Review

Advancements in the treatment of

agitation in Alzheimers disease

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Inga M Antonsdottir, Jessica Smith, Melanie Keltz & Anton P Porsteinsson

1.

Introduction

2.

Dextromethorphan/quinidine

3.

Scyllo-inositol

4.

Brexpiprazole

5.

Prazosin

6.

Cannabinoids

7.

Citalopram

8.

Conclusions

9.

Expert opinion

University of Rochester School of Medicine and Dentistry, Department of Psychiatry, Alzheimer s

Disease Care, Research and Education Program (AD-CARE), Rochester, NY, USA

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimers disease (AD)

are associated with significant negative outcomes for patients and their
caregivers. Agitation, one of the most distressing NPS, lacks well-established
long-term interventions that are both effective and safe. While nonpharmacological interventions are the suggested first-line treatment, it isnt
effective in managing symptoms for every patient. In such cases, clinicians
turn to the use of pharmacological interventions. Traditionally, these interventions consist of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine and antidepressants,
where the efficacy doesnt necessarily outweigh the associated risks.
Areas covered: Gains made in understanding the neurobiological mechanisms underlying agitation have fueled several recent clinical trials.
A comprehensive literature search for published articles evaluating pharmacologic interventions for agitation in AD was done. A review of some of
these clinical trials was completed: dextromethorphan/quinidine, scylloinositol, brexpiprazole, prazosin, cannabinoids, dronabinol and citalopram
show promise in treating agitation.
Expert opinion: Neurobiological findings and enhanced trial designs have
re-ignited the area of pharmacological treatment of NPS. Although further
research is needed to fully determine the safety, tolerability and efficacy of
these treatments, the mission to finding effective treatments for NPS such as
agitation in patients with dementia is well underway.
Keywords: agitation, Alzheimers disease, behavioral and psychological symptoms of dementia,
brexpiprazole, cannabinoids, citalopram, dementia, dextromethorphan/quinidine, dronabinol,
neuropsychiatric symptoms, pimavanserine, prazosin, psychosocial intervention, scyllo-inositol,
treatment
Expert Opin. Pharmacother. (2015) 16(11):1649-1656

1.

Introduction

Alzheimers disease (AD) is the most common form of dementia. It is estimated that
35.6 million people are living with dementia worldwide, with an anticipated
increase to 115.4 million by 2050 [1]. Along with cognitive and functional
impairment, individuals diagnosed with AD often suffer from a range of behavioral
changes, alternatively referred to as neuropsychiatric symptoms (NPS) or behavioral
and psychological symptoms of dementia. These symptoms include depression,
anxiety, apathy, delusions, hallucinations, sleep disturbance, agitation and aggression [2]. NPS are near universal, with 98% of patients with AD experiencing at least
one NPS over the course of their disease [3,4]. NPS present at all stages and etiology
of dementia, often cluster together, causality is usually multi-determined and they
are often persistent and associated with excess morbidity, mortality, increased
healthcare use, earlier institutionalization as well as greater caregiver distress, depression and difficulty with employment [5].

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I. M. Antonsdottir et al.

Article highlights.
.

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Individuals diagnosed with Alzheimers disease (AD)

often experience neuropsychiatric symptoms in addition
to cognitive impairment.
Agitation is common among individuals with AD and is
associated with earlier institutionalization, excess
morbidity and mortality, greater healthcare use and
caregiver burden.
Use of psychosocial interventions may have a positive
impact on both the patient and the caregiver, and are
considered as first-line treatment for agitation in
dementia. For the patients who do not adequately
respond to non-pharmacologic interventions, a judicious
pharmacologic intervention is indicated.
Neurobiological research centered on the pathogenesis
of agitation in AD has fueled a growing number of
randomized controlled trials of drugs for agitation and
other NPS.
Several drugs have shown positive outcomes in clinical
trials, hopefully establishing a new treatment paradigm
for agitation in AD.
It is likely that the CitAD and DM/Q studies will
immediately impact practice in the field as both
medications are commercially available and there is a
large commercial opportunity for medications that are
safe, well tolerated and efficacious for NPS in dementia,
including agitation.

This box summarizes key points contained in the article.

Agitation is one of the most complex, frequent and problematic NPS. While lacking a universally accepted definition,
agitation involves emotional distress, excessive psychomotor
activity, aggressive behaviors, disruptive irritability and disinhibition [6]. The management of agitation is a major priority
in caring for individuals with AD, as agitation is associated
with greater caregiver burden [7], poorer functioning [8], earlier
nursing home placement and death [9].
In order to facilitate clinical research, the International
Psychogeriatric Association (IPA) recently convened a group
of experts to develop and publish a provisional consensus definition where agitation in patients with cognitive disorders
was broadly defined as: i) occurring in patients with a cognitive impairment or dementia syndrome; ii) exhibiting behavior consistent with emotional distress; iii) manifesting
excessive motor activity, verbal aggression or physical aggression and iv) evidencing behaviors that cause excess disability
and are not solely attributable to another disorder (psychiatric, medical or substance-related) [10].
In general, psychological, environmental and pharmacological therapies for agitation are limited. In North America,
there are no FDA-approved drugs for the treatment of
agitation in AD. In the European Union, only risperidone is
indicated for the short-term management of severe aggression.
Use of non-pharmacological interventions as first-line treatment for agitation in dementia is best practice and is recommended for all patients. Examples include caregiver
1650

education, training in problem solving and psychosocial interventions targeting specific behaviors, which involve both the
caregiver and the patient [5,11]. The focus of these interventions is to evaluate the underlying cause of the behavior,
such as triggering events, and educating the caregiver on strategies to understand and prevent the behavior from occurring.
Caregiver education focuses on addressing unmet needs of the
patient, such as pain, hunger, thirst, over/under stimulation,
boredom, overcrowding and fear of endangerment and abandonment, and through environmental and daily routine
changes concentrating on relaxation techniques, distraction,
exercise, individualized outlets for pent up energy and avoidance of behavioral triggers [5]. Several of these approaches have
evidence for lasting effectiveness, but with benefits typically
limited to milder severity of aggression. With nonpharmacological approaches, obstacles such as lack of training
and time constraints hinder clinicians in adequately applying
them [5]. Broader uptake and implementation of nonpharmacological approaches is required to fully institute
them for agitation in real-world settings.
Non-pharmacologic approaches, even if feasible to implement, do not preclude the use of adjunctive pharmacologic
treatments. Furthermore, many patients with AD and agitation fail non-pharmacologic interventions after initial success,
requiring the use of medications. However, as there are
currently no FDA-approved pharmacological treatments for
agitation in AD, clinicians ultimately resort to off-label use
of antipsychotics, sedatives/hypnotics, anxiolytics and antidepressants in an attempt to control symptoms [12]. Unfortunately, these treatments have limited utility given a modest
efficacy that is offset by relatively poor adherence, safety and
tolerability. For decades, antipsychotics have been the pragmatic mainstay of treatment despite their limited efficacy,
and history of adverse events outweighing potential benefits
including FDA black box warnings [13]. Risks surrounding
antipsychotic use, both conventional and atypical, range
from weight gain, falls and drowsiness to increased cerebrovascular events and mortality rate in elderly individuals [14].
Major efforts are underway in the USA and worldwide to
limit the use of antipsychotics in patients with dementia due
to these safety concerns. In atypical antipsychotic medication
studies, meta-analyses have not shown a significant benefit for
the non-aggressive symptoms of agitation [15,16] and efficacy is
only modest, especially given the concerning side effects [16-18].
Conventional antipsychotic medication studies found high
placebo responses in conjunction with high risk of problematic side effects [19-23].
In recent years, there has been significant progress in understanding the neurobiology of agitation in AD [10]. It is
postulated that NPS are associated with a combination of
serotonergic, noradrenergic, cholinergic and dopaminergic
neurotransmitter dysfunction. Neurobiological mechanisms
of agitation in AD include frontolimbic dissociation, imbalance in brain networks underlying affective and executive functions, neuroinflammation and alterations in neurotransmitters

Expert Opin. Pharmacother. (2015) 16(11)

Advancements in the treatment of agitation in AD

(serotonin, glutamate, sigma-1 and cannabinoids). Agitation

in AD is presumably caused by disruption in the afferent brain
monoamine system, specifically by the gradual erosion and
eventual destruction of ascending serotonergic pathways, leading to an imbalance in the serotonergic-dopaminergic axis [24].
Emerging evidence from neurobiological research about the
pathogenesis of agitation in AD has led to the investigation of
both repositioned and new therapeutics for agitation in AD.
Considerable progress has been made in the last years with a
growing number of randomized controlled trials of drugs for
agitation.

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2.

Dextromethorphan/quinidine

Dextromethorphan hydrobromide (DM) modulates glutamate signaling in two ways: a pre-synaptic inhibition of
glutamate release as a high-affinity sigma-1 receptor agonist,
and a modulation of post-synaptic glutamate response as a
low-affinity NMDA receptor antagonist. Furthermore, it
acts as a serotonin and norepinephrine reuptake inhibitor,
and neuronal a3b4 receptor antagonist. With quinidine
sulfate, the bioavailability of DM is increased in the plasma
and CNS [25].
The first randomized, placebo-controlled trial to assess the
efficacy and safety of DM/Q for the treatment of moderateto-severe agitation in AD was recently completed and top
line results have been reported [26]. Study 12-AVR-131 was
a Phase II, 220 patient, randomized, double-dummy, double-blind, placebo-controlled, 2-stage with consecutive
5-week treatment periods, sequential parallel comparison
design study; patients receiving placebo in stage 1 were stratified based on response and re-randomized 1:1 to
AVP-923 or continued placebo for stage 2. Patients were
aged 50 -- 90 years with probable AD, clinically significant
agitation (Clinical Global Impression of Severity [CGI-S]
for agitation score 4), and Mini-Mental State Exam
(MMSE) score of 8 -- 28. Stable doses of cholinesterase
inhibitors, memantine, antidepressants, antipsychotics or
hypnotics were allowed. Dosing consisted of AVP-923 (DM
20 mg/Q10 mg), escalated to AVP-923 (DM 30 mg/Q
10 mg) twice daily or matching placebo. The primary efficacy
analysis analyzed data from both 5-week stages (stage 1: all
patients + stage 2: the re-randomized placebo non-responders). The results of the primary efficacy analysis showed that
AVP-923 significantly reduced agitation compared with placebo (p < 0.001) as measured by the agitation/aggression
domain of the NPI for both stages combined as well as stage
1 only. Standard effect size (SES) for those who received
AVP-923 versus placebo in stage 1 was 0.505, and in stage
2 it was 0.340. The SES for the primary end point in those
that received only AVP-923 versus those who received only
placebo from baseline to end of 10 weeks was 0.480. The
improvement in agitation/aggression was corroborated by
global assessments from clinicians and patients/caregivers, as
shown by improvements in the modified Alzheimers Disease

Cooperative Study-Clinical Global Impression of Change

Rating (ADCS-CGIC) and Patient Global Impression of
Change. The majority of the secondary end points studied,
for example, NPI total, NPI-Agitation Caregiver Distress,
CGI-S Agitation, were statistically significant. Serious adverse
events were seen in 7.9% receiving DM/Q versus 4.7% receiving placebo. There were no deaths. Falls occurred in a greater
percentage of AVP-923 patients (8.6 vs 3.9%); diarrhea
occurred in 5.9% in AVP-923 versus 3.1% placebo, urinary
tract infections occurred in 5.3% in AVP-923 versus 3.9% in
placebo, while dizziness occurred in 4.6% in AVP-923 versus
2.4% in placebo. Vital signs and electrocardiogram showed
no clinically significant difference between groups. Further,
there was no evidence of cognitive decline or somnolence
during the study [26].
3.

Scyllo-inositol

Scyllo-inositol, or ELND005, appears to improve synaptic

activity in networks underlying NPS via a dual mechanism
of action: It regulates brain myoinositol metabolism and
phosphoinositol signaling, as well as providing protection
from oligomer-induced toxicity due to b-amyloid anti-aggregation effects [27]. ELND005 has been shown to have amyloid
and myoinositol-lowering effects [28] and beneficial trends on
agitation and aggression as secondary symptoms of AD [29].
A 78-week, Phase II, randomized, double-blind, placebo
controlled, dose ranging safety and efficacy study of oral
scyllo-inositol looked at 353 participants with mild-tomoderate AD. The 250 mg twice-daily dose demonstrated
acceptable safety and tolerability, reduced CSF A-Beta
x42 significantly compared with placebo, and proved to be
statistically significant on reducing the emergence of new
NPS in patients with mild AD, especially affective NPS,
such as depression and anxiety [28]. Based on those results, a
12-week, randomized, double-blind, placebo-controlled study
is underway (ELND005-AG201). The primary purpose of
this study is to determine whether ELND005 is effective in
treating symptoms of agitation and aggression in patients
with AD. Patients are aged 50 -- 95 years with probable AD,
clinically significant agitation (NPI-agitation/aggression
subscore of 4) and MMSE score of 5 -- 24. Stable doses of
cholinesterase inhibitors, memantine, antidepressants, antipsychotics or hypnotics are allowed. Dosing consists of a loading dose of scyllo-inositol 1000 mg or placebo twice daily for
the first 4 weeks and then a maintenance does of 250 mg or
placebo twice daily. The primary outcome measure is the
change from baseline in the Neuropsychiatric InventoryClinician rating scale combined agitation and aggression
subscores.
4.

Brexpiprazole

Brexpiprazole is an orally available dopamine receptor

D2 partial agonist. This quinolinone derivative is a successor

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to aripiprazole and they share structural molecular characteristics and receptor binding profiles. It has broad activity across
multiple monoamine systems with reduced partial agonism
for D2, D3, 5HT1A receptors and enhanced antagonism for
5-HT2A, and a1-adrenoreceptors [30]. There are subtle differences in the potency of the binding profiles but it remains to
be seen if that provides clinical advantages for brexpiprazole.
In Phase III trials, brexpiprazole is being studied in two
ways: in a 12-week, 560 patients, fixed-dose (1 and 2 mg) efficacy and tolerability study, as well as 230 patients with a flexible dose (range from 5 to 2 mg/day), both to determine
efficacy and tolerability in patients with moderate-to-severe
AD [31]. Patients are 55- to 90-year-old with probable AD,
clinically significant agitation (NPI-NH-agitation/aggression
subscore of 4) and MMSE score of 5 -- 22. The primary
outcome measure in both studies is the Cohen-Mansfield
Agitation Inventory total score.
5.

Prazosin

Neurobiological studies suggest that enhanced responsiveness

to norepinephrine at the a1-adrenoreceptor may contribute
to the pathophysiology of dementia-related agitation and
aggression. Prazosin is a centrally acting a1-adrenoceptor
antagonist that is widely used to treat hypertension and urinary symptoms associated with benign prostatic hypertrophy
as well as nightmares and sleep disturbance associated with
post-traumatic stress disorder. Pre-clinical studies suggest prazosin counteracts b-amyloid-induced vasoconstriction mediated via the a1-adrenergic receptor signaling [32]. Transgenic
APP23 mice treated with prazosin avoided obtaining memory
deficits over time [33]. In an open -label study of patients with
AD and treatment-resistant agitation, prazosin reduced agitation and was well tolerated [34].
In a subsequent 8-week, double-blind, randomized,
placebo-controlled, parallel group study of 22 nursing home
residents with probable or possible AD and agitated or aggressive behaviors, prazosin treatment (n = 11), starting at 1 mg
daily and flexibly raised to 6 mg daily (mean dose 5.7
0.9 mg/day) showed greater improvement than placebo treatment (n = 11) on the Brief Psychiatric Rating Scale and the
NPI [35]. The drug was well tolerated during this pilot study,
encouraging further study. A multicenter study of prazosin
for patients with AD and treatment-resistant agitation is
planned by the Alzheimers Disease Cooperative Study Group
(ADCS) as part of its current 5-year funding cycle.
6.

Cannabinoids

Several neurobiological effects of cannabinoids might be

relevant in the treatment of dementia. These compounds
are the active components derived from the cannabis plant
(Cannabis sativa). An endogenous cannabinoid system has
been identified where these compounds exert their effect by
acting at two specific cannabinoid receptors, CB1 and
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CB2. CB1 receptors are found throughout the CNS, particularly in the hippocampus, basal ganglia and cerebellum,
whereas CB2 receptors are mostly expressed in peripheral
tissues. Delta-9-tetrahydrocannabinol (THC), the most
biologically active isomer of (-)-trans-D9-tetrahydrocannabinol ((6aR,10aR)-delta-9-tetrahydrocannabinol), is a psychoactive compound that activates cannabinoid receptors
(mainly type 1), which represses neurotransmitter release in
the brain and regulates synaptic transmission. Studies are
also showing evidence of neuroprotective effects of cannabinoids. The exact mechanism of action is not known, but
could involve reduced excitotoxicity through regulation of
glutamate and reduced neuroinflammation [36].
The cannabinoid receptor agonist dronabinol is reported to
improve anorexia and agitation as well as nocturnal agitation
in patients with dementia. Furthermore, a retrospective
systematic chart review was conducted on 40 inpatients with
dementia, who received dronabinol for behavioral and appetite disturbances. A significant decrease in all domains of the
Pittsburgh Agitation Scale was found, in addition to improvement in Clinical Global Impression scores, sleep duration and
meal consumption. The drug was generally well tolerated [37].
A Phase II, randomized, multicenter, double-blind, parallel
group study to explore the efficacy and safety of dronabinol
as a treatment for behavioral disturbances and pain in patients
with dementia is underway. This 3-week study enrolls
patients with mild-to-severe dementia that are older than
40 years of age and have clinically relevant behavioral disturbance defined as a score of 10 on the NPI, which also serves
as the primary outcome measure.
7.

Citalopram

Citalopram, a selective serotonin reuptake inhibitor, improves

functional serotonergic neurotransmission. The Citalopram
for Agitation in Alzheimers Disease Study (CitAD) was a
multicenter, randomized, placebo-controlled, double-blind,
parallel group clinical trial, where 186 participants diagnosed
with probable AD (MMSE score 5 -- 28) experiencing clinically significant agitation were randomized to receive either
a 30 mg dose of citalopram or placebo in addition to psychosocial treatment [6]. Withdrawal of psychotropic medications
other than pre-defined rescue medications was required.
Patients with depressive or psychotic symptoms requiring
treatment were excluded. The CitAD study also measured
safety and tolerability of the active treatment as well as its
effect on caregiver distress [14]. The study found statistically
significant and clinically meaningful reduction in agitation
in the citalopram group over placebo on both primary outcome measures: The Neurobehavioral Rating Scale, agitation
subscale estimated treatment difference at week 9 (citalopram
minus placebo) was -0.93 points (95% CI: -1.80 to -0.06;
p = 0.04). Forty percent of citalopram-treated group were
rated as moderately or markedly improved on the modified
ADCS-CGIC compared with 26% of placebo recipients

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Advancements in the treatment of agitation in AD

with estimated treatment effect (odds ratio [OR] being at or

better than a given CGIC category) of OR being 2.13 (95%
CI: 1.23 -- 3.69; p = 0.01). The citalopram-treated group
also showed significant improvement on the short-form
Cohen-Mansfield Agitation Inventory, total Neuropsychiatric
Inventory and caregiver distress scores; but not on the Neuropsychiatric Inventory agitation subscale, Activities of Daily
Living or in less use of rescue lorazepam. Citalopram was
associated with known SSRI-mediated side effects that were
predominantly mild to moderate in severity. On the other
hand, MMSE results revealed a modest but statistically significant cognitive decline in the citalopram group compared
with placebo (--1.05 points; 95% CI: -1.97 to -0.13;
p = 0.03) [6]. The clinical significance of this finding is uncertain. Prolongation of the QTc interval at the 30 mg dose was
demonstrated on ECG (mean elongation 18.12 ms; 95%
CI: 6.1 -- 30.1; p = 0.004), and was consistent with the recent
FDA required change to the label for citalopram, warning
against its use at doses above 20 mg daily in patients older
than 60 years of age [38]. More participants in the citalopram
group had a clinically significant increase of greater than
30 ms from enrollment to week 3 than the placebo group
(Fishers exact p = 0.046). Few patients met the genderspecific threshold for prolonged QTc at any point during follow-up. No participants in either group had a cardiovascularrelated death.
While citalopram is a therapeutic option for the treatment
of agitation in AD, the concerning side effects of cognitive
worsening and delayed cardiac repolarization seen in the
CitAD study urge dose constraints and caution in this patient
population.
8.

Conclusions

NPS of dementia such as agitation are among the most complex, stressful and costly aspects of care, leading to frequent
hospitalizations, early nursing home placement and increased
morbidity and mortality. The causes of agitation in AD are
multifactorial and may include patient discomfort, communication problems, medical comorbidities, environmental
factors, drug effects and neurobiological changes associated
with AD-related neurodegeneration. The optimal approach
to treating agitation in AD thus requires assessing the individual patients circumstances, including symptom severity, value
of improvement, cognitive function and change, cardiac conduction, vulnerability to adverse effects and effectiveness of
behavioral interventions. Use of psychosocial interventions
may have a positive impact on both the patient and the caregiver, and are considered as first-line treatment for agitation in
dementia and recommended for all patients. There is a wide
variety of proposed non-pharmacologic treatments and while
understanding that response to interventions is unpredictable,
a meta-analysis of various psychological approaches found
that behavior management therapies and specific types of
caregiver and residential care staff education had the most

lasting benefits for the management of NPS in dementia

patients in comparison to music therapy and sensory stimulation, which have positive but short-lived effects [39]. For
the patients who do not adequately respond to nonpharmacologic interventions, a judicious pharmacologic intervention is indicated. Many psychotropic drugs are used for
agitation. These include antipsychotics, sedatives/hypnotics,
anxiolytics and antidepressants, but safety concerns and questionable efficacy limit their utility. Neurobiological research
centered on the pathogenesis of agitation in AD has fueled a
growing number of randomized controlled trials of drugs for
agitation and other NPS. Several drugs have shown positive
outcomes in Phase II trials with Phase III trials planned and
underway, hopefully establishing a new treatment paradigm
for agitation in AD. Reducing the use of antipsychotics in
elderly patients with dementia will become an even greater
priority over the next few years. It is likely that the CitAD
and DM/Q studies will immediately impact practice in the
field as both medications are commercially available and there
is a large commercial opportunity for medications that are
safe, well tolerated and efficacious for NPS in dementia,
including agitation. Caution is advised for higher doses of
citalopram.
9.

Expert opinion

NPS are widely acknowledged as a major public-health priority area in the field of neurodegenerative disease. They add
significant disability for patients and caregivers and with
relative scarcity of effective treatments constitute a major
unmet need. Over the past two decades, clinical trials in AD
have produced a sea of disappointing results. One area of
treatment development offers a welcome change and a modicum of hope. After being more or less abandoned for over a
decade, two developments laid the foundation for recent
resurgence and positive signs in the area of pharmacological
treatment of NPS. First, neurobiological research has identified a range of neuroanatomical, neurophysiological and neurochemical changes that are associated with NPS. Second,
enhanced trials design and conduct, marks a significant step
forward. Methodological heterogeneity was a hallmark of
previous clinical trials. The recent positive trials in agitation
and other NPS have certain similarities in design, including
clearer entry criteria and improved outcome measures. The
recent provisional consensus criteria for agitation in AD proposed by the IPA working group to facilitate research may further harmonize entry criteria for trials and thus enhance the
probability of regulatory acceptance by addressing the pseudospecificity concerns often raised regarding NPS. There is
intrinsic variability to NPS such as agitation, which has to
be addressed by incorporating predictors of response into
the design, conduct and analyses of the trials. This may clarify
the regulatory pathway and labeling and give guidance
for clinicians for what interventions work for which patients
and how they might be best applied sequentially.

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Incorporating design features such as placebo lead-in and

sequential parallel comparison design may minimize the
impact of the regularly seen robust placebo response on
efficacy measures. Furthermore, NPS such as agitation have
multifactorial causes that likely will call for multiple interventions for the best outcomes and large treatment effects.
On the clinical care end, the short-term implication means
addressing all potentially modifiable causes such as medical
comorbidities, patient discomfort, communication problems
and environmental factors. Enhancing treatment guidelines
to include careful and systematized work-up and emphasize
implementation of psychosocial interventions is imperative
and calls for better access to training programs or approaches
for assessing and managing agitation and other NPS. This is
an area of particular need.
Similarly, in order to mirror this approach on the clinical
trials end we need to:
1) Include and standardize a psychosocial intervention
included in drug trials both to reduce variance in how
it is conducted between sites and also to better understand and explore predictors of response to the psychosocial intervention as well as the duration and quality of
the response.
2) Define sub-populations of patients in which specific
agents are most effective, and to develop algorithms
to dovetail the use of psychosocial interventions with
medication.
3) Explore not only individual behavioral symptoms, but
also clusters of symptoms.
4) Include careful measures of safety and tolerability consistent with known or suspected adverse event profiles
to include measures of cognition, cardiovascular impact
such as cardiac repolarization and orthostasis, fall risk
and other impact on motor function.
5) Consider that compounds in development have different mechanism of action and thus possibly variable
onset of treatment effect. The duration of double-blind
clinical trials will continue to differ even as entry criteria and outcome measures become more standardized.
Information on extended treatment exposure to ascertain long-term safety, tolerability and efficacy is imperative. That can be done through open-label extensions
of pivotal trials.
In the longer run, we need to understand the impact of new
diagnostic and biomarker approaches to AD. This includes
addressing NPS in preclinical and prodromal stages of AD
where the nature and severity of these symptoms are different.
We know the presence of NPS has an impact on course, even
at this very early disease stage. What is not known yet, is
whether satisfactory treatment of these NPS may impact
course and prognosis. Incorporating reliable and sensitive
instruments for this purpose in early stage trials where the
focus is on prevention or delayed progression will help our
1654

understanding and clarify whether disease-modifying interventions have a suppressive effect on the presence and emergence of NPS or conversely, if there is potential behavioral
toxicity.
NPS are equally troublesome in other dementias, including
dementia with Lewy bodies, Parkinsons dementia, vascular
dementia and frontotemporal dementia. While much of the
current research focus is on AD, we do not know whether
positive impact on agitation in recent trials in patients with
AD will translate into agitated behaviors in these other
dementias. Each one of them has particular and distinct profiles of behavioral disruptions and while there is overlap
between the various dementias, there are also differences.
There is also active exploration of drugs for other behavioral
indications and patient groups as evidenced by positive results
from a recent Phase II trial of pimavanserine, a 5-HT2A
inverse agonist in patients with Parkinsons disease psychosis.
The study revealed reduction in psychotic symptoms,
improved night-time sleep without increasing day-time somnolence and reduced caregiver burden [40]. Furthermore, there
are other trials focused on NPS in AD besides agitation. These
include a trial of methylphenidate for apathy; pimavanserine
for psychosis; encenicline (a7-nicotinic agonist), idalopirdine
(5-HT6 antagonist) and SAM-760 (5-HT6 antagonist),
where all three drugs are in Phase II or III studies as adjunct
therapy, where in addition to cognitive and functional impact,
broad positive impact on NPS is hoped for.
Finding thoughtful, more effective and better tolerated
interventions for NPS is a major challenge for investigators
and clinicians and must remain an urgent priority. The excitement around recent advancements in the treatment of agitation in AD appears well founded and it is reasonable to
expect significant progress in this area over the next several
years that ultimately will greatly improve the quality of life
for patients with dementia and their caregivers.

Declaration of interest
A Porsteinsson reports receipt of a grant to his institution
from AstraZeneca, Avanir, Baxter, Biogen, BMS, Eisai, Elan,
EnVivo, Genentech/Roche, Janssen Alzheimer Initiative,
Medivation, Merck, Pfizer, Toyama, Transition Therapeutics,
the National Institutes of Health (NIH), the National
Institute of Mental Health (NIMH), the National Institute
on Aging (NIA) and the Department of Defense; paid consultancy for Elan, Janssen Alzheimer Initiative, Lundbeck, Pfizer
and TransTech Pharma; membership on data safety and monitoring boards for Quintiles, Functional Neuromodulation
and the New York State Psychiatric Institute; participation
on a speakers bureau for Forest and development of educational presentations for CME Inc and PVI. The authors
have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or
financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.

Expert Opin. Pharmacother. (2015) 16(11)

Advancements in the treatment of agitation in AD

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Affiliation
Inga M Antonsdottir1 BS, Jessica Smith2 BS,
Melanie Keltz2 BA &
Anton P Porsteinsson2 MD

Author for correspondence

1
University of Rochester, Department of Brain
and Cognitive Sciences and Center for Visual
Science, 435 East Henrietta Road, Rochester, NY
14620, USA
2
University of Rochester School of Medicine and
Dentistry, Department of Psychiatry, Alzheimers
Disease Care, Research and Education Program
(AD-CARE), 435 East Henrietta Road,
Rochester, NY 14620, USA
Tel: +1 585 760 6550;
Fax: +1 585 760 6572;
E-mail: Anton_Porsteinsson@URMC.rochester.
edu