Download Preventing overuse of antipsychotic drugs in nursing home care

Balanced information for better care
Preventing overuse of antipsychotic
drugs in nursing home care
Safer alternatives
Preventing overuse of antipsychotic drugs in
nursing home care
Safer alternatives
Principal Consultants: Eran Metzger, M.D., David Osser, M.D.
Series Editors: Jerry Avorn, M.D., Niteesh K. Choudhry, M.D., Ph.D., Michael Fischer, M.D., M.S., Eimir
Hurley, BSc (Pharm), MBiostat.
Medical Writer: Stephen Braun
The Independent Drug Information Service (IDIS) is supported by the Massachusetts Department of Public
Health and the PACE Program of the Department of Aging of the Commonwealth of Pennsylvania.
This material is provided by the Alosa Foundation, a nonprofit organization, which is not affiliated with any
pharmaceutical company. None of the authors accepts any personal compensation from any
pharmaceutical company.
These are general recommendations only; specific clinical decisions should be
made by the treating physician based on an individual patient’s clinical
condition.
For more information, visit www.alosafoundation.org
ii | Preventing
overuse of antipsychotic drugs in nursing home care
Alosa Foundation
Preventing overuse of antipsychotic drugs in nursing home care:
Safer alternatives
Activity overview:
The primary goal of the educational program is to help nursing home clinicians better manage the
behavioral and psychological symptoms of dementia and reduce the reliance on antipsychotic medications
in this population. The program synthesizes the clinical literature on the risk-benefit relationship of
antipsychotic medication use in the elderly, most notably the elevated risk of mortality. It also presents
practical advice on non–pharmacological approaches, and identifying the reversible clinical, psychological
and environmental triggers of behavioral problems in patients with dementia.
In addition to providing this evidence report, the education program uses an innovative approach, academic
detailing, one-on-one educational sessions with specially trained outreach educators (pharmacists, nurses,
physicians) who present the educational material interactively. Reference cards for clinicians and education
materials for family members are also provided.
Key messages of the module:
1. Antipsychotic medications are often overused in older patients in nursing homes, and they increase risk
of death and can cause substantial side effects.
2. In managing behavioral and psychological symptoms in patients with dementia, begin by ruling out any
reversible clinical, psychological, or environmental triggers.
3. Identify specific target behaviors and set realistic treatment goals.
4. Initiate non–drug interventions first in most patients, and continue these even if drug treatment is
required.
5. If an antipsychotic medication must be used to manage a specific, identified, dangerous behavior not
responding to non-drug approaches, do so cautiously.
6. Regularly re-assess and re-evaluate the need for ongoing antipsychotic medication use; discontinue if
the targeted behavior is not improving.
7. Screen for specific side effects at baseline and at regular intervals.
Disclosures:
This material is provided by the Alosa Foundation, a nonprofit organization which is not affiliated with any
pharmaceutical company. No commercial support has been received for this activity. None of the
planners/authors have any financial relationships to disclose. The Independent Drug Information Service
(IDIS) is supported by the Massachusetts Department of Public Health and the PACE Program of the
Department of Aging of the Commonwealth of Pennsylvania.
Preventing overuse of antipsychotic drugs in nursing home care | iii
Faculty and Planners:
Jerry Avorn, M.D. is a Professor of Medicine at Harvard Medical School and Chief of the Division of
Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital. An internist, he has
worked as a primary care physician and geriatrician and has been studying drug use and its outcomes for
over 30 years. Dr. Avorn has no relevant financial relationships to disclose.
Niteesh K. Choudhry, M.D., Ph.D. is an Associate Professor of Medicine at Harvard Medical School and a
hospitalist at Brigham and Women's Hospital. His research focuses on the use of medications to treat
common chronic conditions. Dr. Choudhry has no relevant financial relationships to disclose.
Michael Fischer, M.D., M.S. is an Associate Professor of Medicine at Harvard Medical School and a primary
care internist who studies cost–effective drug use in outpatient practices. Dr. Fischer has no relevant
financial relationships to disclose.
Eran Metzger, M.D. is an Assistant Professor in Psychiatry at Harvard Medical School and Director of
Psychiatry, Hebrew SeniorLife. Dr. Metzger has no relevant financial relationships to disclose.
David Osser, M.D. is an Associate Professor of Psychiatry at Harvard Medical School and a psychiatrist at
the VA Boston Healthcare System. Dr. Osser has no relevant financial relationships to disclose.
Eimir Hurley, BSc (Pharm), MBiostat is the Program Director at the Alosa Foundation. Her interest lies in
the design, implementation and evaluation of programs to improve prescribing. Ms. Hurley has no relevant
financial relationships to disclose.
Stephen R. Braun, B.A. is a medical writer based in Amherst, MA. Mr. Braun has no relevant financial
relationships to disclose.
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Table of Contents
Introduction ................................................................................................................................. 1 Overview of antipsychotic medications ................................................................................... 3 Antipsychotic drug risks and side effects ............................................................................... 3 Mortality ...................................................................................................................................................3 Stroke ......................................................................................................................................................5 Major APM side effects in elderly patients ...............................................................................................5 Strategies for managing behavioral and psychological symptoms of dementia (BPSD) .. 11 BPSD overview ......................................................................................................................................11 Acute vs. non–acute BPSD ...................................................................................................................12 Non–pharmacologic management strategies ........................................................................................14 Pharmacologic management of BPSD: general principles ....................................................................18 Antipsychotic Medications .....................................................................................................................19 Other pharmacological treatment options ..............................................................................................22 Medications with insufficient evidence to support use in patients with BPSD .......................................25 Antipsychotic medications in the management of acute BPSD .......................................... 26 Is it delirium?..........................................................................................................................................27 Non–pharmacologic management .........................................................................................................27 Pharmacologic management .................................................................................................................28 APMs as augmentation for major depressive disorder ........................................................ 30 APMs for psychotic depression .............................................................................................................31 Conclusions .............................................................................................................................. 31 Appendix 1: Key characteristics of 2nd–generation APMs .................................................. 33 Appendix 2: Black box warning concerning mortality risk of antipsychotic drugs ........... 34 Appendix 3: Massachusetts guidance on the use of APMs in long–term care facilities ... 35 References ................................................................................................................................ 40
Preventing overuse of antipsychotic drugs in nursing home care | v
Introduction
Residents of nursing homes, especially those with cognitive impairment, may sometimes present a range
1,2
of symptoms including yelling, physical aggression, apathy, hostility, sexual disinhibition, defiance,
3,4
wandering, psychotic symptoms (hallucinations or delusions), emotional lability, and paranoid behavior.
The term “behavioral and psychological symptoms of dementia” (BPSD) is often used to describe these
symptoms, although they may occur in patients without dementia as well.
BPSD are common. Up to 90% of patients with dementia have such symptoms at some stage during their
1,2,4-6
illness.
The prevalence of some component of BPSD in community–dwelling patients with dementia
7,8
is estimated at 60−88%.
Historically, a range of medications have been prescribed to help manage real or perceived behavior
problems in elderly patients, including antidepressants, benzodiazepines, and antipsychotic medications
(APMs). Since at least the 1980s, however, the widespread use of APMs to manage behavior problems in
nursing homes has been questioned. The clinical literature demonstrates clearly that APMs offer minimal
benefits as chronic treatment for behavioral problems in nursing home residents, and that they have welldocumented risks including cardiac events, pneumonia, stroke, and death – as well as metabolic
derangements including hyperglycemia and elevated cholesterol. In contrast, non-drug strategies can
often effectively address many behavioral issues with far fewer risks than medications. In specific clinical
circumstances, APMs may have a limited role, but such instances are far less common than would be
justified by the current high level of use in this setting.
Figure 1: In a meta-analysis of 15 randomized trials, patients given an atypical antipsychotic drug
9
had higher rates of deaths than patients given placebo
4.0%
3.5%
Death rate
3.0%
2.5%
2.0%
1.5%
1.0%
0.5%
54%
Placebo
Atypical
antipsychotic
relative
increase
in mortality
0.0%
These results are based on a meta-analysis of clinical trials of aripiprazole, olanzapine, quetiapine,
and ripseridone. Other studies, which led to the FDA black box warning, found a 60-70% increased
risk of death.
Following a 1986 Institute of Medicine report citing the overuse of both APMs and physical restraints in
nursing homes, new regulations were added to the federal Nursing Home Reform Act of 1987, aimed at
10
curbing the use of “physical or chemical restraints imposed for purposes of discipline or convenience.”
Preventing overuse of antipsychotic drugs in nursing home care | 1
However, despite this and other federal and state initiatives, APMs continue to be widely used in nursing
homes. A 2009 study found that antipsychotic medications were being administered to 33% of elderly
11
nursing home residents with dementia. In one nationwide study of APM use in nursing homes, 83% of
use was for off-label conditions, and 88% for conditions that were the subject of an FDA black box
12
warning of increased risk of death in patients taking APMs. None of these widely-used drugs has an
FDA-approved indication for the management of behavioral symptoms in elderly patients with dementia.
Figure 2: APMs are often prescribed for nursing home patients with dementia who have no
13
indication for their use
40%
Use not
indicated
Proportion of patients with
non-aggressive behavioral problems who
are prescribed an antipsychotic drug
23%
Proportion of patients with
no behavioral problems who are
prescribed an antipsychotic drug
More recently, the Centers for Medicare & Medicaid Services (CMS) found that more than 1 in 5 nursing
home residents were prescribed antipsychotic medications in the first quarter of 2013, despite the
14
absence of a diagnosis that would warrant such use.
A number of programs have sought to address this problem at all levels of government and in both the
public and private sectors, and have begun to produce some changes. In 2012, CMS launched the
Partnership to Improve Dementia Care, which brought together nursing home leaders, clinicians,
pharmacists, drug makers and patients with the goal of reducing the overuse of APMs in nursing homes.
In 2013, CMS reported a 9% reduction in the number of nursing home residents receiving one of these
14
drugs between 2011 and 2013.
These and other efforts, such as those being made by the Massachusetts Senior Care Foundation, are
important in light of the increasing numbers of people in long-term care facilities. With the aging of the
population – especially the baby-boomer generation – the need for such care in the U.S. is expected to
15
rise from 13 million people in 2000 to 27 million in 2050. About 54% of elderly nursing home residents
16
are diagnosed with dementia, which makes behavioral symptoms such as aggression, delusions, or
11
hallucinations more likely. In addition, about a quarter of newly–admitted nursing home residents have a
psychiatric diagnosis (other than dementia) such as schizophrenia, bipolar disorder, depression, or
17
anxiety. These conditions can also lead to problematic behavior, and may co–exist with dementia.
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This evidence document reviews the evidence base for the use of APMs in nursing home residents and
provides information about non-drug strategies that can be used to reduce the incidence and severity of
disruptive or dangerous behaviors in these vulnerable patients.
BOTTOM LINE: Antipsychotic medications continue to be widely used in older patients in nursing
homes despite: (a) their lack of an approved indication for such use; (b) minimal evidence that
they are effective for chronic use in such settings; and (c) their well–established adverse effects
and increased risk of death.
Overview of antipsychotic medications
The first APMs were introduced to the U.S. market in the early 1950’s. These first-generation drugs were
used primarily to treat major psychiatric conditions such as schizophrenia. The second-generation APMs,
known as “atypical” antipsychotics, were introduced in the mid–1990’s, starting with clozapine in 1989,
then risperidone in 1994 and others in later years (see Appendix 1 for a complete list of secondgeneration APMs available as of early 2014). Although APMs are FD-approved specifically for the
treatment of major psychiatric disorders such as schizophrenia and bipolar disorder, for which they are
quite effective, they have been widely used (and illegally promoted) for off-label for conditions including
anxiety, insomnia, chronic pain, and behavioral symptoms in elderly patients with cognitive
11,18
impairment.
All APMs share the common characteristic of binding to dopamine 2 (D2) receptors in several areas of the
19
brain, with the affinity of such binding related to the potency of the drug. The drugs also differ in their
binding affinity to non–dopamine neurotransmitter receptors.
Antipsychotic drug risks and side effects
Antipsychotic medications pose a range of potential risks and side effects, some life threatening. For
psychotic disorders such as schizophrenia or bipolar disorder, the benefits of these drugs may outweigh
their risks. But for other conditions, such as behavioral management in dementia, or uncomplicated
depression, the risks of these drugs generally outweigh their potential benefits.
Mortality
The risk of death is higher among patients who use an APM versus those who do not, with death caused
9
primarily by cardiac events or stroke.
20
Evidence comes from several studies, most of which were conducted with nursing home residents. A
large meta–analysis of randomized trials found a 54% increase in the risk of death in patients who were
9
on APMs for even a relatively short time (i.e., 8–12 weeks). The risk varied somewhat by drug. This
study calculated a Number Needed to Harm of 100 with a very broad 95% CI from 53 to 1000. If the low
efficacy of APMs are included in the calculation, the authors estimate that for every 9–25 patients who
9
derive some symptomatic improvement from antipsychotics, one will die.
Preventing overuse of antipsychotic drugs in nursing home care | 3
A study of 75,445 new users of APMs in nursing homes found that mortality risk increased with higher
21
doses and seems to be highest for haloperidol and lowest for quetiapine. This trend was also found in a
study of a large cohort of outpatient Veterans Affairs patients with dementia, which found that the risk of
death was higher with haloperidol, and somewhat lower with quetiapine – but the doses of quetiapine
were low and, at those doses, ineffective.
In another study, risk of sudden cardiac death among those on an APM was twice that for non–users
*
(RaR 2.0; 95% CI: 1.7-2.3), with no significant difference in risk between first– and second–generation
22
23
agents. The risk of mortality for all agents was highest in the first 30 to 120 days of use.
Results from a randomized controlled clinical trial of APM withdrawal also supports the contention that
APMs are associated with increased mortality. The 2009 Dementia Antipsychotic Withdrawal Trial
(DART–AD) followed a group of 128 nursing home residents who were on an APM. Sixty-four residents
were randomized to continue with their APM, while 64 were randomized to a placebo. After 24 months,
patients who continued with an APM had significantly lower survival rates compared to those on placebo:
24
46% vs. 71%, a difference that widened further after 36 months (30% vs. 59%).
Figure 3: Survival of patients continuing on an antipsychotic medication compared with those on
24
placebo
APMs can also cause prolongation of the QT interval, which can predispose to a potentially fatal
ventricular arrhythmia, torsades de pointes. Since QT interval varies with heart rate, various formulae or
computerized algorithms are used to produce a corrected QT (QTc) interval. QTc is prolonged if it is ≥450
25
ms in men or ≥460 ms in women.
Second–generation APMs can induce QTc prolongation, most significantly with quetiapine and
ziprasidone and least with aripiprazole; the risk with haloperidol is increased for intravenous or
26
intramuscular administration. Patients started on an APM should have an initial EKG; for those with a
*
Rate Ratio
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baseline prolonged QTc who require an APM, consider an agent with minimal QTc prolongation. The risk
of QTc prolongation in patients prescribed an APM is increased if they are also taking one or more of a
long list of medications, many of which are commonly used in older patients. These include citalopram,
19
amiodarone, and quinolone antibiotics. A list of drugs that can prolong the QTc interval is available at
www.qtdrugs.org. Bradycardia, common in many older patients, increases the risk of torsades.
BOTTOM LINE: The use of APMs in patients with dementia significantly increases the risk of
death, a fact reflected in a black box warning for all APMs. This risk is highest in the first 30–120
days of use, but persists indefinitely thereafter. It is estimated that one patient will die from
antipsychotic use for every 9–25 patients who derive some symptomatic improvement from such
medication. Prolongation of the cardiac QTc interval occurs more often with quetiapine and
ziprasidone, and least with aripiprazole. Baseline EKG monitoring is warranted with these agents,
and avoidance of other QTc prolonging agents is prudent with all APMs.
Stroke
Data on the risk of stroke with APMs have been conflicting. Two large cohort studies of patients with
27,28
dementia comparing users of APMs with non–users of APMs found no increased risk of stroke,
while
a self–controlled case series from a research database found the risk of stroke was 1.7 times higher
29
during “exposed times” (i.e., when a patient was on an APM) compared to “unexposed times.” Stroke
30
risk may be higher with first–generation APMs compared to second–generation APMs.
Major APM side effects in elderly patients
Even when used for their labeled indications, APMs have a narrow therapeutic window, which can
increase the risk of side effects. The focus in this section is on second–generation APMs because they
are more commonly prescribed in the nursing home setting. (Note: although clozapine is considered a
second–generation APM, it is currently on a restricted distribution program in the U.S., due to the risk of
agranulocytosis; as a result, it is rarely used off–label for the types of behavioral symptoms seen in
nursing homes.)
Side effect profiles of different APMs differ by their affinity for non–dopamine neuronal receptors,
including acetylcholine, alpha–1, histamine, cardiac, and serotonin receptors. The table below briefly
outlines side effects associated with blocking of these other receptors.
Preventing overuse of antipsychotic drugs in nursing home care | 5
Table 1: Typical side effects associated with blocking of non–dopamine neuronal receptors
Receptor type
Side effect profile
Muscarinic acetylcholine receptors
Anti-cholinergic effects:
Dry mouth and skin
Blurry vision
Tachycardia
Sedation
Constipation
Urinary retention
Angle closure glaucoma
Alpha–1 adrenergic receptors
Orthostatic hypotension
Reflex tachycardia
Miosis
Nasal congestion
Histamine receptors
Sedation
Hypotension
Appetite stimulation
Serotonin receptors
Headache
Agitation
Nausea
Diarrhea
In general, first–generation APMs are more likely to produce extrapyramidal side effects (EPS), which
mimic Parkinson disease. Second–generation agents are more likely to produce weight gain and
metabolic side effects, including an increased risk of diabetes. Major APM side effect/adverse event
profiles are summarized in Table 2.
6 | Preventing
overuse of antipsychotic drugs in nursing home care
Table 2: APMs with highest rates of specific side effects
Metabolic effects
Weight gain
olanzapine
(Zyprexa)
+++
quetiapine
(Seroquel)
++
risperidone
(Risperdal)
++
Diabetes,
hyperglycemia
olanzapine
+++
quetiapine
++
Extrapyramidal
symptoms
haloperidol
(Haldol) +++
phenothiazines +++
Sedation
olanzapine
++
quetiapine
++
lurasidone
(Latuda) ++
QTc prolongation
quetiapine
++
ziprasidone
(Geodon) ++
iloperidone
++
Orthostatic
hypotension
paliperidone
++
quetiapine
++
risperidone
++
paliperidone
(Invega)
++
iloperidone
(Fanapt)
++
Neurologic effects
Cardiovascular effects
+++ = high incidence or severity, ++ = moderate incidence or severity.
This is not an exhaustive list and represents the drugs most likely to cause the particular adverse effect.
More detailed information on the side effect profile of each drug can be found in the evidence document
accompanying this brochure.
Weight gain/metabolic syndrome
Weight gain and derangement in glucose and lipid metabolism occur with most of the newer APMs, but
vary by specific drug. Impairment in glucose metabolism can progress to frank Type 2 diabetes. Most
31
weight gain occurs during the first 3 months of treatment. In non-elderly patients, metabolic and weight
effects have been most notable for olanzapine and quetiapine, and least notable for risperidone and
aripiprazole, although even aripiprazole produced a 10 lb. weight gain after three months in a younger
31
population. Patterns of insulin resistance were also similar, and highest for olanzapine. These metabolic
32
effects are independent of weight gain; olanzapine induces insulin–resistance even after a single dose.
These drugs also raise triglycerides and serum cholesterol levels.
A large randomized trial (CATIE) in patients with schizophrenia (n=1493) found similar trends in weight
gain and metabolic side effects among all of the agents studied, with the most unfavorable metabolic
33
effects seen with olanzapine and quetiapine (Figure 4).
Preventing overuse of antipsychotic drugs in nursing home care | 7
Figure 4: Mean change in cholesterol, triglycerides, and blood sugar by agent
33
Based on these trials and others, the American Diabetes Association and American Psychiatric
Association endorse the following screening protocol for all patients being initiated on a second–
generation antipsychotic medication Table 3).
8 | Preventing
overuse of antipsychotic drugs in nursing home care
Table 3: Guidelines for screening patients on antipsychotic medications
34,35
BOTTOM LINE: Parkinsonian side effects are most prominent with first–generation APMs;
second–generation APMs can still cause Parkinsonian signs and symptoms, as well as potentially
irreversible tardive dyskinesia, but do so at a lower rate than first-generation drugs. The newer
APMs can cause weight gain and metabolic side effects. Side effects vary significantly by agent.
The risk of diabetes and lipid derangements is highest with olanzapine and quetiapine, is
intermediate for risperidone and aripiprazole, and is minimal for ziprasidone. Weight gain is most
significant with olanzapine and quetiapine. All patients taking any APM should be regularly
screened for weight gain and increases in blood sugar or lipid levels.
Preventing overuse of antipsychotic drugs in nursing home care | 9
Extrapyramidal symptoms (EPS)
Extrapyramidal symptoms include involuntary muscle movements, Parkinsonian symptoms, and late–
appearing, tardive dyskinesia (TD). All APMs may cause these motor syndromes, although, in general,
they are less likely to occur with the second–generation than the first–generation agents, and all appear
to be dose–related, making it imperative to use the lowest possible dose of the drug. Tardive dyskinesia
may be irreversible even after the drug is stopped. Its prevalence in patients on first–generation
antipsychotic drugs is ~20%, with an annual incidence of:
36,37
• 3–5% for first–generation agents
38
• <1% for second–generation agents
A 9–month study of patients ≥45 years old being treated for schizophrenia or dementia with psychotic
symptoms/agitation demonstrated a 5% cumulative incidence of TD in patients prescribed risperidone vs.
39
a 32% incidence in those treated with haloperidol. TD usually occurs after long–term exposure (i.e., 3–6
19,40
months), and is more likely to occur with the following risk factors:
•
•
•
•
•
Older age
Female gender
Diabetes
Higher dose and duration of drug
Patients with early-appearing EPS (especially Parkinsonism)
Acute EPS (such as dystonia) can be managed with anticholinergic agents (e.g. diphenhydramine or
benztropine), though these can cause their own side effects, especially in the elderly. Otherwise, EPS
onset can be reduced by avoiding first–generation agents, and using the lowest dose possible for the
shortest treatment course.
Patients should be screened for EPS at every visit, including asking if they have noticed any symptoms,
and by observing the patient while sitting still, focusing on the face, arms, and legs. The Abnormal
41
Involuntary Movement Scale (AIMS) is a widely accepted assessment of signs of TD. The AIMS should
be administered before initiating antipsychotic treatment and at least semi–annually thereafter. If possible,
show patients and caregivers videos of motor symptoms, so they know what to look for between clinic
visits.
BOTTOM LINE: Parkinsonian symptoms and potentially irreversible tardive dyskinesia occur more
commonly with first–generation APMs, but can also occur with second–generation drugs; the
risks increase with higher dose and longer duration. Patients should be screened for EPS at every
assessment.
Neuroleptic malignant syndrome (NMS):
NMS is an acute and potentially fatal syndrome characterized by fever, rigidity, dysautonomia, and mental
status changes. It is more common with use of first–generation agents, but can occur with any APM. The
estimated prevalence is between 0.02% and 1.4% of elderly patients taking neuroleptics, with males twice
42
as likely as females to develop NMS. Symptoms typically develop within the first 2 weeks of taking the
medication, after rapid dose increases, after switching agents, or after intravenous administration; the risk
43
increases with dose.
10 | Preventing overuse of antipsychotic drugs in nursing home care
In a large case series, most patients developed mental status changes first, followed by rigidity,
44
hyperthermia, and then autonomic dysfunction. Treatment consists of stopping the drug, and
administering supportive treatment in a hospital, including anti-pyretics and fluids. The use of the muscle
relaxant dantrolene and the dopamine agonist bromocriptine have been discussed in the literature, but
42
their efficacy in NMS is not supported by strong evidence. Most cases resolve with supportive care
within 1–2 weeks. Resumption of APMs should be avoided, but if required, should be initiated after two
weeks without NMS symptoms with a low-potency agent at a lowdose, with careful monitoring for
45
symptom recurrence.
Bottom line: NMS is a rare but potentially fatal complication associated with APMs, particularly
first–generation agents. Symptoms typically include mental status changes, rigidity,
hyperthermia, and autonomic dysfunction. Immediately stop the antipsychotic medication and
administer supportive care in an acute care setting.
Strategies for managing behavioral and
psychological symptoms of dementia (BPSD)
The term BPSD describes a wide variety of behavioral problems in older patients, whether or not they
actually have been diagnosed with dementia, although BPSD are four times more common in patients
5
with dementia than older adults without dementia. The prevalence of BPSD is greater in nursing homes
2
than in community settings. The management strategies discussed in this document may be effective
whether or not dementia is present.
BPSD overview
BPSD can range from the merely annoying to those that endanger the patient and/or others. Apathy,
depression, and aggression are the most common features, followed (in descending order) by sleep
1,46,47
disturbance, anxiety, delusions, and hallucinations.
The symptoms with the greatest potential for
1,5
harm are aggression, psychosis, and mood disorders. (Note: the term “agitation,” while occasionally
used to describe some of these symptoms, is non–specific and is rarely helpful in creating a treatment
plan.) This entire set of symptoms is often used as a single primary outcome measure in clinical trials. As
5
a result, the efficacy of therapies for specific symptoms can be difficult to determine.
1,4,48,49
Some BPSD symptoms fluctuate over the course of dementia, while others are more persistent.
A
study of patients with mild Alzheimer disease found that wandering and purposeless/inappropriate
activities persisted or increased in severity over 2 years in about 85% of patients who had these
47
symptoms at baseline, while paranoid ideation persisted in approximately 66% of patients.
Hallucinations and depressive symptoms were the least persistent symptoms: less than half of the
patients with depressive symptoms still had the symptoms one year later. Depressive symptoms often
occur in the early stages of dementia. As dementia progresses, other behavioral and psychological
symptoms may predominate.
Preventing overuse of antipsychotic drugs in nursing home care | 11
Acute vs. non-acute BPSD
Management of BPSD should be based on the characteristics and severity of the symptoms. Therefore, it
is helpful to differentiate between two broad classes of BPSD: acute and non-acute. People with acute
BPSD are in severe distress, pose an imminent danger to themselves or others, or have severely
disruptive or dangerous behaviors. People with non-acute BPSD do not have symptoms that rise to this
level of an emergency situation, though their symptoms may be inconvenient, may disrupt their
functioning, or otherwise may erode quality of life. Non-acute BPSD calls for a different clinical and
behavioral approach than acute BPSD, using a different range of therapeutic options, or options tried in a
different order (Figure 5). APMs may sometimes be needed for management of crises caused by acute
BPSD, but are seldom appropriate for the ongoing management of non-acute BPSD.
Figure 5: Algorithm for managing behavior problems in older patients
Identify the problem behavior to be addressed.
Record intensity, frequency, and consequences.
Rule out reversible causes
RE
A
REASS
~ physical agression
~ violent behavior
~ hallucinations or
delusions that are
distressing to the
patient
~ self-harm
N
Non-acute BPSD (common)
Drug therapy rarely required
~ Focus on non-drug interventions.
~ Avoid APMs if possible.
~ SSRIs may have a limited role:
— avoid fluoxetine (Prozac), citalopram
(Celexa), paroxetine (Paxil).
— consider sertraline (Zoloft),
escitalopram (Lexapro).
12 | Preventing overuse of antipsychotic drugs in nursing home care
LARLY
Drug therapy may be
required for:
GU
Acute BPSD (rare)
RE
Y
Are the symptoms:
— severely disruptive?
— dangerous?
— distressing?
S
SS
ES
S
LY
AR
SE
RE
GU
L
Initiate non-drug approaches
When a patient presents with BPSD, the first course of action should be to perform a comprehensive
assessment of the symptom(s), considering the "ABCs":
• Antecedents: What are the triggers for the behavior(s)?
• Behavior: Which behavior, or behaviors, are appropriate targets for intervention?
• Consequences: What are the consequences of the behavior(s) for the patient and others?
If a patient with acute BPSD is in severe distress or poses a danger to themselves or others, both
pharmacologic and non-pharmacologic strategies may have to be employed (see section on
pharmacologic strategies below). For patients with non-acute BPSD, a more measured approach can be
taken, with input solicited from family, caregivers, and nurses. Understanding the antecedents and
specific behaviors a patient may be experiencing may reveal simple and effective interventions. Complex
management strategies and interventions may not be required.
The assessment of a new–onset behavioral symptom in an older patient with cognitive impairment must
start with an assessment of potentially reversible causes of the behavior (Figure 6).
Figure 6: Clinical, psychological, and environmental causes of BPSD are often reversible
CLINICAL
CONDITIONS
Examples:
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~R^]bcX_PcX^]
PSYCHOLOGICAL
Examples:
~P]cXRW^[X]TaVXRbTV
^ghQdch]X]J3Xca^_P]L
b^[XUT]PRX]JETbXRPaTL
~QT]i^SXPiT_X]TbTV
P[_aPi^[P\JGP]PgLSXPiT_P\
JEP[Xd\L[^aPiT_P\J0cXeP]L
R[^]PiT_P\J:[^]^_X]L
ENVIRONMENTAL
~[^]T[X]Tbb
~SXbR^\U^acUa^\QTX]V
X]^]T_^bXcX^]U^ac^^[^]V
~UadbcaPcX^]
DRUGINDUCED
~X]PQX[Xchc^TPbX[h
R^\\d]XRPcT
~SXbad_cTSa^dcX]Tb
~d]UP\X[XPaXchfXcW
bTccX]VP]S_T^_[T
~bT]b^ahST
RXcb
~X]P__a^_aXPcT[XVWcX]V
~]^XbT
Preventing overuse of antipsychotic drugs in nursing home care | 13
Identifying a potentially reversible trigger can be challenging if the patient's cognitive impairment is
severe. Family and caregivers may be able to help by providing insight into the patient’s routine and
normal level of functioning. Of course, treatment of a reversible medical problem will be more effective
than deploying either non–pharmacologic or pharmacologic interventions.
Adverse drug effects are one of the most common reversible conditions in geriatric medicine. Many
medications routinely used by older adults can cause or worsen behavioral and psychological problems.
For example, anticholinergic agents increase the risk of visual hallucinations, agitation, irritability,
delirium, and aggressiveness. Psychotropics, such as benzodiazepines, can impair cognition, be
disinhibiting, and may contribute to falls. Identifying possible drug–related triggers for BPSD presents an
opportunity to effect a cure by stopping the offending drug or lowering the dose. This has led to the
recommendation that “any new symptom in an older patient should be considered a possible drug side
50
effect until proven otherwise.”
Non-pharmacologic management strategies
Non-drug management of BPSD can produce equivalent outcomes, in a much shorter time, and at less
51,52
overall risk and cost, than pharmacologic therapies.
The evidence base supporting the efficacy of
non–pharmacological interventions is broad (see Table 6), although some studies of non-drug
interventions are relatively small, un-controlled, or non-randomized. In part this may reflect the relative
lack of research funding for non-pharmacologic vs. pharmacologic interventions, but, in addition, many of
the methodologies used in drug testing (e.g., blinding and random assignment) are not possible in
studies that test the efficacy of non-drug interventions. Many trials also use combinations of specific
strategies, which can make it difficult to assess the quality of evidence for individual non-pharmacological
interventions.
Effect sizes in studies of non-pharmacologic interventions tend to be modest, although the same is
true for effect sizes generally found in studies of the efficacy of APMs. For example, a meta–analysis
of 13 non-pharmacologic interventions for BPSD by Brodaty et al., found a pooled–estimate effect
52
size of 0.15 (95% CI: 0.04–0.26; p=0.006). This compares with a net effect size of 0.13 from a 2007
meta-analysis of studies comparing atypical APMs to placebo by Yury and Fisher, and an effect size of
53,54
0.18 in a 2006 meta-analysis of APMs in the treatment of BPSD by Schneider et al.
Non-pharmacological interventions can target patients themselves, or those who care for them. Both
types of interventions have been found to be effective in reducing the incidence of BPSD and/or reducing
caregiver burden (see Table 6). A good resource for nursing home staff training on non-pharmacologic
techniques is the OASIS program, developed by Susan Wehry and the Vermont Local Area Network of
Excellence (and being used by the Massachusetts Senior Care Foundation, which seeks to reduce off–
label use of antipsychotics. See www.maseniorcarefoundation.org/OASIS.aspx for more information.)
Interventions that target nursing home residents generally fall into 3 broad categories:
1. Unmet needs interventions assume that BPSD may sometimes represent a form of
communication about an underlying need, such as for stimulation (e.g., repetitive speech or
calling out, for auditory stimulation). Symptoms may also be a response to inadequately treated
pain, or isolation.
2. Learning and behavioral interventions address the possibility that BPSD may be the product of
unintentional reinforcement (e.g., a patient with dementia learns that he or she can get attention
by screaming).
14 | Preventing overuse of antipsychotic drugs in nursing home care
3. Environmental vulnerability and reduced stress–threshold interventions assume a
mismatch between the person’s environment and their abilities to cope with the situation (e.g., a
resident becomes agitated by too much noise).
Behaviors likely to respond to non-pharmacological interventions include: aggression, disruption,
shadowing, depression, and repetitive behaviors. Non-pharmacologic interventions should be matched to
the specific needs and capabilities of the patient, and they can be used concurrently with any medications
55,56,57
that might be employed.
Optimizing the management of the cognitive symptoms of dementia may help reduce the incidence of
BPSD. For example, using adequate anticoagulation may prevent transient ischemic attacks/microstrokes
in cases of vascular dementia, as evidence suggests an association between transient ischemic attacks
58
and cognitive impairment.
Preventing overuse of antipsychotic drugs in nursing home care | 15
Table 4: Evidence supporting non-pharmacological strategies for BPSD
Interventions supported by large, randomized or controlled clinical trials
Staff training/education
programs
• Avoidance of
unnecessary
psychoactive
medications
• Skills training in
managing patients with
dementia
• Activity planning and
environmental redesign
• Enhancing support for
caregivers
Avorn J, et al. A randomized trial of a program to reduce the use of psychoactive
drugs in nursing homes. New England Journal of Medicine 1992;327(3):168–73.
Brodaty H, Arasaratnam C. Meta–analysis of nonpharmacological interventions
for neuropsychiatric symptoms of dementia. Am J Psychiatry. 2012;169:946–
953.
Fossey J, et al. Effect of enhanced psychosocial care on antipsychotic use in
nursing home residents with severe dementia: cluster randomised trial. British
Medical Journal 2006;332(7544):756–61.
Meador K, et al. Predictors of antipsychotic withdrawal or dose reduction in a
randomized controlled trial of provider education. Journal of the American
Geriatrics Society 1997;45(2):207–10.
McCallion P, et al. An evaluation of a family visit education program. J Am
Geriatr Soc. 1999;47:203–214.
Schmidt I, et al. The impact of regular multidisciplinary team interventions on
psychotropic prescribing in Swedish nursing homes. Journal of the American
Geriatrics Society. 1998;46(1):77–82.
Teri L, et al. Training community consultants to help family members improve
dementia care: a randomized controlled trial. Gerontologist. 2005;45:802–811.
Potentially helpful interventions supported by evidence from small, uncontrolled, or case–control
studies
Environmental modifications
• Support normal
sleep/wake cycles
• Structure activities to
reduce boredom
• Reduce unnecessary
stimulation
• Create home-like
environment
Snowden M, et al. Assessment and treatment of nursing home residents with
depression or behavioral symptoms associated with dementia: a review of the
literature. J Am Geriatr Soc. 2003 Sep;51(9):1305–17.
Music therapy
Ueda T, et al. Effects of music therapy on behavioral and psychological
symptoms of dementia: a systematic review and meta–analysis. Ageing
Research Reviews 2013; 12(2): 628–641.
Bright light therapy
Lovell BB, et al. Effect of bright light treatment on agitated behavior in
institutionalized elderly subjects. Psychiatry Res. 1995; 57:7–12.
Aromatherapy
Fung JK, et al. A systematic review of the use of aromatherapy in treatment of
behavioral problems in dementia. Geriatr Gerontolo Int. 2012;12:372–382.
Behavior modification
• Withdrawing attention for
BPSD
• Rewards for prosocial
behaviors
• Behavioral redirection
Provision/optimization of hearing
aids
Heard K, Watson TS. Reducing wandering by persons with dementia using
differential reinforcement. J Appl Behav Anal. 1999;32:381–384.
O'Connor DW, et al. Psychosocial treatments of behavior symptoms in
dementia: a systematic review of reports meeting quality standards. Int
Psychogeriatr. 2009 Apr:21(2):225–40.
Teri L, et al. Exercise plus behavioral management in patients with Alzheimer
disease: a randomized controlled trial. JAMA. 2003;290:2015–2022.
Palmer CV, et al. Reduction in caregiver–identified problem behaviors in patients
with Alzheimer disease post–hearing–aid fitting. J Speech Lang Hear Res.
1999;42:312–328.
16 | Preventing overuse of antipsychotic drugs in nursing home care
Management of physiological factors
A number of common, though often-overlooked, physiological factors may play a primary or contributing
role in BPSD, and these should be explored whenever possible before pharmacological interventions are
59
attempted:
•
•
•
•
•
•
•
•
•
•
Urinary tract infections
Pain
Constipation
Nocturia
Hunger or thirst
Dehydration
Hyponatremia
Hyper– or Hypothyroidism
Hypercalcemia
B12 or folic acid deficiency
Dietary and eating-related issues should be carefully assessed. An inability to chew properly or swallow
easily can increase agitation, hence a patient’s dental integrity, use of dentures, and swallowing ability
should be considered. If a patient’s appetite or cycle of hunger/satiety is not synchronized with the timing
of meals provided by an institution, consider options to individualize the availability of food and/or food
choice. Difficulty preparing or eating meals, confusion about mealtimes, apathy, agitation, and paranoid
ideation about food and fluids may all contribute to weight loss, which is common in patients with
dementia. Avoidance of alcohol and caffeine can promote good sleep hygiene and may help stabilize
60
mood.
Environmental strategies
Behavioral and psychological symptoms are often predictable responses to a wide range of factors that
make life uncomfortable, frightening, worrisome, irritating, or boring for people with dementia. Paying
close attention to such environmental factors, and eliminating or correcting them, should be the first
3
priority for caregivers. This requires patience, diligence, and a willingness to see the world through the
eyes and other senses of the person whose behaviors are difficult. Because sensory deficits are common
in older adults, and because vision and hearing deficits, in particular, can increase fearfulness, anxiety,
and agitation, any patient displaying non-acute BPSD should be assessed for these deficits, and, if
present, they should be corrected promptly with glasses, improved lighting, magnifying devices, hearing
aids, or other techniques.
Other environmental factors that can worsen BPSD include: temperature (too hot or too cold), noise (in or
outside the room or dwelling unit), lighting (too much, too little, or quality), unfamiliarity (new people, new
furniture, new surroundings), disrupted routines, needing assistance but not knowing how to ask, being
uncomfortable from sitting or lying in one position for too long, or inability to communicate easily because
of language difficulties.
In one key intervention study, the potential effectiveness of non-pharmacologic interventions for nursing
61
home residents was demonstrated in a 2012 randomized, placebo–controlled clinical trial. Agitated
nursing home residents with advanced dementia from 9 nursing homes in 5 locations in Maryland were
randomized into an intervention group (n=89) or a placebo group (n=36). A set of individualized non–
pharmacologic interventions, Treatment Routes for Exploring Agitation (TREA), was used with the
intervention group for 2 weeks, and observations of agitation and affect were recorded. Relative to the
Preventing overuse of antipsychotic drugs in nursing home care | 17
control group, patients receiving the TREA interventions (e.g., social contact, reading, music, physical
activity) showed significant declines in physical agitation (change in agitation score from 6.02 at baseline
to 1.12 in treatment group, versus 4.74 at baseline to 5.08 in placebo group, p<0.001), and verbal
agitation (change from 2.74 at baseline to 0.96 in treatment group, versus 2.41 to 2.84 in placebo group,
p=0.004) and modest increases in pleasure (p<0.001) and interest (p<0.05). The authors conclude that
putting these kinds of non–pharmacologic interventions into practice is “sorely needed” although they
note that this may require structural changes such as dedicating staff time to observing each agitated
resident, determining unmet needs, obtaining appropriate intervention materials, conducting the
individualized interventions, and evaluating results to determine efficacy.
Management of psychological factors
Patients with BPSD may benefit from psychological interventions such as individual, family, or group
psychotherapy, depending on their level of cognitive functioning. Such interventions may help patients
understand or express their feelings, correct or address cognitive errors or maladaptive thinking patterns,
and develop practical steps for changing behaviors or responses to different situations.
BOTTOM LINE: First-line approaches for the management of non-acute BPSD should focus on
identifying any reversible environmental, psychological, or physiological factors that might be
causing or contributing to symptoms. Pursue non-drug strategies before pharmacologic
treatments are initiated.
Pharmacologic management of BPSD: General principles
The evidence base for drug treatment of BPSD is generally modest, and no medications are FDA–
60,62,63
approved for these indications.
Medication use in this setting has evolved over the years without
guidance from large, randomized controlled studies, and in anecdotal ways involving off–label uses of
many classes of medications including antipsychotics, anticonvulsants, antidepressants, anxiolytics,
cholinesterase inhibitors, and NMDA modulators. APMs, while of potential utility in patients with acute
BPSD, should be avoided in patients with non-acute BPSD until other reasonable medications (see
below) have been tried, because of the minimal efficacy of these agents for the symptoms typical of non–
acute BPSD and their relatively high risk of side effects, including death.
If BPSD are not disruptive, dangerous, or distressing to the patient or caregiver (i.e., the patient has non–
acute BPSD) then the medications reviewed in this section are usually not warranted. Reserve drug
intervention for the situations listed below, using it simultaneously with behavioral treatments and only if
potentially reversible or remediable causes have been ruled out:
• physically aggressive or violent behavior that poses a danger to the patient or others
• hallucinations or delusions that are distressing to the patient, lead to dangerous behavior, or
significantly impair normal functioning
If a medication must be used, identify one or more specific target symptoms to address, to provide a
benchmark to assess medication effectiveness on re-evaluation.
Pharmacologic interventions are generally not warranted to address behaviors such as:
• wandering
• unsociability
18 | Preventing overuse of antipsychotic drugs in nursing home care
•
•
•
•
•
•
•
•
•
•
•
poor self–care
restlessness
nervousness
fidgeting
hoarding
sexual disinhibition
sundowning (increased confusion and restlessness in early evening)
shadowing
impaired memory
uncooperativeness without aggressive behavior
inattention or indifference to surroundings
Given that many older adults are prescribed multiple medications and the inherent difficulty of determining
efficacy if multiple medications are used to address a given condition, any therapeutic trial of a medication
for BPSD should be completed with a single medication. If the single medication works poorly in
addressing the target symptom(s) after an adequate trial, the medication should be discontinued and an
alternative medication should be initiated. Assess suboptimal responses to determine whether the partial
effect was due to non-specific causes or other changes in clinical status; do not automatically assume
that the medication should be continued and/or another medication added for additional effect. Before any
medication is administered, inform patients (as feasible), family members, and/or caregivers of the
64,65
possible risks of pharmacotherapy.
Psychotropic medications traditionally used for BPSD may cause a variety of serious adverse effects
including falls, fractures, delirium, and over-sedation. Elderly patients are particularly vulnerable to injury
from psychotropic medications because of slower metabolic clearance, increased CNS receptor
sensitivity, and reduced physiologic reserve. Plan on lower starting and target doses in older people to
reduce the likelihood of these adverse events. A reduced initial dose for elderly patients is endorsed by
the FDA, which mandates that drug manufacturers state a recommended geriatric dose for all
medications that have been evaluated in a significant number of patients older than 65 years.
Unfortunately, drug trials often under–represent older patients — especially those who are over 80 or frail
— so the evidence base for such recommendations is frequently inadequate.
Initiate any medication for non-acute BPSD at the lowest possible dose, with slow titration upwards if
needed to the lowest effective dose, and monitor patients closely for both adverse effects and drug–drug
interactions. If a medication is successful in addressing a specific target symptom, reassess the patient
after 3–6 months, since BPSD symptoms are inherently unstable and subject to remission on their own.
Rarely should psychoactive medication be continued indefinitely; attempt dose reduction and withdrawal
60
regularly.
Antipsychotic medications
No APMs are approved in the U.S. for BPSD, despite at least 17 large randomized trials, most of them
65
unpublished, that sought evidence of effectiveness for this indication. Meta–analysis of these studies
has indicated limited efficacy and significant potential for harm from the side effects or adverse effects
66
noted earlier. (The evidence of these risks has primarily emerged from studies conducted in patients
with non–acute BPSD). Thus, although APMs may help control the acute symptoms of BPSD in certain
patients, they must always be used carefully and with informed consent. (In Massachusetts, this requires
Preventing overuse of antipsychotic drugs in nursing home care | 19
consent, either by a competent patient, an authorized Health Care Agent, or a medical guardian with
appropriate authority.)
Table 5: Starting and maximum doses of antipsychotics in elderly with dementia syndromes
Drug*
Starting dose
Maximum dose
aripiprazole
2 – 5 mg
15 mg
olanzapine
1.25 – 5 mg
10 mg
quetiapine
12.5 – 25 mg
300 mg
risperidone
0.25 – 0.5 mg
2 mg
paliperidone
1.5 mg
3 – 6 mg
*Due to the extremely limited data for dosing of the second–generation APMs lurasidone, iloperidone, and
asenapine in the nursing home population, they are not included in this table and should generally not be
used in these patients. See Appendix 3 for Massachusetts–specific guidance on dosing of APMs.
First-generation antipsychotics
Reviews and meta-analyses of clinical trials involving first-generation APMs (e.g., haloperidol, thioridazine
and chlorpromazine) in the management of BPSD found modest improvement in aggression over 3–8
weeks of treatment compared to placebo, probably because of the strong sedating effects of these
1,57,64,67
drugs.
There is no consistent evidence that any first–generation APM is more effective than
another, and there are insufficient data to draw conclusions about the efficacy of first–generation vs.
2,67
second–generation APMs for BPSD.
Not surprisingly, in clinical trials the discontinuation rates due to adverse effects were significantly higher
with first–generation APMs than with placebo, and the troublesome adverse effects associated with first–
generation APMs (e.g., extrapyramidal side effects, orthostatic hypotension) limited their usefulness.
30,67
Stroke risk also may be higher with first–generation APMs compared to second–generation APMs.
Importantly, recent studies show that haloperidol use is associated with a 50–100% higher risk of death
3,4,21
compared to other APMs.
Chlorpromazine is no longer recommended for intramuscular treatment in
5
emergencies with aggressive psychotic patients due to the risk of severe hypotension.
Second-generation antipsychotic medications
The evidence base for the effectiveness of second-generation APMs for BPSD is generally weak.
Evidence of efficacy and safety from a meta-analyses of published and unpublished trials, as well as
some specific studies, generally favors aripiprazole and risperidone, whereas olanzapine and quetiapine
68,69,65
were found to be less effective.
In England, risperidone is approved for the management of BPSD.
None of the others are approved there and, as noted, none are approved in the U.S. The CATIE–AD
study, which compared the effects of olanzapine, risperidone, or quetiapine to placebo, found that
caregivers of treated patients rated their burden (rated by the “Burden Interview” and “NPI Caregiver
Distress” scales) as significantly lower than caregivers of patients on placebo. This may be a significant
factor in the nursing home setting, although it should be noted that heavily sedated patients are
6
undoubtedly less burdensome even though the sedation may not be in the patient’s best interests.
20 | Preventing overuse of antipsychotic drugs in nursing home care
Risperidone
The evidence for the efficacy of risperidone in patients with BPSD rests on studies showing small
changes on symptom rating scales that were statistically significant. The clinical value of such results,
65
however, is debatable. In patients who responded to treatment, improvement tended to occur within the
first 2–4 weeks. Increased attention to the patient, non–pharmacologic interventions, and symptom
65
fluctuation may have contributed to the improvements seen.
A 2006 Cochrane review found significant improvement in aggression and symptoms of psychosis in
68
Alzheimer’s disease patients treated with risperidone (2 mg) compared with placebo. Risperidone
treated patients, however, had a significantly higher incidence of serious adverse cerebrovascular events
(including stroke), extra–pyramidal side effects, and other important adverse outcomes, which was
68
reflected in the significant drop–out rate among risperidone–treated patients. One review found that
risperidone caused more strokes than olanzapine, but a more recent study found no difference, and
another review found lower association with all–cause risk of death with risperidone compared to other
7,8,9
APMs.
In the CATIE–AD Effectiveness Trial, patients on risperidone showed greater improvement relative to
46
patients on placebo on scores of hostile suspiciousness and psychosis. There were no significant
differences, in this analysis, between risperidone and placebo on cognition, functioning, care needs, or
quality of life. However, in a separate analysis of the CATIE–AD data focusing on cognitive functioning in
patients receiving olanzapine, quetiapine, risperidone or placebo, investigators found significantly greater
cognitive decline in patients receiving the APMs compared to placebo, with no significant differences in
48
the rates of cognitive change among antipsychotic agents.
A double–blind comparison of olanzapine versus risperidone in the acute treatment of dementia–related
behavioral disturbances in extended care facilities showed that both drugs produced significant
reductions in Clinical Global Impression score (CGI) and Neuropsychiatric Inventory (NPI) scores
70
(p<0.0001), and there was no significant difference between drugs. The mean daily doses were:
olanzapine 6.65 mg/day, and risperidone 1.47 mg/day. The positive drug effect was not accompanied by
decreased mobility, and there was improvement on a quality-of-life measure. The chief adverse events
were drowsiness and falls. At baseline, 42% (16/38) of subjects in both groups had extrapyramidal
70
symptoms that increased slightly, but not significantly, by the end of the study.
Aripiprazole
In a meta-analysis, aripiprazole showed small, but statistically significant positive effects on symptom
65
rating scales in patients with dementia. In one study in a population of patients with AD, aripiprazole (10
69
mg/day) significantly reduced psychosis symptoms compared to placebo.
Olanzapine
As noted earlier, in a meta-analysis, no efficacy was observed for olanzapine using standard rating scales
65
of BPSD. A 2006 Cochrane review, however, found a statistically significant improvement in aggression
68
with olanzapine treatment compared to placebo in patients with dementia. Olanzapine-treated patients,
however, had a significantly higher incidence of serious adverse cerebrovascular events (including
68
stroke), extra-pyramidal side effects and other important adverse outcomes.
In the CATIE–AD Effectiveness Trial, patients randomized to receive olanzapine demonstrated no
difference from placebo on the primary outcome measure of time to discontinuation of treatment for any
reason. However, olanzapine showed greater improvement relative to placebo on the Neuropsychiatric
Preventing overuse of antipsychotic drugs in nursing home care | 21
46
Inventory total score, and the Brief Psychiatric Rating Scale (BPRS) “hostile/suspiciousness” factor.
There was worsening on the BPRS “withdrawn/depression” factor and on functioning in activities of daily
living. There were no significant differences between olanzapine and placebo on cognition, care needs, or
46
quality of life.
Sub–population considerations with APMs
Patients with severe liver disease may be considered for the use of paliperidone, which is the active
metabolite of risperidone and is primarily renally excreted. The starting dose would be 1.5 mg and typical
dose 3-6 mg/day with a maximum dose of 3 mg/day for patients with severe renal impairment.
Patients with Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) have an
increased risk of extrapyramidal side effects and neuroleptic sensitivity reactions, hence APMs, and
67
particularly risperidone, should be avoided in these patients. Lewy body dementia patients may be
sensitive to adverse effects from non–APM medications as well: uncontrolled reports suggest gabapentin
71
is poorly tolerated. A case report indicates efficacy of low–dose clozapine for psychosis in DLB, and
72
open trials indicate safety for treatment of psychosis in DLB and PDD with quetiapine. Randomized
controlled trials indicate that quetiapine is less effective than clozapine against psychotic symptoms in
72
both conditions, although comparatively safe. This may be because of the doses used for these agents
in the studies. Cholinesterase inhibitors, especially rivastigmine, are a therapeutic alternative for treating
72
both psychotic and cognitive symptoms in both conditions.
BOTTOM LINE: Antipsychotic medications may sometimes be required to control acute behavioral
symptoms in patients with dementia, including aggression and symptoms resembling psychosis.
The best evidence of efficacy is for aripiprazole and risperidone, depending on the symptom
being targeted. None are FDA–approved for this indication, and the benefits of treating the
73
symptom should outweigh the well–established risks, including mortality. In Massachusetts, use
of an APM requires consent, either by a competent patient, an authorized Health Care Agent, or a
medical guardian with appropriate authority.
Other pharmacological treatment options
Antidepressants
Up to 40% of patients with dementia have significant depressive symptoms at some stage of their illness,
and some of the symptoms related to depression (e.g., irritability, sleep disturbances) overlap with those
60
of BPSD. Alleviating depression in patients with dementia has been reported to lessen behavior
74
disturbances, improve activities of daily living, and reduce caregiver distress. Even in dementia patients
63
without depression, a growing evidence base finds antidepressants helpful for BPSD. Antidepressants,
therefore, may be a reasonable choice for treating symptoms of non–acute BPSD. Among the classes of
antidepressants, the SSRIs have been the most widely studied. Compared to other medication
51
treatments, they have relatively favorable risk and side effect profiles.
A 2011 Cochrane review of antidepressants for BPSD found modest evidence for efficacy and tolerability
75
with certain agents. The SSRIs sertraline and citalopram reduced symptoms of agitation when
compared to placebo in two studies, and sertraline, citalopram, and trazodone appeared to be tolerated
75
reasonably well when compared to placebo or antipsychotics. In the same year, another review
22 | Preventing overuse of antipsychotic drugs in nursing home care
assessed 19 trials of antidepressants (including eleven trials with SSRIs and three trials with trazodone)
for the treatment of BPSD. Effectiveness was demonstrated in 11 of the 19 trials and these agents were
63
well-tolerated in 14 of the trials. A 12-week randomized controlled trial in non–depressed patients with
dementia showed that the SSRI citalopram was as effective as the antipsychotic risperidone in
76
decreasing psychosis and agitation, with a better side effect profile. In addition, a 2014 study found that
citalopram (titrated to 30 mg/d) plus a psychosocial intervention was more effective in controlling
77
symptoms of agitation in patients with Alzheimer disease than the psychosocial intervention alone.
Note, however, that citalopram has a 2011 package insert warning about QTc prolongation; the maximum
78
dose was reduced to 40 mg (20 mg in the elderly). Its S–isomer, escitalopram did not produce this
abnormality, and would therefore be the preferred form of this drug.
A Cochrane review of 2 of the small trials of trazodone found that it was as effective as the APM
79
haloperidol in reducing agitation, with (surprisingly) no difference in adverse event rates. Another
80
randomized controlled trial compared fluvoxamine and risperidone (n=60). The medications were
equally effective but the side effects were less severe with the SSRI, and there was one sudden death on
risperidone, due probably to a myocardial infarction.
It may be prudent to consider one or two antidepressant trials (e.g., an SSRI or trazodone) for non-acute
BPSD, even in the absence of overt symptoms of depression, before proceeding to other medication
options.
In using these drugs, it is important to be alert to the possibility of SSRI-induced Syndrome of
Inappropriate Antidiuretic Hormone Secretion (SIADH) leading to hyponatremia, which is greater in
81,82
elderly patients and in particular those taking a thiazide diuretic.
SSRIs can also increase the risk of
83,84,85
GI bleeding in patients with other risk factors.
Finally, SSRIs (along with other classes of
86
antidepressants) can significantly raise the risk of falling and resulting risk of fracture.
Cholinesterase inhibitors and memantine
Although some studies of cholinesterase inhibitors and memantine have found small, statistically
significant beneficial effects on BPSD as measured by the NPI and other scales, the clinical significance
of these changes is unclear. A 2008 meta-analysis examined the efficacy of cholinesterase inhibitors in
treating BPSD in patients with AD and found a statistically significant improvement on BPSD, but with a
very small effect size: –1.38 points on the NPI overall (on a scale ranging from 0 to 120); –1.92 points in
87
mild AD; –0.06 points in patients with severe AD. A 2007 meta-analysis of cholinesterase inhibitors in
patients with mild to moderate vascular dementia found no behavioral or functional benefits except with
88
10 mg daily of donepezil. A 2006 Cochrane systematic review found that treatment of mild, moderate, or
severe Alzheimer’s disease with a cholinesterase inhibitor for 6 months produced a small, statistically
significant improvement in the NPI (–2.44 points), but, again, the clinical relevance of these results is
89
questionable. Rivastigmine may modestly improve behavioral and psychological symptoms (in particular
90
visual hallucinations) in patients with Dementia with Lewy Bodies.
The situation for memantine is similar. A 2008 pooled analysis of 6 randomized controlled trials of
patients with moderate to severe AD found small but statistically significant beneficial effects of
memantine on the NPI in treatment and prevention of symptoms such as delusions, hallucinations,
91
disinhibition, irritability, agitation, and aggression. A retrospective pooled analysis of randomized
controlled trials found memantine use was associated with a higher percentage of patients having some
improvement in agitation or aggression, compared to placebo (56% versus 44% improved at 12 weeks in
92
treatment versus placebo group, respectively).
Preventing overuse of antipsychotic drugs in nursing home care | 23
If the clinician plans to treat the patient’s cognitive symptoms with a cholinesterase inhibitor or memantine
and the patient also has significant BPSD, it would be prudent to allow some time to assess whether the
agent selected can benefit both problems. If another medication is started at the same time to target the
non–acute BPSD symptoms, it will be difficult to know which medication was responsible for any
subsequent benefits or side effects. Cognitive enhancers would not be the first-line choice for BPSD
management except as above.
Gababentin
There have been 11 case reports of individual patients, and an uncontrolled case series of 7 patients
71,93
employing the anticonvulsant gabapentin across a wide range of doses in BPSD.
These uncontrolled
data indicate potential but clinical studies will be needed to determine whether this agent is a valid
therapeutic option for patients with BPSD.
Carbamazepine
The anticonvulsant carbamazepine (Carbatrol, Equetro, Tegretol, others) may be considered at a low
dose and in a time–limited trial for dementia–related agitation/aggression if other interventions have been
57,94
exhausted, with close monitoring for response, adverse effects, and drug interactions.
One of two
95
recent studies showed positive results.
Prazosin
Prazosin (Minipress, Vasoflex, others) is an alpha–1 receptor antagonist used primarily in the treatment of
benign prostatic hypertrophy and (now, rarely) hypertension. The drug also antagonizes norepinephrine
release in the central nervous system, which may be why it can reduce agitation and aggression in some
patients with dementia. A small (n=22) placebo–controlled 8-week study of prazosin found that patients in
the treatment group had significantly more improvement on two agitation rating scales, with no
96
differences between the groups in blood pressure or adverse events (at a mean dose of 6 mg).
Improvement in the Neuropsychiatric Inventory was large: –19 points versus –2 on placebo. This study
needs replication with larger samples of patients, but prazosin may eventually represent a promising
option for non-acute BPSD. In another neuropsychiatric condition, post–traumatic stress disorder,
prazosin has recently emerged as an unexpected but potentially valuable treatment with larger effect
97,98
sizes than any other drug studied.
Medications for disruptive sexual disinhibition
Patients with aggressive sexual disinhibition can be difficult to manage in the nursing home setting. As
with other types of BPSD, the first step is to rule out medical and medication causes. If none are found,
drug treatment options include SSRI antidepressants as first choice agents; anti–androgens, LNRH
agonists, and estrogen are possible alternatives, since these agents have some support from case
99,100
studies and case reviews.
24 | Preventing overuse of antipsychotic drugs in nursing home care
Medications with insufficient evidence to support use in patients with
BPSD
Melatonin
A number of studies suggest a relationship between decline of melatonin function and the symptoms of
dementia. A Cochrane review of three randomized controlled trials found non–significant effects from the
pooled estimates of changes in the scores on tests of cognition, although individual study estimates for
treatment effect demonstrated a significant improvement for melatonin (2.5 mg/day) compared with
101
placebo in behavioral and affective symptoms. The authors conclude that there is insufficient evidence
to support the effectiveness of melatonin in managing the cognitive and non–cognitive aspects of
dementia.
Quetiapine (Seroquel and others)
In the CATIE–AD Effectiveness Trial, patients randomized to receive quetiapine did not show significant
improvements over placebo on most symptom outcome measures (Neuropsychiatric Inventory total
score, the Clinical Global Impression of Changes, the Brief Psychiatric Rating Scale [BPRS] hostile
46
suspiciousness factor, and the BPRS psychosis factor). This limited impact on symptoms may have
been due to the low dose prescribed (final dose mean 57 mg). Sedation, however, occurred in this group
46
at rates comparable to the other drugs. In another study, quetiapine significantly improved agitation at a
dose of 200 mg/day compared to placebo, but did not do so at lower doses. The practical bottom line with
quetiapin is that the clinically effective dose for many patients with BPSD creates intolerable sedation
102
and/or orthostatic hypotension. In 2011 the FDA required a new package insert warning for quetiapine
regarding QTc prolongation, stipulating that it should not be combined with 12 listed drugs with known
103
QTc problems (amiodarone, ciprofloxacin etc.). A list of drugs that can increase the QT interval can be
found on–line at: www.uspharmacist.com/content/d/health%20systems/c/26648/
The lack of adequate efficacy and the potential adverse effects of quetiapine make it undesirable for the
104
treatment of most patients with acute or non–acute BPSD. It is possible, however, that it could have a
role when a medication is required that has low affinity for the dopamine receptor, as in patients with
Parkinson’s disease. Research is needed to test that hypothesis.
Valproic acid (Valproate)
A 2004 Cochrane review concluded that valproic acid cannot be recommended for management of
105
agitation in dementia. A more recent trial of sodium valproate for BPSD also found it to be no more
106
effective than placebo. Valproic acid also failed to attenuate agitation and clinical progression of
107
Alzheimer’s disease in a 2011 study and was associated with significant toxic effects. Evidence
108
suggests that valproic acid can increase brain atrophy in Alzheimer’s disease patients.
Avoid benzodiazepines and similar drugs (e.g., zolpidem) in managing
BPSD
Avoid the long–term use of benzodiazepines and similar-acting medications, (e.g., zolpidem) in the
treatment of both acute and non-acute BPSD, as the risks of these agents may outweigh their benefits in
109
57,109,110
patients over the age of 60. They may cause or exacerbate a range of problems including:
Preventing overuse of antipsychotic drugs in nursing home care | 25
• cognitive impairment
• rebound insomnia (i.e., if taken as needed, patients sleep worse on the nights that they omit it
111
than if they had taken placebo)
• falls
• accidents
• paradoxical agitation
112
• physical dependence with regular use
• aspiration and its consequences
113
• death
• statements or swearing that do not pose a danger to the patient or others
BOTTOM LINE: Antidepressants such as escitalopram or sertraline appear to provide the most
favorable risk–benefit profile for addressing non-acute BPSD, with or without depression. One or
two trials of these medications should be the first-line approach after all non-drug strategies have
been tried. If the patient is going to receive a trial of a cholinesterase inhibitor or memantine for
cognitive impairment, whenever possible wait to see if this will be helpful for the BPSD before
starting another medication.
Avoid benzodiazepines for patients with new-onset, non-acute BPSD because the risk of falls and
cognitive impairment outweighs any demonstrated benefits. Except in unusual circumstances,
only one psychotropic agent at a time should be started to manage BPSD, to clarify efficacy and
side effects.
Antipsychotic medications in the management of
acute BPSD
Patients with a dementing illness may exhibit potentially dangerous behaviors. This sometimes occurs
after hours, or when there is limited access to medical information and history. Safe and effective
management requires adequate assessment of the possible causes of the behavior, consideration of
reversible causes, implementation of all practical non–pharmacological strategies, and resorting to
pharmacological treatment and/or physical restraint only when necessary and for the shortest time
possible. Medication use should be preceded by identifying the target symptom(s) to be addressed, and
114
obtaining consent whenever possible.
Acute symptoms that may require management with medications include physical aggression, violent
behavior, hallucinations or delusions that are distressing to the patient, or self–harm. When these are
present, plan non-pharmacologic and pharmacologic interventions simultaneously. The immediate goal is
to create a safe environment for the patient and others, and to facilitate assessment and treatment of the
acute situation, followed by implementation of a longer-term management plan once an acute crisis has
passed.
Patients in the midst of acute BPSD may benefit from a range of environmental modifications and nonpharmacological strategies to maximize their safety and well–being. When drugs are necessary, limited
evidence supports a range of pharmacological options, which include both traditional and atypical APMs.
26 | Preventing overuse of antipsychotic drugs in nursing home care
Physical restraints should be considered only after appropriate assessment and trial of alternative
treatments or if the risk of restraint is less than the risk of the behavior.
Is it delirium?
A common differential diagnostic issue when evaluating acute BPSD is distinguishing symptoms of
delirium from those of BPSD. Delirium is a disturbance of attention or awareness accompanied by a
115
change in baseline cognition that cannot be otherwise accounted for. Delirious patients have markedly
reduced attention and are easily distracted; the disturbance in awareness is manifested by a reduced
orientation to the environment or, at times, even to oneself. Importantly, delirium develops over a short
period of time, usually hours or a few days, and its severity tends to fluctuate during the course of the
115
day. By contrast, the deficits in dementia tend to be stable or progressive, and level of consciousness
is unaffected. Because memory impairment occurs in both delirium and dementia, a new diagnosis of
dementia cannot be made when delirium is present. Urgent diagnosis and treatment of the cause(s) of
the delirium is the highest priority: a medication review should focus on any drugs recently started or
increased.
Addressing any underlying reversible causes of delirium is key, and it is imperative not to use sedating
medications that may “cover up” the problem instead of dealing with its actual cause. Perhaps as a result,
pharmacological management of BPSD in patients with delirium has not been extensively studied.
Risperidone and other second–generation APMs may be effective but they are not clearly better or safer
116
than haloperidol, which can be given IM or IV. A recent review underscored the inconsistent findings of
the few placebo-controlled studies undertaken. Quetiapine produced a more rapid resolution of delirium
117
than placebo in two studies, whereas haloperidol and ziprasidone did not. However, these differences
were likely to be due to differences in subject characteristics. For the reasons previously reviewed,
benzodiazepines should be avoided in the management of delirium.
Non-pharmacologic management
All of the non-pharmacologic strategies reviewed previously for the management of non-acute BPSD
should be brought to bear in managing acute BPSD, with the understanding that there may be practical
limitations (e.g., lack of available staff) to implementing all of them. These strategies include:
•
•
•
•
•
identifying any potentially reversible causes of acute behaviors (see Figure 6)
moving the patient to a safe area or facility (which may be an inpatient facility)
preventing access to means of harm (e.g., stairwells, sharp objects)
involving family members (familiar faces) in care and consultation
use of restraints only as a last resort and with great caution
Non-pharmacological interventions should be continued simultaneously with any pharmacological therapy
57
for acute BPSD. The target symptoms or behavior should be identified prospectively, and methodically
documented both before and following medication initiation for at least two weeks, with regular review for
118
response, adverse effects and drug interactions.
Preventing overuse of antipsychotic drugs in nursing home care | 27
Pharmacologic management
General guidance
Begin with a single dose of a medication within the recommended dose ranges. Consider oral
administration first, although some situations may require IM administration (e.g., patient refusal of
medication or inability to swallow). If symptoms are not controlled after the first dose, it may be repeated
or increased. If one drug is ineffective, it should be discontinued before starting another drug.
Monitor for drug–drug interactions and adverse events (e.g., cardiac effects). Reassess the patient after
stabilization and consider whether the medication needs to be continued. Generally a trial of less than 7
days is recommended in acute BPSD. Continue treatment for up to 4 months if it is deemed effective and
is well-tolerated, though the potential risks of treatment should be reiterated to both the patient and
caregivers. In general, psychoactive medications should not be continued indefinitely, and attempts at
60
drug withdrawal should be made regularly. Patients must be closely monitored for symptom relapse
62
following medication discontinuation. A 2012 randomized controlled trial in patients with AD who had
responded to the antipsychotic risperidone showed an increased risk of relapse when the medication was
62
discontinued.
Once a patient has been stabilized and the target symptoms of BPSD addressed, manage according to
the guidelines presented earlier for non-acute BPSD.
Antipsychotic medications
See the full discussion of APM use in non-acute BPSD for analysis of their benefits and risks when used
both short– and long–term. A few additional comments on their specific uses in the acute situation are
presented below.
Aripiprazole
Ten or 15 mg of IM aripiprazole administered in divided doses was found to be safe and well–tolerated for
treatment of problem behaviors associated with Alzheimer’s, vascular, or mixed dementia in long–term
119
care. A higher incidence of adverse events occurred with IM aripiprazole (50% to 60%) than IM placebo
(32.0%), but over 90% of events were mild or moderate in severity. Aripiprazole at the doses studied had
120,26
the least QTc prolongation of any of the second–generation agents.
Olanzapine
A meta-analysis of studies of dementia patients with acute agitation in an emergency department setting
showed that IM olanzapine (2.5 mg) (1–3 injections/24 h) significantly reduced agitation compared with
121
placebo with the same amount of sedation as lorazepam (1.0 mg). As previously noted, in a double–
blind randomized trial comparing the efficacy and safety of IM olanzapine (dosages of 2.5 and 5.0 mg)
with lorazepam (1.0 mg) or placebo in patients with agitation associated with Alzheimer's disease and
vascular dementia, both olanzapine and lorazepam showed superiority after 2 hours over placebo in
112
terms of reduced agitation. Olanzapine is therefore a reasonable second line IM medication (after
aripiprazole) for acute BPSD when immediate medication use is required.
28 | Preventing overuse of antipsychotic drugs in nursing home care
Initiating an antipsychotic medication
Initiate APMs at the lowest possible dose, and gradually titrate upwards according to tolerability and
94
response (see Appendix 3 for Massachusetts–specific guidance). The dose of the APM, or other agent
used to manage acute BPSD, should take into account the weight, age, and general condition of the
patient. A maximal daily dose — including PRN doses — should be clearly specified (e.g., “total dose
within any 24 hour period is not to exceed [specify dose] mg”).
Consider a PRN regimen for the management of episodic or rapidly changing aggression, or symptoms
resembling psychosis. Specifically define the clinical circumstances warranting use, including the target
symptoms to trigger administration, dose, frequency, duration and maximum dose for any 24-hour period.
Carefully defined PRN regimens and drug–free days can help minimize overall psychotropic load. If
appropriate (or legally required), consent should also be sought from the patient’s family or guardian. The
administration of PRN medication may be difficult in the community with a sole caregiver. If symptoms
escalate, the patient may be suffering from delirium and need a full medical workup.
There is no evidence to support the use of more than one APM at a time for BPSD (for example, a
122
regularly dosed APM with another APM dosed on a PRN basis). Using more than one APM at a time is
likely to increase the risk of serious adverse effects.
Withdrawal of APMs in acute BPSD
APMs should be tapered slowly to minimize the risk of a withdrawal syndrome (unless significant adverse
effects or a drug interaction necessitates abrupt cessation). A reduction in APM dose by 25−50% every 2
weeks and ceasing after 2 weeks on the minimum dose is generally recommended. Close attention
should be paid to behavior in response to reducing doses in light of the 2012 study of patients with AD
62
that found an increased risk of relapse when risperidone was discontinued.
Benzodiazepines
For an episode of acute anxiety, a short–acting benzodiazepine (rather than an antipsychotic) has been
found useful in a few studies: lorazepam 1 mg IM was comparable to olanzapine 2.5 or 5 mg at two hours
112
and better than IM placebo. At 24 hours, the lorazepam effect was no longer present while olanzapine’s
effect persisted. Given the many adverse effects of benzodiazepines, such as confusion, ataxia, and falls
documented in other studies, further studies are needed before they can be recommended for acute
cases of BPSD.
BOTTOM LINE: If non-drug interventions do not control symptoms of acute BPSD that require
treatment (e.g., which place the patient or caregivers at risk of harm), APMs are sometimes
necessary. Occasionally, physical restraint may be required if other methods do not work and the
behavior poses a serious risk to the patient or others.
First, try oral medication if the patient will accept it. Aripiprazole and risperidone may provide
modest benefit, but other APMs have questionable benefits and/or even greater risks. If IM
medication is required, the first choice is aripiprazole and the second choice is olanzapine.
Treatment may be repeated once or twice in 30 to 60 minutes if necessary in an acute situation.
Most evidence of efficacy from clinical trials is for aggression, agitation, and psychosis. The use
of APM in elderly patients increases the risk of death.
Preventing overuse of antipsychotic drugs in nursing home care | 29
Patients with dementia requiring APMs may benefit from referral to a psychiatrist when available. In
extreme cases, patients have been admitted to neuropsychiatry units and successfully treated with
electroconvulsive therapy if no other measures are successful in managing behavior that puts the patient
123
or caregivers at risk of harm.
APMs as augmentation for major depressive
disorder
APMs do not have a role as monotherapy in unipolar depression. Although some studies of APMs found
a marginal benefit in monotherapy, the FDA has not approved these agents for monotherapy, because of
their safety problems. Other agents (e.g., lithium or thyroid hormone) are safer as add–on treatment when
SSRI monotherapy, or a combination of antidepressants from different classes, is inadequate. APMs may
have a role in certain patients with continued DSM–5 criteria for major depressive disorder that has not
responded to previous rounds of treatment.
The efficacy of an APM augmentation strategy was evaluated in a large meta-analysis of 16 randomized
trials with 3,480 non–institutionalized participants. The study calculated the efficacy of aripiprazole,
olanzapine, quetiapine, or risperidone, all compared to placebo, in inducing a remission or any response
(improvement in depression rating scale ≥50%) in patients who had failed antidepressant monotherapy.
Remission occurred in:
• 31% of APM group
• 17% of placebo group
• Odds ratio of remission with APM=2.0 (95% CI: 1.7-2.4; p<0.0001)
Any response (at least 50% improvement in depression rating scale) occurred in:
• 44% of APM group
• 30% of placebo group
• Odds ratio of any response with APM=1.7 (95% CI: 1.5-2.0; p<0.00001)
There were no significant differences in remission or response among the active drugs, indicating they
are likely all equally effective, although there are no head–to–head randomized trials of these agents.
Discontinuation rates due to adverse events were significantly higher with APMs than with placebo (OR
124
3.9; 95% CI: 2.7-5.7; p<0.0001). This may be particularly significant since residents of nursing homes
with dementia–related BPSD are probably at higher risk for adverse effects than the non–institutionalized
participants in this study. More recently, these data on adjunctive APMs were re-analyzed with particular
125
attention given to specific adverse events and other secondary outcomes. Shortcomings in study
designs and data reporting methods were thought to have inflated the modest advantages found for the
augmentations, which were no better than a Number Needed to Treat of 9 for any APM. This reanalysis
found that in the original reports, side effects were underemphasized yet important, and there were
almost no benefits on quality of life or functional impairment from depression.
Other second–generation agents have not been studied in randomized placebo controlled trials, and none
of the second–generation agents have been compared to other augmentation treatments such as lithium,
triiodothyronine, or other antidepressants.
30 | Preventing overuse of antipsychotic drugs in nursing home care
BOTTOM LINE: For treatment-resistant major depression, augmentation with an APM is not the
first strategy to consider, because of the drugs’ risk profiles. However, when standard approaches
are inadequate, adding an APM may increase the response rate in some patients. They are not the
augmentations of choice, despite the heavy marketing and advertising of these products. None of
the APMs appear to be any better than another in inducing remission of depression when used as
augmentation therapy. APMs should generally not be used in the primary care setting for
treatment-resistant major depressive disorder. In such cases, consultation with a psychiatrist is
strongly recommended.
APMs for psychotic depression
Major depression with psychotic features is a sub-type of depression characterized by symptoms of
delusions and/or hallucinations. This type of depressive disorder is more severe, and is more likely to
lead to hospitalization and suicidal ideation/attempts. Patients with severe symptoms or suicidal ideation
126
should be referred urgently to a psychiatrist and early ECT may be needed.
Role for antipsychotic medications
Patients who do not require psychiatric hospitalization, should be initially treated with a combination of
127
antidepressant and APM, as endorsed by the American Psychiatric Association. First line treatment
126
should be a combination of the dual–action antidepressant venlafaxine combined with an APM. (Note:
a combination product [Symbyax] containing olanzapine with the SSRI antidepressant fluoxetine is FDA–
approved for depressive episodes associated with bipolar disorder as well as treatment resistant
depression. This agent is not a good choice for nursing home residents because of the important side
effects associated with olanzapine combined with the long half–life and metabolic effects of fluoxetine.)
There is no evidence that any one APM is better than another in the treatment of psychotic depression;
the only second generation drugs that have been studied in placebo–controlled randomized trials are
128
olanzapine and quetiapine. The side effect profiles of the second–generation drug should dominate the
decision for which APM is the most appropriate for the patient being treated, and there are better choices
than olanzapine or quetiapine, owing to the more severe side effect profiles for these two drugs.
BOTTOM LINE: Managing patients with psychotic depression in the nursing home is difficult, and
a psychiatrist should be involved in most cases. First-line treatment should be with a combination
of venlafaxine and an APM.
Conclusions
Managing nursing home residents with behavioral problems can be challenging for clinicians and family
members because no optimal treatments exist. Nonetheless, the appropriate use of non-pharmacologic
management strategies can improve the well-being of many patients with BPSD, and may reduce the
burden on family members and caregivers.
Preventing overuse of antipsychotic drugs in nursing home care | 31
The severity of potential APM side effects in the elderly population, including their risks of cardiovascular
events and death, should limit their use in older patients, especially in the nursing home setting. Because
there are as yet no completely satisfactory approaches to BPSD, clinicians must develop a treatment plan
based on the characteristics and needs of the patient and a careful assessment of the risks and possible
benefits of the different treatment options.
For non-acute BPSD, begin by trying to identify any reversible causes of the behaviors. Then implement a
non-drug approach based on the behaviors to be targeted, patient characteristics, and the local
availability of therapeutic options. Such non–drug interventions may reduce or eliminate troublesome
behaviors. If non-drug approaches fail, the SSRIs sertraline or escitalopram may be options. Avoid APMs
if possible.
For patients with acute BPSD (i.e., with severely disruptive, dangerous, or distressing behaviors) for
whom non–drug strategies have failed, APMs may play a role, with aripriprazole and risperidone
preferred over other agents.
In trying to help any patient with behavior problems, there is no substitute for good communication with
other members of the clinical team as well as the patient’s decision maker, who is often a family member,
about the rationale for treatment and the risks and benefits of a recommended intervention. A
collaborative approach to decision-making is essential when all pharmacological options carry some risk.
32 | Preventing overuse of antipsychotic drugs in nursing home care
Appendix 1: Key characteristics of 2nd-generation
APMs129,130
Preventing overuse of antipsychotic drugs in nursing home care | 33
Appendix 2: Black box warning concerning
mortality risk of antipsychotic drugs
The FDA requires this warning on the official labeling information for all APMs.
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA–
RELATED PSYCHOSIS
Elderly patients with dementia–related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of seventeen placebo–controlled trials (model duration of 10
weeks) largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug–
treated patients of between 1.6 to 1.7 times the risk of death in placebo–treated patients. Over
the course of a typical 10–week controlled trial, the rate of death in drug–treated patients was
about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of
death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure,
sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that,
similar to atypical antipsychotic drugs, treatment with first–generation antipsychotic drugs may
increase mortality. The extent to which the findings of increased mortality in observational
studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the
patients is not clear. 34 | Preventing overuse of antipsychotic drugs in nursing home care
Appendix 3: Massachusetts' guidance on the use
of APMs in long-term care facilities
Antipsychotics covered
Indications
First generation (conventional) agents, including:
• chlorpromazine
• fluphenazine
• haloperidol
• loxapine
• mesoridazine
• molindone
• perphenazine
• promazine
• thioridazine
• thiothixene
• trifluoperazine
• triflupromazine
Second generation (atypical) agents, including:
• aripiprazole
• clozapine
• olanzapine
• quetiapine
• risperidone
• ziprasidone
An antipsychotic medication should be used only for the following
conditions/diagnoses as documented in the record and as meets the
definition(s) in the Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Training Revision (DSM–IV TR or subsequent editions):
• Schizophrenia
• Schizo–affective disorder
• Delusional disorder
• Mood disorders (e.g. mania, bipolar disorder, depression with
psychotic features, and treatment refractory major depression)
• Schizophreniform disorder
• Psychosis NOS
• Atypical psychosis
• Brief psychotic disorder
• Dementing illnesses with associated behavioral symptoms
• Medical illnesses or delirium with manic or psychotic symptoms
and/or treatment–related psychosis or mania (e.g., thyrotoxicosis,
neoplasms, high dose steroids)
In addition, the use of an antipsychotic must meet the criteria and applicable,
additional requirements listed below:
Preventing overuse of antipsychotic drugs in nursing home care | 35
1. Criteria: Since diagnoses alone do not warrant the use of antipsychotic
medications, the clinical condition must also meet at least one of the following
criteria (A or B or C):
A. The symptoms are identified as being due to mania or psychosis (such
as: auditory, visual, or other hallucinations; delusions (such as paranoia or
grandiosity)); OR
B. The behavioral symptoms present a danger to the resident or to others;
OR
C. The symptoms are significant enough that the resident is experiencing
one or more of the following: inconsolable or persistent distress (e.g., fear,
continuously yelling, screaming, distress associated with end-of-life, or
crying); a significant decline in function; and/or substantial difficulty receiving
needed care (e.g., not eating resulting in weight loss, fear and not bathing
leading to skin breakdown or infection).
2. Additional requirements:
Acute psychiatric situations
When an antipsychotic medication is being initiated or used to treat an acute
psychiatric emergency (i.e., recent or abrupt onset or exacerbation of
symptoms) related to one or more of the aforementioned
conditions/diagnoses, that use must meet one of the above criteria and all of
the following additional requirements:
A. The acute treatment period is limited to seven days or less; and
B. A clinician in conjunction with the interdisciplinary team must evaluate
and document the situation within 7 days, to identify and address any
contributing and underlying causes of the acute psychiatric condition and
verify the continuing need for antipsychotic medication; and
C. Pertinent non-pharmacological interventions must be attempted, unless
contraindicated, and documented following the resolution of the acute
psychiatric situation.
Enduring psychiatric conditions
Antipsychotic medications may be used to treat an enduring (i.e., non–acute,
chronic, or prolonged) condition, if the clinical condition/diagnosis meets the
criteria in #1 above. In addition, before initiating or increasing an antipsychotic
medication for enduring conditions, the target behavior must be clearly and
specifically identified and monitored objectively and qualitatively, in order to
ensure the behavioral symptoms are:
A. Not due to a medical condition or problem (e.g., headache or joint pain,
fluid or electrolyte imbalance, pneumonia, hypoxia, unrecognized hearing or
visual impairment) that can be expected to improve or resolve as the
underlying condition is treated; and
B. Persistent or likely to reoccur without continued treatment; and
C. Not sufficiently relieved by non–pharmacological interventions; and
D. Not due to environmental stressors (e.g., alteration in the resident’s
36 | Preventing overuse of antipsychotic drugs in nursing home care
customary location or daily routine, unfamiliar care provider, hunger or thirst,
excessive noise for that individual, inadequate or inappropriate staff response,
physical barriers) that can be addressed to improve the psychotic symptoms
or maintain safety; and
E. Not due to psychological stressors (e.g., loneliness, taunting, abuse), or
anxiety or fear stemming from misunderstanding related to his or her cognitive
impairment (e.g., the mistaken belief that this is not where he/she lives or
inability to find his or her clothes or glasses) that can be expected to improve
or resolve as the situation is addressed
After initiating or increasing the dose of an antipsychotic medication, the
behavioral symptoms must be reevaluated periodically to determine the
effectiveness of the antipsychotic and the potential for reducing or
discontinuing the dose
Exception: When antipsychotic medications are used for behavioral
disturbances related to Tourette’s disorder, or for non–psychiatric indications
such as movement disorders associated with Huntington’s disease, hiccups,
nausea and vomiting associated with cancer or cancer chemotherapy, or
adjunctive therapy at end of life. Inadequate indications
In many situations, antipsychotic medications are not indicated. They should
not be used if the only indication is one or more of the following: 1) wandering;
2) poor self–care; 3) restlessness; 4) impaired memory; 5) mild anxiety; 6)
insomnia; 7) unsociability; 8) inattention or indifference to surroundings; 9)
fidgeting; 10) nervousness; 11) uncooperativeness; or 12) verbal expressions
or behavior that are not due to the conditions listed under “Indications” and do
not represent a danger to the resident or others.
Dosage
Doses for acute indications (e.g., delirium) may differ from those used for
long–term treatment, but should be the lowest possible to achieve the desired
therapeutic effects
Generic medication dosage
• First generation
⎯ chlorpromazine
⎯ fluphenazine
⎯ haloperidol
⎯ loxapine
⎯ molindone
⎯ perphenazine
⎯ pimozide*
⎯ prochloroperazine*
⎯ thioridazine
⎯ thiothixene
⎯ trifluoperazine
75 mg
4 mg
2 mg
10 mg
10 mg
8 mg
75 mg
7 mg
8 mg
• Second generation
⎯ Aripiprazole 10 mg
Preventing overuse of antipsychotic drugs in nursing home care | 37
⎯
⎯
⎯
⎯
⎯
clozapine
50 mg
olanzapine
7.5 mg
quetiapine
150 mg
risperidone
2 mg
ziprasidone*
* Not customarily used for the treatment of behavioral symptoms
Duration
The regulation addressing the use of antipsychotic medications identifies the
process of tapering as a “gradual dose reduction (GDR)” and requires a GDR,
unless clinically contraindicated. Within the first year in which a resident is
admitted on an antipsychotic medication or after the facility has initiated an
antipsychotic medication, the facility must attempt a GDR in two separate
quarters (with at least one month between the attempts), unless clinically
contraindicated. After the first year, a GDR must be attempted annually,
unless clinically contraindicated.
For any individual who is receiving an antipsychotic medication to treat
behavioral symptoms related to dementia, the GDR may be considered
clinically contraindicated if:
• The resident’s target symptoms returned or worsened after the most recent
attempt at a GDR within the facility; and
• The physician has documented the clinical rationale for why any additional
attempted dose reduction at that time would be likely to impair the resident’s
function or increase distressed behavior.
For any individual who is receiving an antipsychotic medication to treat a
psychiatric disorder other than behavioral symptoms related to dementia (for
example, schizophrenia, bipolar mania, or depression with psychotic
features), the GDR may be considered contraindicated, if:
• The continued use is in accordance with relevant current standards of
practice and the physician has documented the clinical rationale for why any
attempted dose reduction would be likely to impair the resident’s function or
cause psychiatric instability by exacerbating an underlying psychiatric
disorder; or
• The resident’s target symptoms returned or worsened after the most recent
attempt at a GDR within the facility and the physician has documented the
clinical rationale for why any additional attempted dose reduction at that time
would be likely to impair the resident’s function or cause psychiatric instability
by exacerbating an underlying medical or psychiatric disorder.
Monitoring/Adverse
Consequences
The facility assures that residents are being adequately monitored for adverse
consequences such as:
38 | Preventing overuse of antipsychotic drugs in nursing home care
Anticholinergic effects
•
•
•
•
•
•
•
•
•
•
•
•
•
Akathisia
Neuroleptic malignant syndrome
Cardiac arrhythmias
Death secondary to heart–related events (e.g., heart failure, sudden
death)
Falls
Lethargy
Increase in total cholesterol and triglycerides
Parkinsonism
Blood sugar elevation (including diabetes mellitus)
Orthostatic hypotension
Cerbrovascular event (e.g., stroke, TIA)
Tardive dyskinesia
Excessive sedation
When antipsychotics are used without monitoring they may be considered
unnecessary medications because of inadequate monitoring.
Preventing overuse of antipsychotic drugs in nursing home care | 39
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About this publication
These are general recommendations only; specific clinical decisions should be made by the
treating physician based on an individual patient’s clinical condition.
The Independent Drug Information Service (IDIS) is supported by
the Massachusetts Department of Public Health and the PACE Program
of the Department of Aging of the Commonwealth of Pennsylvania.
This material is provided by the Alosa Foundation, a nonprofit
organization which is not affiliated with any pharmaceutical company.
IDIS is a service of the Alosa Foundation.
This material was produced by Eran Metzger, M.D., Assistant Professor of Psychiatry, Harvard Medical
School; David N. Osser, M.D., Associate Professor of Psychiatry, Harvard Medical School; Jerry Avorn,
M.D., Professor of Medicine, Harvard Medical School; Niteesh K. Choudhry, M.D., Ph.D., Associate
Professor of Medicine, Harvard Medical School; Michael A. Fischer, M.D., M.S., Associate Professor
of Medicine, Harvard Medical School; Eimir Hurley, BSc(Pharm). MBiostat, Program Director, Alosa
Foundation. Drs. Avorn, Choudhry, and Fischer are all physicians at the Brigham and Women’s Hospital
in Boston, while Dr. Metzger is the Chief of Psychiatry at Hebrew SeniorLife. None of the authors accepts
any personal compensation from any drug company.
Medical writer: Stephen Braun.
Copyright 2014 by the Alosa Foundation. All rights reserved.