Psychotropic medication use for behavioral symptoms of dementia

Abstract

Behavioral disturbances associated with dementia are common and burdensome. Although no psychotropic medications are currently approved by the US Food and Drug Administration (FDA) to treat such behavioral symptoms, a variety of drug classes are commonly used for these purposes. Atypical antipsychotic medications may be somewhat effective and are generally considered the pharmacologic treatments of choice; however "black box" warnings have recently been added to their labels by the FDA, warning of significantly increased risks of short-term mortality. Older conventional antipsychotic medications may also be somewhat effective but appear to pose risks that can be at least as great as those of the newer atypical drugs. Although antidepressants, benzodiazepines, mood stabilizers, acetylcholinesterase inhibitors, and N-methyl-D-aspartate (NMDA) receptor antagonists may be considered, particularly in patients with specific types of symptomatology, even less is known about their effectiveness and safety. Also, although various psychotropic medications used for behavioral disturbances in dementia patients may be somewhat effective, they have been increasingly associated with important safety risks.

Full text

Psychotropic Medication Use for Behavioral
Symptoms of Dementia
Philip S. Wang, MD, DrPH, M. Alan Brookhart, PhD, Soko Setoguchi, MD, DrPH,
Amanda R. Patrick, MPH, Sebastian Schneeweiss, MD, ScD
Corresponding author
Philip S. Wang, MD, DrPH
Department of Psychiatry and Division of Pharmacoepidemiology
and Pharmacoeconomics, Brigham and Women’s Hospital,
Harvard Medical School, 1620 Tremont Street, Suite 3030,
Boston, MA 02120, USA.
E-mail: pwang@rics.bwh.harvard.edu
Current Neurology and Neuroscience Reports 2006, 6:xx–xx
Current Science Inc. ISSN 1528-4042
Copyright © 2006 by Current Science Inc.
Behavioral disturbances associated with dementia
are common and burdensome. Although no
psychotropic medications are currently approved by
the US Food and Drug Administration (FDA) to treat
such behavioral symptoms, a variety of drug classes
are commonly used for these purposes. Atypical
antipsychotic medications may be somewhat effective
and are generally considered the pharmacologic
treatments of choice; however “black box” warnings
have recently been added to their labels by the FDA,
warning of significantly increased risks of short-term
mortality. Older conventional antipsychotic
medications may also be somewhat effective, but
appear to pose risks that can be at least as great as
those of the newer atypical drugs. Although
antidepressants, benzodiazepines, mood stabilizers,
acetylcholinesterase inhibitors, and N-methly-D-
aspartate (NMDA) receptor antagonists may be
considered, particularly in patients with specific types
of symptomatology, even less is known about their
effectiveness and safety. Also, although various
psychotropic medications used for behavioral
disturbances in dementia patients may be somewhat
effective, they have been increasingly associated with
important safety risks.
Introduction
Dementia is highly prevalent in older populations. Alzheimer’s
disease alone, which accounts for as many as two thirds of
dementia cases, can affect 10% of those over the age of 65
years and 50% of those over the age of 85 years [1].
Neuropsychiatric symptoms (eg, agitation, aggression,
irritability, disinhibition, and wandering) are present in up to
90% of dementia patients [2]. Such behavioral disturbances
have been shown to be a major reason for the reduced quality of
life in patients, emotional distress in caregivers, nursing home
placements, poor prognosis, and nearly one third of the
economic burdens from dementia [3•,4–7].
Common Interventions for Behavioral
Disturbances in Dementia Patients
Psychosocial and behavioral interventions
A variety of psychosocial and behavioral interventions have
been developed to manage the neuropsychiatric symptoms of
dementia [8]. Components of such nonpharmacologic
management strategies often include insuring safety (eg, of
patients and staff), searching for and removing stressors (eg,
both medical and environmental), behavioral therapy, and
providing environmental and supportive interventions (eg, to
reorient, reassure, and provide optimal levels of sensory, social,
or psychomotor stimulation). Although the effectiveness of
many such strategies is uncertain [9], they are nearly
universally recommended for dementia patients with behavioral
disturbances on the basis of common sense and their generally
benign nature [10]. In practice, though, implementation of
nonpharmacologic interventions can often be hampered by
financial, staffing, and other structural barriers within long-term
care facilities [11].
Pharmacologic interventions
Because nonpharmacologic management strategies are often
insufficient to control behavioral disturbances in dementia

patients, pharmacologic interventions are frequently attempted.
For example, although no medications are currently approved
by the US Food and Drug Administration (FDA) to treat the
behavioral disturbances associated with dementia, psychotropic
medications such as antipsychotics, anxiolytics, sedative-
hypnotics, antidepressants, and mood stabilizers may be given
to as many as half of dementia patients and two thirds of
dementia patients in nursing homes, largely for this purpose
[12].
Effectiveness and Safety of Psychotropic Drugs
Used for Behavioral Disturbances in Dementia
In spite of this widespread use of psychotropic medications to
manage behavioral disturbances in dementia patients,
surprisingly little is known about their effectiveness or safety.
Furthermore, data that have been emerging recently have raised
important concerns. In the following text we briefly cover what
is known about the utilization, effectiveness, and safety of
psychotropic medications in elderly dementia patients.
Atypical antipsychotic medications
Utilization
The widespread use of antipsychotic medications during earlier
decades (by as many one quarter to one half of dementia
patients in nursing homes) led to federal legislation in the 1980s
to restrict such use. On the basis of this legislation,
antipsychotic medications used to control behavioral
disturbances in long-term care patients with dementia
temporarily declined in the 1990s [13]. However largely due to
the introduction and heavy marketing of a newer, atypical class,
antipsychotic drugs are once again being widely given to
patients with dementia. One recent study estimated that one
quarter of Medicare beneficiaries in nursing homes were taking
atypical antipsychotics and that the majority of these regimens
were being given at inappropriately high dosages and for
inappropriate reasons [14••].
Effectiveness
Reviews of trials of atypical antipsychotic medications used to
treat psychosis and agitation in dementia patients have
generally found statistically significant but only modest
improvements with these medications; unfortunately some trials
did not employ prospective designs, randomization, blinding,
placebo controls, or comparator drugs, making it difficult to
draw firm conclusions [15••,16••,17]. However, on the basis of
such results, atypical antipsychotic drugs have generally been
recommended as the pharmacologic treatment of choice for
behavioral disturbances in dementia patients
[15••,16••,17,18••].
Safety
The safety of using atypical antipsychotic medications in
dementia patients has recently been called into question. In
2005, the FDA issued an advisory warning that the atypical
antipsychotics aripiprazole, olanzapine, quetiapine, and
risperidone were associated with a 60% to 70% increased risk
of death versus placebo in 17 short-term randomized placebo-
controlled trials among elderly dementia patients [19••]. “Black
box” warnings were added to the labels of all atypical
antipsychotics describing these risks and advising that the
atypical antipsychotics are not approved for use in elderly
patients with dementia. Another meta-analysis by Schneider et
al. [20••] of 15 short-term randomized controlled trials also
found a statistically significant 54% increased relative risk of
death (and 1% absolute risk difference) for atypical
antipsychotics versus placebo.
Potential mechanisms through which atypical agents
might increase short-term mortality are unclear. Based upon
signals observed in trials of atypical agents [21], the FDA
issued a warning in 2004 of increased risks for strokes and
transient ischemic events from the atypical agents risperidone,
olanzapine, and aripiprazole [22–24]. Using trial data that were
available, a recent Cochrane review estimated the risk of
cerebrovascular events to be over threefold higher in
risperidone versus placebo-treated elderly with dementia [25].
Other potential mechanisms are suggested by the FDA’s
reanalysis, in which heart-related events (including heart failure
and sudden death) and infections (mostly pneumonia)
accounted for most deaths [19••]. Heart failure from
myocarditis and cardiomyopathy has been linked to one
atypical agent, clozapine, although clozapine was not used in
any trials in the FDA’s reanalysis [26•]. Whether changes in
blood pressure or heart rate that have been observed with
atypical agents in older populations [16••] could exacerbate pre-
existing heart failure is another possibility. Antipsychotic
medication use has long been suspected as playing a potential
role in the development of arrhythmias, cardiac arrest, and
sudden death [27–31]. The atypical agent ziprasidone has
received particular attention in this regard [32], although it was
not used in any trial in the FDA’s reanalysis. Metabolic side
effects from atypical psychotic medications (ie, glucose and
lipid abnormalities, weight gain) observed in elderly
populations [16••] could, in theory, cause cardiovascular events
over time; however, this seems an unlikely explanation of the
excess mortality associated with atypical use in short-term
trials. Potential mechanisms through which atypical
antipsychotic use might lead to pneumonia include the
excessive sedation observed in risperidone and olanzapine trials
as well as extrapyramidal symptoms (eg, leading to swallowing
problems) observed in risperidone trials [25].
Conventional antipsychotic medications
Utilization
The rapid increase in use of atypical agents during the past
decade has been accompanied by a corresponding decline in use
of conventional antipsychotics, to the point where only one fifth
of elderly antipsychotic users were being given conventional
agents by the early 2000s [33•]. However, the FDA’s recent
advisories and black box warnings on antipsychotic use applied
only to atypical agents and may have caused clinicians to
simply switch elderly patients to older agents [34], particularly

because their replacement by the newer drugs occurred so
rapidly and recently [35]. Unfortunately, up-to-date data are
lacking that shed light on how patterns of antipsychotic use
have been changing more recently in older populations with
dementia.
Effectiveness
Haloperidol and other typical antipsychotics have been
examined in numerous trials [15••,16••,17]. Most report
improvements in dementia-related psychosis and agitation from
the use of conventional agents; however, many trials were not
prospective, randomized, blinded, or placebo-controlled.
Prescribing recommendations for older patients with dementia
usually include conventional antipsychotics as possible
treatment considerations, despite lack of clear evidence
supporting such use [15••,16••,17,18••].
Safety
Because of insufficient data on morbidity and mortality
associated with conventional antipsychotic use in elderly
dementia patients, the FDA did not include these agents in its
recent advisories [19••,36]. However, extrapolating mainly
from studies in younger populations, some have suggested that
conventional antipsychotic medications could pose risks greater
than those of the newer drugs in older populations [37–40]. In a
recent observational study of elderly patients beginning use of
antipsychotic medications, we found that patients prescribed
conventional agents had a 37% greater dose-dependent risk of
short-term mortality than those prescribed atypical
antipsychotics [41••]. A recent meta-analysis of randomized
trials among elderly patients with dementia found that the
conventional agent haloperidol increased short-term mortality
versus placebo by 107%, a risk numerically greater than that
seen for atypical agents [20••]. Another observational study also
found higher mortality in those given haloperidol versus two
atypical drugs (risperidone or olanzapine) [42•].
The potential mechanism through which conventional
antipsychotic medications may pose greater hazards than
atypical agents is unclear. Soon after their introduction,
conventional antipsychotic medications were suspected of being
involved in the development of arrhythmias, cardiac arrest, and
sudden death [27–31]. Prolongation of cardiac repolarization
and QTc intervals is thought to be responsible and is generally
more common with conventional than atypical agents (an
exception possibly being ziprasidone) [36]. Anticholinergic
properties affecting blood pressure and heart rate, as well as
sedation and extrapyramidal symptoms causing potential
swallowing problems, are also all more common with
conventional than atypical agents [18••,37–40,41••]. For these
reasons, cardiac (eg, myocardial infarction and ventricular
arrhythmias), cerebrovascular (eg, stroke and transient ischemic
events), and infection (eg, aspiration pneumonia) outcomes may
all be potential mediators of any increased risk of death from
conventional compared with atypical agents. To date, some
[32,43•] but not all [28] epidemiologic studies comparing
antipsychotic agents have found higher risks of ventricular
arrhythmia and cardiac arrest with conventional versus atypical
use. Similarly, some [44•] but not all [45,46•] epidemiologic
studies have found significantly greater risks of stroke with
conventional versus atypical antipsychotic medication use.
Antidepressants
Some investigators have found that as many as one fifth of
elderly dementia patients in long-term care facilities are
prescribed antidepressants, although the reasons for such use
are unclear [12]. Selective serotonin reuptake inhibitors (SSRIs)
have become especially popular for elderly patients because
they lack the anticholinergic properties associated with older
tricyclic classes; however, only some [47], not all [48,49],
studies have found improvements in agitation and disordered
behavior with SSRI use. Trazodone has also been widely used
to manage behavioral disturbances, despite data suggesting little
benefit of this agent for this purpose [50]. For these reasons,
antidepressants have generally been recommended for dementia
patients with depressive symptomatology, but not necessarily
for behavioral disturbances [15••,16••,18••]. Although few
studies of the safety of antidepressants in dementia patients
have been performed, one reported that the risk of falls in
elderly nursing home residents on SSRIs was as high as for
those patients taking older anticholinergic tricyclic agents [51].
Benzodiazepines and other sedative hypnotics
Benzodiazepines and other sedative hypnotics are also used by
over one third of dementia patients in nursing homes [12], yet
few data are available to support the use of benzodiazepines to
manage behavioral symptoms [16••,52,53]. Some investigators
have also reported that newer sedative-hypnotic agents such as
zolpidem may be helpful for treating agitation in dementia
patients [54]. In light of the limited data on effectiveness,
benzodiazepines and other sedative hypnotics have generally
been recommended in only specialized circumstances (eg, for
prominent anxiety) in dementia patients with behavioral
disturbances; if used, regimens employing shorter half-life
agents, lower dosages, and shorter durations are advised
[15••,16••,18••]. However there may be risks of adverse effects
such as worsening of memory loss or hip fracture, even with
shorter half-life agents, modest dosages, medium durations of
use, and the newer sedative hypnotics [55–57].
Mood stabilizers
Mood stabilizers, such as lithium, carbamazepine, valproate,
and the newer agents gabapentin or topiramate, are an
increasingly used class of medication to treat dementia-
associated behavioral disturbances. They have been reported to
improve agitation in only some studies [15••,16••,17]; however,
the studies’ generally small sizes and methodologic limitations
prevent definitive conclusions from being drawn regarding the
effectiveness of this medication class for this purpose. Although
some safety concerns have been observed with mood stabilizers
(including sedation and ataxia from carbamazepine as well as
memory and language difficulties with topiramate), observation
of many adverse outcomes may not have been possible [17].

Despite this general paucity of evidence, mood stabilizers
continue to be considered treatment options for the management
of dementia-associated behavioral disturbances, particularly if
mood lability or mania-like features are present [16••,18••].
Acetylcholinesterase inhibitors and newer agents
Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine,
and galantamine) and N-methly-D-aspartate (NMDA) receptor
antagonists (eg, memantine), are fairly recent additions to the
pharmacologic armamentarium used to treat dementia but
already have attracted considerable attention as being potential
treatments for associated neuropsychiatric symptoms. Trials of
these agents have shown promise for this purpose, with
generally small but statistically significant improvements in
behavioral disturbances [15••,16••,58••]. However because
acetylcholinesterase inhibitors may take longer to achieve these
effects (eg, up to 1 month), some have suggested they are better
used for more chronic and less acute behavioral disorders [10].
Safety profiles for these newer agents when used for
neuropsychiatric symptoms in dementia have not been well
established. For example, although confusion has been
described as a side effect of memantine, one recent study
actually reported less confusion in dementia patients given this
drug [58••].
Conclusions
Although the behavioral disturbances associated with dementia
are clearly burdensome, it remains unknown how to optimally
manage them. Nonpharmacologic interventions should be
attempted and properly implemented, but are unlikely to be
sufficient in and of themselves for many cases. For this reason,
pharmacologic interventions will likely continue to be
mainstays in the management of behavioral disturbances in this
growing population.
However, the data emerging recently suggest that the
various psychotropic medications used for these purposes may
be only marginally effective at best and may be associated with
important safety risks. Until further light is shed, it seems
prudent to assume that no class or agent is free of such
concerns. Clinicians considering these medications for their
elderly patients should carefully weigh the potential benefits
against the potential risks when making their prescribing
decisions.
Additional research is clearly needed to define the
comparative effectiveness and safety of the variety of
psychotropic medications currently being used in populations
with dementia. Results from the National Institute of Mental
Health (NIMH) Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE) study [59] conducted among
Alzheimer’s disease patients offer promise in this regard for
helping clinicians choose between atypical antipsychotics
(risperidone, olanzapine, or quetiapine) and an SSRI
(citalopram). However, because it is unclear that one or even
several of these agents will prove to have strong, durable
benefits for large numbers of dementia patients, even the
CATIE trial will likely leave many pressing clinical and
practice questions unanswered for the many patients with
inadequate responses. Furthermore, it is unclear that new large
federal or industry-sponsored trials will be conducted in the
foreseeable future due to the safety concerns and financial
considerations.
For this reason, pharmacoepidemiologic studies may be
the best option available for defining the comparative safety and
effectiveness of the many psychopharmacologic treatment
regimens being used to manage behavioral disturbances in
dementia patients. The large size and statistical power of
pharmacoepidemiologic databases may be essential for
answering these questions, and would be difficult to attain even
if new large trials or meta-analyses of such trials became
possible. However, new methodologic advances will need to be
applied to ensure that any epidemiologic studies are rigorous
and unbiased by the inevitable selective prescribing that occurs
in observational data. Finally, when the effectiveness and safety
of different psychopharmacologic regimens have been defined,
analytic and pharmacoeconomic analyses may be necessary to
help balance any benefits and risks. In this way, it may be
possible to determine optimal treatment strategies to maximize
the health, functioning, and well-being of the large and
extremely vulnerable population of elderly with dementia.
References and Recommended Reading
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Dr. Wang: Only References from year 2003 to
Present can have bullets, which is why they were
dropped from Ref. 17.