US Pharm. 2013;38(11):HS8-HS14.
ABSTRACT: During the moderate and late stages of dementia,
patients experience behavioral and psychological symptoms of dementia
(BPSD), such as agitation, psychosis, and aggression. There is no
FDA-approved treatment for BPSD, but antipsychotics are frequently
prescribed off-label. Antipsychotics yield only modest improvements in
BPSD and have been shown to increase death in elderly patients with
dementia. It is recommended that, as a part of patient-centered care,
nursing homes involve consultant pharmacists in the development and
review of medication-safety procedures.
Dementia is a disorder characterized by cognitive and functional
impairment. Alzheimer disease (AD), the most common form of chronic
dementia, affected 4.7 million Americans in 2010. The number of patients
with AD is expected to approach 13.8 million by 2050 and will cost the
United States an estimated $1.1 trillion per year in drug and medical
In the moderate to late stages of AD, patients have difficulty
communicating, completing complex tasks, and remembering new
information. Additionally, behavioral and psychological symptoms of
dementia (BPSD), such as delusions, wandering, aggression, and
agitation, occur in 60% to 90% of patients with dementia.2 These symptoms are associated with greater functional impairment and frequently lead to nursing home placement.3
Currently, there is no FDA-approved treatment for BPSD.
Antipsychotics have evidence of slight efficacy; however, reports of
increased mortality, cerebrovascular events, and cardiovascular effects
in elderly patients prompted the FDA to issue a black box warning for
Mortality: There is strong evidence that both atypical antipsychotics and typical antipsychotics (TABLE 1)
increase mortality in elderly patients with dementia. An FDA
meta-analysis of trials involving elderly patients with BPSD who were
taking aripiprazole, olanzapine, quetiapine, or risperidone revealed a
4.5% incidence of death in treatment groups versus a 2.6% incidence in
placebo groups. The relative risk—1.7—was consistent among all treatment
groups.4 However, in a retrospective study, the highest
mortality occurred with risperidone compared with olanzapine and
quetiapine. The difference in risk between agents appeared to decrease
after 2 months, despite risk persisting for up to 24 months. The most
common causes of death were pulmonary infection and cardiovascular
events.5,6 Overall, the Agency for Healthcare Research and
Quality (AHRQ) estimates 1 death per 100 patients receiving an atypical
antipsychotic for BPSD per 10-week period.7
Prior to 2005, very little data existed regarding the safety of
typical antipsychotics, leading some clinicians to believe that the
older agents were safer. Data on comparative safety are conflicting. One
study found a dose-dependent 37% increase in death in the first 6
months of treatment with typical agents.8 A large community
cohort study also found higher mortality with typical agents (12.7%)
than with atypical agents. In this study, the most frequently used
typical and atypical antipsychotics were loxapine and quetiapine,
respectively.9 Likewise, a small retrospective analysis found
a statistically significant increase in mortality over 2 years in
patients taking haloperidol compared with those taking risperidone or
olanzapine (21.4% vs. 4.75%, P <.00001).10
Studies examining the risk of death from pneumonia with use of
atypical agents versus typical agents also have produced conflicting
results. Observational studies have shown a higher risk of pneumonia in
community dwellers taking atypical agents, but in the nursing home
setting, typical agents are associated with an increased risk of
pneumonia.11,12 The likely cause of pneumonia is aspiration precipitated by excessive sedation and/or extrapyramidal side effects (EPS).
Cerebrovascular Events: Both classes of
antipsychotics carry a black box warning for increased risk of
cerebrovascular events. The risk of stroke or transient ischemic attack
is estimated to be two times greater in antipsychotic users with
dementia than in antipsychotic users without dementia.12 The
risk, which appears to decline after 3 months, is greatest during the
first week of treatment and in patients who are already at high risk for
stroke.13 Risperidone was the first drug to receive a black
box warning for cerebrovascular events, but subsequent trials have shown
a similar incidence among all antipsychotics in both classes.6
Cardiovascular Events: The risk of
cardiovascular events such as myocardial infarction, arrhythmias, and
syncope are similar between both classes of antipsychotics. A
meta-analysis from the AHRQ found that 1 in every 48 elderly patients
taking olanzapine will have a cardiovascular event, compared with 1 in
every 34 taking risperidone.7 Ziprasidone and the low-potency
typical antipsychotics chlorpromazine and thioridazine appear to be
associated with the greatest risk of QTc prolongation, which can lead to
fatal arrhythmias.6 Periodic ECGs are recommended for
patients with risk factors for arrhythmia who are taking an
antipsychotic or who are taking medications that prolong the QTc
Other Side Effects: Anticholinergicity, weight
gain, and EPS (abnormal involuntary movements) are well-known side
effects of antipsychotics. In the elderly, anticholinergic agents
increase the risk of falls, constipation, and urinary retention.
Olanzapine, clozapine, quetiapine, and low-potency typical
antipsychotics have pronounced anticholinergic effects and can worsen
cognition.7 Therefore, the anticholinergic load of all patient medications should be monitored.
Weight gain appears to be less pronounced in older patients than in
younger patients. Even so, the risk of hyperglycemia and
hypercholesterolemia should be considered in patients with preexisting
diabetes or heart disease. Classwide, atypical agents are more likely to
cause metabolic disturbances, with clozapine, risperidone, and
olanzapine conferring the greatest risk.7
EPS include dystonia, parkinsonism, and tardive dyskinesia. The AHRQ
reports that olanzapine carries the greatest risk of inducing EPS in the
elderly population; 1 out of every 10 patients taking olanzapine will
experience EPS. Risperidone causes 1 case for every 20 patients treated.7
It is recommended that all facilities administer the Abnormal
Involuntary Movements Scale at baseline and every 6 months thereafter
(or sooner, if clinically indicated).
Reducing Inappropriate Use
Despite serious safety concerns and minimal overall effect on
symptomatology, antipsychotics are frequently prescribed off-label for
BPSD. In 2010, the Centers for Medicare and Medicaid Services (CMS)
reported that 39% of U.S. nursing home residents were inappropriately
prescribed an antipsychotic without having a clinical indication for
According to CMS guidelines, it is appropriate to consider the use of
an antipsychotic to treat delusions, hallucinations, and/or aggression
in patients with dementia, but only if these symptoms are dangerous
and/or severely distressing to the patient or others. Behaviors such as
wandering, hoarding, and apathy are not considered appropriate treatment
targets (TABLE 2).15 Additionally, modifiable causes
of behavioral problems should always be definitively ruled out prior to
beginning treatment with an antipsychotic. TABLE 3 lists conditions that can cause behavioral problems and/or mimic dementia.15,16
To thwart the practice of prescribing antipsychotics for the chief
purpose of behavior control or sedation, the CMS issued a mandate in
2012—since renewed for 2013—that all nursing homes reduce unnecessary
use of antipsychotics by at least 15%. CMS regulation F329 (commonly
known as F-Tag 329) defines unnecessary use as excessive
dose, excessive duration, inadequate monitoring, lack of clinical
indication for use, and presence of adverse events.15
It is important to note that none of the regulations is meant to
impede patient care; the CMS recognizes that the benefit may exceed the
risk in patients with appropriate clinical indications.15 The
risks and benefits of therapy, as well as the establishment of a
reasonable expectation of symptom control, should be discussed with the
patient and caregivers prior to initiation.
Gradual Dose Reduction
To be considered fully compliant with F-Tag 329, a facility must
attempt a gradual dose reduction (GDR) of all antipsychotics—including
those used for psychiatric diagnosis—twice within the first year of
antipsychotic treatment. Attempts should be made in two separate
quarters at least 1 month apart. After the first year, a GDR should be
attempted annually. To avoid discontinuation syndrome, the dose should
be reduced by no more than 50% every 2 weeks.15
However, not all patients are candidates for a dose reduction. GDR is
contraindicated in patients with dementia if the patient’s symptoms
worsened as a result of a prior GDR attempt or if the physician provides
a specific rationale for why a GDR would harm the patient. For patients
without dementia who are taking antipsychotics for a psychiatric
condition, a GDR is contraindicated if the treatment is in accordance
with current practice guidelines or if the patient’s symptoms had
worsened after a previous GDR attempt. Reasons for contraindication
should be documented in the medical record; otherwise, the facility
could be cited as noncompliant.15
Even in the absence of a GDR, all patients should be given the lowest
clinically effective dose for the shortest duration. Since many adverse
events, particularly EPS and cardiovascular events, appear to be
dose-related, the CMS has published maximum daily doses for
antipsychotics used to treat BPSD (TABLE 4).15
If the patient has not exhibited the expected treatment response by
the time the dose approaches the upper threshold, modifiable causes of
BPSD should be reevaluated and an alternative therapy should be
Initial antipsychotic drug selection should be guided by
comparative-efficacy data. The Clinical Antipsychotic Trials of
Intervention Effectiveness—Alzheimer’s Disease (CATIE-AD) evaluated
median time to discontinuation in elderly AD subjects taking olanzapine
(mean end-study dose 5.5 mg), quetiapine (56.5 mg), or risperidone (1
mg) compared with placebo.17 The median time to
discontinuation due to lack of efficacy was 26.1 weeks for risperidone
and 22 weeks for olanzapine; the median time for both quetiapine and
placebo was 9 weeks (P = .002). There were no significant
differences in clinical-improvement scales among the treatment groups,
however. Discontinuation due to intolerability was greatest for
olanzapine (24%); risperidone and quetiapine had similar discontinuation
rates (18% and 16%, respectively), but placebo was favored, with a
discontinuation rate of 5% (P = .009).17
The AHRQ conducted a comparative-efficacy review to examine the
strength of evidence of efficacy of atypical agents in treating overall
BPSD, agitation, and psychosis compared with placebo. Based on results
of this review, risperidone is the only agent with strong evidence of
efficacy for overall BPSD, agitation, and psychosis; aripiprazole also
has strong evidence of efficacy for treating overall BPSD in dementia,
whereas olanzapine and quetiapine have low evidence of efficacy.
Risperidone is the only agent with strong efficacy data for treatment of
psychosis in dementia; for agitation, olanzapine has proven efficacy.
Because of a paucity of evidence supporting its use, quetiapine is not
recommended unless other agents have failed. The AHRQ noted, however,
that despite strong evidence of efficacy, the magnitude of treatment
effect on clinical improvement was small and did not reach statistical
The efficacy of typical agents used to treat BPSD has not been
studied as extensively as that of the newer agents. Of these agents,
haloperidol has the most clinical data for agitation in dementia.18 However, its utility is diminished by reports of high mortality and risk of EPS.
Role of the Pharmacist
The Nursing Home Reform Act, which is part of the Omnibus Budget
Reconciliation Act of 1987, requires facilities to provide
patient-centered care to all residents.15 As part of its
quality-improvement plan, the CMS recommends that all facilities include
a consultant pharmacist on their quality-care committees, particularly
to help develop and review procedures for medication safety.7
Patient-centered care of the elderly is possible when a team-based
approach including representatives from all healthcare professions is
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home residents. May 2011.
http://oig.hhs.gov/oei/reports/oei-07-08-00150.pdf. Accessed July 28,
15. Centers for Medicare and Medicaid Services. Dementia care in
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Accessed July 28, 2013.
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