APPENDIX D
Agitation and aggression in Alzheimer’s disease:
selective review and research priorities
David L. Sultzer1, Lon S. Schneider2, Nathan Herrmann3
for the Neuropsychiatric Syndromes Professional Interest Area of ISTAART
1
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA; and Psychiatry Service, VA
Greater Los Angeles Healthcare System, Los Angeles, CA
2 Department of Psychiatry and the Behavioral Sciences, and Department of Neurology, Keck School of Medicine of the
University of Southern California, and the Leonard Davis School of Gerontology of USC, Los Angeles, CA
3 Department of Psychiatry, University of Toronto and Brain Sciences Program, Sunnybrook Health Sciences Center, Toronto,
ON
1
Abstract
Agitation and aggressive behaviors are among the most distressing symptoms of Alzheimer’s disease
(AD). The etiology, phenomenology, and optimal management of these behaviors are not understood.
The term “agitation” is used broadly and inconsistently, although distinct behavioral syndromes probably
occur. Several rating scales are used to measure agitated behaviors, yet the scales measure different
symptoms in different ways, the construct of agitation is often unclear and the term is inconsistently
defined in research studies and clinical practice. Neuroimaging, neuropathology, neurochemistry, and
genetic studies suggest that agitation behaviors are fundamental expressions of the neurodegenerative
process, and these studies can help reveal specific phenotypes of agitated behavior with shared biological
substrate to improve nosology and treatment. Current behavioral and pharmacological interventions for
agitation and aggression are insufficiently effective and may carry substantial risk. Attention to four key
research areas can improve our understanding and management of agitation in AD: 1) improving the
definition and measurement of agitation and aggression, 2) characterizing state and trait biomarkers for
distinct symptoms, 3) understanding environmental and caregiver factors that promote or ameliorate
agitation, and 4) developing practical, effective, and safe behavioral and medication interventions for
specific behavioral syndromes, and identifying patient characteristics associated with maximal
effectiveness and safety.
2
delusions, hallucinations, depression, and apathy
are cognitive or psychological states with links
to traditional psychiatric syndromes, agitation in
AD invariably includes prominent and
observable behaviors and motor acts, extending
beyond an internal psychological state and likely
to be more heterogeneous. Finally, agitated
behaviors
in
AD
are
substantially
environmentally dependent. While they often
reflect the patient’s internal mental state and
include
elements
of
anxiety,
fear,
misunderstanding, irritability, and impulsivity,
the agitated behavior that emerges depends in
great part on environmental stimuli and the
reactions of others. Thus, understanding the
phenomenology of agitated behavior in AD and
optimal management approaches must take into
account a fluctuating external environment.
Introduction
Agitation and aggressive behaviors are among
the most challenging neuropsychiatric symptoms
in older adults with Alzheimer’s disease (AD).
They are unfortunately common; agitated
behaviors occur in about 20% of outpatients
with AD and in 40-60% of care home residents.
In practice, “agitation” can include a variety of
disturbing behaviors. Aggression, a subset of
agitated behavior with overt threats, gestures, or
violence, is expressed by 10-25% of those with
AD. Agitated behaviors are more prominent in
those with moderate or severe dementia and tend
to persist over the course of AD. Agitation and
aggression typically reflect patient distress, and
contribute to emergency room visits, acute
hospitalizations, long-term institutionalization,
and caregiver burden. Aggressive behaviors
also compromise safety for the patient,
caregivers, and others. Despite the frequency of
these symptoms and their contributions to
distress and disability, many aspects of the
agitation syndrome are not well understood.
Available management strategies can be difficult
to implement, are modestly effective at best, and
can have adverse effects. This paper prepared
by the Neuropsychiatric Syndromes Professional
Interest Area (NPS-PIA) agitation workgroup
provides a brief review of selected issues related
to agitation in AD, and proposes a research
agenda to improve understanding and develop
better treatments.
Several definitions of agitation have been
offered for clinical and research purposes.
Expert conferences have attempted to develop
consensus definitions or criteria, with uncertain
impact. In clinical settings, the term agitation is
used variably and without careful consideration
of specific behaviors, which complicates shared
understanding. In both clinical and research
environments, terms such as “disruptive”,
“inappropriate”, or “disturbing” are sometimes
used to help define agitation, but these terms are
susceptible to subjective interpretation and may
reflect the impact of the behavior rather than the
behavior itself. The “agitation” that is addressed
in an individual research study is defined largely
by the items on the rating instrument, rather than
a clear a priori definition.
Concepts, definitions, and criteria
Several factors contribute to the limited
understanding of agitated behaviors in AD.
Most importantly, the term “agitation” is used
broadly to refer to a wide range of behaviors;
agitated behavior as viewed by different groups
of clinicians or researchers may have nothing
more in common than their disturbing nature.
Researchers may define agitation for the purpose
of an individual study, but the findings apply
only to those behaviors measured by the study’s
instrument, and results may not be consistent
with other research or translatable to clinical
care where agitation is defined or measured
differently. Second, while symptoms such as
Several dimensions of agitated behaviors are
apparent and can be used to improve nosology
for clinical communication and research study.
Examples include: 1) physical agitation vs.
verbal
behaviors,
2)
aggressive
vs.
nonaggressive behaviors, 3) directed behaviors
(e.g., targeted hostility or aggression) vs. less
purposeful behaviors (e.g., intense pacing), and
4) context-dependent behaviors (e.g., those that
occur during care assistance, such as bathing) vs.
generalized behaviors without precipitant. Such
dimensions have face validity and are consistent
with some research findings.
3
For example, the Cohen-Mansfield Agitation
Inventory (CMAI) was developed to assess
patients in nursing home settings and has three
subscales: physically aggressive, physically
nonaggressive, and verbal behaviors (1).
Principal components analysis of a large sample
of CMAI ratings revealed three factors that
reflect this construct (aggressive behavior,
physically non-aggressive behavior, and verbally
agitated behavior), and a fourth factor with
hiding and hoarding behaviors (2).
others measure symptom severity. NPI ratings
are based on caregiver observations, although a
variant in development, the NPI-C (10), includes
clinician input. Ratings on the NRS, BPRS, and
BEHAVE-AD include both clinician and
informant observations. Most importantly, how
agitated behaviors are defined varies
considerably across instruments. For example,
the agitation/aggression item on the NPI
addresses
predominantly
resistive
or
oppositional behaviors, but on some other scales
“agitation” is defined as increased motor activity
specifically. Thus, the meaning and implications
of results using different scales can vary.
Principal components analysis of behavioral
ratings on several different instruments has shed
light on how individual agitated behaviors are
related to each other and to other NPS. These
findings can help to empirically define
phenomenologically distinct syndromes.
In an analysis of Neuropsychiatric Inventory
(NPI) ratings of AD patients, two components
with different dimensions of agitated behavior
were apparent: behavioral dyscontrol (euphoria,
disinhibition, aberrant motor behavior, and
sleep/appetite disturbances) and agitation
(agitation/aggression and irritability/lability)
(3). Defining agitation syndromes with specific
behaviors can provide a coherent and clinically
meaningful framework, and can improve
classification, assessment, and treatment.
Etiology and Neurobiological
Underpinnings
Structured Assessment
A variety of factors affect the expression of
agitated behaviors that occur in AD. The
cognitive deficits of AD can promote
misunderstanding and lead to agitation or
aggression. Also, the environment and the
individual’s interactions with it contribute to
behavior: excessive noise, boredom, or
perceived family distress can all raise the
likelihood of patient distress and agitation.
However, key aspects of the neurodegenerative
process itself likely play an independent or
important interactive role. Neuropathology in
specific cortical regions, altered neurochemistry,
and regional cortical dysfunction as seen on
neuroimaging are associated with agitated or
aggressive behavior. For example, NPI-rated
agitation over the course of AD was associated
with greater neurofibrillary tangle density in the
orbitofrontal cortex and anterior cingulate (11)
at autopsy, and aggressive behavior was
associated with low choline acetyltransferase
level in the superior and middle frontal gyri (12).
Neuroimaging
studies
have
explored
relationships between regional atrophy, lower
neuronal metabolic activity, or specific
neuroreceptor binding alterations and the
Agitated behaviors can be assessed using
instruments that measure a broad range of NPS
or those that measure only agitated behaviors.
Instruments that are commonly used to measure
several NPS include the NPI (4), the BEHAVEAD (5), the Neurobehavioral Rating Scale (6, 7),
and the Brief Psychiatric Rating Scale (8).
Because agitated behaviors often co-occur with
other NPS in AD, the opportunity to explore
relationships between agitated behavior and
other NPS is valuable. Other instruments, such
as the CMAI and the Overt Aggression Scale (9)
measure agitation or aggression only.
Each instrument measures “agitation” in a
different way and interpreting results from
different
scales
can
be
challenging.
Furthermore, instruments may measure change
in agitation symptoms in response to treatment
differently as well (ref: Ismail et al AJGP Jan
2012). Some assess a broad range of behavioral
disturbances, whereas others are focused on
particular agitated or aggressive behaviors.
Some scales measure symptom frequency and
4
expression of individual agitated behaviors or
aggression in AD (13, 14). A recent preliminary
report showed that aggressive, hostile, and
irritable symptoms in AD, but not impulsive or
disinhibited behaviors, were associated with
hypometabolism in right frontal/temporal and
bilateral cingulate cortex (15).
Genetic
underpinnings may also play a role. For
example, the presence of the long allele of an
insertion/deletion polymorphism in the promoter
region of the serotonin transporter was
associated with both psychosis and aggression in
AD (16). Collectively, these studies suggest that
individual
behaviors
are
fundamental
expressions of the degenerative disorder, and
specific neurobiological determinants mediate
their expression along with environmental
factors. Neuroimaging, neurochemistry, and
neuropathology studies may thus help to define
biologically specific phenotypes of agitated
behavior, which can improve understanding of
clinical symptom clusters, their course over
time, and treatment based on biological markers.
generally modest. Implementing behavioral
interventions requires adequate training &
monitoring.
Some
require
substantial
investments in time, training, and changes to the
physical environment. Finally, how best to apply
specific interventions to particular patients and
behaviors is not always clear.
A variety of pharmacological interventions have
been used to treat agitated or aggressive
behaviors,
including
antipsychotic,
anticonvulsant, serotonergic antidepressant, and
antidementia
drugs
(i.e.,
cholinesterase
inhibitors and memantine). While there have
been many clinical trials and clinicians
commonly use medications to treat agitated
behavior, evidence supporting their efficacy is
inconsistent and side effects can be limiting.
The majority of trials have studied atypical
antipsychotic medications. Meta-analyses of
results have shown statistically significant
benefit for agitated or aggressive behaviors,
although the magnitude of benefit has been
small, on average (22, 23). A secondary
analysis of the CATIE-AD results suggested that
treatment response with antipsychotic drugs may
be greater for symptoms such as anger,
aggression, and paranoid ideas (24). As with
studies of nonpharmacological interventions, the
specific behavioral symptoms required for study
entry vary across studies and are often not well
defined, and several different rating scales and
outcome criteria were used. “Agitation” was
often defined as a cutoff score on a rating scale,
rather than having a clear construct that
identifies specific behaviors and their severity
required for trial inclusion. Similarly, clinical
efficacy was usually defined as an improved
score on a rating scale, rather than meeting a
benchmark criterion for improved agitation.
Most treatment trials lasted 6-12 weeks, and
effects of longer-term treatment are unclear.
Greater symptomatic efficacy and capture of
distinct elements of “agitation” that improve
with treatment are critical research goals.
Treatment
Ideal
treatments
for
agitated/aggressive
behaviors in AD are lacking. Two categories of
interventions have been considered: behavioral
and pharmacological. Behavioral interventions
are targeted towards the patient with AD, the
caregiver, and/or the environment. Patientcentered approaches include exercise, activities,
socialization, or reassurance.
Caregiver
interventions may include education, support, or
developing practical approaches to identify and
contain precipitating factors or to extinguish
agitated
behaviors
as
they
develop.
Environmental interventions can address
architecture, lighting, or music elements that can
ameliorate agitated behaviors.
Published
treatment guidelines strongly recommend the
use of behavioral interventions before or along
with
any
pharmacological
intervention.
Moreover, several reviews or meta-analyses
indicate that some behavioral strategies are
effective (17-21). However, in some of the
individual studies the target behaviors and
outcome measures are not well described, results
may vary across studies, and benefits are
Medication treatments have adverse effects that
can be very serious. Atypical antipsychotic
medications can cause sedation, fatigue, extrapyramidal motor changes, urinary symptoms,
abnormal gait, edema, and cognitive decline.
5
Short-term atypical antipsychotic treatment in
patients with dementia is associated with
cerebrovascular adverse events and a 1-2%
increased risk of mortality compared to placebo
(25). An assessment of the individual patient’s
circumstances, including symptom severity,
value of modest improvement, vulnerability to
adverse effects, and effectiveness of behavioral
interventions can help guide appropriate
antipsychotic prescription for some patients with
marked agitation or aggression.
alterations in functional neuronal systems, or
genetic risk that, along with environmental and
interpersonal factors, mediate individual agitated
behaviors. These markers may help to define
particular clusters of clinical symptoms with a
unitary neurobiological alteration, and thus
support the validity of the syndrome.
Caregiver and other environmental factors can
clearly impact the development, severity, and
longitudinal course of agitated behaviors.
However, current understanding of these
important factors is limited.
Better
characterization can help identify strategies to
prevent agitated behavior or to extinguish
prodromal behaviors.
Similarly, behavioral
interventions to improve agitated behaviors need
additional study. Many behavioral approaches
are used in clinical settings, often successfully,
and many have been tested in clinical trials.
However, better understanding of standardized,
practical, and relatively simple interventions that
foster improvement is needed.
Moreover,
strategies that can be tailored to individual
patients and implemented with modest training,
and are consistently effective across community
home settings or across skilled care facilities
have been elusive. Finally, a reimbursement
mechanism for staff training and evidence-based
behavioral interventions in care home settings is
essential.
Research Priorities & Next Steps
Several key research issues can be addressed to
improve understanding and management of
agitated/aggressive behaviors (Table 1) in
several areas: improve definition, description,
and measurement of agitated behaviors: identify
pathophysiological factors contributing to
specific behaviors; gain understanding of
environmental precipitants and caregiver
influences on agitated behaviors, and develop
better behavioral or pharmacological treatments.
Most importantly, the spectrum of “agitated”
behaviors in AD and other cognitive disorders
needs to be more carefully catalogued and
distinct phenotypes, syndromes and criteria need
to be better defined.
The validity and
longitudinal stability of distinct syndromes, such
as aggressive/hostile behavior, excitable/anxious
behavior, and excessive motor behavior, require
further study. Reliable instruments to measure
such syndromes are needed, and should be used
in larger samples and in longitudinal studies of
AD, mild cognitive impairment, and other
cognitive disorders. Better understanding of
interactions among these syndromes and their
overlaps with other NPS such as psychosis and
depressed mood are important.
Such
relationships are likely different over the stages
of dementia and have important implications for
clinical understanding and management.
Several strategies may help to incrementally
improve the benefit/risk equation of medication
interventions. Greater efficacy, fewer risks,
improved patient function, and reduced
caregiver burden are all important goals.
Current datasets can be used to identify
individual patients or specific behaviors with the
most benefit or least harm from the drug
intervention. New treatment trials of available
or newly emerging drugs that employ carefully
selected criteria for agitation and appropriate
outcomes are reasonable.
In the future, drugs outside the antipsychotic
class or novel compounds with targeted antiagitation effects may provide greater benefit or
lower risk. Trials that take advantage of more
basic research advances in phenomenology and
neurobiological markers for distinct agitated
Neurobiological factors associated with specific
agitation syndromes in AD deserve additional
study using neuroimaging, genotyping, or tissuebased techniques
to explore
regional
neuropathology,
neuroreceptor
changes,
6
syndromes will likely promote development of
more efficacious treatments. Targeting novel
neuroreceptors or processes, based on improved
understanding of agitated behavior in AD, may
lead to greater efficacy, and matching particular
treatments to distinct behavioral syndromes may
substantially enhance clinical benefit. Studies
that systematically integrate behavioral and
medication interventions, either concurrently or
sequentially, would be valuable. Finally, trials
of new agents to prevent or treat the
neurodegenerative process of AD should include
measures of agitation, and longitudinal efforts to
treat both the cognitive and behavioral aspects of
AD should be better aligned.
Overall, research efforts towards agitation and
aggression in AD need to address definitions,
criteria, and measurement. Additional research
to examine course of symptoms, neurobiology,
environmental influences, and management can
begin with the principles presented here, which
can be refined further and translated to testable
hypotheses. Key clinical research studies can
then be initiated with the attention and support
of healthcare systems, national agencies, and
advocacy groups.
7
Table 1.
Key issues and research priorities regarding agitation and aggression in AD
1.
Improve the conceptual framework, definition, and criteria for “agitation” in AD
2.
Identify specific behavioral syndromes of agitation and aggression
a.
Characterize the course of agitated behaviors in AD, relationships with other NPS, and differences across
dementia diagnoses
3.
Develop instruments to better measure agitation and aggression in cognitive disorders
4.
Define the neurobiological underpinnings of distinct agitated behaviors
5.
a.
Develop biomarkers
b.
Study biological risks for developing agitated behaviors
Develop practical and efficient treatments, both behavioral and pharmacological
a.
Identify specific agitated behaviors that respond best to treatment
b.
Use more refined definitions of agitated behaviors in targeted clinical trials
c.
Evaluate combined behavioral/pharmacological approaches to treatment
d.
Identify predictors of adverse treatment effects
e.
Characterize the optimal duration of treatment and predictors for relapse
8
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