptive behavioral

syndromes according to associated etiology, as agitation and aggression of 1) psychosis, 2)

dementia with psychosis, and 3) nonpsychotic dementia (Jeste et al. 2006). At present, there are

no specific diagnostic categories of “psychosis with dementia” or “dementia-related agitation,” so

that all treatments are “off label.” Psychotic and nonpsychotic patients have been mixed together in

clinical trials, which may have confused the outcomes and clinical recommendations. A distinct

category of “psychosis of Alzheimer’s disease and related dementia” may improve research into

late-life agitation and aggression (Jeste and Finkel 2000).

No drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of

persisting psychosis, agitation, or aggression associated with dementia. Nevertheless, despite only

modest benefits and frequent warnings about adverse effects and inappropriate use, antipsychotic

drugs continue to be used as first-line agents. An increasing number of other medication classes,

including anticonvulsants, antidepressants, and cognitive enhancers, are also being used as

second-line choices for management of agitation and aggression in dementia that cannot be

managed without medication (Docherty et al. 1998; Jeste et al. 2008; Kindermann et al. 2002;

Raivio et al. 2007; Salzman 2000; Salzman and Tune 2001; Salzman et al. 2008; Small et al. 1997).

ANTIPSYCHOTIC TREATMENT

First-Generation (Conventional, Typical) Antipsychotics

Before the second-generation (atypical) antipsychotics, with their superior side-effect profiles,

became available, first-generation antipsychotics (FGAs; sometimes called conventional or typical

antipsychotics), especially haloperidol, were the mainstay of treatment of late-life agitation.

Extrapyramidal side effects (EPS), however, are common with haloperidol, especially in the elderly,

limiting its usefulness. Tardive dyskinesia, a late-appearing EPS, develops more rapidly and at

lower antipsychotic doses in elderly patients than in younger ones (Caligiuri et al. 1999; Jeste et al.

1999; Karson et al. 1990; Lieberman et al. 1984; Saltz et al. 1989). Tardive dyskinesia is also more Print: Chapter 57. Treatment of Agitation and Aggression in the Elderly http://www.psychiatryonline.com/popup.aspx?aID=434762&print=yes…

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common in patients with evidence of cortical atrophy and in dementia patients (Sweet and Pollock

1992). When antipsychotics are discontinued, tardive dyskinesia symptoms are less likely to

disappear in older patients than in younger adults (Smith and Baldessarini 1980; Yassa et al. 1984),

although the symptoms may not increase in severity (Yassa et al. 1992). These concerns regarding

tardive dyskinesia and other EPS have contributed to the switch in clinical preference for the newer

antipsychotic drugs.

Second-Generation Antipsychotics

Second-generation antipsychotics (SGAs; sometimes called atypical antipsychotics) have replaced

conventional antipsychotics as the first-choice treatment for agitation and aggression in the elderly.

As a class, these newer antipsychotics carry a lower risk of EPS and tardive dyskinesia. Although

pharmacokinetic data are not available for all of the newer SGAs, studies of risperidone indicate

that clearance of risperidone and its 9-hydroxy metabolite does not decline with age, whereas

clearance of quetiapine is reduced with increasing age (Jaskiw et al. 2004; Maxwell et al. 2002).

SGAs are as effective as FGAs for treating agitation and aggression, with or without associated

psychosis (Ballard and Waite 2006; Sink et al. 2005). Ballard and Waite (2006), for example, found

a significant improvement in aggression with risperidone and olanzapine compared with placebo

and a significant improvement in dementia-associated psychosis among risperidone-treated

patients. These observations have been supported by numerous other studies. Katz et al. (1999)

reported the superiority of risperidone compared with placebo for the treatment of agitation in

Alzheimer’s disease. Street et al. (2000) reported that olanzapine was superior to placebo for

agitation associated with Alzheimer’s disease. Meehan et al. (2002) studied acute treatment of

agitation with intramuscular olanzapine in 272 inpatients or nursing home residents with

Alzheimer’s disease and/or vascular dementia. Patients were given up to three injections of

olanzapine (2.5 mg or 5.0 mg), lorazepam (1.0 mg or 0.5 mg), or placebo and assessed within a

24-hour period. Olanzapine was found to be superior to placebo in treating agitation at 2 hours and

24 hours. Adverse events were not significantly different between groups. Aripiprazole was also

reported to be superior to placebo for treatment of psychosis of Alzheimer’s disease in outpatients

(Laks et al. 2006).

Not all studies of SGAs have reported positive results, however. In a placebo-controlled multicenter

trial comparing quetiapine and haloperidol versus placebo for psychosis associated with dementia,

Tariot et al. (2006) reported no benefit of either active treatment, with one secondary measure of

agitation suggesting benefit. This led to a subsequent placebo-controlled multicenter trial of

quetiapine at fixed dosages (100 mg/day and 200 mg/day), which found overall superiority for

quetiapine compared with placebo in the management of agitation (Zhong et al. 2006, 2007).

Ballard and Waite (2006) conducted a placebo-controlled trial of quetiapine versus rivastigmine in

which no benefit of either treatment was observed on behavioral outcomes; cognition worsened in

the quetiapine group, a worrisome result that has not been seen in any other study of quetiapine.

The Clinical Antipsychotic Trials of Intervention Effectiveness—Alzheimer’s Disease (CATIE-AD)

addressed the relative effectiveness of commonly used atypical antipsychotics (Schneider et al.

2006). Outpatients with Alzheimer’s disease and psychosis, aggression, or agitation were randomly

assigned to treatment with olanzapine (mean dosage

5 mg/day), quetiapine (mean dosage

50

mg/day), risperidone (mean dosage

1 mg/day), or placebo. No conventional antipsychotic was

included in the study because of concerns about tardive dyskinesia. The primary measure of

effectiveness was time to all-cause discontinuation; secondary measures addressed time to

discontinuation due to lack of efficacy, significant safety concerns, or death, as well as

improvement in Clinical Global Impression Scale Change scores. There was no significant difference

among the drugs in the primary outcomes, although time to discontinuation due to lack of efficacy

was longer with olanzapine and risperidone versus quetiapine or placebo. Conversely, time to

discontinuation due to adverse events or drug intolerability was longer for all active treatments

than for placebo. The CATIE-AD trial, therefore, confirmed the modest efficacy of atypical

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Meta-analytic reviews also suggest that the overall efficacy of SGAs for treatment of agitation and

aggression is modest, as is the difference between active drug and placebo. Overall response rates

in CATIE-AD ranged from 48% to 65% with active treatment versus 30%–48% with placebo,

showing an incremental treatment benefit of about 18% for active drug over placebo (Schneider et

1. 2006).

Studies comparing SGAs with FGAs have reported significantly greater efficacy for

second-generation agents than for first-generation ones (Suh et al. 2004), and in all studies, the

FGAs were associated with more EPS than the SGAs (Chan et al. 2001; De Deyn et al. 1999; Suh et

1. 2004). The CATIE-AD study, lacking an FGA arm, could not add to these observations.

Side Effects of Antipsychotic Drugs

In addition to modest efficacy, reports of serious side effects other than EPS and tardive dyskinesia

have raised concerns regarding the use of antipsychotics as first-line treatments for agitation or

aggression, with or without psychosis, in elderly populations. An initial report indicating an

increased risk of cerebrovascular adverse events (CVAEs; e.g., stroke, transient ischemic attack

[TIA], death) in male nursing home residents older than 85 years who were treated with

risperidone (Wooltorton 2002) led to further investigation. Similar suggestive evidence was

reported for olanzapine and ultimately for other SGAs (Kryzhanovskaya et al. 2006; Percudani et al.

2005; Wooltorton 2004). Taken together, these observations of increased CVAEs in elderly

individuals receiving SGAs stimulated an examination of all studies, which supported concerns

regarding a possible increased risk of CVAEs when either of these drugs is given to elderly patients

with dementia. Data from 11 olanzapine or risperidone studies collectively suggested that 2.2% of

drug-treated subjects experienced CVAEs, compared with 0.8% of placebo-treated subjects. The

combined relative risk was 2.7. Ballard and Waite (2006) concluded that despite the modest

efficacy of these drugs, the significance of the adverse events dictates that “neither risperidone nor

olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless

there is marked risk or severe distress.”

In 2003, the FDA issued a black box warning regarding a possible increased risk of CVAEs

associated with use of atypical antipsychotics in older adults with dementia. The warning was

eventually extended to include aripiprazole, olanzapine, and risperidone. The death rate in clinical

trials was 3.5% with SGAs versus 2.3% with placebo, leading the FDA to impose a black box

warning for all SGAs. Studies examining large public databases (Ballard and Waite 2006; Schneider

et al. 2006) have found similar rates of death among elderly people receiving FGAs (Schneeweiss et

1. 2007; Wang et al. 2005).

The FDA warning has generated considerable controversy. Some researchers, examining the data

on which the FDA’s warning was based, have become concerned that methodological faults in many

of the studies may have compromised the meta-analyses and led to an overly harsh interpretation

of the data and an unwarranted concern for safety. Some studies failed to find an increase in death

rate or incidence of CVAEs. For example, Herrmann et al. (2004), as well as Haupt et al. (2006) and

Gill et al. (2005), found no significant increase in the risk of ischemic stroke with either FGAs or

SGAs or among those receiving SGAs compared with FGAs. The American College of

Neuropsychopharmacology has issued a White Paper (Jeste et al. 2008) concluding that further

research data are needed to clarify the ongoing significance, if any, of increased development of

CVAEs. An expert consensus conference held in 2006 (Salzman et al. 2008) essentially made the

same point.

Most recently, a retrospective study of 254 very frail patients with dementia (mean age = 86 years)

from seven nursing homes and two hospitals in Finland found that neither SGAs nor FGAs increased

mortality (the use of SGAs actually should lower the risk of mortality) (Raivio et al. 2007).

Clinicians currently struggle with a difficult treatment dilemma when confronted with an elderly

patient with dementia who is possibly psychotic and whose behavior is characterized by extreme

agitation and/or aggression that cannot be controlled without medications. The essentialPrint: Chapter 57. Treatment of Agitation and Aggression in the Elderly http://www.psychiatryonline.com/popup.aspx?aID=434762&print=yes…

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conclusion of the CATIE-AD study, and a sensible statement about the role of antipsychotics (Jeste

et al. 2008; Salzman et al. 2008; Sink et al. 2005), was that on average, patients receive modest

benefit without being harmed: these are the patients for whom continued therapy is rational. The

following clinical conclusions appear to be warranted at this time:

Recognizing that the use of antipsychotic drugs to treat agitation or aggression is “off label,” clinicians

must be certain that the behavior cannot be managed nonpharmacologically and that the severity of the

disruptive behavior warrants the selection of this class of drugs. If an FGA such as haloperidol is

selected, doses should be kept low to minimize the likelihood of developing EPS.

1.  
2. SGAs are still preferred to FGAs because of the lower likelihood of EPS and tardive dyskinesia.

Clinicians should confer with the patient’s family or significant others regarding the use of these drugs

and should attempt to obtain some form of informed consent, balancing the possible risk of using these

medications against the likelihood of worsening behavior and clinical status without such treatment.

3.  
4. Clinicians should follow these patients closely for early warning signs of a CVAE.

NON-ANTIPSYCHOTIC TREATMENT

A growing body of clinical experience, research, and anecdotal reports suggests that agents such as

trazodone, anticonvulsants (mood stabilizers), buspirone, serotonergic antidepressants, and

cognitive enhancers may help manage a variety of agitated behaviors refractory to more

conventional treatment. These drugs, however, are ineffective in treating symptoms of psychosis.

Benzodiazepines

Although benzodiazepines are quite widely used in this population, there have been no studies of

benzodiazepine treatment of agitation or aggression in nearly a decade. Most of the older studies

were not placebo controlled, but they nonetheless suggested that on average, agitation could be

reduced with short-term benzodiazepine therapy (Loy et al. 1999). For example, Coccaro et al.

(1990) compared oxazepam (10–60 mg/day) with low-dose haloperidol in patients with mixed

dementia diagnoses. Five percent of patients in the benzodiazepine group improved, compared with

24% of those in the haloperidol group, a difference that was not statistically significant, perhaps

because of the small sample size. Christensen and Benfield (1998) compared alprazolam (0.5 mg

twice daily) with haloperidol (0.6 mg/day) in a crossover study. Adverse events were not

significantly different between groups. The dosages of both agents used in this study were probably

too low to expect an effect, and none was seen. Meehan et al. (2002) noted that intramuscular

lorazepam 1.0 mg or 0.5 mg was superior to placebo at 2 hours but not at 24 hours.

Possible side effects of benzodiazepines given to elderly individuals include ataxia, falls, confusion,

anterograde amnesia, sedation, light-headedness, and tolerance and withdrawal syndromes (Patel

and Tariot 1995). This profile, along with the scant evidence of efficacy, suggests that use of

benzodiazepines for agitation should be time limited or on an as-needed basis, with chronic use

only for those patients in whom other agents have proven ineffective. Drugs with simpler

metabolisms and relatively short half-lives, such as lorazepam, are always preferred.

Anticonvulsants (Mood Stabilizers)

Although Chambers et al. (1982) reported no benefit of carbamazepine in a crossover study in 19

patients with agitation, most subsequent studies suggest that anticonvulsants are modestly helpful

for controlling agitation and aggression in elderly individuals with dementia. In a

placebo-controlled crossover study in 25 agitated dementia patients, Tariot et al. (1994) reported

improvement with carbamazepine. This was supported by a confirmatory parallel-group study of 51

patients in which the mean daily dosage was 300 mg (Tariot et al. 1998). Carbamazepine was well

tolerated in both studies; sedation and ataxia were the most common side effects (Tariot et al.

1998, 2002). Another small (n = 21) placebo-controlled study of carbamazepine (400 mg/day)

reported modest benefit. Adverse events were reported as mild (Olin et al. 2001). Despite these

preliminary findings, there is a relative dearth of evidence of efficacy from controlled clinical trials.

Given the high risk of drug–drug interactions with carbamazepine and the frequent side effects

seen in other populations (including rashes, sedation, hematological abnormalities, hepaticPrint: Chapter 57. Treatment of Agitation and Aggression in the Elderly http://www.psychiatryonline.com/popup.aspx?aID=434762&print=yes…

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dysfunction, and altered electrolytes), carbamazepine should not be considered a first-choice

treatment in this population.

Valproic acid, and its enteric-coated derivative divalproex sodium, has been the subject of a number

of case reports or case series in patients with dementia and agitation, in which about two-thirds of

patients with dementia and agitation have been described as clinically improved. The first

randomized, placebo-controlled, parallel-group study of valproate was conducted as a precursor to

a larger multicenter trial (Porsteinsson et al. 2001); a secondary measure of agitation showed

improvement that was also seen in an open-label extension (Porsteinsson et al. 2003). Side effects

seen with valproate included sedation, gastrointestinal distress, and ataxia, as well as the expected

decrease in average platelet count (about 20,000/mm3 ). A small placebo-controlled crossover

study of valproate used for aggressive behavior found no benefit on primary measures of

aggression (Sival et al. 2002). There were no drug–placebo differences in rates or types of adverse

events. A 6-week randomized, placebo-controlled multicenter study of divalproex sodium in 172

nursing home residents with dementia and agitation who also met criteria for secondary mania

used a target dosage of 10 mg/kg/day for 10 days (Tariot et al. 2001b). There was a high dropout

rate (n = 100 completers), with 19 divalproex sodium–treated patients (22%) and 3

placebo-treated patients (4%) withdrawing from the study because of adverse events, primarily

somnolence (typically occurring at daily dosages 15 mg/kg).There were no significant

drug–placebo differences in change in manic features, although a significant drug effect on

agitation was seen. Sedation occurred in 36% of the drug group versus 20% of the placebo group,

and mild thrombocytopenia occurred in 7% of the drug group versus none of the placebo-treated

patients. There were no other significant drug–placebo differences in adverse effects. The results

from this trial were used to amend prescribing information by cautioning against the use of similar

high doses and/or titration rates in the elderly. The largest (n = 153) placebo-controlled trial

prospectively addressing agitation, conducted by the Alzheimer’s Disease Cooperative Study, found

no benefit from divalproex (Tariot et al. 2005). In a comprehensive review, Sink et al. (2005)

likewise failed to find benefit for divalproex, and they noted mixed results regarding the efficacy of

carbamazepine in patients with dementia. A Cochrane review of valproate for agitation in dementia

(Lonergan et al. 2004) concluded that low-dose valproate was ineffective and that high-dose

valproate was associated with an unacceptable rate of adverse effects.

There are no placebo-controlled studies of lamotrigine, gabapentin, or topiramate in the treatment

of behavioral symptoms in dementia. Despite the absence of controlled studies, however,

anticonvulsants are used in clinical practice when other drug treatments fail or are poorly tolerated.

The greatest amount of clinical data are available for gabapentin, with almost all reports noting

improvement in a majority (but not all) of the subjects. Dosages used ranged from 200 to 1,200

mg/day (Alkhalil et al. 2004; Goldenberg et al. 1998; Herrmann et al. 2000; Moretti et al. 2003;

Roane et al. 2000). A review of case reports described worsening of behavior in Lewy body

dementia patients who received gabapentin (Rossi et al. 2002). A small retrospective review of

topiramate found that agent modestly helpful for aggressive behavior in dementia (Fhager et al.

2003). A single letter to the editor reported the usefulness of lamotrigine for the treatment of

aggression in dementia (Devarajan and Dursun 2000).

In an effort to develop more innovative clinical trial designs, as well as to address the public health

significance of psychopathology in Alzheimer’s disease, the Alzheimer’s Disease Cooperative Study

organized the first multicenter trial addressing secondary prevention of psychopathology in

Alzheimer’s disease (Tariot et al. 2002). This multicenter study is examining whether valproate

therapy can delay, attenuate, or prevent the emergence of agitation or psychosis in patients lacking

these features at baseline. The design incorporates traditional measures of illness progression as

secondary outcomes, based on the potential for neuroprotective effects of chronic administration,

and may contribute to improved understanding of mechanisms of action of valproate therapy via

use of biological markers selected for their relevance to mechanism of action as well as

pathobiology of Alzheimer’s disease. The study has completed enrollment and will end in early

2009.Print: Chapter 57. Treatment of Agitation and Aggression in the Elderly http://www.psychiatryonline.com/popup.aspx?aID=434762&print=yes…

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Serotonergic Drugs

Sink et al. (2005) found little overall evidence of efficacy for antidepressants in the treatment of

neuropsychiatric symptoms other than depression. However, because depression, including

irritability, is commonly seen in people with dementia, serotonergic antidepressants are often used

in their treatment.

The antidepressant drug trazodone has been reported to be effective in treating agitation and

severely disruptive behavior (Greenwald et al. 1986; Nair et al. 1973; Pinner and Rich 1988;

Simpson and Foster 1986; Tingle 1986), although these studies did not distinguish between

psychotic and nonpsychotic patients. Extensive clinical experience suggests that trazodone is

effective at dosages of 50–200 mg/day, with few side effects other than sedation. The mechanism

of trazodone’s effect is unknown. There have been two double-blind, controlled studies of

trazodone in the treatment of dementia-associated agitation. The first was a brief crossover study

in only 28 patients, comparing trazodone at a mean dosage of 220 mg/day with haloperidol at a

mean dosage of 2.5 mg/day (Sultzer et al. 1997). Agitation improved equally in both drug groups,

with better tolerability seen in the trazodone group. The Alzheimer’s Disease Cooperative Study

reported negative results for all active treatments in a multicenter outpatient study contrasting

trazodone, haloperidol, placebo, and caregiver training (Teri et al. 2000). Although there is

negative as well as positive evidence of trazodone’s efficacy, clinical experience suggests that

trazodone is often extremely helpful as an add-on medication when antipsychotics or other drugs

alone cannot control disruptive behavior. Priapism is a rare side effect of trazodone in elderly men.

Selective serotonin reuptake inhibitor (SSRI) antidepressants may also have modest antiagitation

properties in elderly patients with dementia (Burke et al. 1997; Swartz et al. 1997). Citalopram

(Kim et al. 2000; Pollock et al. 2002) and sertraline (Kaplan 1998), in particular, have

demonstrated efficacy. In a double-blind study, citalopram was found to be effective, and superior

to perphenzine, in treating behavioral disturbances in hospitalized elderly patients with dementia

(Pollock et al. 2002). Sertraline in combination with a cognitive-enhancing medication (donepezil)

was reported to decrease agitation, although a fulminant chemical hepatitis developed in one

patient, necessitating discontinuation (Verrico et al. 2000). In contrast to these positive reports,

Olafsson et al. (1992) failed to show the effectiveness of fluvoxamine in the treatment of

behavioral disruption in elderly patients with dementia. One review suggested that when

antipsychotics cannot be used, SSRIs should be considered first-line treatment (Burke et al. 1997),

especially for verbal aggression (Ramadan et al. 2000). Further research of the antiagitation

properties of the SSRIs is essential, however, because these antidepressants also tend to be

activating and may actually increase agitation, especially in the late stages of a dementing illness.

Buspirone, a nonbenzodiazepine antianxiety agent with effects at serotonin receptors, was reported

to be effective in controlling disruptive behavior in older patients in one study (Colenda 1988) but

not in another (Strauss 1988). No randomized, placebo-controlled, double-blind studies of

buspirone have been conducted, and available studies were small in size. There is insufficient

evidence to inform about dosing, titration, safety, tolerability, and efficacy. A small (n = 20)

single-blind, placebo-controlled trial reported improvement on measures of aggression, but only

60% of the 20 subjects completed that study (Levy et al. 1994). In a crossover study (n = 10)

comparing buspirone with trazodone, Lawlor (1994) found no relative benefit of buspirone.

Cantillon et al. (1996) compared buspirone 15 mg/day versus haloperidol 1.3 mg/day in a nursing

home population with Alzheimer’s disease (n = 26); they reported no significant benefit of either

drug. Even when buspirone is effective, disruptive behavior may not decrease for 1 or 2 weeks at

full therapeutic doses. Side effects are modest, although one elderly patient with dementia

experienced oral dyskinesia that persisted for at least 4 months after symptom onset (Strauss

1988). An occasional patient may become more agitated. Research studies have not yet compared

buspirone’s effect with that of placebo or other drugs for treating agitation. The average total daily

dosage range is 20–80 mg in divided doses.

Beta-BlockersPrint: Chapter 57. Treatment of Agitation and Aggression in the Elderly http://www.psychiatryonline.com/popup.aspx?aID=434762&print=yes…

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-Blockers, given at low dosages (10–100 mg/day), have been used to reduce agitated and

assaultive behavior in elderly patients (Greendyke et al. 1984; Petrie and Ban 1981; Sky and

Grossberg 1994). Not all studies of -blockers have yielded positive findings, however (Risse and

Barnes 1986; Weiler et al. 1988). Most evidence is derived from older reports in patients with

nonspecific diagnoses (Tariot et al. 1995). Shankle et al. (1995) reported decreased aggression in 8

of 12 patients treated with low doses of propranolol (30–80 mg/day). Side effects of note include

bradycardia, hypotension, worsening of congestive heart failure, and asthma. -Blockers should be

used only sparingly for this purpose. Furthermore, these drugs can be given only to those elderly

patients without cardiovascular disease and chronic obstructive pulmonary disease (particularly

asthma). Typical side effects include sedation, orthostatic hypotension, and decreased cardiac

output.

Hormones

There are no rigorous studies of either estrogenic or antiandrogenic approaches, although roughly a

dozen published anecdotes exist (Rosenquist et al. 2000). The available evidence suggests

occasional benefit for hormonal agents, but this is unproven. A single case report (Kyomen et al.

1991) noted that estrogen (diethylstilbestrol 1 mg/day or conjugated estrogen 0.625 mg/day)

reduced the number of incidents of physical aggression, but not of verbal aggression or physical or

verbal repetitive behaviors, in elderly male patients with dementia. Medroxyprogesterone has been

reported to rapidly and safely treat sexual acting-out behavior in elderly men with dementia

(Cooper 1987).

Cognitive-Enhancing Drugs

Cholinergic Agents

As summarized by Cummings (2000), there is increasing evidence that cholinergic agents,

especially cholinesterase inhibitors, may have modest behavioral benefits in some patients with

dementia. However, most data come from multicenter studies primarily addressing cognitive or

global outcomes, using behavioral measures as secondary outcomes.

A prospective clinical trial of metrifonate versus placebo found modest average reductions in

neuropsychiatric symptoms, as assessed with the Neuropsychiatric Inventory (NPI), in the drug

group versus the placebo group (Morris et al. 1998). A retrospective analysis of two 26-week

double-blind, placebo-controlled multicenter trials of metrifonate found a behavioral effect size of

15%, with significant improvement observed on measures of agitation/aggression and aberrant

motor behavior as well as hallucinations, dysphoria, and apathy (Cummings et al. 2001; Raskind

and Risse 1986).

In a 5-month study of galantamine, Tariot et al. (2000) showed reduced symptoms of cognitive and

attentional dysfunction on drug versus placebo in outpatients who generally lacked

psychopathology at baseline. In a placebo-controlled trial of donepezil in nursing home residents

with probable Alzheimer’s disease complicated by behavioral symptoms, there was no evidence of

improved behavior on a global measure, although a secondary analysis showed some evidence of

reduced agitation (Tariot et al. 2001a). Another study of donepezil in mild to moderate Alzheimer’s

disease found overall improvement, with modest improvement in behavioral symptoms (Holmes et

1. 2004). A subsequent study, however, failed to find improvement in behavioral symptoms with

rivastigmine (Ballard and Waite 2006). There appears to be no reliable evidence for the therapeutic

effect of this drug on psychosis or behavioral symptoms of dementia and related behavioral

disruption. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have each been

reported to reduce restlessness in a small number of elderly individuals with Lewy body dementia

(Herrmann et al. 2004; Maclean et al. 2001; Skjerve and Nygaard 2000).

Memantine

Memantine, a noncompetitive inhibitor of N-methyl-D-aspartate (NMDA) receptors approved by the

FDA for treatment of moderate to severe Alzheimer’s disease, has been examined in severalPrint: Chapter 57. Treatment of Agitation and Aggression in the Elderly http://www.psychiatryonline.com/popup.aspx?aID=434762&print=yes…

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multicenter trials, none addressing behavior as a primary objective. A placebo-controlled study of

memantine 10 mg/day in patients with severe dementia showed no benefit on the single behavior

item that was used (Winblad and Poritis 1999). A subsequent placebo-controlled study of

memantine 20 mg/day also did not find significant behavioral benefit (Reisberg et al. 2003).

However, a study in which memantine or placebo was administered to patients already receiving

donepezil found significant benefit from memantine on behavior (Cummings et al. 2006a, 2006b;

Tariot et al. 2004). In a meta-analysis, Sink et al. (2005) found that cholinesterase inhibitors had a

small but statistically significant benefit for behavioral symptoms, whereas memantine had no

significant benefit. Trinh et al. (2003) also reported slight overall benefit from cholinesterase

inhibitors in patients with mild to moderate Alzheimer’s disease. More recently, modest behavioral

benefits of memantine have been reported (Swanberg 2007; Winblad and Poritis 1999; Winblad et

1. 2007), including data from unpublished trials. Memantine added to donepezil also has been

shown to have modest benefit for behavioral disruption in Alzheimer’s disease (Tariot et al. 2004).

More research is needed on the use of these drugs for treatment of dementia-associated agitation.

CONCLUSION

Good clinical care of the agitated and/or aggressive elderly patient with dementia requires careful

appraisal of factors that may be contributing to the disruptive behavior. Special attention should be

paid to recent changes in medical status, treatment with nonpsychiatric medications, and

alterations in the environment (Jeste et al. 2008; Salzman et al. 2008). When psychiatric

medications become necessary, clinicians now may choose among several classes of psychotropic

agents: antipsychotic drugs, mood stabilizers, and serotonergic antidepressants. Available data

would suggest that antipsychotic agents are still the first-choice class of drugs, especially for the

most severely agitated and aggressive elderly person. This class of drugs, however, carries a

potential increased risk of side effects, including extrapyramidal symptoms, cerebrovascular events

(including stroke), and possibly premature death. Clinicians must endeavor to use these

medications carefully, therefore, monitoring patients closely and informing family members (or

significant responsible individuals) of these risks. Initial doses should be modest, with careful dose

increments, following the geriatric maxim “Start low and go slow.” Other recommended classes of

psychotropic drug treatment, in order of preference, are mood stabilizers, serotonergic

antidepressants, and cognitive enhancers. These medications are less reliably effective but lack the

side effects of antipsychotic drugs. Clinical choice depends on the physical health, prior drug

response, and vulnerability to side effects of the elderly individual.

Future research will continue to elucidate the risks versus benefits of different classes of

psychotropic drugs while also developing nonpharmacological approaches for the treatment of the

common yet serious disruptive behavioral problems associated with dementia.

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