Alzheimer’s & Dementia: Translational Research & Clinical Interventions 3 (2017) 440-449

Review Article

Neuropsychiatric signs and symptoms of Alzheimer’s disease:

New treatment paradigms
Krista L. Lanct^ota,*, Joan Amatniekb, Sonia Ancoli-Israelc,d, Steven E. Arnolde, Clive Ballardf,g,
Jiska Cohen-Mansfieldh, Zahinoor Ismaili, Constantine Lyketsosj, David S. Millerk, Erik Musiekl,
Ricardo S. Osoriom, Paul B. Rosenbergn, Andrew Satlino, David Steffensp, Pierre Tariotq,
Lisa J. Bainr, Maria C. Carrillos, James A. Hendrixs, Heidi Jurgenss, Brendon Boott,u
a
Hurvitz Brain Sciences Program, Sunnybrook Research Institute and Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Canada
b
Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA
c
Department of Psychiatry, University of California, San Diego, CA, USA
d
Department of Medicine, University of California, San Diego, CA, USA
e
Interdisciplinary Brain Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
f
Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
g
University of Exeter, Exeter, UK
h
Department of Health Promotion, School of Public Health, Sackler Faculty of Medicine and Minerva Center for the Interdisciplinary Study of End of Life, Tel
Aviv University, Tel Aviv, Israel
i
Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
j
Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine Institutes, Baltimore, MD, USA
k
Bracket Global, Wayne, PA, USA
l
Department of Neurology, Hope Center for Neurological Disorders, and Knight Alzheimer Disease Research Center, Washington University School of
Medicine, St. Louis, MO, USA
m
Center for Brain Health, NYU Langone Medical Center, New York, NY, USA
n
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
o
Eisai, Inc., Woodcliff Lake, NJ, USA
p
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
q
Banner Alzheimer’s Institute, Phoenix, AZ, USA
r
Elverson, PA, USA
s
Alzheimer’s Association, Chicago, IL, USA
t
Department of Neurology, Brigham and Women’s Hospital, Harvard University School of Medicine, Boston, MA, USA
u
Voyager Therapeutics, Cambridge, MA, USA

Abstract Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimer’s disease (AD), causing substan-
tial distress for both people with dementia and their caregivers, and contributing to early institution-
alization. They are among the earliest signs and symptoms of neurocognitive disorders and incipient
cognitive decline, yet are under-recognized and often challenging to treat. With this in mind, the Alz-
heimer’s Association convened a Research Roundtable in May 2016, bringing together experts from
academia, industry, and regulatory agencies to discuss the latest understanding of NPSs and review
the development of therapeutics and biomarkers of NPSs in AD. This review will explore the neuro-
biology of NPSs in AD and specific symptoms common in AD such as psychosis, agitation, apathy,
depression, and sleep disturbances. In addition, clinical trial designs for NPSs in AD and regulatory
considerations will be discussed.
Ó 2017 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).

*Corresponding author. Tel.: 11-4164806100; Fax: 11-4164806022.

E-mail address: krista.lanctot@sunnybrook.ca

http://dx.doi.org/10.1016/j.trci.2017.07.001
2352-8737/ Ó 2017 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 K.L. Lanct^ot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 3 (2017) 440-449
Keywords: Alzheimer’s disease; Neuropsychiatric symptoms; Trial design; Delusions; Hallucinations; Agitation; Apathy;
Depression; Sleep disturbance
1. Introduction
Neuropsychiatric symptoms (NPSs) are hallmarks of Alz-
heimer’s disease (AD), causing substantial distress for both
people with dementia and their caregivers, and contributing
to early institutionalization. They are among the earliest signs
and symptoms of neurocognitive disorders and incipient cogni-
tive decline, yet are under-recognized and often challenging to
treat. The Alzheimer’s Association’s Research Roundtable, a
consortium of experts from academia, industry, and regulatory
agencies first addressed these challenges in 2010 [1].
Since then, there is renewed interest in mechanisms of
NPSs and identification of effective treatments for these
symptoms, in part through the efforts of the NPS professional
interest area within the International Society to Advance
Alzheimer’s Research and Treatment [2]. In May 2016, the
Research Roundtable revisited the topic, bringing together
experts in the field to advance therapy development through
a more comprehensive understanding of underlying mecha-
nisms and application of novel clinical trial approaches.
2. History and overview
NPSs affect almost all individuals with dementia (97%)
over the course of the disease [3], and although they fluctuate
[4], they rarely disappear [5]. The effects on both patients
and caregivers are severe: they are associated with impair-
ment in activities of daily living [6], poor quality of life
[7], earlier institutionalization [8], accelerated disease
progression, increased mortality [9], caregiver stress [10],
and increased cost of care [11].
Medical, environmental, and caregiver issues can impact
the expression of NPSs, making the categorization of the
symptoms challenging [12]. Each of these approaches has
limitations because nosology does not always reflect patho-
physiology. The top-down classification system of the Diag-
nostic and Statistical Manual, 5th edition, provides various
syndrome categories, yet NPSs overlap substantially among
these syndromes. For example, agitation may accompany
depression, anxiety, or psychosis. The Research Domain
Criteria project classifies NPSs based on neurobiological di-
mensions and behaviors rather than clinical syndromes,
grouping them into five domains: (1) negative valence; (2)
positive valence; (3) cognitive systems; (4) processes for so-
cial systems; and (5) arousal or regulatory systems [13]. Yet
here, too, there is tremendous overlap. For example, impair-
ment of cognitive systems may manifest in delusions, hallu-
cinations, agitation, aggression, depression or dysphoria,
anxiety, elation or euphoria, apathy, disinhibition, irritabil-
ity, motor disturbance, sleep disorder, appetite disorder,
aberrant vocalization, and ruminative, repetitive, and soma-
toform behaviors. Extensive overlap is also evident when
441
NPSs are mapped to domains such as memory, visuospatial,
executive function, or others.
The Neuropsychiatric Inventory (NPI) [14] is commonly
used to assess NPSs in clinical trials. A meta-analysis of studies
using this scale found that apathy was the most common NPS,
followed by depression, aggression, anxiety, sleep distur-
bances, irritability, appetite disturbances, motor problems, de-
lusions, disinhibition, hallucinations, and euphoria [15]. The
NPI has some limitations: it multiplies severity and frequency
scores resulting in noncontinuous and non-normal total scores
[16], it fails to capture ruminative, repetitive, compulsive, and
somatoform behaviors, and is dependent on caregiver report.
The Clinician Rating of the NPI (NPI-C) expands the range
of the symptoms assessed by the NPI [17].
NPSs can present in advance of dementia. Among
cognitively normal individuals, symptoms of depression,
irritability, agitation, and apathy predict more rapid cogni-
tive decline [18–20]; some NPSs are more powerful
predictors of incident mild cognitive impairment (MCI)
than hippocampal atrophy [21]. One MCI study found
NPSs in 59% of participants and were associated with poorer
cognitive and psychosocial function [22]. Their presence
predicted faster progression from MCI to dementia in two
very large cohort studies [9,23].
NPSs typically emerge in three phases: (1) irritability,
depression, and nighttime behavior changes; (2) anxiety,
appetite changes, agitation, and apathy; and (3) elation, motor
disturbances, hallucinations, delusions, and disinhibition [24].
This emergence of NPSs in later life is core to the construct of
mild behavioral impairment (MBI), which describes later life
acquired, sustained, and impactful NPS as an “at-risk” state
for cognitive decline and dementia. Operationalized in
the recently published Alzheimer’s Association International
Society to Advance Alzheimer’s Research and Treatment
(ISTAART) MBI criteria [25], NPSs can emerge in advance
of, or in concert with MCI, must be of at least 6-month dura-
tion, and not better accounted for by conventional psychiatric
nosology. MBI symptoms are categorized into five domains:
decreased drive and motivation, affective and emotional
dysregulation, impulsivity, social inappropriateness, and
abnormal perceptions or thoughts (e.g., delusions and halluci-
nations). Many rating scales used in dementia do not differen-
tiate between new symptoms and chronic psychiatric illness,
and they have short reference times that may not allow time
to rule out reactive states. The MBI checklist was developed
to remedy these issues [26] (available at www.MBItest.org).
The MBI criteria and MBI checklist will provide a screening
method to capture neurodegenerative disease early, foster sys-
tematic research into the effect or predictive value of NPSs on
cognitive and functional outcomes, and improve clinical trial
enrollment and design [25,27].
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Although the presence of NPSs in the early stages of
dementia predict disease progression, it is not clear whether
NPSs reflect a more aggressive form of disease [28]. In
addition, there are few pharmacologic treatment options
with proven efficacy and acceptable levels of risk that target
NPSs. Only one medication is approved in AD for treatment
of NPSs (Canada and Europe only): risperidone for
short-term treatment of aggression. Nonpharmacologic inter-
ventions are considered by most clinicians to be first-line treat-
ments, yet translation from clinical studies to the real world
has been limited [29], in part because these interventions are
not reimbursed, and caregivers are not trained to provide
them. They are generally based on psychosocial models for
understanding these conditions across the continuum of the
disease and in the presence of comorbid conditions [30–33].
3. The neurobiology of NPSs in AD
Understanding the neurobiology of NPSs in the context of
the AD brain could greatly advance the development of new
therapies. Most efforts to map the progression of AD pathol-
ogy have focused on the cortex (e.g. [34]). For NPSs, however,
distinct syndromes have different neurobiological underpin-
nings, so understanding the dysfunction or dysregulation of
subcortical forebrain, diencephalic, and brainstem nuclei
that generate or mediate visceral, emotional, motivational,
and other psychiatric symptoms will be required. Early
studies recognized significant involvement of AD pathology
in key components of the limbic system, including the amyg-
dala, basal forebrain, hypothalamus, and brainstem. Neurofi-
brillary tangles, for example, are abundant in the amygdala of
the Alzheimer’s brain [35], as well as in the basal nucleus of
Meynert [36], the locus coeruleus [37], substantia nigra [38],
dorsal raphe nucleus [39], and hypothalamus [40]. Neuronal
loss in the basal nucleus of Meynert and locus coeruleus
also correlates with progression of AD dementia [41]. The hy-
pothalamus is important for the regulation of appetite, sleep,
and circadian rhythms, and mediates many aspects of
emotional experience. However, the degree to which patho-
logic involvement of these structures correlates with NPSs
has not been well studied. The relevance of neuropathology
is fundamental to drug development, where currently
approved treatments for mood and psychotic symptoms,
such as antidepressants and antipsychotics, may not work
because of lack of target engagement in a degenerating brain.
4. Neuropsychiatric symptoms
This section will review the neurobiology, epidemiology,
and current treatments for psychosis, agitation, apathy,
depression, and sleep disturbances.
4.1. Psychotic symptoms in AD
Both delusions and hallucinations are reported in AD
[42]. In a study of 124 demented patients, 67% had psychotic
symptoms. They occurred two to six times per week, per-
sisted for 12 weeks among 32% and recurred in 50% within
12 months [43]. They were associated with accelerated
cognitive and functional decline and increased mortality
[44]. These frequencies were higher still among patients
with dementia with Lewy bodies. Hallucinations occur less
frequently than delusions in AD and rarely occur in isola-
tion; the opposite is true for dementia with Lewy bodies
and Parkinson’s disease dementia. The hallucinations and
delusions in AD are phenomenologically different to those
in schizophrenia, psychotic depression, or mania. Hallucina-
tions in AD are usually visual, less commonly auditory, and
rarely tactile or olfactory [45]. Persecutory delusions occur
earlier in AD than misidentification delusions; both kinds in-
crease with dementia severity.
Psychotic symptoms are correlated with increased
neocortical neurofibrillary tangles [46], increased levels of
intraneuronal hyperphosphorylated tau [47], disruption of
serotoninergic signaling [48], decreased neuronal density,
and increased myoinositol/creatinine ratio assessed using
proton magnetic resonance spectroscopy [49]. Individuals
with MCI who develop delusions also have greater gray-
matter atrophy, particularly in the right frontal areas that
regulate inhibitory control [50,51]. Some psychotic
presentations are associated with distinct neuroanatomic
substrates. For example, misidentifications, which might
be understood as a disconnect between memory and
familiarity, are associated with lower cell counts in the
hippocampal CA1 region. Persecutory delusions are
associated with cell loss in the dorsal raphe nucleus [52].
Genetics may play a role in AD psychosis: the serotonin
2A receptor single-nucleotide polymorphism 102 T allele is
associated with the presence of delusions, whereas the C
allele is protective [53]. The apolipoprotein E (APOE) 34
allele is associated with an increased risk for AD, but the as-
sociation between APOE 34 and NPSs in AD is weak [54].
In recent years, atypical antipsychotics such as risperi-
done, olanzapine, quetiapine, and aripiprazole have largely
replaced conventional antipsychotics such as haloperidol
for the treatment of psychosis in dementia. They have mini-
mal efficacy on psychotic symptoms [55] but are associated
with many adverse effects, such as somnolence, cognitive
decline, movement disorders, infections, edema, weight
gain, metabolic syndrome, and hypotension, which leads to
an increased risk of falls and stroke [55]. The major concern
is their association with an increased risk of death [56]. Alter-
native treatments, such the 5-HT2A receptor antagonists/in-
verse agonists and 5-HT6 receptor antagonists, are
undergoing clinical evaluation in AD psychosis. Part of the
challenge in the development of new therapies is that psycho-
sis in AD is difficult to define and clinically heterogeneous,
and there is a paucity of clinically relevant outcome measures.
An alternative approach conceptualizes dementia psy-
chosis as the combined impact of memory loss with other
personal factors, such as post-traumatic stress disorder
[57,58]. For example, a dementia sufferer might forget
 K.L. Lanct^ot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 3 (2017) 440-449
where she placed her makeup and presume someone has
stolen it, but will change this perception when the makeup
is found. The core symptom is memory loss and not a
psychotic episode. Thus, treatments targeting memory
rather than psychosis would be more appropriate. Effective
psychological interventions for functional psychosis might
also be adapted for people with AD [59].
4.2. Agitation in AD
Agitation occurs frequently in AD. The prevalence varies
greatly between studies due to the use of different defini-
tions. The International Psychogeriatric Association
consensus statement defines agitation as excessive motor ac-
tivity, or verbal or physical aggression that associated with
emotional distress: (1) severe enough to produce disability;
(2) beyond what would be expected from cognitive impair-
ment by itself; and (3) not solely attributable to another dis-
order, environmental conditions, or the physiological effects
of a substance [60]. Agitation tends to persist; it increases as
disease severity increases and is often associated with psy-
chosis, anxiety, and disinhibition. Agitation and psychosis
together are predictive of more rapid decline, increased insti-
tutionalization, and earlier death.
As recently reviewed, agitation in AD is associated with
structural and functional abnormalities of the brain regions
associated with emotional regulation and salience: the
frontal, anterior cingulate, and posterior cingulate cortices,
amygdala, and hippocampus [61]. Degeneration of these cir-
cuits may result in the overestimation of threat and/or
affective dysregulation that induces hypervigilance.
Agitation and aggression are associated with decreased cholin-
ergic and serotoninergic markers, increased tau and phospho-
tau, and regional decreases in the N-acetylaspartate/creatine
ratio and increases in the myoinositol/creatine ratio [49,62].
Psychological theoretical frameworks provide alternative
models with which to understand agitation in dementia [63].
The behavioral model focuses on triggers to the agitated
behavior and reinforcements, which maintain the behavior.
Interventions focus on eliminating the triggers and changing
the relationship between behavior and reinforcement. The
reduced stress threshold model posits that persons with
dementia have a reduced threshold for stress, necessitating
a very calm and quiet environment. The unmet needs model
describes how people with dementia are unable to address
their own needs or communicate them to others. These needs
are unmet because their caregivers are unaware of the needs
or of ways to meet them [64].
Both nonpharmacologic and pharmacologic approaches are
used to manage agitation in patients with AD [12].
Nonpharmacologic approaches are based on psychosocial par-
adigms for NPSs and address them based on the specific model
used. However, several general principles apply, including a
detailed assessment of potential unmet needs and environ-
mental or interpersonal stressors. The intervention is tailored
to the NPS, the person with dementia’s preferences and cogni-
443
tive, motor, and sensory abilities. These approaches educate
caregivers, make changes to the physical environment, increase
social engagement, exercise and activities, and address sleep
problems. They produce significant positive impacts on NPSs
in randomized controlled trials [65,66]. The comprehensive
assessment includes assessing pain, discomfort, and other
medical conditions, as sometimes treating other medical
conditions may relieve agitation. For example, many patients
with dementia have pain, which may increase agitation and
anxiety [67]. Indeed, treatment of pain has been shown to alle-
viate agitation in persons with dementia [68].
A range of medications—antipsychotics, benzodiaze-
pines, cholinesterase inhibitors, memantine, anticonvul-
sants, and selective serotonin reuptake inhibitor (SSRI)
antidepressants—have been used to treat agitation in
patients with dementia but have shown minimal efficacy
and/or substantial adverse effects. In a recent study, the
SSRI citalopram was shown to reduce agitation and care-
giver distress but was associated with cognitive decline
and corrected QT interval prolongation [69]. A combination
of dextromethorphan hydrobromide and quinidine sulfate,
which is approved for the treatment of pseudobulbar affect
in amyotrophic lateral sclerosis, is being investigated as a
treatment for agitation in AD [70]. Several other drug devel-
opment efforts targeting N-methyl-D-aspartate, dopamine
D2, and serotonin receptors (5-HT1A and 5-HT2A), and
cannabinoids are also being assessed.
4.3. Apathy in AD
Apathy, characterized by lack of motivation, decreased
initiative, akinesia, and emotional indifference, is the most
common NPS associated with AD and a primary cause of
caregiver distress [71]. It is common in predementia states,
increases in frequency as the disease progresses, and predicts
conversion from normal cognition to MCI and MCI to
dementia [72]. An international task force published
diagnostic criteria for apathy in 2009, which require that
two of three dimensions of diminished motivation must be
present for at least 4 weeks with identifiable associated func-
tional impairment [73]. The Apathy Evaluation Scale is
commonly used to assess apathy across the AD continuum
[72,74]. The NPI also includes an apathy subscale, but it
has not yet been validated for use on its own. Apathy can
occur alone or as a symptom of depression [75].
In neuroimaging studies of preclinical or prodromal AD,
apathy is associated with cortical dysfunction in the posterior
cingulate or inferior temporal cortex as well as atrophy,
hypometabolism, and hypoperfusion in these regions.
Abnormalities in cholinergic, GABAergic, and dopaminergic
function have also been associated with apathy, as well as
high levels of tau and phospho-tau in the cerebrospinal fluid
(CSF) [76]. Dopaminergic circuits have been targeted in
treatment trials using methylphenidate, with a significant
reduction in apathy symptoms, improvement in global
cognition, and minimal adverse events, for more than the
444 K.L. Lanct^ot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 3 (2017) 440-449
6-week study [77]. Interim results from another study also
suggest that the combination of an acetylcholinesterase
inhibitor (donepezil) with a cholinergic precursor
(choline alphoscerate) decreased apathy and caregiver
distress [78]. Open label studies of cholinesterase inhibitors
(donepezil, galantamine, and rivastigmine) showed improve-
ment in apathy for all three medications [58].
4.4. Depression in AD
Depression is found in 16% in population-based AD
studies, and 44.3% in hospital-based studies [79]. Depres-
sion is also common in MCI. A meta-analysis of 57 studies
found an omnibus prevalence of 32%, but depressive symp-
toms more prevalent in clinical (40%) versus community-
based (25%) samples [68] reflecting their clinical relevance
in the cognitively impaired. Depression is also a predictor of
progression from normal cognition to MCI and from MCI to
dementia. However, whether depressive symptoms represent
a risk factor or early manifestation of the AD brain disease or
both is unclear. Supporting the latter notion, the presence of
MCI in depression has been shown to predict later develop-
ment of AD [80].
More severe neuropathology (tau, amyloid, and vascular
disease) is seen in patients with AD with depression
compared to those without. These patients also show severe
loss of serotonin receptors and serotonin transporter binding,
which may have implications for treatment [81].
Several studies have examined antidepressant efficacy in
the context of AD. The Depression in Alzheimer’s Disease
Study (DIADS) demonstrated improvement with sertraline
compared with placebo in patients with AD with major
depression for more than 12 weeks [82]. A follow-up study,
DIADS-2, included patients meeting criteria for “depression
of AD,” but found no differences in depression outcomes for
more than 12 weeks of treatment with sertraline or placebo
[83]. There were no differences in outcome in a 13-week
trial comparing sertraline, mirtazapine, or placebo [84].
A meta-analysis of SSRI and serotonin-norepinephrine reup-
take inhibitors (SRNI) treatment for depression in AD found
“small to null”effect sizes [85], with small responses in those
with subsyndromal levels of depression. Standardized psy-
chosocial interventions were given to caregivers concomi-
tantly in both DIADS and DIADS-2. There is some
evidence that psychosocial interventions such as these, as
well as exercise, increasing social contact, reminiscent ther-
apy, and others can be efficacious (reviewed in [64,86]). For
example, cognitive rehabilitation may decrease depression
among women with AD and mild dementia [87].
4.5. Sleep disturbances and AD
A bidirectional relationship between sleep disturbances
and dementia has been demonstrated in both humans and
animals. For example, sleep problems and sleep disruption
are associated with increased risk of cognitive decline
[88,89] and higher risk for developing dementia [90].
Cognitively normal people with biomarkers of AD have
slightly decreased sleep efficiency [91]. A similar relation-
ship is seen between the presence of sleep apnea and de-
mentia: those with sleep apnea are more likely to
develop MCI and dementia [92,93] and those with more
severe dementia have more severe sleep apnea [94]. In
addition, sleep apnea has been associated with a younger
age of decline to MCI or AD [95]. Circadian rhythm
disruption has also been linked to a greater risk of MCI
and dementia [96], as well as neuroinflammation and syn-
aptic loss in mice [97].
The link between disrupted sleep and dementia may be
the accumulation of amyloid b (Ab) in the brain, according
to studies in mice [98] and humans [99]. Ab dynamics in the
brain and CSF are strongly influenced by the sleep-wake
cycle, and sleep deprivation accelerates Ab plaque
deposition in mice [68,69]. Orexin, a hypothalamic
neurotransmitter implicated in sleep homeostasis, may
play a role in Ab regulation as genetic or pharmacologic
inhibition of orexin function suppresses Ab pathology in
mice [100,101]. The glymphatic system—an astrocyte-
driven system of perivascular fluid flow through which the
brain removes toxic waste products—may also play an
important role because slow-wave sleep (SWS) dramati-
cally increases glymphatic influx and efflux [102]. SWS is
also the stage of sleep where there is a greater reduction
in corticocortical connectivity [103–107] and cerebral
blood flow [108,109], indicating that it may also play a
role in decreasing Ab production (which is closely
associated with neuronal activity [110]) as shown by two
recent human studies in which slow-wave activity was asso-
ciated with decreased CSF Ab40 and Ab42 levels in healthy
control subjects [111].
These data suggest that behavioral and pharmacologic
interventions targeting SWS enhancement, sleep disorders,
and circadian disturbances may improve cognitive func-
tion or slow deterioration. These include both nonpharma-
cologic approaches such as bright-light therapy [112,113]
and pharmacologic approaches using cholinesterase
inhibitors, trazodone, melatonin or melatonin agonists,
and orexin antagonists. However, a recent meta-analysis
of drug treatment versus placebo for sleep disorders in pa-
tients with AD found insufficient evidence to help guide
drug treatment of sleep problems in AD [114], and there
is some uncertainty about the balance of benefits and risks
associated with these common treatments. Continuous
positive airway pressure for sleep apnea may also delay
the progression of cognitive impairment in patients with
sleep apnea [95,115,116]. Given the growing evidence of
the link between sleep and dementia, and the high
prevalence of sleep disorders in patients with AD,
objective sleep measures should be included in all AD
studies and NPS measures should be included in all
sleep research in AD.
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5. Design for NPS trials
Only two drugs are indicated for NPSs in dementia: pima-
vanserin for hallucinations and delusions associated with PD
psychosis (USA), and risperidone for short-term treatment
of persistent aggression in moderate-to-severe AD (only in
Canada and Europe). There are 16 ongoing trials, mostly
for agitation and aggression. This low productivity raises
several questions: are the drugs ineffective or the trials inap-
propriately designed? Are syndromes phenomenologically
similar but neurobiologically diverse? Are diagnostic
criteria and assessment tools for behavioral syndromes
capturing study populations that will enable detection of a
positive signal? Do nonpharmacologic paradigms and treat-
ments show more promise than pharmacologic ones? Has an
effective dose range been established and are sufficient dose
arms used? If titration is used, has enough time been allowed
to reach the optimal treatment effect? Which outcome mea-
sures should be used? What is a clinically significant effect
size?
NPS treatment studies are particularly affected by large
placebo effects. Sequential parallel comparison designs
[117] use a two-stage approach to mitigate these effects:
placebo nonresponders from the first randomization are
rerandomized to receive active treatment or placebo. Studies
using historical data, run-in designs, or multiple clinical and
biomarker variables might enroll more homogeneous popu-
lations and more accurately predict effect sizes.
Several tools are available for assessing NPSs. Each has
its pros and cons. The appropriate tool depends on the clin-
ical condition and trial design. Informant-based measures
such as the NPI-Q, Behavioral Pathology in Alzheimer’s
Disease Rating Scale (BEHAVE-AD), and Cohen-
Mansfield Agitation Inventory are low cost and clinically
relevant but reflect the biases of the informant. Their validity
depends on the extent of contact the informant has with the
person with dementia and caregiver depression and cogni-
tive status [118]. Of the informant-based tools, only the
NPI prescribes the minimum contact the caregiver must
have with the patient: 4 hours per day at least 4 days per
week, and knowledge of daytime and nighttime behaviors.
Sponsors set lower standards: all seven current trials have
less stringent NPI criteria.
Clinician ratings such as with NPI-C are relatively free
from this “caregiver filter.” They have higher inter-rater reli-
ability but cost more. Video recordings are more objective
but are not appropriate for low-frequency behaviors. They
are intrusive, costly, and can have questionable clinical rele-
vance. Wearable sensors are good for low-frequency behav-
iors but may introduce noise and have questionable clinical
relevance [33].
The commonly used rating scales (e.g., BEHAVE-AD,
Neurobehavioral Rating Scale, and NPI) characterize symp-
toms similarly, but they assess severity differently. For
example, BEHAVE-AD uses an impact scale, NPI-Q as-
sesses frequency and severity, and NPI-C produces
445
symptom-specific severity ratings. They may therefore differ
in detecting response to treatment, so researchers should
select the scale that maximizes sensitivity in their population
and indication.
Psychosocial interventions and concomitant medications,
if introduced during a trial, increase variability and affect the
placebo response. Ideally, both should be in place (and their
benefit assessed) before trials begin. Standardized psychoso-
cial interventions such as those used in DIADS [82],
DIADS-2 [83], and the Citalopram for agitation in
Alzheimer’s Disease (CitAD) study [119]) enhance recruit-
ment and retention, and minimize variability by standard-
izing procedures across sites.
6. Regulatory considerations
US Food and Drug Administration and Health Canada
representatives at the Roundtable were asked whether com-
posite end points for NPSs in AD might be accepted. They
noted that composite end points are approved when validated
and when accepted as clinically meaningful by academics,
physicians, patients, and caregivers. Also, trials may be
required to use a primary end point and a coprimary global
end point. To obtain approval for therapies to prevent the
emergence of symptoms, the key for regulators is that a
meaningful outcome is measurable and can be interpreted.
Pimavanserin was recently approved to treat hallucina-
tions and delusions associated with psychosis in Parkinson’s
disease. The sponsor was granted breakthrough therapy
designation by the Food and Drug Administration, allowing
approval based on a single small study rather than the usual
requirement for two pivotal studies. Would NPS therapies in
AD qualify for breakthrough designation? Regulators
emphasized that breakthrough status and priority review
are for potentially transformative therapies that address un-
met medical needs.
7. Conclusions
There is renewed enthusiasm among industry, academic,
regulatory, and patient and family advocacy groups to accel-
erate the development of new treatments for NPSs in AD. Ma-
jor challenges for clinical trials include the need to (1) allocate
sufficient funds to develop nonpharmacologic interventions
and implement them in routine clinical practice, these funds
are crucial as nonpharmacologic intervention studies gener-
ally do not have a sponsor; (2) better define entry criteria
(e.g., diagnosis and severity of patients and the presence of co-
morbidities); (3) develop, validate, and standardize outcome
measures that are clinically meaningful to patients and care-
givers; (4) continue to seek biomarkers of NPSs; (5) stan-
dardize issues related to caregiver, informant involvement
and care setting (outpatient vs. nursing home) in clinical tri-
als; (6) incorporate designs that account for increased placebo
responses; and (7) reach consensus on the use of psychosocial
interventions as background therapy in trials.
446 K.L. Lanct^ot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 3 (2017) 440-449
RESEARCH IN CONTEXT
1. Systematic Review: This review summarizes the pre-
sentations made at the May 2016 Research Roundta-
ble Meeting. Each presenter reviewed the literature
of recent work of their specific topic area within
the overall area of neuropsychiatric symptoms in
Alzheimer’s disease.
2. Interpretation: The present article posits that new
treatments for neuropsychiatric symptoms in Alz-
heimer’s disease are needed and with sufficient
research support can be developed to improve the
quality of life for people with dementia and their
care partners.
3. Future directions: Develop, validate, and standardize
outcome measures that are clinically meaningful to
patients and caregivers and incorporate the use of
biomarkers to help enable the development of better
treatments.
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