Escolar Documentos
Profissional Documentos
Cultura Documentos
1.
Introduction
2.
Dextromethorphan/quinidine
3.
Scyllo-inositol
4.
Brexpiprazole
5.
Prazosin
6.
Cannabinoids
7.
Citalopram
8.
Conclusions
9.
Expert opinion
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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Article highlights.
.
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
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
Scyllo-inositol
Brexpiprazole
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I. M. Antonsdottir et al.
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
Cannabinoids
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
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
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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I. M. Antonsdottir et al.
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.
Bibliography
Papers of special note have been highlighted as
either of interest () or of considerable interest
() to readers.
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Affiliation
Inga M Antonsdottir1 BS, Jessica Smith2 BS,
Melanie Keltz2 BA &
Anton P Porsteinsson2 MD