Antipsychotics in dementia: Beyond ‘black-box’ warnings

Diagnosed 7 years ago with Alzheimer’s disease (AD), Mrs. B, age 82, resides in an assisted living facility whose staff is trained to care for older persons with dementia. Over the past 2 months she has shown an escalating pattern of psychosis and aggression, despite one-to-one attention and verbal reassurance.

At first Mrs. B’s psychosis was restricted to occasional rape accusations during assisted bathing and aggression manifested by banging her hand repetitively on furniture, causing skin tears. In the last week, she has been accusing staff and patients of stealing her belongings and has assaulted a staff member and another resident. When supervisors at the facility advise Mrs. B’s husband that she can no longer stay there, he takes her to a local emergency room, from which she is admitted involuntarily to a geriatric psychiatry inpatient unit.

For many patients and families, the most problematic aspects of dementia are neuropsychiatric symptoms—depression, sleep disturbance, psychosis, and aggression. Psychosis affects approximately 40% of persons with AD, whereas ≥80% of persons with dementia experience agitation at some point in the illness.¹ These symptoms can lead to:

• caregiver morbidity
• poor patient quality of life
• early patient institutionalization.²

Although no drug has been FDA-approved for treating dementia’s neuropsychiatric symptoms, psychiatrists often use off-label psychotropics—especially antipsychotics—to ameliorate them. This practice is controversial because of public perception that antipsychotics are used in dementia patients to create “zombies” to lighten healthcare workers’ burden. Nonetheless, because dementia patients with psychosis and severe agitation/aggression can pose risks to themselves and those around them, efforts to treat these symptoms are warranted.

Box

The FDA’s “black-box” warnings about using atypical agents in patients with dementia add another layer of complexity to your treatment decisions (Box).^3,4 The public is well served by evidence identifying risks associated with prescription medications, but the FDA data do little to help millions of families answer the question, “And so, what now?”

Recognizing that solid empiric evidence is lacking, we attempt to address this lingering question for clinicians, patients, and caregivers who must deal with these symptoms while science tries to provide a more definitive answer.

5-step evaluation

A 5-step initial evaluation of persons with dementia who present with psychosis and/or agitation/aggression includes establishing the frequency, severity, and cause of these symptoms as well as the effectiveness of past treatments and strategies (Algorithm).⁵

Because adverse drug effects are a potentially reversible cause of psychosis and agitation, review the patient’s drug list—including “as needed” medications—from records at a facility or from family report. Mrs. B’s record from the assisted living facility reveals she was receiving:

• atenolol, 25 mg/d
• aspirin, 81 mg/d
• extended-release oxybutynin, 10 mg at bedtime
• psyllium, one packet daily
• hydrocodone/acetaminophen, 5/500 mg every 4 hours as needed for pain
• lorazepam, 1 mg every 6 hours as needed for agitation
• diphenhydramine, 25 mg at bedtime
• paroxetine, 20 mg/d
• haloperidol, 5 mg at bedtime
• memantine, 10 mg twice a day.

Mrs. B’s medication list is revealing for reasons that, unfortunately, are not rare. She is receiving 3 anticholinergic medications—oxybutynin, diphenhydramine, and paroxetine—that may be worsening her mental status and behavior directly through CNS effects, possibly in combination with frequent benzodiazepine use.

Anticholinergics also can lead to behavior changes via peripheral side effects. Constipation and urinary retention may cause discomfort that an aphasic patient “acts out.” A patient may be experiencing pain related to these side effects and receiving opioid analgesics, which can worsen constipation and urinary retention. Uncontrolled pain related to musculoskeletal disease or neuropathy may merit treatment that will reduce behavioral disturbances.

Mrs. B also was being catheterized every 8 hours as needed for urinary retention. The invasive and unpleasant nature of urinary catheterization is likely to worsen behavior and increases the risk of one of the most common “asymptomatic” etiologies of behavioral symptoms in dementia—urinary tract infection (UTI).

Algorithm

5-step evaluation of dementia patients
with psychosis and/or agitation/aggression*

CASE CONTINUED: Persistent agitation

After evaluating Mrs. B, the psychiatrist limits her medications to atenolol, aspirin, psyllium, and memantine, and begins to taper lorazepam and paroxetine. Laboratory, radiologic, and physical examinations reveal UTI, fecal impaction, bladder distension, and mild hyponatremia. She is given a phosphosoda enema and ciprofloxacin, 250 mg/d for 5 days.

Despite one-to-one nursing care, frequent reorientation, and attempts to interest her in art therapy, Mrs. B remains agitated and postures to strike staff members and other patients. She denies pain or discomfort. Fearing that someone might be injured, the nurse pages the on-duty psychiatrist.

The nurse then calls Mr. B, who has durable power of attorney for his wife’s healthcare. When the nurse advises Mr. B that the psychiatrist has ordered risperidone, 0.5 mg, he immediately interjects that the psychiatrist at the assisted living facility told him haloperidol should be used for his wife’s symptoms because other antipsychotics can cause strokes and death.

Typical vs atypical antipsychotics

Mrs. B’s nurse may have to delay administering risperidone while she puts Mr. B in contact with the psychiatrist. In an emergent situation when well-trained staff have assessed for common reversible causes of agitation and tried reasonable nonpharmacologic means to calm the patient, few people would argue against using medication to preserve the safety of the patient and others. To avoid questions such as this during a crisis, obtain informed consent at admission from the patient or (more likely) the proxy decision-maker for medications you anticipate the patient might receive during hospitalization.

The larger question is whether typical antipsychotics are preferred for dementia-related psychosis and agitation/aggression because the FDA has not issued the same global black-box warning for this class. Astute clinicians realize that a lack of evidence of harm is not evidence of a lack of harm. In fact, since the black-box warnings for atypical antipsychotics in dementia emerged, several studies have examined whether the same risks exist for typical agents.

Evidence regarding risk of stroke and death with the use of typical and atypical antipsychotics in patients with dementia is summarized in Table 1.^6-13 Most evidence, including numerous studies in the past year, comes from retrospective database analyses. Prospective head-to-head comparisons of atypical and typical antipsychotics in dementia are scarce, and future prospective comparisons would be unethical.

No evidence suggests that typical antipsychotics mitigate the risks of stroke or death in dementia compared with atypical agents. Moreover, typical agents are more likely than atypicals to cause movement-related side effects—especially tardive dyskinesia and parkinsonism—in older adults with dementia.¹⁴

Table 1

Typical antipsychotics: Safer than atypicals for older patients?

CASE CONTINUED: Moderate relief from risperidone

After the psychiatrist explains the data on atypical vs typical antipsychotics in dementia—and the lack of FDA-approved treatments—Mr. B consents to the use of risperidone. He believes his wife would have wanted to try a medication with a moderate chance of relieving her internal distress and preventing her from harming anyone.

Risperidone provides moderate relief of Mrs. B’s aggression and paranoia. The next day Mr. B visits the unit and asks to speak with the psychiatrist. Although he appreciates the staff’s caring attitude, he says, “There must be safer or better ways to deal with these symptoms than medications like risperidone. I just don’t want the guilt of causing my wife to have a stroke or pass away.” He also asks, “How long will she have to take this medication?”

Evidence for efficacy

In addition to discussing antipsychotics’ risk in dementia, we also need to highlight their efficacy and effectiveness. A recent meta-analysis of 15 randomized controlled trials of atypical antipsychotics for agitation and/or psychosis in dementia included studies with risperidone, olanzapine, aripiprazole, and quetiapine.³ Most study participants were institutionalized, female, and had AD.

Psychosis scores improved in pooled studies of risperidone, whereas global neuropsychiatric disturbance improved with risperidone and aripiprazole. Effects were more notable in:

• persons without psychosis
• those living in nursing homes
• patients with severe cognitive impairment.

Subsequent placebo-controlled trials of risperidone, quetiapine, and aripiprazole—most focusing on patients with AD—reveal that atypical and typical antipsychotics have modest efficacy in reducing aggression and psychosis.^15-19 However, to some extent the National Institute of Mental Health Clinical Antipsychotic Trial of Intervention Effectiveness Study for Alzheimer’s Disease (CATIE-AD)—the largest nonindustry-funded study conducted to address this question—called this conclusion into question.²⁰ Risperidone and olanzapine (but not quetiapine) were efficacious in that fewer patients taking them vs placebo dropped out because of lack of efficacy. Antipsychotics were not effective overall, however, because the primary outcome—all-cause discontinuation rate—was similar for all 3 drugs and placebo. This indicates that on average these medications’ side effect burden may offset their efficacy, though individual patients’ responses may vary.

Alternatives to antipsychotics

Mr. B also raised the issue of treatment alternatives, such as no treatment, other psychotropics (Table 2),^5,21 and nonpharmacologic methods (Table 3).²²

“No treatment” does not imply a lack of assessment or intervention. Always examine patients for iatrogenic, medical, psychosocial, or other precipitants of behavioral symptoms. No treatment may be viable in mild to moderate cases but is impractical for patients with severe psychosis or agitation. Untreated, these symptoms could compromise safety or leave the patient without housing options.

Although possibly underused because of time constraints, reimbursement issues, or lack of training, nonpharmacologic strategies to treat aggression and psychosis in dementia are appealing alternatives to antipsychotics. Little empiric evidence supports nonpharmacologic strategies, however.²²

Treatment decisions need to consider patients’ and caregivers’ value systems. Proxy decision-makers should examine treatment decisions in terms of how they believe the patient would view the alternatives. Without a specific advance directive, however, even well-intentioned decision-makers are likely to “contaminate” decisions with their own values and interests.

After discussing with the decision-maker various treatments’ risks and benefits, it might be useful to ask, for example, “If Mrs. B could have foreseen her behaviors 10 years ago, what do you think she would have wanted us to do? Some people might have been mortified by the thought of attacking other people, whereas other people would not mind this as much as the fear of being ‘overmedicated.’ Which end of the spectrum do you think she would have leaned toward?”

When medical research does not offer clear answers for the “right” next clinical step, clinicians can:

• acknowledge our own limits and those of human knowledge
• engage the caregiver (or, when appropriate, the patient) in shared decision-making, recognizing that some people will appreciate the opportunity for “equal partnership” whereas others will want us to decide based on our best clinical judgment.

Table 2

Pharmacologic alternatives to antipsychotics: What the evidence says

Table 3

How well do psychosocial/behavioral therapies manage
psychosis/agitation in dementia?*

Duration of treatment

Limited evidence leaves psychiatrists largely on our own in regards to how long to continue pharmacotherapy with antipsychotics. Neuropsychiatric symptoms such as psychosis and agitation exhibit variable patterns. Symptoms may wax and wane for unclear reasons.

Given the tenuous nature of the risk-benefit profile for atypical antipsychotics in dementia, consider a gradual taper for persons with dementia who remain asymptomatic after 3 to 6 months of atypical antipsychotic treatment. Monitor them closely for symptom recurrence.⁵

Carefully consider the necessary duration of antipsychotic therapy in patients (such as Mrs. B) in whom you can identify possibly reversible precipitants of psychosis and aggression. Patients may have a delayed beneficial response to the correction of precipitating factors such as medical illness, physical discomfort, or medication side effects.

Mrs. B received risperidone, but evidence for efficacy and safety in dementia-related psychosis or agitation does not yet significantly distinguish among the atypical agents (except that data are limited for ziprasidone and clozapine). Usual starting and target doses are provided in Table 4.²³

Table 4

Atypicals in dementia: Starting and target doses

Related resources

• Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5):957-70.
• American Association for Geriatric Psychiatry position statement: principles of care for persons with dementia resulting from Alzheimer disease. www.aagponline.org/prof/position_caredmnalz.asp.

Drug brand names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Ciprofloxacin • Ciloxan
• Citalopram • Celexa
• Clozapine • Clozaril
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Donepezil • Aricept
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Lortab, Vicodin
• Lorazepam • Ativan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxybutynin • Ditropan
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Sertraline • Zoloft
• Trazodone • Desyrel
• Ziprasidone • Geodon

Disclosure

Dr. Meeks receives research/grant support from the John A. Hartford Foundation, the Mental Health Research Foundation, NARSAD, and the U.S. Department of Health and Human Services’ Health Resources and Services Administration.

Dr. Jeste receives research/grant support from the John A. Hartford Foundation, the National Institute of Aging, and the National Institute of Mental Health. AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Janssen, L.P. provide free medications for an NIMH-funded study for which Dr. Jeste is the principal investigator.

Diagnosed 7 years ago with Alzheimer’s disease (AD), Mrs. B, age 82, resides in an assisted living facility whose staff is trained to care for older persons with dementia. Over the past 2 months she has shown an escalating pattern of psychosis and aggression, despite one-to-one attention and verbal reassurance.

At first Mrs. B’s psychosis was restricted to occasional rape accusations during assisted bathing and aggression manifested by banging her hand repetitively on furniture, causing skin tears. In the last week, she has been accusing staff and patients of stealing her belongings and has assaulted a staff member and another resident. When supervisors at the facility advise Mrs. B’s husband that she can no longer stay there, he takes her to a local emergency room, from which she is admitted involuntarily to a geriatric psychiatry inpatient unit.

For many patients and families, the most problematic aspects of dementia are neuropsychiatric symptoms—depression, sleep disturbance, psychosis, and aggression. Psychosis affects approximately 40% of persons with AD, whereas ≥80% of persons with dementia experience agitation at some point in the illness.¹ These symptoms can lead to:

• caregiver morbidity
• poor patient quality of life
• early patient institutionalization.²

Although no drug has been FDA-approved for treating dementia’s neuropsychiatric symptoms, psychiatrists often use off-label psychotropics—especially antipsychotics—to ameliorate them. This practice is controversial because of public perception that antipsychotics are used in dementia patients to create “zombies” to lighten healthcare workers’ burden. Nonetheless, because dementia patients with psychosis and severe agitation/aggression can pose risks to themselves and those around them, efforts to treat these symptoms are warranted.

Box

The FDA’s “black-box” warnings about using atypical agents in patients with dementia add another layer of complexity to your treatment decisions (Box).^3,4 The public is well served by evidence identifying risks associated with prescription medications, but the FDA data do little to help millions of families answer the question, “And so, what now?”

Recognizing that solid empiric evidence is lacking, we attempt to address this lingering question for clinicians, patients, and caregivers who must deal with these symptoms while science tries to provide a more definitive answer.

5-step evaluation

A 5-step initial evaluation of persons with dementia who present with psychosis and/or agitation/aggression includes establishing the frequency, severity, and cause of these symptoms as well as the effectiveness of past treatments and strategies (Algorithm).⁵

Because adverse drug effects are a potentially reversible cause of psychosis and agitation, review the patient’s drug list—including “as needed” medications—from records at a facility or from family report. Mrs. B’s record from the assisted living facility reveals she was receiving:

• atenolol, 25 mg/d
• aspirin, 81 mg/d
• extended-release oxybutynin, 10 mg at bedtime
• psyllium, one packet daily
• hydrocodone/acetaminophen, 5/500 mg every 4 hours as needed for pain
• lorazepam, 1 mg every 6 hours as needed for agitation
• diphenhydramine, 25 mg at bedtime
• paroxetine, 20 mg/d
• haloperidol, 5 mg at bedtime
• memantine, 10 mg twice a day.

Mrs. B’s medication list is revealing for reasons that, unfortunately, are not rare. She is receiving 3 anticholinergic medications—oxybutynin, diphenhydramine, and paroxetine—that may be worsening her mental status and behavior directly through CNS effects, possibly in combination with frequent benzodiazepine use.

Anticholinergics also can lead to behavior changes via peripheral side effects. Constipation and urinary retention may cause discomfort that an aphasic patient “acts out.” A patient may be experiencing pain related to these side effects and receiving opioid analgesics, which can worsen constipation and urinary retention. Uncontrolled pain related to musculoskeletal disease or neuropathy may merit treatment that will reduce behavioral disturbances.

Mrs. B also was being catheterized every 8 hours as needed for urinary retention. The invasive and unpleasant nature of urinary catheterization is likely to worsen behavior and increases the risk of one of the most common “asymptomatic” etiologies of behavioral symptoms in dementia—urinary tract infection (UTI).

Algorithm

5-step evaluation of dementia patients
with psychosis and/or agitation/aggression*

CASE CONTINUED: Persistent agitation

After evaluating Mrs. B, the psychiatrist limits her medications to atenolol, aspirin, psyllium, and memantine, and begins to taper lorazepam and paroxetine. Laboratory, radiologic, and physical examinations reveal UTI, fecal impaction, bladder distension, and mild hyponatremia. She is given a phosphosoda enema and ciprofloxacin, 250 mg/d for 5 days.

Despite one-to-one nursing care, frequent reorientation, and attempts to interest her in art therapy, Mrs. B remains agitated and postures to strike staff members and other patients. She denies pain or discomfort. Fearing that someone might be injured, the nurse pages the on-duty psychiatrist.

The nurse then calls Mr. B, who has durable power of attorney for his wife’s healthcare. When the nurse advises Mr. B that the psychiatrist has ordered risperidone, 0.5 mg, he immediately interjects that the psychiatrist at the assisted living facility told him haloperidol should be used for his wife’s symptoms because other antipsychotics can cause strokes and death.

Typical vs atypical antipsychotics

Mrs. B’s nurse may have to delay administering risperidone while she puts Mr. B in contact with the psychiatrist. In an emergent situation when well-trained staff have assessed for common reversible causes of agitation and tried reasonable nonpharmacologic means to calm the patient, few people would argue against using medication to preserve the safety of the patient and others. To avoid questions such as this during a crisis, obtain informed consent at admission from the patient or (more likely) the proxy decision-maker for medications you anticipate the patient might receive during hospitalization.

The larger question is whether typical antipsychotics are preferred for dementia-related psychosis and agitation/aggression because the FDA has not issued the same global black-box warning for this class. Astute clinicians realize that a lack of evidence of harm is not evidence of a lack of harm. In fact, since the black-box warnings for atypical antipsychotics in dementia emerged, several studies have examined whether the same risks exist for typical agents.

Evidence regarding risk of stroke and death with the use of typical and atypical antipsychotics in patients with dementia is summarized in Table 1.^6-13 Most evidence, including numerous studies in the past year, comes from retrospective database analyses. Prospective head-to-head comparisons of atypical and typical antipsychotics in dementia are scarce, and future prospective comparisons would be unethical.

No evidence suggests that typical antipsychotics mitigate the risks of stroke or death in dementia compared with atypical agents. Moreover, typical agents are more likely than atypicals to cause movement-related side effects—especially tardive dyskinesia and parkinsonism—in older adults with dementia.¹⁴

Table 1

Typical antipsychotics: Safer than atypicals for older patients?

CASE CONTINUED: Moderate relief from risperidone

After the psychiatrist explains the data on atypical vs typical antipsychotics in dementia—and the lack of FDA-approved treatments—Mr. B consents to the use of risperidone. He believes his wife would have wanted to try a medication with a moderate chance of relieving her internal distress and preventing her from harming anyone.

Risperidone provides moderate relief of Mrs. B’s aggression and paranoia. The next day Mr. B visits the unit and asks to speak with the psychiatrist. Although he appreciates the staff’s caring attitude, he says, “There must be safer or better ways to deal with these symptoms than medications like risperidone. I just don’t want the guilt of causing my wife to have a stroke or pass away.” He also asks, “How long will she have to take this medication?”

Evidence for efficacy

In addition to discussing antipsychotics’ risk in dementia, we also need to highlight their efficacy and effectiveness. A recent meta-analysis of 15 randomized controlled trials of atypical antipsychotics for agitation and/or psychosis in dementia included studies with risperidone, olanzapine, aripiprazole, and quetiapine.³ Most study participants were institutionalized, female, and had AD.

Psychosis scores improved in pooled studies of risperidone, whereas global neuropsychiatric disturbance improved with risperidone and aripiprazole. Effects were more notable in:

• persons without psychosis
• those living in nursing homes
• patients with severe cognitive impairment.

Subsequent placebo-controlled trials of risperidone, quetiapine, and aripiprazole—most focusing on patients with AD—reveal that atypical and typical antipsychotics have modest efficacy in reducing aggression and psychosis.^15-19 However, to some extent the National Institute of Mental Health Clinical Antipsychotic Trial of Intervention Effectiveness Study for Alzheimer’s Disease (CATIE-AD)—the largest nonindustry-funded study conducted to address this question—called this conclusion into question.²⁰ Risperidone and olanzapine (but not quetiapine) were efficacious in that fewer patients taking them vs placebo dropped out because of lack of efficacy. Antipsychotics were not effective overall, however, because the primary outcome—all-cause discontinuation rate—was similar for all 3 drugs and placebo. This indicates that on average these medications’ side effect burden may offset their efficacy, though individual patients’ responses may vary.

Alternatives to antipsychotics

Mr. B also raised the issue of treatment alternatives, such as no treatment, other psychotropics (Table 2),^5,21 and nonpharmacologic methods (Table 3).²²

“No treatment” does not imply a lack of assessment or intervention. Always examine patients for iatrogenic, medical, psychosocial, or other precipitants of behavioral symptoms. No treatment may be viable in mild to moderate cases but is impractical for patients with severe psychosis or agitation. Untreated, these symptoms could compromise safety or leave the patient without housing options.

Although possibly underused because of time constraints, reimbursement issues, or lack of training, nonpharmacologic strategies to treat aggression and psychosis in dementia are appealing alternatives to antipsychotics. Little empiric evidence supports nonpharmacologic strategies, however.²²

Treatment decisions need to consider patients’ and caregivers’ value systems. Proxy decision-makers should examine treatment decisions in terms of how they believe the patient would view the alternatives. Without a specific advance directive, however, even well-intentioned decision-makers are likely to “contaminate” decisions with their own values and interests.

After discussing with the decision-maker various treatments’ risks and benefits, it might be useful to ask, for example, “If Mrs. B could have foreseen her behaviors 10 years ago, what do you think she would have wanted us to do? Some people might have been mortified by the thought of attacking other people, whereas other people would not mind this as much as the fear of being ‘overmedicated.’ Which end of the spectrum do you think she would have leaned toward?”

When medical research does not offer clear answers for the “right” next clinical step, clinicians can:

• acknowledge our own limits and those of human knowledge
• engage the caregiver (or, when appropriate, the patient) in shared decision-making, recognizing that some people will appreciate the opportunity for “equal partnership” whereas others will want us to decide based on our best clinical judgment.

Table 2

Pharmacologic alternatives to antipsychotics: What the evidence says

Table 3

How well do psychosocial/behavioral therapies manage
psychosis/agitation in dementia?*

Duration of treatment

Limited evidence leaves psychiatrists largely on our own in regards to how long to continue pharmacotherapy with antipsychotics. Neuropsychiatric symptoms such as psychosis and agitation exhibit variable patterns. Symptoms may wax and wane for unclear reasons.

Given the tenuous nature of the risk-benefit profile for atypical antipsychotics in dementia, consider a gradual taper for persons with dementia who remain asymptomatic after 3 to 6 months of atypical antipsychotic treatment. Monitor them closely for symptom recurrence.⁵

Carefully consider the necessary duration of antipsychotic therapy in patients (such as Mrs. B) in whom you can identify possibly reversible precipitants of psychosis and aggression. Patients may have a delayed beneficial response to the correction of precipitating factors such as medical illness, physical discomfort, or medication side effects.

Mrs. B received risperidone, but evidence for efficacy and safety in dementia-related psychosis or agitation does not yet significantly distinguish among the atypical agents (except that data are limited for ziprasidone and clozapine). Usual starting and target doses are provided in Table 4.²³

Table 4

Atypicals in dementia: Starting and target doses

Related resources

• Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5):957-70.
• American Association for Geriatric Psychiatry position statement: principles of care for persons with dementia resulting from Alzheimer disease. www.aagponline.org/prof/position_caredmnalz.asp.

Drug brand names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Ciprofloxacin • Ciloxan
• Citalopram • Celexa
• Clozapine • Clozaril
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Donepezil • Aricept
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Lortab, Vicodin
• Lorazepam • Ativan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxybutynin • Ditropan
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Sertraline • Zoloft
• Trazodone • Desyrel
• Ziprasidone • Geodon

Disclosure

Dr. Meeks receives research/grant support from the John A. Hartford Foundation, the Mental Health Research Foundation, NARSAD, and the U.S. Department of Health and Human Services’ Health Resources and Services Administration.

Dr. Jeste receives research/grant support from the John A. Hartford Foundation, the National Institute of Aging, and the National Institute of Mental Health. AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Janssen, L.P. provide free medications for an NIMH-funded study for which Dr. Jeste is the principal investigator.

Diagnosed 7 years ago with Alzheimer’s disease (AD), Mrs. B, age 82, resides in an assisted living facility whose staff is trained to care for older persons with dementia. Over the past 2 months she has shown an escalating pattern of psychosis and aggression, despite one-to-one attention and verbal reassurance.

At first Mrs. B’s psychosis was restricted to occasional rape accusations during assisted bathing and aggression manifested by banging her hand repetitively on furniture, causing skin tears. In the last week, she has been accusing staff and patients of stealing her belongings and has assaulted a staff member and another resident. When supervisors at the facility advise Mrs. B’s husband that she can no longer stay there, he takes her to a local emergency room, from which she is admitted involuntarily to a geriatric psychiatry inpatient unit.

For many patients and families, the most problematic aspects of dementia are neuropsychiatric symptoms—depression, sleep disturbance, psychosis, and aggression. Psychosis affects approximately 40% of persons with AD, whereas ≥80% of persons with dementia experience agitation at some point in the illness.¹ These symptoms can lead to:

• caregiver morbidity
• poor patient quality of life
• early patient institutionalization.²

Although no drug has been FDA-approved for treating dementia’s neuropsychiatric symptoms, psychiatrists often use off-label psychotropics—especially antipsychotics—to ameliorate them. This practice is controversial because of public perception that antipsychotics are used in dementia patients to create “zombies” to lighten healthcare workers’ burden. Nonetheless, because dementia patients with psychosis and severe agitation/aggression can pose risks to themselves and those around them, efforts to treat these symptoms are warranted.

Box

The FDA’s “black-box” warnings about using atypical agents in patients with dementia add another layer of complexity to your treatment decisions (Box).^3,4 The public is well served by evidence identifying risks associated with prescription medications, but the FDA data do little to help millions of families answer the question, “And so, what now?”

Recognizing that solid empiric evidence is lacking, we attempt to address this lingering question for clinicians, patients, and caregivers who must deal with these symptoms while science tries to provide a more definitive answer.

5-step evaluation

A 5-step initial evaluation of persons with dementia who present with psychosis and/or agitation/aggression includes establishing the frequency, severity, and cause of these symptoms as well as the effectiveness of past treatments and strategies (Algorithm).⁵

Because adverse drug effects are a potentially reversible cause of psychosis and agitation, review the patient’s drug list—including “as needed” medications—from records at a facility or from family report. Mrs. B’s record from the assisted living facility reveals she was receiving:

• atenolol, 25 mg/d
• aspirin, 81 mg/d
• extended-release oxybutynin, 10 mg at bedtime
• psyllium, one packet daily
• hydrocodone/acetaminophen, 5/500 mg every 4 hours as needed for pain
• lorazepam, 1 mg every 6 hours as needed for agitation
• diphenhydramine, 25 mg at bedtime
• paroxetine, 20 mg/d
• haloperidol, 5 mg at bedtime
• memantine, 10 mg twice a day.

Mrs. B’s medication list is revealing for reasons that, unfortunately, are not rare. She is receiving 3 anticholinergic medications—oxybutynin, diphenhydramine, and paroxetine—that may be worsening her mental status and behavior directly through CNS effects, possibly in combination with frequent benzodiazepine use.

Anticholinergics also can lead to behavior changes via peripheral side effects. Constipation and urinary retention may cause discomfort that an aphasic patient “acts out.” A patient may be experiencing pain related to these side effects and receiving opioid analgesics, which can worsen constipation and urinary retention. Uncontrolled pain related to musculoskeletal disease or neuropathy may merit treatment that will reduce behavioral disturbances.

Mrs. B also was being catheterized every 8 hours as needed for urinary retention. The invasive and unpleasant nature of urinary catheterization is likely to worsen behavior and increases the risk of one of the most common “asymptomatic” etiologies of behavioral symptoms in dementia—urinary tract infection (UTI).

Algorithm

5-step evaluation of dementia patients
with psychosis and/or agitation/aggression*

CASE CONTINUED: Persistent agitation

After evaluating Mrs. B, the psychiatrist limits her medications to atenolol, aspirin, psyllium, and memantine, and begins to taper lorazepam and paroxetine. Laboratory, radiologic, and physical examinations reveal UTI, fecal impaction, bladder distension, and mild hyponatremia. She is given a phosphosoda enema and ciprofloxacin, 250 mg/d for 5 days.

Despite one-to-one nursing care, frequent reorientation, and attempts to interest her in art therapy, Mrs. B remains agitated and postures to strike staff members and other patients. She denies pain or discomfort. Fearing that someone might be injured, the nurse pages the on-duty psychiatrist.

The nurse then calls Mr. B, who has durable power of attorney for his wife’s healthcare. When the nurse advises Mr. B that the psychiatrist has ordered risperidone, 0.5 mg, he immediately interjects that the psychiatrist at the assisted living facility told him haloperidol should be used for his wife’s symptoms because other antipsychotics can cause strokes and death.

Typical vs atypical antipsychotics

Mrs. B’s nurse may have to delay administering risperidone while she puts Mr. B in contact with the psychiatrist. In an emergent situation when well-trained staff have assessed for common reversible causes of agitation and tried reasonable nonpharmacologic means to calm the patient, few people would argue against using medication to preserve the safety of the patient and others. To avoid questions such as this during a crisis, obtain informed consent at admission from the patient or (more likely) the proxy decision-maker for medications you anticipate the patient might receive during hospitalization.

The larger question is whether typical antipsychotics are preferred for dementia-related psychosis and agitation/aggression because the FDA has not issued the same global black-box warning for this class. Astute clinicians realize that a lack of evidence of harm is not evidence of a lack of harm. In fact, since the black-box warnings for atypical antipsychotics in dementia emerged, several studies have examined whether the same risks exist for typical agents.

Evidence regarding risk of stroke and death with the use of typical and atypical antipsychotics in patients with dementia is summarized in Table 1.^6-13 Most evidence, including numerous studies in the past year, comes from retrospective database analyses. Prospective head-to-head comparisons of atypical and typical antipsychotics in dementia are scarce, and future prospective comparisons would be unethical.

No evidence suggests that typical antipsychotics mitigate the risks of stroke or death in dementia compared with atypical agents. Moreover, typical agents are more likely than atypicals to cause movement-related side effects—especially tardive dyskinesia and parkinsonism—in older adults with dementia.¹⁴

Table 1

Typical antipsychotics: Safer than atypicals for older patients?

CASE CONTINUED: Moderate relief from risperidone

After the psychiatrist explains the data on atypical vs typical antipsychotics in dementia—and the lack of FDA-approved treatments—Mr. B consents to the use of risperidone. He believes his wife would have wanted to try a medication with a moderate chance of relieving her internal distress and preventing her from harming anyone.

Risperidone provides moderate relief of Mrs. B’s aggression and paranoia. The next day Mr. B visits the unit and asks to speak with the psychiatrist. Although he appreciates the staff’s caring attitude, he says, “There must be safer or better ways to deal with these symptoms than medications like risperidone. I just don’t want the guilt of causing my wife to have a stroke or pass away.” He also asks, “How long will she have to take this medication?”

Evidence for efficacy

In addition to discussing antipsychotics’ risk in dementia, we also need to highlight their efficacy and effectiveness. A recent meta-analysis of 15 randomized controlled trials of atypical antipsychotics for agitation and/or psychosis in dementia included studies with risperidone, olanzapine, aripiprazole, and quetiapine.³ Most study participants were institutionalized, female, and had AD.

Psychosis scores improved in pooled studies of risperidone, whereas global neuropsychiatric disturbance improved with risperidone and aripiprazole. Effects were more notable in:

• persons without psychosis
• those living in nursing homes
• patients with severe cognitive impairment.

Subsequent placebo-controlled trials of risperidone, quetiapine, and aripiprazole—most focusing on patients with AD—reveal that atypical and typical antipsychotics have modest efficacy in reducing aggression and psychosis.^15-19 However, to some extent the National Institute of Mental Health Clinical Antipsychotic Trial of Intervention Effectiveness Study for Alzheimer’s Disease (CATIE-AD)—the largest nonindustry-funded study conducted to address this question—called this conclusion into question.²⁰ Risperidone and olanzapine (but not quetiapine) were efficacious in that fewer patients taking them vs placebo dropped out because of lack of efficacy. Antipsychotics were not effective overall, however, because the primary outcome—all-cause discontinuation rate—was similar for all 3 drugs and placebo. This indicates that on average these medications’ side effect burden may offset their efficacy, though individual patients’ responses may vary.

Alternatives to antipsychotics

Mr. B also raised the issue of treatment alternatives, such as no treatment, other psychotropics (Table 2),^5,21 and nonpharmacologic methods (Table 3).²²

“No treatment” does not imply a lack of assessment or intervention. Always examine patients for iatrogenic, medical, psychosocial, or other precipitants of behavioral symptoms. No treatment may be viable in mild to moderate cases but is impractical for patients with severe psychosis or agitation. Untreated, these symptoms could compromise safety or leave the patient without housing options.

Although possibly underused because of time constraints, reimbursement issues, or lack of training, nonpharmacologic strategies to treat aggression and psychosis in dementia are appealing alternatives to antipsychotics. Little empiric evidence supports nonpharmacologic strategies, however.²²

Treatment decisions need to consider patients’ and caregivers’ value systems. Proxy decision-makers should examine treatment decisions in terms of how they believe the patient would view the alternatives. Without a specific advance directive, however, even well-intentioned decision-makers are likely to “contaminate” decisions with their own values and interests.

After discussing with the decision-maker various treatments’ risks and benefits, it might be useful to ask, for example, “If Mrs. B could have foreseen her behaviors 10 years ago, what do you think she would have wanted us to do? Some people might have been mortified by the thought of attacking other people, whereas other people would not mind this as much as the fear of being ‘overmedicated.’ Which end of the spectrum do you think she would have leaned toward?”

When medical research does not offer clear answers for the “right” next clinical step, clinicians can:

• acknowledge our own limits and those of human knowledge
• engage the caregiver (or, when appropriate, the patient) in shared decision-making, recognizing that some people will appreciate the opportunity for “equal partnership” whereas others will want us to decide based on our best clinical judgment.

Table 2

Pharmacologic alternatives to antipsychotics: What the evidence says

Table 3

How well do psychosocial/behavioral therapies manage
psychosis/agitation in dementia?*

Duration of treatment

Limited evidence leaves psychiatrists largely on our own in regards to how long to continue pharmacotherapy with antipsychotics. Neuropsychiatric symptoms such as psychosis and agitation exhibit variable patterns. Symptoms may wax and wane for unclear reasons.

Given the tenuous nature of the risk-benefit profile for atypical antipsychotics in dementia, consider a gradual taper for persons with dementia who remain asymptomatic after 3 to 6 months of atypical antipsychotic treatment. Monitor them closely for symptom recurrence.⁵

Carefully consider the necessary duration of antipsychotic therapy in patients (such as Mrs. B) in whom you can identify possibly reversible precipitants of psychosis and aggression. Patients may have a delayed beneficial response to the correction of precipitating factors such as medical illness, physical discomfort, or medication side effects.

Mrs. B received risperidone, but evidence for efficacy and safety in dementia-related psychosis or agitation does not yet significantly distinguish among the atypical agents (except that data are limited for ziprasidone and clozapine). Usual starting and target doses are provided in Table 4.²³

Table 4

Atypicals in dementia: Starting and target doses

Related resources

• Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5):957-70.
• American Association for Geriatric Psychiatry position statement: principles of care for persons with dementia resulting from Alzheimer disease. www.aagponline.org/prof/position_caredmnalz.asp.

Drug brand names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Ciprofloxacin • Ciloxan
• Citalopram • Celexa
• Clozapine • Clozaril
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Donepezil • Aricept
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Lortab, Vicodin
• Lorazepam • Ativan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxybutynin • Ditropan
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Sertraline • Zoloft
• Trazodone • Desyrel
• Ziprasidone • Geodon

Disclosure

Dr. Meeks receives research/grant support from the John A. Hartford Foundation, the Mental Health Research Foundation, NARSAD, and the U.S. Department of Health and Human Services’ Health Resources and Services Administration.

Dr. Jeste receives research/grant support from the John A. Hartford Foundation, the National Institute of Aging, and the National Institute of Mental Health. AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Janssen, L.P. provide free medications for an NIMH-funded study for which Dr. Jeste is the principal investigator.