Agitation is one of the more prevalent as well as clinically distressing symptoms in the geriatric psychiatric patient. Agitation has myriad presentations and numerous possible causes. It can be the primary symptom for which a psychiatric consultation is sought, both for the cognitively intact and the cognitively impaired patient. In this article, the definition, diagnosis, etiology, and initial management strategy of agitation will be delineated. The aim of the article is to provide a practical overview and a clinical perspective on this topic.
Agitation is generally defined as observable, situation-inappropriate behavior that is characterized by excessive motor or verbal activity (1). Agitation is differentiated from aggression, which is behavior—either physical or verbal—that is directed against an object or another person or being. Hostility, another term often used in conjunction with agitation and aggression, denotes a state of increased potential for aggression or agitation with affective overtones of anger, irritability, suspiciousness, and/or fearfulness (2). Although agitation is seen in patients of all ages, it is particularly troubling in the geriatric patient and usually indicative of an underlying medical or neurobehavioral impairment. Although it is commonly associated with severe neurocognitive impairment, agitation can also be clinically evident in nondemented patients. Agitation can manifest in a wide variety of behaviors, including physical and verbal agitation, aggressive and nonaggressive behavior, and nondirected behavior, such as general restlessness, pacing, or hoarding (3).
According to U.S. Census Bureau projections, some 35 million Americans are 65 years of age and older today—about 12.6% of the population. This figure is expected to rise to about 70 million by 2030, by which time this age group will constitute 20% of the population. This tremendous growth in the geriatric population will most likely be accompanied by increases in the numbers of older patients presenting to general psychiatrists in the coming years.
The most rapidly increasing segment of the older population is the "oldest old"—those 85 years of age and older. By 2010, it is estimated that 1.9 of every 100 persons will be 85 or older. This group has a high risk of psychiatric disorders, largely because of age-related medical conditions, changes in functional and physical abilities, and vulnerability to economic and psychosocial stressors (4). In addition to functional and physical impairments, this group also has the highest risk of developing neurodegenerative and neurocognitive impairment disorders.
Most epidemiological studies examining psychiatric disorders have overlooked the geriatric population. In an analysis based on several different studies and information specific to disorders in the elderly, Jeste and colleagues have estimated the prevalence of psychiatric symptoms in the elderly to be approximately 19.6%, not including those with delirium or other mental disorders secondary to a general medical condition (5, 6).
Agitation in the geriatric patient is most commonly but by no means exclusively associated with neurocognitive impairment, such as delirium and dementia. Not surprisingly, the prevalence of agitation increases in proportion with the severity of the dementia—37.5% in patients with mild dementia to 66.5% in patients with severe dementia (7). The more severely impaired a dementia patient is, the more likely he or she is to reside in a long-term care setting such as a nursing home. As many as 80% of nursing home residents display some form of agitation (8). In the outpatient setting, estimates of the prevalence of agitation in patients with dementia range from 35% to 58%, and among persons with dementia who live in the community, estimates range from 57% to 65%. Although the data on noninstitutionalized dementia patients are not definitive, one consistent difference between institutionalized and noninstitutionalized elderly has been noted: the agitation of nursing home residents tends to be more physically aggressive than that of the noninstitutionalized elderly (9). Appropriate and optimal management of agitation on an outpatient basis may be a key factor in delaying nursing home placement.
To date, some 2,500 psychiatrists have obtained the Added Qualifications in Geriatric Psychiatry since the examination was first administered in 1991. Given the growing geriatric population, and particularly the increase in the population of the oldest old, the general psychiatrist will see an increasing proportion of elderly patients in daily practice.
An essential step in the management of agitation is the determination of its underlying cause. One approach to evaluating agitation is to carefully characterize the quality of the agitation, the time of day and setting in which it occurs, whether it occurs in a cyclical or a noncyclical pattern, and any possible environmental stimuli. Cohen-Mansfield takes these factors into account and succinctly summarizes the various theories proposed for the causes of agitation, using four models: direct impact of dementia, unmet needs, behavioral, environmental vulnerability (2). In the first model, the agitation is proposed to be secondary to the direct effect of neurodegenerative changes to the brain that result in disinhibition and/or dyscontrol. In the second model, the agitation occurs in response to an unmet need that cannot otherwise be expressed by the demented patient. The inability to communicate affective states of fear, anxiety, depression, or frustration may lead to the expression of these feelings in behavior such as pinching, screaming, falling, or incessant crying. Another type of unmet need may be the experience of pain, fatigue, hunger, or physical discomfort. The presence of an underlying medical or psychiatric illness is another form of an unmet need. The behavioral model suggests that the problem behavior is reinforced because the patient receives attention when the behavior occurs (2). Repeated reinforcement leads to more frequent and severe agitation. The fourth model proposes that agitation results when the demented patient is unable to adapt to the surrounding environment. The "environment" can denote a physical environment in which there is either too little or too much stimulation, or a situation in which a patient is unable to cope with demands placed on his or her limited and rigid coping ability. Examples are a change in routine or setting, a different staff member, an office visit, or the start of a caregiving activity. Given the limitations on coping ability, a severely demented patient is likely to have a catastrophic reaction to what appears to be a relatively minor stimulus such as a change in routine.
The initial assessment of a geriatric patient with agitation should begin, as with all patients, with a thorough psychiatric and medical examination. Key components of the evaluation of agitation include collateral information from the primary caregiver; a diurnal and longitudinal record of the behavior, noting onset, severity, and possible precipitating factors; an accounting of any changes in environment or routine; an assessment of functional ability; and a schedule of daily activity.
An assessment of the patient’s environment is absolutely essential. A change of room, roommate, regular staff, or caregiver is often the precipitating event for agitation, even in the absence of any acute medical or psychiatric illness. For example, on an inpatient geropsychiatry unit, an increased census of patients is accompanied by an increase in the number of staff on duty. While neither of these changes is inherently harmful, both lead to increases in the degree of activity and in stimuli on the unit, particularly during shift changes. The incidence of agitated behavior can be expected to be greater among severely demented patients in these circumstances than on a less densely populated unit (10).
Evaluating the patient for an occult trauma or injury may reveal unaddressed pain as a cause of agitation. In the frail and cognitively impaired elderly, a group that is vulnerable to falls and fractures, pain can be easily overlooked unless a high index of suspicion is maintained. Unaddressed pain can often produce nighttime agitation or poor sleep, and the resultant insomnia compounds the agitation.
Recommended initial laboratory tests include at least a complete blood count with a hematocrit determination, a basic metabolic panel with renal and hepatic function tests, a thyroid-stimulating hormone level determination, and a random glucose level determination. Keep in mind that these tests may have been done recently (in the past 7 days) by the patient’s primary care physician. Other tests to consider, depending on the patient’s pre-sentation, include an electrocardiogram, an imaging study of the brain, and a urinalysis. Delirium with agitation accounts for a large number of admissions to inpatient geriatric psychiatry units. It is not uncommon for these patients to have an underlying infection, such as a urinary tract infection. These recommended studies are essential not just for the diagnosis of an affective or behavioral disorder but also to evaluate the possibility of an underlying medical illness. A chronic subdural hematoma from a fall several months earlier can be the primary cause of agitation in an elderly patient.
All prescription and nonprescription medications should be reviewed; the likelihood of adverse drug reactions and drug-drug interactions increases with the number of daily medications taken. A common cause of confusion and agitation in el-derly patients is the anticholinergic effects of many common over-the-counter cough and cold preparations as well as prescription medications for incontinence, such as oxybutynin, and conventional antipsychotics, such as chlorpromazine (11). Finally, evaluation for the possibility of a substance use disorder or withdrawal is essential.
Nonpharmacological interventions are effective in addressing some of the common types of agitation, such as "sundowning," restlessness, and incessant yelling or crying. One nonpharmacological intervention is to decrease stimuli, which can be accomplished by having the patient in a separate area or dayroom during the more active times of the day. Maintaining consistency and structure in setting and schedule decreases the need for the patient to adjust to new, potentially anxiety-inducing situations or environments. Providing reassurance to the agitated patient can often diffuse or lessen the agitation (1).
Maintenance of a "no-fail" environment minimizes the demands placed on a patient’s ability to adapt to his or her surroundings or to new situations. Other novel, effective methods to manage agitation behaviors such as wandering or escape seeking include placing a red "STOP" sign on the exit door, placing a couch (a new stimulus) in front of a door, and painting the door, including the doorknob, the same color as the surrounding walls. The enormous value of disciplines such as occupational therapy and recreational therapy cannot be overemphasized in the management of agitation (12). Replacement activities as well as physical exercises and structured group activities such as arts and crafts and reminiscence groups can greatly enhance patients’ sense of well-being while decreasing agitation (13).
A key strategy in the management of agitation in patients with dementia is the involvement of the caregiver, the family, and the staff working with the patient. Psychosocial and behavioral interventions such as functional performance assistance, music therapy, pet therapy, and reminiscence therapy can significantly enhance the quality of life of both the patient and the caregiver. Environmental interventions such as use of white noise or nature sounds, modulated lighting intensity, and way-finding cues such as photographs can also decrease stress and agitation (14—16).
For patients whose agitation does not resolve with management of acute underlying medical illnesses and does not respond to nonpharmacological interventions, the next step in clinical management is to consider pharmacotherapy. Over the past four decades, a great variety of pharmacological agents have been used in the treatment of psychosis and agitation in elderly demented patients (17, 18). The following sections review each class of medication and the recommended guidelines for use.
In general, the antipsychotics constitute the most widely prescribed class of medication in the management of agitation (with or without a comorbid psychosis) in patients with dementia. According to double-blind, placebo-controlled trials with agitated patients with dementia, the antipsychotics as a group—conventional and atypical—are effective in 61% of patients, compared with 35% with placebo (17). Although the newer atypical antipsychotics are preferable and show great promise because of their lower potential for troublesome side effects, no definitive conclusions can be drawn about their efficacy in the treatment of agitation in patients with dementia, because the number of double-blind, placebo-controlled trials conducted thus far with this patient population is relatively small (18). In addition, federal law (embedded in the Omnibus Budget Reconciliation Act of 1987) restricts the use of antipsychotics in the nursing home setting to situations in which a patient is dangerous to self or others, significantly functionally impaired, or unable to tolerate necessary delivery of care because of a behavioral disturbance. Given the wide array of behaviors that present in agitation, passive nonaggressive agitation symptoms that may respond to antipsychotic therapy may not be addressed with these medications. Since the regulations went into effect, the use of antipsychotics in the long-term care setting has decreased considerably, in some cases to the detriment of patients who might otherwise have benefited.
Conventional antipsychotics such as haloperidol and chlorpromazine have been shown to be effective in the long-term management of agitation and psychosis in dementia (19). However, their use is limited by their side effect profile, which includes orthostasis, akathisia, tardive dyskinesia, and severe anticholinergic effects such as dry mouth, confusion, urinary retention, and constipation. These side effects are troublesome for an otherwise healthy adult patient with psychosis; they can be potentially life-threatening in the more frail and medically ill geriatric patient. Despite their therapeutic efficacy, conventional antipsychotics are to be avoided in geriatric patients unless antipsychotic medication is absolutely necessary and atypical antipsychotics are ineffective or unavailable. While the atypical antipsychotics lack most of the above-mentioned side effects, they are associated with other potential side effects such as weight gain, altered glucose metabolism, and QTc segment prolongation (20—22). Although these are not absolute contraindications for use of atypical antipsychotics, appropriate monitoring is essential.
The atypical antipsychotics that have been studied with the geriatric population are clozapine, risperidone, olanzapine, and quetiapine. Risperidone and olanzapine have been examined more closely than the others in the treatment of geriatric agitation. Given the results of several studies, risperidone is generally recommended as the first atypical agent to be initiated (23). Of course, an individual patient’s presentation may warrant the use of another medication. For example, a patient with parkinsonism (associated with the dementia in the case of Lewy body dementia) may not be able to tolerate even the minimal extrapyramidal system side effects of risperidone; in this case a trial of olanzapine or quetiapine may be initiated (24). When considering use of risperidone, it is important to bear in mind that the Food and Drug Administration (FDA) had issued a warning regarding a higher incidence of cerebrovascular events associated with risperidone compared with placebo in older patients with dementia-related psychosis (4% of the risperidone group compared with 2% of the placebo group in a clinical trial with 1,200 patients) (25). Whether this finding is applicable to the general practice setting has yet to be determined. Table 1T1 offers recommended dosing strategies for conventional and atypical antipsychotics for geriatric patients.
This is the newest class of medications to be introduced in the treatment of dementia. Although the primary focus of research in this class has been on the cognitive aspect of dementia, some studies have suggested that the cholinesterase inhibitors (also referred to as cognitive enhancers) may be helpful in reducing behavioral disturbances in dementia patients. Table 2T2 lists dosing strategies. In general, these medications are relatively well tolerated, although 10%—20% of patients experience gastrointestinal distress. The use of cholinesterase inhibitors is currently recommended, although studies suggest a limited range of benefits (18). If therapy is initiated, benefit with any of these agents is most likely at the highest tolerated dose (26). Below the minimum dose, treatment is ineffective regardless of the duration of treatment. The effect of cholinesterase inhibitors on behavior is considered to be secondary to the hypothesis that maintaining or slightly improving the level of cognition preserves a higher level of daily function and decreases the rate of the development of agitation (27, 28). In general, the four agents in this class available in the United States have similar side effects: nausea, gastrointestinal distress, dizziness, and headache. Well-designed placebo-controlled studies are needed to identify more definitively the mechanism of action as well as the clinical efficacy of cholinesterase inhibitors in the treatment of agitation in patients with dementia.
By their sedative and anxiolytic effects, benzodiazepines are effective for the management of acute behavioral agitation. However, long-term use of benzodiazepines can eventually be more harmful than therapeutic (29, 30). Use of benzodiazepines in dementia patients also has been related to episodes of disinhibition and increased agitation (31). In addition, the risk of ataxia and falls is increased significantly with benzodiazepines, as is the likelihood of increasing confusion and oversedation (32).
When a benzodiazepine is used, it should be started at the lowest dose possible, and the patient should be monitored closely for any confusion, change in cognition, or other signs of possible toxicity (33). In general, older patients tend to metabolize and clear these medications more slowly than younger patients. The longer the agent’s half-life, the more likely a patient is to eventually develop higher steady-state levels, which in turn increases the risk of toxicity (34). Thus, great caution must be used when treatment with clonazepam is initiated in an elderly patient. Because of its long elimination half-life, clonazepam would not be a first-line choice of benzodiazepine for the geriatric patient. If a benzodiazepine is to be used at all, a limited course with one of the short-acting agents is recommended. Table 3T3 lists dosing strategies.
Mood stabilizers and anticonvulsants
Few studies have examined the use of mood stabilizers and anticonvulsants in the treatment of dementia with agitation. In general, these agents may be initiated in patients who exhibit affective lability and impulsivity that have not responded to other agents (17). In a few studies, lithium has been shown to be moderately useful (35), although it is limited by its significant toxicity and side effects. Of the mood stabilizers, carbamazepine and valproic acid have been the most closely examined and have been shown to be moderately effective in patients with aggressiveness and affective lability (36). Unfortunately, their use is greatly limited by their side effect profile, which includes ataxia, oversedation, drug-drug interactions, hepatotoxicity, weight gain, and hematological toxicity. If these agents are to be initiated, careful serum monitoring is essential. The newer anticonvulsants gabapentin and lamo-trigine are being studied with this population. To date, little evidence is available on their use in treating agitation in patients with dementia, although there is evidence of their usefulness in other patient populations for agitation (37—40). They are to be used with caution. See Table 4T4 for dosing strategies.
Beta blockers have been used in a wide variety of neuropsychiatric syndromes, including agitation, but their application in agitation associated with dementia has not been well studied with placebo-controlled, randomized trials of adequate duration in a homogeneous population of dementia patients. When beta blockers have been effective in limited trials, the symptoms that responded to therapy were impulsivity, hostility, and assaultiveness (35). Their use in elderly patients is limited by the side effects of hypotension, dizziness, bradycardia, orthostasis, depression, and sedation. Table 5T5 lists dosing strategies.
In this class of medications, memantine recently received FDA approval for the treatment of dementia. Memantine is a modulator of the glutamate receptor subtype N-methyl-d-aspartate (NMDA). Glutamate is the primary excitatory amino acid in the human brain; it functions by binding to various receptors, resulting in extended activation of the CNS neuron. In a disease state, this extended activation or excitation becomes excessive and leads to cell damage (41). In neuropathological and neurochemical studies, degeneration of the glutamatergic pathways has been associated with Alzheimer’s dementia. Chronic stimulation of the glutamatergic NMDA receptors has resulted in death of CNS neurons. Memantine functions as an uncompetitive NMDA receptor antagonist—it binds to the NMDA receptor and inhibits excitotoxity in the condition of excessive glutamatergic activity. Several published trials of memantine therapy with mixed dementia patient groups have shown improvement in function, a slowed rate of cognitive decline, and acceptable levels of safety and tolerability. Although none of these studies focused primarily on agitation in dementia, memantine may have a beneficial effect on agitation in the same manner that the cholinesterase inhibitors have through their effect on cognition and function (42, 43).
Recommended algorithm for the evaluation and initial management of agitation in dementia
Although there are many recommended approaches to the management of agitation in the dementia patient, in the general psychiatry practice the following approach is recommended for the initial evaluation and management. This is by no means a definitive or rigid regimen: it is meant to provide a guideline that may be modified according to the patient’s presentation and the treatment setting—outpatient clinic, inpatient unit, or nursing home care unit.
Please refer to the tables included with the discussions of the each of the classes of medication.
One recent trial showed efficacy for a memantine-donepezil combination over a placebo- donepezil combination (44). The recommended starting dose is 5 mg/day with a weekly increase in 5 mg increments to a target dose of 20 mg/day. The side effect profile was similar to placebo in the clinical trials, with headache, dizziness, and confusion reported in about 5% of patients. The initial reports of memantine in the treatment of dementia are promising, but its use in the initial management of agitation in dementia is not yet known.
Despite public perceptions and controversy, electroconvulsive therapy (ECT) remains, in appropriate cases and indications, one of the most clinically effective treatment modalities in modern medicine and psychiatry (45). In the past two decades, growing interest in the use of ECT in dementia patients has led to several key reports and case series about its potential in the management of agitation in el-derly dementia patients (46). Given its established efficacy in the treatment of depression, ECT is particularly suited to treating dementia and agitation that are associated with a comorbid depressive disorder. In patients with a previous positive response to ECT or in those with medication-refractory illness, ECT may be the intervention of choice. Although randomized, double-blind, placebo-controlled studies are not available and would be difficult to conduct for this particular indication and patient population, ECT has been shown to be effective in case reports and limited studies (47, 48).
The general caveats regarding postictal confusion and exacerbation of cognitive impairment must be taken into account when considering ECT (49, 50). The use of unilateral nondominant hemisphere electrode placement is the recommended method of initiating treatment (51). Unilateral lead placement decreases the likelihood of increased postictal confusion, which is balanced against the decreased potency of unilateral lead treatments compared with bilateral lead treatments. The course of ECT for the dementia patient can be modified with a combination of unilateral and bilateral lead placement treatments, based on the patient’s response and degree of postictal confusion (45). The side effect of postictal confusion tends to be time limited and manageable by adjusting the frequency and duration of the individual treatments. As in the case of nondementia patients receiving ECT, elderly dementia patients are screened for any medical or physical contraindications to the treatment or to general anesthesia (45).
Given the wide variety of types of agitation encountered in geriatric patients with dementia, careful assessment and evaluation are the key step in initiating treatment. A variety of pharmacological agents are used in the management of agitation, although the evidence for their use is limited because of a lack of large-scale, randomized, double-blind, placebo-controlled studies. Such studies would be particularly difficult to conduct, given the heterogeneity of this patient population and the range of symptom presentations and comorbid medical conditions. This clinical synthesis attempts to provide a focused overview of the available therapies and literature. Although far from comprehensive, it is meant to give the reader a practical starting point from which to manage this patient population.