Web audio at CurrentPsychiatry.

com
Dr. Kales: Risks and benefits of
antipsychotics and other psychotropics
for behavioral and psychological
symptoms of dementia

T H I R D O F 3 PA R T S

Prescribing antipsychotics in geriatric

patients: Focus on dementia
When to use SGAs for behavioral
and psychological symptoms
of dementia

A
ccording to the U.S. Department of Health and Human
Services, in 2007, 88% of 1.4 million Medicare claims
for second-generation antipsychotics (SGAs) in older
adult nursing home residents were associated with a dementia
diagnosis. Similar trends have been observed in Canada and
Europe.1-4 In a retrospective analysis of medication data from
older residents with dementia in 6 care homes in England,
long-term (ie, >1 month) use of antipsychotics was the most
frequent potentially inappropriate prescribing practice.3 In
another study in 7 European countries and Israel, the overall
prevalence of antipsychotic use among long-term care resi-
TRINA DALZIEL

dents with dementia was 33%.1 Similarly, a recent literature

review5 found that 22% to 86% of antipsychotic prescriptions
to older individuals were off-label; this practice was particu-
Helen C. Kales, MD Martha Sajatovic, MD larly common for individuals with agitation.
Professor of Psychiatry Professor of Psychiatry Because of the aging population and widespread prescrip-
Program for Positive Aging and Professor of Neurology
Department of Psychiatry Department of Psychiatry tion of antipsychotics to older patients, clinicians need infor-
University of Michigan and Department of Neurology mation on the relative risks of using these medications in this
VA Center for Clinical Case Western Reserve University population. In the United States, all antipsychotics carry a
Management Research University Hospitals Cleveland
Ann Arbor, Michigan Medical Center
FDA “black-box” warning of the increased risk of death in
Cleveland, Ohio
Benoit H. Mulsant,
Disclosures
MD, MS Dr. Kales has received research support from the National Institutes of Health (NIH), Department
Professor and Chair of Defense, and Veterans Affairs, and reports no financial relationships with any companies whose
Department of Psychiatry products are mentioned in this article or with manufacturers of competing products. Dr. Mulsant
Senior Scientist has received research support from Brain Canada, the Centre for Addiction and Mental Health, the
Centre for Addiction Canadian Institutes of Health Research, the NIH, Bristol-Myers Squibb (medications for an NIH-
and Mental Health funded clinical trial), Eli Lilly (medications for an NIH-funded clinical trial), and Pfizer (medications
University of Toronto for an NIH-funded clinical trial). Within the past 5 years, he also has received travel support
Toronto, Ontario from Roche. Dr. Sajatovic has received research grants from Alkermes, Merck, Janssen, Reuter
Foundation, Woodruff Foundation, Reinberger Foundation, NIH, and the Centers for Disease
Control and Prevention; has been a consultant to Bracket, Prophase, Otsuka, Sunovion, Supernus
and Neurocrine; and has received royalties from Springer Press, Johns Hopkins University Press,
Current Psychiatry Oxford Press, UpToDate, and Lexicomp, and compensation for CME activities from American
24 December 2017 Physician’s Institute, MCM Education, and CMEology.
older adults with dementia. In addition, the base, although benefits are modest at best
risk of death is increased when prescribing (standardized effect size 0.13 to 0.16).19,20
antipsychotics to older adults with other In terms of individual SGAs, only risperi-
conditions, such as Parkinson’s disease,6 done is indicated for aggression in Canada
and other safety and tolerability concerns, and in Europe (not in the United States);
including falls and fractures, sedation, risperidone has the best evidence for effi-
metabolic abnormalities, and extrapyrami- cacy, with a meta-analysis of 5 published
dal effects, are highly relevant to geriatric randomized controlled trials (RCTs) report-
patients. ing that risperidone is superior to other
This 3-part review summarizes findings SGAs for aggression in dementia.21,22 As a
and recommendations on prescribing anti- class, first-generation antipsychotics (FGAs)
psychotics to older individuals with schizo- have no clear evidence for BPSD as defined
phrenia, bipolar disorder, depression, and broadly; however, there may be slight ben-
dementia. This third and final installment: efit for haloperidol for aggression.23,24
• briefly summarizes the major studies and
analyses relevant to prescribing antipsy-
chotics to older patients with dementia Clinical Trials Clinical Point
• provides a summative opinion on safety Adverse effects. A meta-analysis of RCTs of SGAs have the
and tolerability issues in these older SGAs found that, compared with placebo,
patients SGAs have increased rates of several adverse
strongest evidence
• highlights the gaps in the evidence base effects. These include somnolence (17% base for BPSD,
and areas that need additional research. drug vs 7% placebo; odds ratio [OR], 2.84; although benefits
95% confidence interval [CI], 2.25 to 3.58; are moderate at best
P < .00001); extrapyramidal symptoms (13%
Summary of benefits, place drug vs 8% placebo; OR, 1.51; 95% CI, 1.20
in treatment armamentarium to 1.91; P = .0005; primarily attributable to
Behavioral and psychological symptoms of risperidone); abnormal gait (10% drug vs
dementia (BPSD) include agitation, delu- 2% placebo; OR, 3.42; 95% CI, 1.78 to 6.56;
sional beliefs, repetitive questioning, halluci- P = .0002; attributable to olanzapine and
nations, aggression, wandering, and various risperidone); edema (9% drug vs 4% pla-
socially inappropriate behaviors.7 These cebo; OR, 1.99; 95% CI, 1.20 to 3.30; P = .008;
occur almost universally in all types and attributable to olanzapine and risperidone);
stages of dementia.7 BPSD are among the urinary tract infections/incontinence (16%
most complex, stressful, and costly aspects drug vs 12% placebo; OR, 1.28; 95% CI, 1.02
of dementia care, and lead to a myriad of to 1.61; P = .04); cognitive impairment mea-
poor health outcomes, including excess mor- sured as difference in Mini-Mental State
bidity, mortality, hospital stays, and early Examination score (95% CI, 0.38 to 1.09;
nursing home placement.8-11 Because BPSD P < .0001)25; and stroke (1.9% drug vs 0.9%
usually occur across all types and stages of placebo, OR, 2.13; 95% CI, 1.20 to 3.75;
dementia,7,12-16 the prevalence of BPSD mir- P = .009).21,26
rors the overall prevalence of dementia. In the 42-site Clinical Antipsychotic
Although all expert organizations, includ- Trials of Intervention Effectiveness
ing the American Psychiatric Association,17 Alzheimer’s disease RCT, 421 outpatients
recommend nonpharmacologic strategies with Alzheimer’s disease and BPSD were
as first-line treatment for BPSD, for the randomized to an SGA (risperidone,
most part, these recommendations have olanzapine, or quetiapine) or placebo. Discuss this article at
not been translated into standard clinical Compared with placebo, SGAs had a higher [Link]/
CurrentPsychiatry
management or routine care.18 Because of rate of parkinsonism or extrapyramidal
a perceived lack of other options, the cur- signs (olanzapine and risperidone groups);
rent mainstay of treatment is the off-label sedation; confusion/changes in mental sta-
use of psychotropics such as antipsy­ tus (olanzapine and risperidone); psychotic
chotics. Of all the agents currently used for symptoms (olanzapine); and increase in
Current Psychiatry
BPSD, SGAs have the strongest evidence body weight and body mass index.26 Vol. 16, No. 12 25
continued
 In the 2005 FDA black-box warning, controlling for other psychiatric medica-
pneumonia and cardiac adverse effects were tions,10 and varying lengths of follow-up.10
cited as primary causes of death for patients An FDA black-box warning for FGAs was
with dementia taking SGAs. A subsequent announced in 200830 based on 2 observational
observational study confirmed that use of studies that showed an increased risk of mor-
either FGAs or SGAs in geriatric patients tality in older adults taking FGAs vs SGAs.35,36
was associated with an increased risk of In terms of specific SGAs, Kales et al37
Antipsychotics pneumonia, in a dose-dependent manner.27 examined the mortality risk associated
for dementia Although there is limited data on cardiac with individual antipsychotics using vari-
adverse effects in older adults, especially ous methods to control for confounding.
those with dementia taking antipsychotics,28 Among a national sample of >33,000 older
1 observational study of nursing home resi- veterans with dementia newly started on
dents29 found that those taking FGAs had a haloperidol, risperidone, olanzapine, que-
significantly higher risk of hospitalization tiapine, or valproic acid and derivatives (as
for ventricular arrhythmia or cardiac arrest a nonantipsychotic comparator), the high-
compared with those who were not taking est mortality across all analyses (intent to
Clinical Point FGAs. In contrast, there was no increased treat, exposure, propensity-adjusted) was
risk with SGAs. associated with haloperidol, followed by
Although there
risperidone and olanzapine, valproic acid,
is limited data on Mortality.
In 2005, the FDA announced that and quetiapine.
cardiac adverse based on a reanalysis of 17 placebo-con- Most recently, a retrospective case-
effects, 1 study trolled trials (many of which were unpub- control study (90,786 patients age ≥65 with
found an increase in lished) that SGAs were associated with a dementia) examined the number needed to
1.7-fold increase in mortality compared harm (NNH; ie, number of patients needed
those taking FGAs with placebo.30 As a result, the FDA issued to receive treatment that would result in 1
compared with SGAs a black-box warning for using SGAs in death) over 180 days following initiation
patients with dementia. The overall OR in of an FGA or SGA.38 This study found the
a published meta-analysis of mortality with following NNHs: haloperidol, 26 (95% CI,
SGAs was 1.54 (1.06 to 2.23; z = 2.28; P = .02), 15 to 99); risperidone, 27 (95% CI, 19 to
with pooled events of 3.5% mortality vs 2.3% 46); olanzapine, 40 (95% CI, 21 to 312); and
(drug vs placebo).21 This meta-analysis21 also quetiapine, 50 (95% CI, 30 to 150).38 These
included ad hoc analyses of haloperidol; results are congruent with a review of
using combined data from 2 contrasts of hal- observational studies that found the high-
operidol (with risperidone and quetiapine; est risk of mortality was associated with
243 patients receiving haloperidol and 239 haloperidol and chlorpromazine, and  the
receiving placebo) they also found 15 deaths lowest risk with olanzapine, quetiapine,
(6.2%) with haloperidol and 9 (3.8%) with and ziprasidone.28
placebo, resulting in an OR of 1.68.

Patterns of antipsychotic use

Other clinical data in older dementia patients
Observational studies. Most observational There are high rates of antipsychotic use
studies have confirmed concerns regarding in patients with dementia. Before the FDA
increased mortality in patients with BPSD issued the black-box warning, the Aging
who take antipsychotics, with FGAs having Demographics and Memory study found
a higher risk than SGAs18,31 and SGAs hav- that the rate of antipsychotic use in commu-
ing a higher risk compared with most other nity (outpatient) older adults with dementia
psychotropics.32 Three studies that found no was approximately 19% between 2002 and
increase in mortality with antipsychotics in 2004 in a representative sample of 307 older
patients with dementia had methodologi- adults.39 Another study examining trends
cal issues, including examining prevalence in community antipsychotic use in the U.S.
as opposed to new users,33,34 not control- Department of Veterans Affairs (VA) found
Current Psychiatry
26 December 2017 ling for exposure,10,33,34 power issues,10,34 not that in the 1990s, SGA use was increasing;
approximately 18% of outpatients with Table
dementia were taking these agents.40 Use
of SGAs began to decline in 2003, ahead of
Using antipsychotics in older
the 2005 black-box warning, in tandem with
patients with dementia: A
other advisories (eg, diabetes, metabolic syn- summary of the evidence
drome,41 and stroke risk).42,43 Olanzapine and Of all agents currently used for BPSD, SGAs
have the strongest evidence base (from
risperidone showed declining rates between
RCTs for agitation, aggression, or psychosis),
2003 and 2005, whereas quetiapine use sig- although benefits are moderate at best
nificantly increased during this period. All In terms of individual SGAs, the best evidence
3 SGAs declined after the black-box warn- is for risperidone for aggression
ing. However, by the end of 2007, the use of FGAs have no clear evidence for BPSD.
SGAs had leveled off to approximately 12% There may be slight benefit for haloperidol for
aggression, but this medication has a higher
of VA patients with dementia. A recent U.S.
mortality risk than SGAs
Government Accountability Office (GAO)
In terms of mortality risk, FGAs have a higher
report found that in 2012, 14% of older adult risk than SGAs, and SGAs have a higher risk
Medicare Part D enrollees with dementia than most other psychotropics
living in the community were prescribed Individual SGAs also differ in mortality risk, with Clinical Point
an antipsychotic.44 risperidone having the highest risk, followed by
olanzapine, then quetiapine There might be a
Use in nursing home residents. Because Because of the nature of risk–benefit with both slight benefit for
FGAs and SGAs in dementia, these agents
BPSD are one of the main reasons people should be reserved for cases where there is
haloperidol for
with dementia are placed in nursing homes, considerable risk of harm to self or others aggression; however, it
it is not surprising that rates of antipsy- (eg, aggression or psychosis or after
substantial efforts to utilize behavioral or has a higher mortality
chotic use are higher in these settings than
in the community. Prior to the black-box
environmental strategies have failed) risk than SGAs
BPSD: behavioral and psychological symptoms of
warning, studies found that 24% to 32% of dementia; FGA: first-generation antipsychotic; RCT:
randomized controlled trial; SGA: second-generation
nursing home residents were treated with antipsychotic
antipsychotics.45-47 A study examining VA
nursing homes (n = 133 facilities, n = 3,692
veterans) found that approximately 26% of
residents were prescribed antipsychotics least 1 psychotropic, and up to one-third are
in 2004 to 2005.48 The Center for Medicare prescribed SGAs.50 European data similarly
and Medicaid Services (CMS) National show that antipsychotics continue to be
Partnership to Improve Dementia Care in prescribed to up to one-third of long-term
Nursing Homes has appeared to lower anti- care residents with dementia, with 7 out of
psychotic medication use in nursing homes; 10 receiving an SGA.1
the rate decreased from 24% in long-stay
nursing home residents nationwide in
2011 to 19% by the end of 2014. Specific Conclusions
to dementia, a 2010 CMS report49 indi- The Table provides a summary of the evi-
cated that approximately 40% of nursing dence regarding the use of antipsychotics in
home residents with cognitive impairment patients with dementia. Expert consensus
and behavioral issues, without psychosis, is that among BPSD, aggression and psy-
received antipsychotics. The GAO data chosis are the primary indications for using
indicated that approximately 33% of older antipsychotics.51 Based on multiple RCTs
Medicare Part D enrollees with dementia and meta-analyses, the evidence for using
who spent >100 days in a nursing home SGAs to treat these symptoms is moderate
were prescribed an antipsychotic in 2012.44 at best. However, in real-world practice set-
A recent Canadian study using drug claims tings, SGAs are widely used for symptoms,
data found that overall psychotropic use in such as wandering, inappropriate behaviors,
patients with dementia remains high, find- resistance to care, etc., for which there is no
ing that three-fourths of all patients with evidence for efficacy other than sedation.
Current Psychiatry
dementia in long-term care are given at Furthermore, even when there is a potential Vol. 16, No. 12 27
 Box

Use DICE before prescribing an antipsychotic to a person with dementia

1. Describe the behavioral symptom fully • enhancing the caregiver’s communication
(including who, what, when, and where). with the person with dementia
For example, “agitation” is not an adequate • creating meaningful activities for the
description, just as shortness of breath would person with dementia
not be fully descriptive to an internist. Inquire as • simplifying tasks
to the degree of distress the symptom is causing • ensuring the environment is safe
Antipsychotics the patient and caregiver. • adjusting the stimulation in the
for dementia 2. Investigate the possible underlying causes of environment (increase if under-stimulating,
the behavior: decrease if overstimulating).
• person with dementia (eg, pain, infection, 4. Evaluate the impact of any interventions
sensory changes, medication adverse that have been implemented. If they are
effects) working, have the caregiver keep doing
• caregiver (eg, negative communication style, them. If they are ineffective, devise a new
such as yelling at the person with dementia, strategy.
mismatch of expectations with level of First-line use of antipsychotics should
dementia) be limited to psychosis or aggression that
• environment (eg, overstimulation with clutter is causing harm or the potential for harm:
Clinical Point and blaring TV). significantly distressing to the person with
dementia (eg, do not medicate hallucinations
Among BPSD, 3. Create a treatment plan to address the
that are experienced as benign), impairing
underlying causes found by responding to
aggression and physical problems and strategizing behavioral/ function (eg, not eating out of fear of
environmental interventions, such as: being poisoned), or creating a safety risk
psychosis are • providing the caregiver with education/ (eg, aggression toward caregiver that is
endangering their safety).
the primary support

indications for using Source: Reference 51

antipsychotics

for benefit, this must be balanced against atric patients is not growing substantially.
the risk of adverse effects, including somno- Pharmacotherapy evidence is not keeping
lence, worsened cognition, extra­pyramidal up with demographic trends. Key develop-
symptoms, stroke, and mortality. ments in RCTs will be the inclusion of bio-
Clinicians who care for older adults with markers via neuroimaging, drug serum or
BPSD should strive to increase the use of brain levels, and genetic profiling. Because
first-line nonpharmacologic strategies, by of the modest findings of benefits of anti-
using structured approaches such as DICE psychotics in dementia and safety concerns
(Describe, Investigate, Create, Evaluate) addressing brain health in preclinical or
described in the Box.51 Antipsychotics early stages, identification of effective non-
should be reserved for situations in which drug interventions and identifying true
nonpharmacologic approaches are unsuc- disease-modifying agents will be the next
cessful, or there is concern for serious or challenges of dementia research.
imminent risk to the patient or others.
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Bottom Line
Second-generation antipsychotics should be prescribed for patients with behavioral
and psychological symptoms of dementia only when nonpharmacological
approaches are unsuccessful, or there is an imminent risk to the patient or others
Current Psychiatry
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