Chapter 19. Agitation in Older Adults
© American Psychiatric Publishing
We would like to thank Harold W. Goforth, M.D., who was a co-author on the previous edition of this chapter.
Agitation in older adults is associated with a variety of diagnoses, including mood disorders, psychotic disorders, neurocognitive disorders, and substance use disorders. While “agitation” is not a diagnostic category, it is overwhelmingly one of the most common referral questions in geriatric psychiatry. The geriatric psychiatrist is frequently called upon to guide the management of agitation seen in the context of major neurocognitive disorders, particularly of the moderate to severe variety. Delirium, particularly hyperactive delirium, is another frequent referral question where geriatric psychiatrists are called upon to help with managing agitation. Agitation, which is characterized by disruptive motor or vocal activity, is very distressing to patients and greatly affects their quality of life. It frequently interferes with delivery of care in medical and nursing homes settings, causes frustration for family members, and often limits the capacity for home care. In this chapter we focus on the diagnostic workup of agitation as well as the pharmacological and nonpharmacological management of agitation in the context of delirium and neurocognitive disorders. We use the term neurocognitive disorder (DSM-5; American Psychiatric Association 2013) interchangeably with the term dementia throughout this chapter.
Diagnostic Approach to Patients With New-Onset Agitation
Behavioral manifestations of major neurocognitive disorder are common (Lyketsos et al. 2000) and represent major predictors of caregiver depression, burden, and stress across cultures (Chen et al. 2000; Gallicchio et al. 2002; Gitlin et al. 2012; Shankar et al. 2014; Teri 1997). Anxiety and agitation, the most commonly cited psychiatric manifestations of major neurocognitive disorder, can be as disruptive and painful for the patient as they are for family caregivers. Disruptive or resistive behaviors resulting from anxiety and agitation increase the risk of harm to the affected individual and others (Chow and MacLean 2001; Tractenberg et al. 2001), and caregivers frequently become frightened, upset, or simply exhausted by the demands of caring for a family member with agitation. Agitation is also commonly seen in hyperactive delirium, and patients with neurocognitive disorders are at an increased risk for delirium, making delirium a likely cause of agitation in neurocognitive disorders.
A careful psychiatric evaluation and history are key components of the initial approach to the individual who is presenting with agitation. It is important to determine whether the onset of agitation is acute, subacute, or chronic. A sudden onset of disruptive behavior typically suggests a medical etiology, whereas a slower, insidious onset of agitation may represent a distress response to a change in caregiver, routine, or environment in a patient who is losing capacity to express him- or herself. Agitation may also be seen without obvious precipitants in the course of gradual progression of neurocognitive disorder in an elderly individual. In addition to identifying the type of onset, it is important to delineate the actual features of the behavior. The term agitation may be used to describe behaviors ranging from increased verbal complaining, at one end of the spectrum, to significant aggression, at the other, depending on the care setting and the informant. Therefore, it is very important to determine what the label actually signifies in a given patient. This may alert the clinician to possible etiologies such as pain/discomfort or suspiciousness.
A laboratory workup is usually required in cases of sudden onset of agitation to rule out medical contributors. Blood chemistry, a complete blood count, and urinalysis and urine culture should be obtained. If respiratory symptoms are present, a chest X ray may be needed. A computed tomography or magnetic resonance imaging brain scan may be indicated, especially if focal neurological findings are present or there is a sudden change in mental status. Because agitation is often associated with sensory impairment, particularly visual and auditory deficits, audiometric and visual testing may identify potential areas for further intervention. Potential medical causes of agitation are shown in Table 19–1. In patients with neurocognitive disorders, causes of agitation can also include constipation, fatigue, dehydration, a full bladder, caffeine, incontinence, sensory loss, immobility, depression, aphasia and delusions, hallucinations, and misidentifications.
Diagnostic Approach to Patients With New-Onset Agitation Common medical causes of agitation in elderly persons
Medication
|
Drug-drug interaction
|
Accidental misuse
|
Central nervous system toxic side effect
|
Systemic disturbance (e.g., medication-induced electrolyte imbalance)
|
Urinary tract infection
|
Poor nutrition, decreased oral intake of food and fluid
|
Respiratory infection
|
Recent stroke
|
Occult head trauma if patient fell recently
|
Pain
|
Constipation
|
Alcohol or substance withdrawal
|
Chronic obstructive pulmonary disease
|
If an agitated patient is paranoid, part of the task of the clinician is to determine whether the individual’s mistrustful and suspicious demeanor may be warranted. Older adults with major neurocognitive disorders are at high risk of abuse or neglect; therefore, exploring with family members or relevant others a patient’s accusation of harm or neglect is often part of the assessment. If after such exploration the clinician is not convinced that the accusations are wholly explained by a delusion, a social services agency or department should be requested to investigate further.
Approaches to Management of Agitation
Treatment of agitation can be broadly divided into nonpharmacological and pharmacological approaches. Current recommendations emphasize instituting measures to prevent agitation in delirium (Inouye et al. 2006) and reserving pharmacological treatment for situations that compromise safety. Similarly, in neurocognitive disorders, the preferred approach to management is nonpharmacological, with pharmacological approaches used as second-line. In this section we first discuss nonpharmacological approaches to preventing and managing agitation in individual patients with neurocognitive disorders. We then discuss the pharmacological interventions available to clinicians and the specific situations in which their use may be appropriate.
Nonpharmacological Approaches
Current person-centered dementia care assumes that most resistive behaviors in dementia are responses to unmet needs or to environmental or interpersonal triggers. Nonpharmacological strategies are recommended as first-line approaches for agitation in dementia. These approaches can be taught effectively to family and nonprofessional caregivers (Belle et al. 2006; Cohen-Mansfield et al. 2007; Doody et al. 2001; Hepburn et al. 2007; Logsdon et al. 2007; Teri et al. 2005). These strategies focus on changing the patient’s activities, routines, and/or human, physical, and social environments to provide reassurance, appropriate stimulation and cues, and security. As the individual with dementia becomes less adaptable to change, the human and physical environment must adapt to him or her. Behavioral approaches generally include person-specific problem solving, enriched cues, adapted work or expressive activities, exercise, communication strategies, and caregiver skills training.
Key Messages for Families About Agitation in Dementia
Families of persons with dementia should be told directly that anxiety, suspiciousness, and restless agitation are common symptoms of brain disorders, even in the context of excellent, well-intentioned family care. At the same time, it is helpful to suggest that disruptive behaviors do not occur in a vacuum. Agitation has a person-specific situational context and meaning that may often, but not always, be understood. Agitated or even aggressive behavior is often beyond a dementia patient’s control or intentionality. In fact, he or she may not be aware of agitation or a change in behavior.
Frequent or escalating agitation requires a prompt and multimodal response. Ignoring agitated or disruptive behaviors will not make them go away. Persons with dementia are most likely to be angry at what they perceive as an intolerable situation that no longer makes sense. For this reason it is wise for families not to take attacks or accusations personally. Families should also be reminded that persons with dementia are more likely to take out their frustration on those closest to them while appearing gracious and appropriate with strangers.
Families should be told that individuals with dementia generally cannot “try harder.” A corollary is that reasoning, arguing, coaxing, pleading, extracting promises, confronting, or punishing agitated persons may only escalate the distressing behavior. Families respond effectively if they understand that agitated people with dementia are likely to be scared and overwhelmed by disorientation and that they may forget appropriate public or private behavior. Agitation is frequently accompanied by a loss of impulse control and a decrease in frustration tolerance that can result in uncharacteristic cursing, insensitivity, tactlessness, or sexually inappropriate behavior. Although people with dementia may seem insensitive to others’ feelings, they are extremely sensitive to and will respond negatively to patronizing, angry, tense, rushed, or demanding verbal or nonverbal communication from family members.
Agitated individuals with dementia generally respond well to calm, dignified, familiar settings with predictable routines and to requests tailored to their retained noncognitive capacities, remaining strengths, and energy levels. Although patients with Alzheimer’s disease may appear to do less as a result of apathy, they can become fatigued from just trying to make sense of what is going on around them. Late-day fatigue or wearing out may explain some agitated behavior associated with “sundowning” (patients’ becoming more confused, agitated, or psychotic in the late afternoon or early evening) and extremely exaggerated reactions to minor incidents. Furthermore, patients with mild to moderate Alzheimer’s disease may resist activities they perceive as too difficult or too demeaning in order to limit embarrassment or failure.
Questions to Guide Problem Solving for Agitation in Dementia
Consideration of the following nine questions can help pinpoint and resolve caregivers’ problems with a patient’s agitated behavior:
- Which agitated, anxious, or resistive behaviors are most disruptive to family life at this stage of dementia and in the current family context?
- Describe the behavior, including its frequency, intensity, duration, and timing. Is it harmful or does it cause distress to the person with dementia or to others? Can the family change expectations or increase tolerance for this change in the person as they knew him or her?
- Is there any pattern, trigger, or time of day that sets off the behavior (e.g., a move, travel, hospitalization, request to do a complex task)?
- Does anything happen afterward that makes the behavior worse (e.g., caregiver anger, abandonment, patient failure)?
- Is the person uncomfortable (e.g., due to pain, hunger, thirst, constipation, full bladder, fatigue, infection, cold, fear, misperceived threats, difficult communication)?
- Is the person looking for something familiar from the past (e.g., rummaging in drawers, searching for a toilet or an old employer)?
- Will a change in environment help (e.g., reduction of number of people, confusion, stimuli, noise)?
- Can the caregiver use familiar phrases to calm or reassure the person (e.g., “I’ll get right on it”; “Ain’t that the truth?”; “Even the Lord rested on Sundays”)?
- Can routines be changed or adapted to prevent future occurrences of the behavior (e.g., exercising early in the day, bathing less frequently, avoiding rush-hour shopping)?
Common Strategies to Reduce Agitation
Nonpharmacological strategies to reduce agitation begin with assessment of retained abilities, patient preferences, and available family or staff resources. Reducing triggers by treating medical or physical problems, especially undiagnosed pain or delirium, and providing reassurance and redirection may help as well.
Nonpharmacological strategies for reducing agitation in patients with dementia usually involve redirection of the individual’s attention away from triggering events or contexts or distraction with offers of pleasant events specific to the person (e.g., going for ice cream or a ride, listening to personalized calming or engaging music, exercise routines, watching old videotapes). Other strategies include breaking down complex tasks into one-step guided directions, simplifying instructions, guided choices when decision making is overwhelming, and allowing adequate rest or passive observation between stimulating activities. Environmental strategies include using labels, cues, or pictures; hazard-proofing the environment to reduce dangers of exploration or egress; removing guns or hazardous power tools or kitchen equipment; and using lighting or security objects to reduce nighttime confusion or daytime fear or uncertainty.
Communication Begins With Understanding
Families begin to communicate effectively when they can understand the experience and perspectives of people with dementia. With the current focus on early diagnosis and treatment of Alzheimer’s disease, more individuals with insight who have new diagnoses of Alzheimer’s disease are willing to provide direction. The following excerpts from a Canadian support group of individuals living with early-stage dementias can offer guidance to family caregivers:
Please don’t correct me. Remember, my feelings are intact and I get hurt easily. Try to ignore offhand remarks that I wouldn’t have made in the past. If you focus on my mistakes, it just makes me feel worse. I may say something that is real to me but not factual to you. It is not a lie. Don’t argue—it won’t solve anything. (Snyder 2001, p. 2)
When a person with dementia is agitated, he or she may be thinking along the following lines (Gwyther 2000, p. 998):
How dare you question me? I have always taken care of myself.
I make sense—you and events don’t.
Your reality and reasoning wear me out.
I am only protecting what is mine from those people—things keep disappearing.
Can’t you see this is not a good time? I’m overwhelmed and scared.
Communication Strategies to Reduce Agitation
The following are suggestions for trying to communicate with an agitated person with dementia: Get the person’s attention. Take time to support the person’s dignity. Make sure vision and hearing are adequate or “tuned up.” Make eye contact; using a clear adult tone, call the person by a preferred or recognizable name that serves as a reminder or that props up the person’s identity or social roles (e.g., “Good morning, Coach”); approach slowly from the side or front or crouch down at his or her level; and offer your hand, palm up. Listen, but do not feel compelled to talk constantly. Words are not as important as a calm tone, pleasant expression, and nondistracting environment (turn off the TV or turn down the radio). Use familiar words and speak in a normal tone and tempo, but give the person time to process and respond. Repeat your words exactly, if necessary. If you are unsure of the person’s meaning, ask questions (e.g., “Am I getting closer to what you want?”). Be patient—you may need to repeat yourself to reassure him or her.
If frustration mounts, take a deep breath and suggest a better time to talk or another topic. Avoid expressions that may be ambiguous or vague, such as “Don’t go there,” “NOT,” or “bottom line.” Use concrete subjects, names, and references. Avoid pronouns. Do not test or ask the person if he or she remembers you. Use positive statements such as “It’s time for lunch—let’s go” rather than “Do you want to go now?” Alternatively, offer guided choices; for example, show two shirts and ask, “Would you like to wear the red shirt or blue shirt to lunch?” Explain what happens next, but wait until just before it will happen. Demonstrate or model so the person can follow your lead. Use appropriate, respectful humor or his or her favorite phrases (“See ya later, alligator”). It is always appropriate to make fun of yourself, especially if you forget. Smile, nod, gesture, or use singing, music, rhymes, or photos when words fail.
Summary of Nonpharmacological Approaches
Families often want brief, concrete suggestions for dealing with agitation. The following format may be helpful (Alzheimer’s Association 2014a, 2014b; Gwyther 2001):
DO—slow down, soothe the person, or structure the situation. Join the person in your sincere wish to solve the problem. Respond to his or her emotions (“You seem frustrated or sad” or “This must be hard for you”). Encourage and reinforce positive adaptations that work for the person (“I depend on my husband for brute strength in carrying those grocery bags”). Be extra gracious and polite. Back off and ask permission. Repeatedly reassure. Use visual and verbal cues; reduce glare and/or add light. Offer guided choices between two options. Avoid complex multistep directions or ambiguity. Distract with a favorite snack, or ask for help with raking or another adult repetitive task. Increase time spent in pleasant activities such as sitting in a porch glider at sunset. Offer a security or tactilely appealing object, rest, or privacy after an upset. Limit caffeine and alcohol. Use comforting rituals such as holding hands during grace, an afternoon tea break, checking the bird feeder, or a hand massage or manicure. Do for the person what he or she can no longer comfortably do alone. Join the person in modified favorite activities—social, creative, exercise, or sports. Remove the person from confusing, frustrating, or scary experiences such as TV shows that the person believes are happening to him or her.DO NOT—raise your voice, take offense, corner, crowd, restrain, rush, criticize, ignore, confront, argue, reason, shame, blame, demand, lecture, condescend, moralize, force, explain, teach, show alarm, or make a sudden move out of the person’s view.SAY—May I help you? Do you have time to help me? Let’s take a break now—we have earned it. You’re safe here. I will get right on it. Everything is under control. I apologize (even if you didn’t do it). I’m sorry you are upset. I know it’s hard. We’re in this together. I will make sure those men can’t get in here. Do what you can and I’ll finish up. We’re doing fine now.
Pharmacological/Medical Approaches
There are times when agitation warrants pharmacological intervention, and the risks of persistent agitation versus the risks and benefits of treating the agitation must be weighed carefully. Most clinicians view agitation as a condition manifested by excessive verbal and/or motor behavior. It is distinguished from aggression, which can also be verbal (e.g., cursing, threats) or physical (e.g., hitting, kicking, shoving objects or people, biting, scratching). Agitation can escalate to aggression, so it is vital for the clinician to intervene early in approaching agitated patients. However, it is imperative to determine the cause of agitation so that interventions can then be directed at both treating the underlying cause and managing the agitation itself, given that uncontrolled agitation has been demonstrated to have multiple deleterious effects on patient and family safety and welfare. Agitation most commonly occurs in the context of delirium or dementia, and often these conditions coexist in frail elderly patients. These conditions are discussed in depth in the next two subsections of the chapter. Agitation can also be a feature of late-life depression, and although treatment of the underlying depression should also treat the agitation, the full effect of antidepressant medications may not be apparent for several weeks. However, acute, severe, or escalating agitation may require medication such as the newer atypical neuroleptics for adequate control. Benzodiazepines should generally be avoided in an agitated patient because of their high potential for worsening delirium as well as potentially disinhibiting the patient further; however, they may be appropriately used in cases of alcohol or benzodiazepine withdrawal, or when the agitation can be assumed to be the result of severe anxiety rather than delirium or the nonspecific agitation that can accompany dementia.
Agitation in the Context of Delirium
Delirium is a common disorder, with an estimated prevalence of 15%–50% among hospitalized elderly patients (Inouye et al. 2007; Levkoff et al. 1991). Management of delirium is focused on primary prevention, identifying and treating the underlying causes, minimizing psychoactive medications, reorientation, safe and early mobilization, and normalization of the sleep-wake cycle (Inouye et al. 2006). However, the severely agitated delirious patient may require immediate attention if the behavior interferes with workup or ongoing medical care, or puts the patient or care providers at risk of physical harm.
Although the efficacy of antipsychotic agents in the acute management of agitation is not supported by substantial evidence (Flaherty et al. 2011), these agents remain the treatment of choice for lack of effective alternatives. The exception is delirium secondary to alcohol or benzodiazepine withdrawal delirium, in which case benzodiazepines become the treatment of choice. Haloperidol has been studied as a prophylactic agent for the prevention of delirium in older hospitalized patients after hip surgery (Kalisvaart et al. 2005). In this randomized placebo-controlled study, low-dose haloperidol did not reduce the incidence of delirium but did reduce the duration and severity of the episodes, suggesting its effectiveness for symptomatic management. Haloperidol should be initiated at 0.5–1 mg orally or intramuscularly, and doses should be repeated judiciously as needed. Although haloperidol typically does not cause hypotension or significant sedation, it may produce extrapyramidal symptoms at higher doses and should be avoided in patients with parkinsonism. Intravenous haloperidol, although associated with significantly fewer extrapyramidal side effects, is associated with prolongation of the QT interval, calling for added precaution for use of the medication. In patients with delirium who also have dementia, the use of antipsychotics should be carefully considered in view of the black box warning for increased all-cause mortality for patients treated with these agents.
Oral administration of atypical antipsychotics at low doses is frequent in practice; risperidone, olanzapine, and quetiapine may have comparable efficacy and tolerability to low-dose haloperidol (Lonergan et al. 2007; Maneeton et al. 2013). The use of ziprasidone or aripiprazole in delirium currently is limited to case reports or retrospective chart reviews (Alao et al. 2005; Boettger et al. 2011; Leso and Schwartz 2002).
Treatment of alcohol or benzodiazepine withdrawal delirium depends primarily on administration of sufficient doses of benzodiazepines to arrest the withdrawal process; identification of this form of delirium is important because of the high morbidity and mortality associated with it if it is not treated appropriately. Similarly, delirium secondary to hepatic encephalopathy has its own treatment pathway and relies primarily on the administration of either lactulose or nonabsorbable antibiotics (rifaximin).
Agitation in the Context of Dementia
Agitation is a frequent behavioral symptom in dementia, with 24% of caregivers in one survey reporting agitation and/or aggression (Lyketsos et al. 2000). Agitation in dementia occurs most often in response to unmet needs and inability to tolerate stressful unfamiliar human and physical environments, depression, unrecognized delirium, or pain (Kales et al. 2014). A person with dementia may become agitated throughout the day, intermittently through the day, or at specific times of day. One-fourth of inpatients with Alzheimer’s disease were found on nursing evaluation to exhibit sundowning behavior (Little et al. 1995). Behaviors associated with agitation in patients who have dementia include aggression, combativeness, disinhibition, wandering, and hyperactivity.
As with all behavioral problems, the first step in treatment is to identify potential precipitants. The specific behavior must be clearly described, and its timing, duration, intensity, and impact on the patient’s routine and care need to be considered. Evaluation should include assessment for common systemic causes (e.g., pain, infection, dehydration, constipation, other illnesses) as well as changes in medication. Patients should also be evaluated for depression and psychotic symptoms. Psychological factors, such as loneliness or lack of privacy in institutional care, should be considered. Environmental factors, such as overstimulation or lack of stimulation, or change in surroundings also need to be considered and addressed. Identified potential precipitants must be addressed before consideration of treatment. In long-term-care facilities, interprofessional teams must be involved in assessment and ongoing care of patients with agitation.
Pharmacological Treatment
Currently, no treatments have been approved by the U.S. Food and Drug Administration (FDA) for the management of agitation in dementia. Moreover, nonpharmacological treatments are considered first line in the management of these patients. Given the potential risks and limited efficacy associated with most medications that have been studied for this indication, pharmacological treatments are reserved for the following situations: 1) to alleviate persistent distress, to maintain function, or to allow delivery of needed care when nonpharmacological treatments have been tried and have failed and 2) if the situation is serious enough to warrant urgent pharmacological intervention (i.e., the patient is a danger to self or others). Several medication classes have been studied for management of agitation in dementia and are reviewed here.
Antipsychotics
Haloperidol, risperidone, aripiprazole, olanzapine, and possibly quetiapine are the only antipsychotic agents that have shown efficacy in placebo-controlled trials of agitation in dementia. In general, atypical antipsychotics are the class that has been best studied; a systematic review of all available placebo-controlled trials of atypical antipsychotics suggests that risperidone and aripiprazole are more effective than olanzapine, and quetiapine may be only marginally effective in addressing dementia-related behaviors (Maglione et al. 2011). The overall effectiveness of these agents is modest, with an effect size of 0.16 (Schneider et al. 2006). Haloperidol has comparable efficacy to atypical antipsychotics. Atypical antipsychotics have been found to increase the risk of somnolence, urinary tract infection or incontinence, extrapyramidal symptoms or abnormal gait, and worsening of cognition (Schneider et al. 2006). Perhaps the biggest concern regarding the use of antipsychotics stems from data regarding increased mortality. In 2004, the FDA conducted a meta-analysis of 17 placebo-controlled trials of atypical antipsychotics and found an increased risk of all-cause mortality of 4.5% in the drug group versus 2.6% in the placebo group over a mean trial duration of 10 weeks; as a result, all atypical antipsychotics received a black box warning for use in patients with dementia. Jeste et al. (2008) calculated the number needed to treat and number needed to harm and concluded that for every 9–25 agitated patients with dementia treated with an atypical antipsychotic, there would be one death. Of the six large cohort studies comparing the mortality risk of typical antipsychotics and atypical antipsychotics, four found a higher risk of mortality with typical antipsychotics, and two found no difference (Maglione et al. 2011). The FDA expanded the black box warning to include typical antipsychotics in 2008. Whether there are individual differences in mortality risks for different antipsychotics is not known. Kales et al. (2012) conducted a retrospective cohort study using data from the U.S. Department of Veterans Affairs for dementia patients ages 65 and older who began outpatient treatment with an antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol) or valproic acid and its derivatives (as a nonantipsychotic comparison). The total sample included 33,604 patients, and individual drug groups were compared for 180-day mortality rates. Risperidone was used as a reference; haloperidol was found to have the highest mortality risk, followed by risperidone, olanzapine, and valproic acid, which were similar, and quetiapine had the lowest mortality risk. Although this study had limitations because of its retrospective pharmacoepidemiological design, the authors did try to account for confounders such as site of care (haloperidol may have been prescribed in medical settings, suggesting greater medical comorbidity and therefore greater mortality) as well as dosage (quetiapine may have been dosed inadequately). However, even after controlling for these confounders, the above findings held true. Lower mortality associated with quetiapine in this study should be correlated with the systematic review by Maglione et al. (2011), which showed that quetiapine has marginal efficacy at best.
Mood stabilizers
Carbamazepine and valproic acid have been studied in placebo-controlled trials for agitation in dementia. In a double-blind study of nursing home patients, Tariot et al. (1998) found that compared with the placebo group, patients taking carbamazepine showed significant improvement in agitation and aggression. The drug was well tolerated. The modal dose of carbamazepine was 300 mg/day, achieving a mean serum level of 5.3 μg/mL. Another smaller study of outpatients treated with carbamazepine 400 mg/day versus placebo suggests similar efficacy, but with a trend toward worsening hallucinations (Olin et al. 2001). Patients receiving carbamazepine should be monitored for hyponatremia, agranulocytosis, and the possibility of drug interactions because of hepatic cytochrome P450 enzyme induction by carbamazepine. Although valproic acid is used quite widely in clinical practice in management of agitation, double-blind placebo-controlled trials did not support its efficacy and in fact revealed high rates of adverse events for valproic acid compared with placebo (Lonegan and Luxenberg 2009; Tariot et al. 2001, 2005) In the study by Tariot et al. (2001), 54% of the treated patients dropped out compared with 29% of control patients. Of all treated patients, 22% dropped out because of adverse effects, and the study had to be discontinued prematurely. Moreover, in a retrospective study comparing mortality rates of atypical antipsychotics and valproic acid in dementia patients (Kales et al. 2012), valproic acid was found to have mortality rates comparable to those of risperidone, underscoring the point that although antipsychotic risks in dementia are well known, other agents are less well studied and often are used based on the assumption of their safety rather than certainty of their safety.
Antidepressants
Citalopram has been shown to be efficacious in double-blind placebo-controlled trials for treating agitation in dementia (Pollock et al. 2002; Porsteinsson et al. 2014). In the study by Porsteinsson et al. (2014), citalopram’s effect was similar to what has been shown for antipsychotics in dementia. Citalopram was associated with increased risk of QT prolongation, as well as slight worsening of cognition, as seen in previous antipsychotic trials. Lyketsos et al. (2003) found sertraline to be effective in the treatment of depression among patients with dementia; however, there was no significant benefit of sertraline on neuropsychiatric symptoms. The authors did report that in subgroup analyses of full responders versus nonresponders (in terms of depression symptoms), full responders had significantly greater improvement on nonmood items of the Neuropsychiatric Inventory (NPI). A placebo-controlled study of trazodone, haloperidol, and behavior management techniques did not find a difference between placebo and any of the treatment groups (Teri et al. 2000). In another very small study, trazodone was found to be efficacious for treating agitation in patients with frontotemporal dementia (Lebert et al. 2004).
Cholinesterase inhibitors and memantine
The Cholinesterase Inhibitor and Atypical Neuroleptic in the Management of Agitation in Alzheimer’s Disease (CALM-AD) study (Howard et al. 2007) was a placebo-controlled trial of donepezil 10 mg/day for treatment of agitation in Alzheimer’s disease. Unfortunately, donepezil was no better than placebo in this 12-week study. Rodda et al. (2009) conducted a systematic review of randomized, placebo-controlled trials of donepezil, rivastigmine, and galantamine to examine their efficacy in the treatment of behavioral and psychological symptoms of Alzheimer’s disease. Fourteen studies were included (nine with donepezil), and median treatment duration was 24 weeks. Most studies used the NPI as a behavioral outcome measure, and generally NPI scores at baseline were low. Four studies were designed specifically to assess behavioral outcomes, whereas in the majority of studies behavioral outcomes were only secondary measures. Three studies found statistically significant, albeit modest, differences in the change of NPI total score between drug and placebo. Perhaps the strongest evidence for use of cholinesterase inhibitors to target agitation was in individuals with Lewy body dementia. McKeith et al. (2000) demonstrated that rivastigmine 12 mg/day is superior to placebo in addressing behavioral symptoms in patients with Lewy body dementia. Patients treated with rivastigmine were significantly less apathetic and anxious, and had fewer delusions and hallucinations than control subjects. This finding is particularly exciting given the neuroleptic sensitivity of patients with Lewy body pathology. In our experience, this is the patient group in whom cholinesterase inhibitors can make a significant impact in improving quality of life by addressing agitation and visual hallucinations. A prospective double-blind, placebo-controlled trial of memantine in moderate to severe Alzheimer’s dementia failed to show its efficacy for improving agitation (Fox et al. 2012). However, a pooled retrospective analysis of three trials of memantine in patients who had moderate to severe Alzheimer’s disease with agitation, aggression, or psychotic symptoms at baseline suggests efficacy and tolerability of memantine at 12 and 24 weeks (Wilcock et al. 2008).
Propranolol augmentation (mean dose of 106 mg/day) was found to be superior to placebo for treating agitation in patients with Alzheimer’s disease who were maintained on stable doses of their baseline psychotropics (Peskind et al. 2005). Unfortunately, the gains were lost at 6-month follow-up. The α-blocker prazosin (mean dose of 6 mg/day for 8 weeks) has also been found to be efficacious in a small placebo-controlled study for treatment of agitation in dementia (Wang et al. 2009). Individuals with orthostasis or with systolic blood pressures of less than 110 were excluded from this study, which nevertheless had a dropout rate of 50%. Both propranolol and prazosin should be titrated very gradually in carefully selected patients, who should then be monitored for orthostasis and falls. Most recently, Husebo et al. (2011) demonstrated, in a cluster randomization study of nursing home patients with moderate to severe dementia, that implementation of a pain management protocol for 8 weeks was better than treatment as usual at targeting agitation (which, rather than pain, was the primary outcome measure in the study). Patients received acetaminophen, buprenorphine patch (for those who could not take medication orally), morphine (when acetaminophen had failed), or pregabalin (for neuropathic pain). Seventy percent of patients in the study took only scheduled acetaminophen, and effect size of the intervention was comparable to that seen in atypical antipsychotic trials. Thus, a systematic approach to the management of pain can significantly reduce agitation in dementia. Transdermal estrogen has been found to be no better than placebo for treatment of aggression in dementia, with in fact a rebound increase in agitation on removal of estrogen patches at the end of the 8-week study period (Hall et al. 2005). Finally, there are no placebo-controlled trials of benzodiazepines for agitation in dementia, and there are no trials of medication combinations versus individual medications.
In summary, antipsychotics are the class of medicines that are best studied for agitation in dementia, perhaps with the best evidence for (modest) efficacy and also evidence for harm, including an increased mortality risk. Other agents that have shown benefit in double-blind, randomized, placebo-controlled trials include citalopram, carbamazepine, propranolol, prazosin, and pain medication. Table 19–2 lists the different medication classes that can be used to treat agitation in dementia. Informed consent of the patient or a legal representative must be obtained following discussion of potential risks (including the black box warning in case of antipsychotics) and benefits.
Other medications Medication classes showing efficacy in double-blind, randomized, placebo-controlled trials in addressing agitation and aggression in patients with dementia and suggested daily dosages (subject to tolerability)
Medication class | Suggested daily dosage (mg/day) |
|---|---|
Antipsychotics
|
Risperidone (0.5–2 mg)
|
Aripiprazole (2–10 mg)
| |
Olanzapine (2.5–10 mg)
| |
Quetiapine (50–200 mg)
| |
Haloperidol (0.5–2 mg)
| |
Antidepressant
|
Citalopram (20 mg)
|
Anticonvulsant
|
Carbamazepine (300–400 mg)
|
β-Blocker
|
Propranolol (100 mg)
|
α-Blocker
|
Prazosin (6 mg)
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Because all efficacious treatments of agitation in dementia have inherent risks, the need for continued pharmacological treatment of agitation should be regularly reassessed. Devanand et al. (2012) carried out a well-designed study of antipsychotic discontinuation in patients with Alzheimer’s disease and psychosis or agitation. One hundred eighty patients received open-label treatment with risperidone for 16 weeks. Responders were then randomized to continuation of risperidone or transition to placebo. At 16 weeks, 60% in the placebo group had relapsed versus 33% in the risperidone group. In contrast, the Dementia Antipsychotic Withdrawal Trial in Alzheimer’s Disease (DART-AD) study (Ballard et al. 2008) did not show detrimental effects of stopping antipsychotic treatment when compared with placebo. There was some evidence to suggest that patients with higher baseline scores of agitation are more likely to benefit from continued treatment. This study also showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (Ballard et al. 2009). Together, these findings suggest that although there is a risk of reemergence of agitation after stopping antipsychotic medications, particularly in those patients with higher baseline scores of agitation, there may be increased mortality from long-term antipsychotic use. Given the paucity of long-term data for most psychotropics, it is judicious to attempt dose reduction after several weeks and discontinuation of medication if appropriate. If symptoms reemerge, careful consideration and documentation of risks and benefits of ongoing psychopharmacological treatment are necessary.
Conclusion
Geriatric psychiatrists are frequently called upon to guide the management of agitation in elderly persons in different settings. It is important to understand and address underlying contributors to agitation, whether they be medical, psychological, or environmental. Instituting measures to prevent agitation is critical, as is educating caregivers about nonpharmacological approaches for managing agitation. Unfortunately, most pharmacological options for treating agitation are associated with risks. More research is needed to address what nonpharmacological interventions are best suited to which patients and in what situations. Safer pharmacological options are also needed to manage agitation so as to improve the quality of life of our older patients.
Key Points
- Agitation is a common and disabling condition in elderly people.
- The causes of agitation include a wide differential that must be evaluated and corrected prior to consideration of treatment.
- Nonpharmacological approaches are the preferred treatment for agitation in older adults.
- When the patient does not respond to nonpharmacological approaches or if symptoms are severe, pharmacological approaches may be warranted.
- If pharmacological means are used, ongoing risk-benefit analyses should guide treatment; the lowest possible dosages should be used for the shortest possible times.
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