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IDENTIFYING BETTER OUTCOME MEASURES TO IMPROVE TREATMENT OF AGITATION IN DEMENTIA: A REPORT FROM THE EU/US/CTAD TASK FORCE

 

M. Sano1, M. Soto2, M. Carrillo3, J. Cummings4, S. Hendrix5, J. Mintzer6, A. Porsteinsson7, P. Rosenberg8, L. Schneider9, J. Touchon10, P. Aisen11, B. Vellas2, C. Lyketsos8, and the EU/US/CTAD Task Force members*

 

*E.U./U.S. CTAD TASK FORCE: Susan Abushakra (Framingham); Joan Amatniek (Princeton); Sandrine Andrieu (Toulouse); Randall Bateman (Saint Louis); Joanne Bell (Wilmington); Gene Bowman (Lausanne); Sasha Bozeat (Utrecht); Samantha Budd Haeberlein (Cambridge); Marc Cantillon (Livingston); Marither Chuidian (Aliso Viejo); Doina Cosma-Roman (Aliso Viejo); Anne De Jong-Laird (Wexham); Rachelle Doody (Basel); Sanjay Dubé (Aliso Viejo); Michael Egan (North Wales); Laura Eggermont (Utrecht); Phyllis Ferrell (Indianapolis); Erin Foff (Princeton);  Terence Fullerton (New York); Sylvie Gouttefangeas (Suresnes);  Michael Grundman (San Diego); David Hewitt (Wilmington); Carole Ho (South San Francisco); Patrick Kesslak (Princeton); Valérie Legrand (Nanterre), Stefan Lind (Valby); Richard Margolin (New York); Thomas Megerian (Aliso Viejo); Annette Merdes (Munich); David Michelson (North Wales); Mark Mintun (Philadelphia); Tina Olsson (Cambridge); Ronald Petersen (Rochester); Jana Podhorna (Ingelheim am Rhein); Stephane Pollentier (Ingelheim am Rhein); Rema Raman (San Diego); Murray Raskind (Seattle); Gary Romano (Beerse); Juha Rouru (Turku); Ivana Rubino (Cambridge); Ricardo Sainz-Fuertes (Wexham); Stephen Salloway (Providence); Cristina Sampaio (Princeton); Philip Scheltens (Amsterdam); Rachel Schindler (New York); Mark Schmidt (Beerse); Jeroen Schmitt (Lausanne); Peter Schüler (Langen); Märta Segerdahl Storck (Valby); Eric Siemers (Indianapolis); John Sims (Indianapolis); LeAnne Skordos (Cambridge); Bjorn Sperling (Cambridge); Reisa Sperling (Boston); Joyce Suhy (Newark);  Serge Van der Geyten (Beerse); Philipp Von Rosenstiel (Cambridge); Michael Weiner (San Francisco); Glen Wunderlich (Ridgefield); Haichen Yang (North Wales); Jerry Yang (New York)

1. Mount Sinai School of Medicine, Bronx, NY, USA; 2. Gerontopole, INSERM U1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France; 3. Alzheimer’s Association, Chicago, IL USA; 4. Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada, USA; 5. Pentara Corporation, Salt Lake City, UT, USA; 6. Roper St. Francis CBRT, Charleston, SC, USA; 7. University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; 8. Johns Hopkins University School of Medicine, Baltimore, MD, USA; 9. University of Southern California, Los Angeles, CA, USA; 10. University Hospital of Montpellier, 34025 Montepellier Cedex 5, and INSERM 1061, France; 11. Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of Medicine, University of Southern California, San Diego, CA, USA

Corresponding Author: Mary Sano, Mount Sinai School of Medicine, Bronx, NY, USA, mary.sano@mssm.edu

J Prev Alz Dis 2018;5(2):98-102
Published online March 21, 2018, http://dx.doi.org/10.14283/jpad.2018.15

 

 


Abstract

For the second time in the past 3 years, the EU-US CTAD Task Force addressed challenges related to designing clinical trials for agitation in dementia, which is one of the most disruptive aspects of the condition for both patients and caregivers. Six recommendations emerged from the Task Force meeting: 1 – Operationalizing agitation criteria established by the IPA; 2 – Combining clinician- and caregiver-derived outcomes as primary outcome measures; 3 – Using global ratings to define clinically  meaningful effects and power studies; 4 – Improving the accuracy of caregiver reports by better training and education of caregivers; 5 – Employing emerging technologies to collect near real-time behavioral data; and 6 – Utilizing innovative trial designs and increasing the use of biomarkers to maximize the productivity of clinical trials for neuropsychiatric symptoms.

Key words: Neuropsychiatric symptoms, agitation, dementia, Alzheimer’s disease, clinical trials, NPS outcome measures.


 

 

Introduction

Agitation and other neuropsychiatric symptoms (NPS) are the most disruptive aspects of dementia for both patients and caregivers. They are associated with worse quality of life (1), greater dementia severity, earlier institutionalization, and accelerated mortality (2, 3). Despite being a major driver of high cost care (4, 5), agitation and other NPS are poorly understood and inadequately studied. In a population-based study, agitation in dementia occurred in up to 40% of community-dwelling dementia patients and 80% of patients living in nursing homes (6). Cross-sectional studies show somewhat lower prevalence estimates (7). For persons with mild cognitive impairment (MCI) the prevalence of agitation is nearly as high, according to some studies (8). There are no approved pharmacological treatments for agitation in dementia in the USA and in Europe and Canada only short-term use of risperidone is approved for severe persistent physical aggression. Several medications with conventional and novel mechanisms of action are in development.
In 2014, the International Psychogeriatric Association (IPA) published provisional consensus definition for agitation in cognitive disorders for clinical and research use. According to this definition, agitation in dementia is characterized by emotional distress associated with the presence of at least one of the following: excessive motor activity, verbal aggression, or physical aggression. These symptoms must be severe enough to cause significant impairment in interpersonal relationships, social functioning, and/or the ability to perform or participate in activities of daily living. These symptoms must not be attributable to another psychiatric disorder, environmental or medical conditions, or the physiological effects of substance use (9).
Reaching consensus on a definition of agitation in dementia represents an important step towards identifying new treatments since improved nosology can reduce heterogeneity in defining target conditions.  These criteria need to be operationalized, so that the clinical characteristics can be aligned with what is understood about the biology and phenomenology of agitation in dementia. This will allow for the selection and assessment of measures that best capture clinically important outcomes. With this in mind, the European Union-North American Clinical Trials in Alzheimer’s Disease Task Force (EU-US CTAD Task Force) focused its 2017 meeting in Boston, Massachusetts on finding the best outcome measure for agitation in dementia trials. This Task Force comprises an international collaboration of Alzheimer’s disease (AD) investigators from industry and academia who meet yearly to review recent progress in developing effective treatments for AD, and reach agreement on common clinical trial approaches, while promoting collaboration and data sharing. The fact that the Task Force previously addressed some of the challenges in designing clinical trials for agitation and aggression only three years ago (10) attests to the importance of this issue.

 

Overview of Agitation in Dementia

Clinical presentation

In addition to the core symptoms, irritability, disinhibition, and aberrant motor activity are common. Moreover, agitation and other NPS fluctuate and overlap. For example, agitation overlaps with many other NPS, particularly depression, irritability, and anxiety, but also apathy (11). These fluctuating symptoms cluster into predictable groups with complex etiologies (12, 13). Caregivers often notice increased agitation in the late afternoon and evening, a phenomenon referred to as “sundowning” (even though it has more to do with fatigue and sensory experiences than with the sunset).

Biological mechanisms

Agitation may be due to underlying biological mechanisms or may be a consequence of delirium, environmental factors, medication, or caregiver and environmental interactions (14). Distinguishing the underlying factors that result in agitation – both biological and environmental — is important for treatment decisions. For example, sundowning may be associated with sleep disturbances, circadian rhythm disruption, or disorientation. If associated with circadian rhythm dysfunction, this symptom may be a target for chronobiologic treatments. Moreover, the underlying biology that disrupts behavior in persons with AD interacts with short-term and long-term environmental factors, medical comorbidities, etc, due to patient vulnerability.
The neurobiological mechanisms underlying agitation in dementia may differ from those that underlie agitation in other psychiatric diseases such as schizophrenia or major depressive disorder (15). These differences likely explain the fact that drugs used to treat NPS in depression and schizophrenia seem to be less effective in dementia leading to the need for novel approaches to treatment mechanism. Notably, the US Food and Drug Administration (FDA) recently approved pimavanserin for dementia-related psychosis in Parkinson’s disease, and this drug is currently in clinical trials to treat both psychosis and agitation in patients with AD and in a trial for dementia-related psychosis in multiple types of neurodegenerative disorders. Pimavanserin is a selective 5-HT2A receptor inverse agonist. If treatment responsiveness emerges across dementia causes, this could open a new window into understanding the biology and treatment of some NPS.
Neurodegeneration disrupts brain circuitry, resulting in NPS. In agitation, at least two different circuits are disrupted (15). These may be the same circuits that are disrupted in dementia-related apathy, which could explain how apathy and agitation are closely linked (16). Further understanding of how these circuits are disrupted in different patients may provide clues about patients’ differential response to treatment.  Assessment of circuit function might also play a role as a biomarker to assess or predict treatment response.
Agitation in dementia is also associated with alterations in the function of serotonergic, noradrenergic, cholinergic, and dopaminergic neurotransmitters, related to neurodegeneration of associated brain nuclei (17). Neurodegeneration also contributes indirectly to the emergence of NPS by making patients very vulnerable to short-term and long-term environmental factors, or medical comorbidities, and other influences, such that patients express the impact of these in their behavior.  Understanding the neurophysiological factors that underlie agitation in dementia should lead to more effective treatments.
With several medications with novel mechanisms in development, a question considered by the Task Force is whether treatment development should continue to focus on phenomenology or move towards targeting neurobiologic mechanisms. A focus on phenomenology may identify those more likely to respond to a specific treatment; however, the lack of attention to the complex mechanisms and genetic and environmental factors that contribute directly and indirectly to symptoms may ultimately lead to failure to identify underlying processes that need to be targeted in order to prevent these disabling NPS. For example, both affective and executive functions impaired in agitation, suggest that multiple neural circuits are disrupted. Citalopram primarily targets the affective phenotype (18).

Available treatments

Treatment options for NPS in AD have been disappointing. Antipsychotics, anticonvulsants, benzodiazepines, and antidepressants are frequently prescribed despite little evidence of efficacy and an increased risk of adverse side effects. Citalopram, a selective serotonin reuptake inhibitor (SSRI) is one apparent success story, since clinical trials showed that this drug reduces agitation without the negative side effects associated with other SSRIs (17). Worsening cognition and cardiac side effects were observed in some patients on citalopram, potentially limiting usefulness, although these side effects might be mitigated by using the S-enantiomer of racemic citalopram (19) A subgroup analysis investigating the heterogeneity of the treatment response concluded that patients with moderate agitation and lower levels of cognitive impairment were more likely to benefit from citalopram, while those with more severe agitation and greater cognitive impairment were at higher risk of adverse responses (20).

 

Assessing agitation in clinical trials

Choosing the best outcome measure for clinical trials is key to treatment development for NPS. Over time, different trials have used different outcome measures, as no gold standard has previously emerged. Instruments used to assess agitation in clinical trials include broad-spectrum scales such as the Neuropsychiatric Inventory (NPI) (21) and the clinician-rated NPI-C (22), the Neurobehavioral Rating Scale (NBRS), and the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) (23); as well as agitation subscales of these instruments (NBRS, NPI, and NPI-C) or agitation-focused scales such as the Cohen-Mansfield Agitation Inventory (CMAI) (24).
The Neuropsychiatric Inventory (NPI) and its variants the NPI-Q and NPI-NH (for nursing homes), which is based on informant report, are widely used but may miss granularity as they are not designed for use as free-standing agitation instruments. The NPI-C, the clinician-rated form of the NPI (22) has a broader range that includes NPS characteristics of MCI and severe dementia, high inter-rater reliability, strong convergent validity for depression (assessed with the Cornell Scale for Depression in Dementia [CSDD]), psychosis (assessed with the Brief Psychiatric Rating Scale [BPRS]), apathy (vs. Apathy Evaluation Scale [AES]), and agitation/aggression (vs. the CMAI). The main strength of the NPI-C is that final scoring is based on experienced clinician ratings and not on subjective caregiver’s input that include the so called “filter” whereby NPS reported to affect the patient reflect the caregiver’s mental state instead (25). NPI-C has been translated into several languages offering advantages for international multi-site trials. Limitations of the NPI-C include its length as it has twice as many items as the NPI, and takes longer to complete, and it may be more costly as it must be administered by a skilled clinician.  To date there is a lack of data concerning the agitation and aggression components of the NPI-C since this new measure has been rarely used in cohorts or trials.  (Note: NPI-C was found to be feasible to use in a multi-center trial of scyllo-inositol for agitation but results have not been published).
Global scales have been widely used in clinical trials of treatments for NPS including agitation. The Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), published in 1997 following a consensus process involving AD clinicians [26], has been modified for NPS trials (27, 28). The mADCS-CGIC uses an interview structure with worksheets to remind raters to evaluate specific NPS (e.g., depression, apathy, agitation) as well as the broader dementia. While its administration is less structured than a rating scale, this is intentional and allows the focus to be on “gestalt” of the NPS syndrome being rated. As such, it is less likely pick up trivial effects that are irrelevant to the clinical setting. In the Citalopram for Agitation in Alzheimer’s Disease Study (CitAD), significant improvement compared to placebo was seen using two instruments as primary outcome measures — the mADCS-CGIC and the NBRS-A (17).
The CMAI is agitation specific and very detailed although it historically was developed for use in nursing homes. It covers a range of clinically-relevant agitation behaviors (not symptoms) and can usually be administered in 15-20 minutes. Drawbacks include its subjective nature, since it is administered to caregivers with no clinician input, and the observation that it focuses on the assessment of many behaviors seen in advanced dementia, typically not relevant to outpatients. In addition, questions remain about what is a clinically meaningful effect size on the CMAI. In CitAD, CMAI and the NPI were used as secondary outcome measures, enabling investigators to compare these measures in terms of sensitivity to change.

 

Evidence for a single construct vs. symptom clusters

CMAI calculates agitation scores using a diverse group of behaviors, which are grouped into symptom clusters. Although the manual  states that it is not useful to add all categories to calculate a total score since different agitated behaviors occur under different circumstances and in different people, it also indicates that behaviors may be weighted according to disruptive impact and then combined (29, 30). The long version’s 29-items tend to fit models involving 3-4 factors in principal component analyses: aggressive behavior, physically non-aggressive behavior, verbally agitated behavior, and/or hiding and hoarding. The question remains of whether symptom clusters provide more clinically relevant information for clinical trials than a total score calculated by summing all categories. Further, if a total score is used, should the factors be weighted differently? Weighting would have to be clinically determined and take into account the shape of behavioral trajectories and the clinical importance of behavioral changes.
Factor analyses from studies in different populations suggest that CMAI item scores do not cluster in a way that supports the use of factor (31). In different studies, different items “load” onto different factors and in some cases do not load at all or load on more than one factor (31, 32). If factor scores were to be used as separate endpoints, claims could be based on any one of those factors; however, this only makes sense if the different factors are independent, which is not the case. Since CMAI items as a whole represent a single construct (e.g., agitation, aggression), reflect aspects of the IPA provisional criteria, and have change scores consistent across factors (31, 32), it is most appropriate to combine them into a single total CMAI score. Separating factors may also reduce the power from the convergence of evidence across multiple domains. Change scores cluster to a greater extent than endpoint scores, and within each factor there are items that show significance while others do not, depending on the study (i.e., there is litle consistency across studies). For example, using data from a risperidone study, only change in “hitting behaviors” was significant in the physical aggression factor (33). Moreover, this study indicated that the biggest predictor of which items will show significance in treatment effects is how big the placebo effect is; thus signal-to-noise in the placebo group negatively predicts treatment effect (32).

 

Conclusions

To accelerate development of improved treatments for agitation, novel measures are needed to better capture behaviors that are of most concern to patients and caregivers. Operationalizing the IPA criteria is a needed first step, for diagnosis and to establish entry criteria for clinical studies. Some Task Force members advocated developing a single measure that reflects agitation as a unitary phenomenon. Since the development of new scales from whole cloth will result in additional regulatory challenges the consensus was that the best approach moving forward is to use existing datasets to construct an evidence-based single novel measure of agitation by selecting item subsets of existing scales (e.g., NPI-C or CMAI) that best reflect the IPA criteria and the situations in which agitation occurs. These data sets may include critical descriptors of setting, demographic or clinical characteristics, disease severity which could be used to improve sensitivity of outcomes for specific trials.  [Recommendation #1].
The Task Force agreed that since clinician-derived and caregiver-reported assessments have overlapping strengths primary outcome measures in agitation trials should combine the two as is the case with mADCS or NPI-C, with secondary outcomes focusing on caregiver report alone, as with CMAI or NPI [Recommendation #2].
Further, global ratings should be used to define clinically meaningful effect sizes and to power studies [Recommendation #3]. This will mitigate concerns about defining meaningful benefit based on individual symptoms that are not relevant to the specific care setting. It will also streamline trials by supporting the use of smaller samples sizes and making “no-go” decisions easier.
Better engagement of caregiver-informants is critical to future treatment development [Recommendation #4]. Caregivers play an important role in the management of NPS. They not only feel the consequences of disruptive behaviors but may also be the cause of those behaviors. Giving caregivers a greater voice in management and treatment development should be coupled with efforts to improve data quality. To improve accuracy of caregiver reports it is essential to reduce the effects of inexperience and subjectivity (e.g., the caregiver “filter”). To this end, caregivers should be trained to understand what is meant by the term “agitation” and about the phenotype of individual symptoms which may provide data that is more valid and has less inherent variance.
Collection of near real-time data on agitation symptoms through briefer more frequent (e.g., daily) data collection contacts or caregiver diaries should be pursued. Technology may offer novel solutions for this objective, for example, by using digital assistants to remind people to submit assessments [Recommendation #5].
Critical improvements in clinical trial design should be implemented to ensure the provision of high quality care and to minimize placebo responses [Recommendation #6]. Trials should use systematic approaches to ensure that non-pharmacologic therapies have been considered prior to enrolling patients in medication trials (e.g, the DICE (Describe, Investigate, Create, Evaluate) approach (14)). Further, to exclude participants who do not need to be on medication, a placebo lead-in or withdrawal design should be considered. In clinical trials for severe agitation, there has been a strong bias for not selecting people who are easier to manage, although these patients may be less responsive to medication.
In the future, assessing levels of agitation or response to treatment could be improved through the use of biomarkers. The fact that agitation reflects multiple biological pathways suggests that multiple types of biomarkers – genetic, pharmacogenetic, proteomic, and performance – will be needed. In clinical and observational studies, these biomarkers will need to be validated in populations with a range of behaviors and in different settings.
Since agitation has multiple causes and mechanisms, there is no simple, single, or unique treatment. This observation demands that treatment development move towards better understanding the causes of agitation, including neurobiological factors, and the interaction with patient factors (e.g, dementia severity, co-morbidities), and environmental factors. Since different phenotypes may reflect different types of agitation addressing causes should precede treating the symptoms. Ultimately, the field should coalesce around the development of sequential algorithms that combine “eco-psycho-social” with pharmacologic treatments for agitation, and by extension for all NPS.

 

Acknowledgements: The authors thank Lisa J. Bain for assistance in the preparation of this manuscript. JC is supported in part by Keep Memory Alive (KMA) and NIGMS grant P20GM109025.

Conflict of interest: JC owns the copyright of the NPI. Other authors have no conflicts of interest with this paper. The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work.

 

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A LITERATURE REVIEW OF METHODOLOGIES USED IN RANDOMIZED CLINICAL TRIALS OF AGITATION IN ALZHEIMER’S DISEASE

 

S. Dubé, J.T. Megerian, R. Malamut

 

Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA, *Former employee of Avanir Pharmaceuticals, Inc.

Corresponding Author: Sanjay Dubé, Avanir Pharmaceuticals, Inc., 30 Enterprise, Aliso Viejo, CA 92656, Tel: 949-389-6700, Fax: 949-643-6800, Email: SDube@avanir.com

J Prev Alz Dis 2018;5(2):120-133
Published online March 16, 2018, http://dx.doi.org/10.14283/jpad.2018.17

 


Abstract

Agitation is a common and burdensome symptom associated with Alzheimer’s disease (AD). This is a narrative literature review of the designs and methods used in randomized clinical trials of agitation in patients with AD; sources range from published, to completed but not published, to ongoing studies in the past 10 years. Selection for review included blinded, randomized trials conducted to assess the effect of a pharmacological intervention for which agitation in patients with AD was among the prespecified end points. Key criteria for exclusion included open-label studies, trials of dementia not specific to AD, or mixed populations of AD and unspecified dementia. A search of PubMed and clinicaltrials.gov databases identified 36 trials for which agitation was among the prespecified end points: 18 were published trials and 18 were completed but not published or ongoing. There was significant heterogeneity among AD studies in terms of diagnostic criteria, assessment of severity of disease and agitation, sample size and powering assumptions, treatment duration, patient age and cognitive status, and outcomes measurements. Few studies used a mitigation strategy for placebo response. Accumulating evidence suggests that it is important to consider the following in trial design: thresholds for baseline severity of agitation and AD; use of prespecified accepted criteria to define agitation; and use of standardized, validated tools to measure treatment effects during a trial. Adoption of these design strategies might help improve signal detection and bring us closer to identifying the most appropriate, effective, and safe treatments for agitation in patients with AD.

Key words: Alzheimer’s disease, agitation, assessment tools, methodology, trial design.


 

Introduction

Neuropsychiatric symptoms (NPSs), such as agitation, apathy, depression, and delusion, are reported in approximately 56% to 88% of patients with dementia (1). In particular, agitation/aggression is estimated to affect approximately 20% to 35% of patients with dementia (1), and the incidence of dementia-associated agitation increases over time (2, 3). Agitation may lead to reduced quality of life for patients and caregivers, earlier institutionalization of a patient, and accelerated progression of dementia (4-8).
Despite the recognition by the 2002 Psychopharmacological Drugs Advisory Committee of a significant unmet need for the treatment of patients with NPSs (9), no pharmacological treatments for agitation—or any other NPSs—associated with Alzheimer’s disease (AD) have been approved by the US Food and Drug Administration (FDA). Many factors make drug development in this area particularly complicated; foremost is that, as AD progresses, associated behavioral and psychological symptoms worsen and are intermittently chronic, making assessment particularly challenging. Furthermore, until recently, the definition of agitation in AD was unclear, adding to the difficulty in diagnosis, conduct of clinical research, and, hence, development of effective therapies (10). In 2015, the International Psychogeriatric Association (IPA) Agitation Definition Work Group developed a provisional consensus definition of agitation in patients with cognitive impairment (10). This definition provides specific criteria for the diagnosis of agitation in AD, thereby addressing concerns related to diagnostic heterogeneity among patients. This aspect in earlier clinical trials probably contributes to the variability of results and the inability to compare results across studies (11).
This narrative literature review aims to examine the designs and methods used in randomized clinical trials (RCTs) of pharmacological agents for the treatment of agitation in AD. The scope of this article is to evaluate changes in methods used in clinical trials designed to assess pharmacological treatments for agitation in AD since the publication of a consensus statement on this topic (11) by use of published articles and completed or ongoing/recruiting RCTs of the past 10 years identified on PubMed and ClinicalTrials.gov. Finally, we will consider strategies that might improve the design of future trials.

 

Methods

A search was conducted on July 21, 2017, in PubMed to identify clinical trials published from January 1, 2007, through July 21, 2017. Search criteria for manuscript titles and abstracts combined “agitation” AND “Alzheimer’s” or “Alzheimer-type dementia.” The scope of this analysis was to perform a narrative literature review that included blinded, RCTs conducted to assess the effect of a pharmacological intervention on agitation (primary and/or secondary end points must include measurement of agitation). Additional selection criteria for this review included English-language studies in patients with AD that were published or in press in peer-reviewed journals. Criteria for exclusion included open-label studies; trials of dementia not specific to AD, or mixed populations of AD and unspecified dementia; trials in which separation between psychosis and agitation was unclear; neuropsychiatric symptoms not related to agitation; post hoc analyses of agitation; trials conducted to assess caregiver impact or non-pharmacological interventions; reviews, editorials, and commentaries; and studies presented in non¬–peer-reviewed abstracts. Because this is not a systematic review, it was not registered in PROSPERO.
An additional search was conducted on the clinicalttrials.gov website (12) to identify clinical trials that have been completed or that are recruiting or ongoing and for which details had not yet been published or that were in press in peer-reviewed journals. The selection criteria for review were the same as those used to evaluate published articles identified in the PubMed database, except that extension and safety studies were not included.

 

Results

Trial designs

In total, 36 studies were included in this review (Figure 1). A PubMed search identified 633 articles; 18 met inclusion criteria for review (Table 1) (13-30). One article was a pooled evaluation of three double-blind, placebo-controlled RCTs of memantine (28), and the remaining 17 described individual double-blind RCTs; 14 were placebo controlled and three had active comparator arms. Of these, one was phase 1/2, seven were phase 2, eight were phase 3, and two were phase 4 studies. More than half the published studies (10 of 18) evaluated agitation as a primary end point (Table 1). Only two studies were designed to mitigate placebo effect, including a recent study of dextromethorphan-quinidine with a sequential parallel-comparison design (SPCD) (14) and an earlier study of donepezil that used a 4-week psychosocial treatment period before pharmacotherapy could begin (26). One study of citalopram included psychosocial counseling concurrently with study treatment to ensure that placebo-treated patients received adequate support during the trial (16, 31).

Table 1. Overview of published articles meeting search criteria (N=18)

Table 1. Overview of published articles meeting search criteria (N=18)

Abbreviations: ABRS, Agitated Behavior Rating Scale; AD, Alzheimer’s disease; ANCOVA, analysis of covariance; ANOVA, analysis of variance; BARS, Brief Agitation Rating Scale; BP, blood pressure; BPRS, Brief Psychiatric Rating Scale; CGII, Clinical Global Impressions-Improvement; CGIS, Clinical Global Impressions-Severity; CMAI, Cohen-Mansfield Agitation Inventory; DSM, Diagnostic and Statistical Manual; FAST, Functional Assessment Staging; ICD, International Statistical Classification of Diseases and Related Health Problems; LOCF, last observation carried forward; mADCS-CGIC, modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change; MMSE, Mini Mental State Examination; NBRS-A, Neurobehavioral Rating Scale Agitation subscale; NIA-AA, National Institute on Aging-Alzheimer Association; NINCDS/ADRDA, National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association; NINDS/AIREN, National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche en l’Enseignement en Neurosciences; NMDA, N-methyl-D-aspartate; NPI A/A, Neuropsychiatric Inventory Agitation/Aggression domain; RCT, randomized controlled trial; SD, standard deviation; SPCD, sequential parallel comparison design; SSRI, selective serotonin reuptake inhibitor; THC, tetrahydrocannabinol. *Means and/or standard deviations for treatment groups in study. †Sum of the subscale scores for agitation-aggression, hallucinations, and delusions (29).

Figure 1. Flow Diagram

Figure 1. Flow Diagram

 

A clinicaltrials.gov search identified 41 completed or ongoing RCTs, 18 of which met inclusion criteria (12); three of those have been completed and 15 are ongoing (Table 2). All the completed/ongoing studies evaluated agitation as a primary end point. Two trials included active comparators (NCT03226522, bupropion and placebo comparator arms; NCT00018291, risperidone comparator arm), and the rest were placebo controlled. Two of the ongoing studies used methodologies designed to mitigate the effects of placebo: NCT02351882 (nabilone vs. placebo) used a crossover design with a washout period between treatments and NCT03108846 (escitalopram vs. placebo) required a lead-in period of psychosocial intervention as a prerequisite for randomization. Two studies (NCT01862640 and NCT01922258, both brexpiprazole vs. placebo) included a trial of non-pharmacological intervention before enrollment.

Table 2. Overview of clinical trials meeting search criteria (N=18) (12)

Table 2. Overview of clinical trials meeting search criteria (N=18) (12)

Abbreviations: AD, Alzheimer’s disease; ADCS-CGIC, Alzheimer Disease Cooperative Study-Clinical Global Impression of Change; ASI, agitation screening inventory; BPRS, Brief Psychiatric Rating Scale; CDR, clinical dementia rating; CGII, Clinical Global Impressions-Improvement; CGIS, Clinical Global Impressions-Severity; CMAI, Cohen-Mansfield Agitation Inventory; mADCS-CGIC, modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change; DSM, Diagnostic and Statistical Manual; IPA, International Psychogeriatric Association; mADCS-CGIC, modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change; MDD, major depressive disorder; MHIS, Modified Hachinski Ischemia Score; MMSE, Mini-Mental State Examination; NIA-AA, National Institute on Aging-Alzheimer Association; NPI A/A, Neuropsychiatric Inventory Agitation/Aggression domain; NPI-C A/A, NPI-Clinician Rating Scale Agitation/Aggression Domains; PAS, Pittsburgh Agitation Scale; RLS, restless legs syndrome. *All studies identified in ClinicalTrials.gov assessed agitation as a primary end point.

 

Patient numbers varied widely among studies, from as few as 20 (NCT01126099 and (27)) to up to 880 (NCT02168920) (Tables 1 and 2). Number of enrolled patients was not linked to phase of clinical development. Patient subpopulations also differed among studies and included inpatients, nursing home patients, and community-dwelling patients. This adds to the heterogeneity of the target population, thereby limiting the ability to compare outcomes between studies.
Statistical methodology was available for published trial results only (Table 1). Nine studies used mixed-effects models, five used analysis of variance/covariance, three used Mann-Whitney tests, one used stratified log-rank, one used Cox proportional hazards, and one did not state which analyses were used. Other published details of the statistical methodology have been generally minimal. Eight studies (13, 14, 17, 18, 20, 23, 25, 28) used previous observations to impute missing data, and one incorporated a sensitivity analysis with a missing-at-random mechanism (14). Four studies made no adjustments for multiplicity (16, 28-30). Only one mentioned controlling for type 1 error using a hierarchical test procedure (25). No relevant information was given for nine studies.

Treatment

Therapies evaluated for the treatment of agitation in AD encompass a wide range of drug classes. Those on which data were published include atypical antipsychotic agents (risperidone, aripiprazole, olanzapine, quetiapine), selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram), anticonvulsants (topiramate, oxcarbazepine, valproate), cholinesterase inhibitors (donepezil, rivastigmine), an antiadrenergic agent (prazosin), cannabinoid receptor agonists (delta-9-tetrahydrocannabinol [THC]), an N-methyl-D-aspartate receptor antagonist (memantine), a hormone (melatonin), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator (mibampator), and a morphinan/antiarrhythmic combination (dextromethorphan-quinidine) (Table 1). Agents in completed (but not published) or ongoing clinical trials included aripiprazole, brexpiprazole, AVP-786, AXS-05, THC (dronabinol), ELND005, escitalopram, gabapentin enacarbil, ITI-007, lithium, mirtazapine, nabilone, pimavanserin, prazosin, and ORM-12741 (Table 2).
Treatment duration in the published studies varied widely, from 10 days to 24 months; 9 of 18 (50%) had durations between 8 and 12 weeks. Among the completed or ongoing trials identified on clinicaltrials.gov, durations were less variable; in 14 of 18 trials (78%) duration was between 8 and 12 weeks. Clinical studies with durations of three weeks or fewer included two trials of THC for three weeks (NCT02792257 and (15)), one for rivastigmine for two weeks (27), and one for melatonin for 10 days (22).
Most studies (15 of 18 published studies and 6 of 18 completed/ongoing studies) allowed for the use of concomitant antipsychotics, cholinesterase inhibitors, memantine, SSRIs, benzodiazepines, and/or other agents. Of the other trials, 12 (2 published, 10 completed/ongoing) did not state which, if any, concomitant medications were permitted, and 3 stated none were allowed (NCT02992132, NCT00018291, and (21)).

Patients and Measurement Tools

Patient inclusion criteria varied across studies. Although most studies (all 18 published and 15 of 18 completed/ongoing) included patients 50 years of age or older, 2 ongoing trials (NCT03108846 and NCT03031184) allowed for patients as young as 18 years.
AD diagnostic criteria and assessment of disease severity were also inconsistent across studies. Of the published trials (Supplemental Table 1), most (10 of 18) used the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) criteria (32, 33). Of the completed/ongoing trials (Supplemental Table 2), several (6 of 18) used NINCDS/ADRDA and/or the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (34), or (6 of 18) the National Institute on Aging Alzheimer Association (NIA-AA) criteria. The majority of published studies (15 of 18) and completed/ongoing trials (11 of 18) used Mini-Mental State Examination (MMSE) (35) criteria to assess AD severity. However, baseline severity inclusion criteria varied among studies. Some included patients with a broad range of cognitive impairment ranging from mild to severe AD (MMSE <10 points to 23 points), whereas others included only patients with moderate to severe AD (MMSE <10 points to 18 points). Severe AD (MMSE score <10 points) was a commonly used inclusion criterion in agitation trials; of studies in which the MMSE was specified in the inclusion criteria, only three (NCT02471196 and (21, 30)) required scores ≥10 points at baseline.
Methods measuring change in agitation were inconsistent across studies (Tables 1 and 2). Tools to assess agitation included the Neuropsychiatric Inventory (NPI) (36), Cohen-Mansfield Agitation Inventory (CMAI) (37), Clinical Global Impressions scale (CGI) (38), modified Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change (mADCS-CGIC) (39), Neurobehavioral Rating Scale—agitation subscale (NBRS-A) (40), Behavioral Pathology in AD rating scale (BEHAVE-AD) (41), Pittsburgh Agitation Scale (PAS) (42), Brief Psychiatric Rating Scale (BPRS) (43), and Brief Agitation Rating Scale (BARS) (44). All studies that used the CMAI to assess agitation (10 of 18 published studies, 12 of 18 completed/ongoing clinical trials) analyzed the total score as an outcomes measure. The NPI total score was used in 6 of 18 published studies and in 5 of 18 completed/ongoing clinical trials, whereas the NPI-agitation/aggression subscale was used in 7 of 18 published studies and 2 of 18 in completed/ongoing clinical trials.
Most published studies did not describe the use of a specific agitation diagnostic measure as a component of the inclusion criteria. Sometimes patients/caregivers were required to report agitation for a select period or frequency before enrollment as an index of persistent agitation, but duration and reporting methods varied. Nearly all completed/ongoing studies (14 of 18) reported using IPA (10), NPI (36), CMAI (37), or Agitation Screening Inventory as criteria to diagnose agitation at baseline (45).

Table 3. Scales and subscales commonly used to measure agitation in AD patients

Table 3. Scales and subscales commonly used to measure agitation in AD patients

Abbreviations: AD, Alzheimer’s disease; BARS, Brief Agitation Rating Scale; BPRS, Brief Psychiatric Rating Scale; CGII, Clinical Global Impressions-Improvement; CGIS, Clinical Global Impressions-Severity; CMAI, Cohen-Mansfield Agitation Inventory; mADCS-CGIC, modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change; mADCS-CGIC, modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change; NBRS-A, Neurobehavioral Rating Scale Agitation subscale; NPI, Neuropsychiatric Inventory; NPI-A/A, Neuropsychiatric Inventory Agitation/Aggression domain; NPS, neuropsychiatric symptom; PAS, Pittsburgh Agitation Scale.

 

Discussion

In this narrative analysis, a total of 36 studies—18 articles each from PubMed and clinicaltrials.gov—met inclusion criteria for review. As described in previously published reviews of the same topic (11, 46), there continues to be marked variability in trial design, duration of treatment, concomitant medications, patient population, and how agitation is defined and assessed.
Variability in trial designs

End point

Heterogeneity in trial design makes it difficult to compare the results between studies to draw meaningful conclusions. For nearly half the published studies, agitation was assessed as a secondary end point; however, we included these in this review because so few studies have been conducted to assess agitation in AD. Nonetheless, this is an important distinction because studies designed to evaluate agitation as a secondary outcome are unlikely to be powered to detect significant clinical differences between treatment groups.

Placebo response

Despite a recent study (47) that demonstrated marked improvement in agitation scores after placebo treatment, attempts to mitigate the placebo effect within the study design were only made in a few studies (NCT02351882, NCT03108846, and (14, 26)). Rosenberg et al. (47) found that the reduction in agitation was largest for patients with more severe agitation at baseline and when NBRS-A and NPI tools were used, suggesting that results might influenced by baseline severity of agitation and unless powering is adequate (sample size) to overcome the placebo response. Nonetheless, a simple crossover design (e.g., NCT02351882) or a run-in period of psychosocial therapy before pharmacological treatment (e.g., NCT03108846 and (26)) have inherent limitations that may be insufficient to mitigate unwanted placebo responses (48).

Variability in treatment

Duration of treatment

Although many studies assessed treatment effects after 8 to 12 weeks, several evaluated treatment efficacy as early as 10 days to 3 weeks after initiation (15, 22). In patients with chronic, progressive conditions such as AD who require long-term therapy, a three-week treatment period may be insufficient to evaluate the true benefit-to-risk profile of any pharmaceutical agent. In the placebo-controlled, double-blind, parallel-group CiTAD study, ≥50% of patients were late responders to active therapy, and few between-group differences in response rates (citalopram vs. placebo) were observed on the NBRS-A after three weeks (49). Based on these results, the study authors concluded that clinical trials designed to assess the effectiveness of pharmacological treatments for agitation in AD should last at least nine weeks (49). Data from the trial of dextromethorphan-quinidine by Cummings et al. (14) demonstrated that significant benefits observed during the first 5 weeks of treatment were durable and continued for up to 10 weeks of treatment, suggesting that a trial duration of 5 to 10 weeks may be sufficient to obtain clinically relevant data. However, given the chronic nature of AD, long-term data are important. Many clinical development programs incorporate long-term, open-label extension studies, but they were not included in this review.

Concomitant medications

Overall, 21 of 36 publications and the completed/ongoing studies allowed the use of concomitant medications, including agents previously used for control of agitation in AD (antipsychotics, cholinesterase inhibitors, SSRIs, and memantine) and antidementia treatments. Given that medication for agitation in AD is for symptom relief, use of concomitant medications in clinical trials must be carefully evaluated because of the risk for adverse events and drug interactions. It is unreasonable to expect a single agent to provide benefit for all the NPSs coexisting with AD, and a tailored therapeutic regimen is key. These add-on trial designs raise the bar for signal detection and for safety.

Variability in patients and measurement tools

Patient populations are not comparable

The symptomatology and severity of agitation may vary depending on the environment and the care setting. There were many differences in inclusion criteria, further complicating assessment of the results and comparisons across studies. Studies were conducted in various settings, including inpatient clinics, nursing homes, and community settings, therefore, increasing the heterogeneity of target symptom manifestation and of who is responsible for performing outcomes assessments. Without controlling for these factors, it might be difficult to demonstrate improvement in each aspect of agitation and to detect treatment benefits.
Interpretation of treatment efficacy in the identified studies might also be confounded by the broad range of patient age and severity of AD in the inclusion criteria. Although most studies enrolled patients >50 years, one study allowed for inclusion of AD patients of all ages, and two studies allowed for adults ≥18 years. Baseline severity of AD was broad in some studies, ranging from mild to severe, whereas other studies included only patients with moderate to severe AD. In the CiTAD study (which evaluated the use of citalopram for agitation in AD patients), age and severity of cognitive impairment and other factors (e.g., place of residence) were associated with treatment outcome (50). Secondary analyses suggested that citalopram responders had milder disease and more symptoms in the affective spectrum than dysexecutive impairments (50, 51). In a review evaluating the effects of memantine based on cognition levels in subsets of patients, no treatment effect of memantine was observed in patients with mild disease, and only minimal effect was observed in patients with moderate AD, suggesting some interplay between severity of cognitive impairment and responsiveness. Furthermore, reliable assessment of agitation in patients with more severe cognitive impairment is difficult, and the inclusion of a broad range of cognitive function in a trial might skew the results. This factor should be considered when inclusion criteria are developed (52).

Agitation definition and assessment is not standardized

Because the provisional definition of agitation in dementia was not published until 2015, it was not used as a diagnostic inclusion criterion for entry into any of the published studies. The inclusion criteria for most studies did not specify an agitation scale, and few completed or ongoing studies required that a specific agitation severity level be demonstrated before enrollment. However, although the HARMONY AD study of ELND005 did not meet the primary end point for reduction of agitation/aggression (53), a post hoc analysis showed that ELND005 provided significant improvement in patients with more severe agitation and aggression (NPI-Clinician Rating Scale Agitation/Aggression Domains [NPI-C A/A] ≥22) (54). Conversely, in secondary analyses of the CitAD trial, citalopram was most effective in patients with moderate agitation (middle tertile, score 6-8) according to NBRS (50). In addition, pharmacotherapy may be more appropriate than non-pharmacological interventions for patients with moderate to severe agitation.
Although the studies described here list change in agitation as a primary or secondary end point, no consensus has been reached on use of a standardized assessment tool. Ideally, a standard tool to measure agitation in AD would be easy to use and quick to administer, would have proven reliability and validity psychometric properties, and would be applicable to all stages of AD severity (55). Although several well-validated measures are available (e.g., CMAI and NPI), studies to date have used many different assessment tools (Tables 1 and 2). Although all these scales measure the construct of agitation, comparing the magnitude of treatment benefit across studies is more difficult because of the differences between the scales. Some studies used scales that assess overall NPSs, whereas others used their subscales. Most studies used well-validated measures such as the CMAI total score or the NPI Agitation/Aggression (NPI-A/A) subscale.

Next steps in clinical trial design

Our evaluation of studies to treat agitation in AD suggests that further improvement in trial design methodology might be necessary because most results of clinical trials do not produce sufficiently robust evidence for approval of new therapies. The first consideration is to design trials with specific inclusion criteria and a clear definition of agitation associated with AD. Use of accepted criteria such as the IPA provisional definition and confirmation of a predefined minimum cognition level of AD at baseline can help facilitate reliable assessments. Additional considerations include adequate screening of the patient population for eligibility, acceptable AD diagnostic criteria, the presence of moderate to severe persistent symptoms of agitation unresponsive to non-pharmacological treatment (11), and, if necessary, a lead-in period with psychosocial interventions to ensure that agitation is secondary to AD rather than another condition. The Describe, Investigate, Create, Evaluate (DICE) Approach might improve identification and subtyping of patients for inclusion, thereby ensuring the selection of appropriate patient populations in these studies and possibly minimizing noise secondary to other factors that may cause agitation (56).

In addition, trial designs and statistical methodologies might also be improved. Adaptive or Bayesian clinical trial designs should be considered instead of the typical RCT design (57, 58). Indeed, according to a 2006 report, the FDA strongly encourages the use of adaptive design methods in clinical research and development (59). Studies of agitation in AD have been adversely affected by issues stemming from the non-random distribution of behavior test scores and the lack of consideration of effect size (11). In the current analysis, statistical methods are poorly reported, and few studies take steps to control for type 1 error. In future trials, consideration could be given to a repeated-measures design to record improvement over time rather than a simple comparison of pretreatment and posttreatment scores. This would reduce the need for the last-observation-carried-forward approach used by many recent studies and would increase the power to detect treatment effects. Finally, measurement of changes in agitation severity should be assessed with validated agitation assessment tools, though subdomains of the NPI specific to the purpose of the study might provide more meaningful interpretation of data than the total NPI score. The CMAI seems to be the most relevant tool because it was specifically designed to evaluate the frequency of symptoms of agitation over time and is consistent with the symptomatology that forms part of the IPA provisional definition (10, 37).

 

Conclusions

Because of the significant burden that agitation confers on patients with AD and their caregivers, there is an urgent need for pharmacological therapies. The lack of an approved therapy for agitation in AD may, in part, be a result of how clinical trials for this condition have been designed. This article provides a broad overview of the methods used in studies of agitation in AD in the past decade. One limitation of the current analysis is the inclusion of only two electronic databases (i.e., PubMed and clinicaltrials.gov). Although considerable data on AD are available, much remains to be understood about treating this burdensome condition. Improvement in clinical trial design and methodologies to assess therapies for agitation in AD might help bring us closer to identifying the most appropriate, effective, and safe treatments for AD.

 

Funding: Funding for this study was provided by Avanir Pharmaceuticals, Inc. The sponsor had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Acknowledgments: Medical writing and editorial support was provided by ApotheCom, New York, NY.

Conflict of Interest: SD and RM are employees of Avanir Pharmaceuticals, Inc. TM is a former employee of Avanir Pharmaceuticals, Inc.

Author Contributions: All authors participated in study design, data analysis, and preparation of the manuscript.
Ethical standards: The authors followed the ethical guidelines of the Journal for this manuscript.

SUPPLEMENTAL TABLE 1

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PROGRESS IN TREATMENT DEVELOPMENT FOR NEUROPSYCHIATRIC SYMPTOMS IN ALZHEIMER’S DISEASE: FOCUS ON AGITATION AND AGGRESSION. A REPORT FROM THE EU/US/CTAD TASK FORCE

M. Soto1, S. Abushakra2, J. Cummings3, J. Siffert4, P. Robert5, B. Vellas1, C.G. Lyketsos6 and Task Force Members*

1. Gerontopole, INSERM U1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France; 2. Transition Therapeutics, San Matteo, California, USA; 3. Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, USA; 4. Avanir Pharmaceuticals, Inc. Aliso Viejo, USA; 5. EA CoBTeK/ICMRR University of Nice Sophia Antipolis – CHU, France; 6. Department of Psychiatry, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA. 

Corresponding Author: M.E. Soto-Martin, Gerontopole, INSERM U1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France, soto-martin.me@chu-toulouse.fr

*Task Force Members:  Susan Abushakra (San Matteo), Sandrine Andrieu (Toulouse), Joanne Bell (Cambridge), Gene Bowman (Lausanne), Sasha Bozeat (Utrech), Robert Brashear (San Francisco), Marc Cantillon , Maria Carrillo (Chicago), Jesse Cedarbaum (Cambrdige), Er Chen (San Francisco), Isabelle Clavier (Chilly Mazarin), Caroline Cohen (Chilly Mazarin), Eskild Colding-Jorgensen (Valby), Csilla Csoboth (San Francisco), Jeffrey Cummings (Las Vegas), Rachelle Doody (Houston), Bruno Dubois (Paris), Jane Durga(Vevey), Michael Egan (North Wales), Laura Eggermont (Utrech), Laura Gault (Chicago), Serge Gauthier (Verdun), Bram Goorden (Vevey), Mark Gordon (Ingelheim), Michael Grundman (San Diego), Harald Hampel (Paris), Paul Hartung (Acton), Roza Hayduk (San Diego), Suzanne Hendrix (USA), Robert Hoerr (Karlsruhe), Michael Keeley (San Francisco), Ara Khachaturian (Potomac), Zaven S. Khachaturian (Potomac), Robert Lasser (Basel), John Lawson (Malvern), Valérie Legrand (Nanterre), Constantine Lyketsos (Baltimore), Richard Meibach (East Hanover), Annette Merdes (Munich), Mark Mintun (Philadelphia), Hans Moebius (Brunnen), Cristina Murat (Marly le Roi), Philip Nichols (Lausanne), Pierre Jean Ousset (Toulouse), Jana Podhorna (Ingelheim), Maria Pueyo (Suresnes), Christopher Randolph (Hamilton), David  Raunig (New Hope), Vanessa S. Reddy (Basel), Philippe Robert (Nice), Gary Romano (Titusville), Allen Roses (Chapel Hill), Juha Rouru (Turku), Ivana Rubino (Basel), Michael Ryan (East Hanover), Stephen Salloway (Providence), Philip Scheltens (Amsterdam), Rachel J.  Schindler (New York), Achim Schneeberger (Vienna), Lon Schneider (Los Angeles), Jeffrey Sevigny (Cambridge), Klaudius Siegfried (Langen), Eric Siemers (Indianapolis), João Siffert (Aliso Viejo), Chang-Heok Soh (Basel), Maria E. Soto (Toulouse), Johannes Streffer (Beerse), Joyce Suhy (Newark), Jacques Touchon (Montpellier), Gabriel Vargas (Thousand Oaks), Estelle Vester-Blokland (Basel), Michael Weiner (San Francisco), Glen Wunderlich (Ingelheim)

J Prev Alz Dis 2015;2(3):184-188
Published online June 24, 2015, http://dx.doi.org/10.14283/jpad.2015.77


Abstract

Background: The management of neuropsychiatric symptoms (NPS) such as agitation and aggression is a major priority in caring for people with Alzheimer’s disease (AD). Agitation and aggression (A/A) are among the most disruptive symptoms, and given their impact, they are increasingly an important target for development of effective treatments. Considerable progress has been made in the last years with a growing number of randomized controlled trials (RCTs) of drugs for NPS. The limited benefits reported in some RCTs may be accounted for by the absence of a biological link of the tested molecule to NPS and also by key methodological issues. In recent RCTs of A/A, a great heterogeneity design was found. Designing trials for dementia populations with NPS presents many challenges, including identification of appropriate participants for such trials, engagement and compliance of patients and caregivers in the trials and the choice of optimal outcome measures to demonstrate treatment effectiveness.  The EU/US -CTAD Task Force, an international collaboration of investigators from academia, industry, non-profit foundations, and regulatory agencies met in Philadelphia on November 19, 2014 to address some of these challenges. Despite potential heterogeneity in clinical manifestations and neurobiology, agitation and aggression seems to be accepted as an entity for drug development. The field appears to be reaching a consensus in using both agitation and aggression (or other NPS)-specific quantitative measures plus a global rating of change for agitation outcomes based on clinician judgment as the main outcomes.

Key words: Behavior, agitation, aggression, Alzheimer’s, measurement, therapeutics, clinical trial.  


 

Introduction 

The management of neuropsychiatric symptoms (NPS) such as agitation and aggression is a major priority in caring for people with Alzheimer’s disease (AD). NPS are frequent and associated with a number of adverse outcomes including accelerated transition from prodromal AD to AD dementia (1), and faster progression from early dementia to severe dementia or death (2). NPS have serious consequences for patients and caregivers such as greater disability, worse quality of life, earlier institutionalization, increased caregiver burden, and higher health care costs (3).    

Given their impact, NPS are increasingly an important target for development of effective treatments. However, the heterogeneity of NPS complicates treatment development; they are heterogeneous in both phenomenology and cause. NPS consist of distinct clinical syndromes, which are thought to have a common neurobiological basis. Therefore, pharmacological intervention must focus on specific syndromes. Agitation and aggression (A/A) are among the most disruptive symptoms, and are currently the focus of several drug development programs. There are limited non-pharmacological and pharmacological options available for the management of these symptoms. The most studied and widely used medication class has been atypical antipsychotics for the treatment of A/A and psychosis in AD. However, their efficacy is modest and use is associated with harmful adverse events and mortality (4-6). In North America there are no approved drugs for the treatment of NPS in AD. In the European Union, only risperidone is indicated for the short-term treatment of severe aggression in AD. As a result, most agents are used off-label due to the lack of other options (7). Thus, currently the management of clinically significant, persistent or recurrent dementia-related A/A unresponsive to non-pharmacologic intervention is a major challenge for clinicians and caregivers waiting for newer therapies.

Emerging evidence from neurobiological research about pathogenesis, such as links to monoaminergic system degeneration or specific neuronal circuit dysfunction, has led to the investigation of both repositioned and new therapeutics for NPS in AD, including A/A.  Considerable progress has been made in the last years with a growing number of randomized controlled trials (RCTs) of drugs for NPS. The majority of recent RCTs focused on A/A (8). The limited benefits reported in some RCTs may be accounted for by the absence of a biological link of the tested molecule to NPS and also by key methodological issues. In recent RCTs of A/A, primary endpoints were based on different behavior rating scales or subscales, with proxy-based scales being more common than direct clinical observation. A high response on placebo was observed in many trials. Moreover, variable definitions of “clinically significant A/A” were used, but most required at least moderate severity of A/A (8).

Designing trials for dementia populations with NPS presents many challenges, including identification of appropriate participants for such trials, engagement and compliance of patients and caregivers in the trials and the choice of optimal outcome measures to demonstrate treatment effectiveness.  The EU/US -CTAD Task Force, an international collaboration of investigators from academia, industry, non-profit foundations, and regulatory agencies met in Philadelphia on November 19, 2014 to address some of these challenges.

Definition of Agitation in Dementia

A range of NPS have been reported although they tend to aggregate into predictable groups such as A/A, depression, apathy, psychosis, and sleep disturbances (9). Recent treatment development has targeted presumptive or proposed syndromes in these areas (10, 11).

Until recently, there were no widely accepted diagnostic criteria for a syndrome of agitation associated with dementia, which had been a topic of discussion in past FDA meetings.  The lack of a consensus definition for A/A in trials has contributed to the lack of progress in the field. To address this gap, The International Psychogeriatric Association (IPA) formed an Agitation Definition Work Group (ADWG) to develop a consensus definition of agitation in patients with cognitive disorders that could be applied in different studies such as epidemiologic, pharmacologic, non-pharmacologic interventional, and neurobiological (12). This consensus proposed the following criteria for a provisional definition shown in table 1.

The key elements of this definition to be considered are its provisional intent awaiting validation studies; the subjective aspect (emotional distress) associated with observable behaviors; that agitation must be sustained for 2 weeks and represent a change from previous behavior; the presence of excess disability from agitation, which in the clinician’s opinion is beyond that due to the cognitive impairment; and exclusion of delirium or other aggravating medical or iatrogenic conditions.

However, this definition presents some areas of controversy that were discussed by members of the task force:

• Is it a syndrome or a complication of another syndrome, such as psychosis, or depression?

• Is the phenomenology of agitation specifically related to Alzheimer’s dementia? Or is agitation common to AD and other type of dementias?

• Are agitation and aggression the same?

• Is there more than one type of agitation?

It should be no surprise that NPS are universal in diseases that affect key brain areas regulating behavior, or that disrupt multiple brain areas over time. Therefore, A/A is most likely not specific to AD but occurs in other diseases with cognitive impairment.

Accordingly to recent IPA consensus, aggression is considered to be subsumed under the broad symptom cluster of agitation. Better understanding the phenotypes of agitation and identifying variables that may help differentiate sub phenotypes will be crucial for targeting specific treatments to sub phenotypes.  Consequently, there is a need for RCTs to target both the phenomenology of agitation as well as its underlying neurobiology. There are probably more than one type of agitation and more than one underlying neurobiological pathway. Currently, The Food and Drug Administration (FDA) is accepting agitation as a clinical target for treatment development, with several programs now entering Phase 3.

Table 1. Provisional IPA definition criteria of Agitation

Adapted from Cummings et al., 2015 (12); IPA: The International Psychogeriatric Association

Determining severity of NPS as inclusion criteria

Once agitation is defined: How is the severity of “clinically significant agitation/aggression” as inclusion criteria in RCTs best defined?  In recent and on-going trials two approaches have been used: 1) judgment of experienced clinicians that medication is deemed necessary and/or 2) severity rating above a cut-off indicative of moderate or more severe agitation on a scale (e.g. the Neuropsychiatric Inventory (NPI-A/A) (13) and global measures, such as clinical global impression of severity. The CitAD (citalopram for agitation in AD) trial combined both approaches (14). The recent AVP-923 phase II trial (study 12-AVR-131; NCT 01584440) required “agitation that interferes with daily routine and for which a prescription medication is deemed indicated, in the opinion of the investigator with a Clinical Global Impression of severity (CGI-S) score ≥ 4”. The HARMONY-AD trial (NCT01735630) and the brexpiprazole (NCT 01862640) trial, utilized the NPI-A/A ≥ 4 cutoff which indicates at least moderately severe A/A occurring at least weekly.  It will be interesting to compare the final patient characteristics once these trials will be completed. Despite that the eligibility criteria differ in these recent RCTs, a consensus definition for the minimum agitation severity for RCT inclusion seems to be emerging.

Outcomes Measures

Central to treatment development for NPS is clinical measurement. The choice of the efficacy outcome measure has varied across RCTs. In fact there has been no gold standard for assessing the response to treatment.  Direct assessments of behavior until now available (e.g., actigraphy, audio and video sensors) are mostly developed in research settings but are not fully compatible with multicenter RCT requirements. Recently, it seems that this situation is changing for the actigraphy. In most cases, measurement relies on reporting of observable behaviors and mental state by patients and caregivers/informants. This approach is affected by aspects of the cognitive disorder that may limit the patient’s ability to report their mental state, or may lead to forgetting prior experiences and behaviors. As a result, measurement depends on input from caregivers who themselves are “filters,” which may be biased by the caregiver’s emotional state. Further, because NPS are episodic, relapsing and remitting frequently, often “real-time” in response to environmental situations, the quantification of NPS frequency and severity over longer time frames may be difficult.

Two approaches have been used to assess treatment response in RCTs of NPS: 1) outcomes based on judgment of experienced clinicians such as the Clinical Global Impression of Change (CGIC); and/or 2) the use of outcomes measuring the severity of NPS over the treatment period such as the NPI. Validated scales for the measurement of NPS fall into two categories: narrow spectrum measures, for example of depression or agitation, and broad-spectrum measures (15), including the NPI that covers several NPS domains: 10 NPS domains (in its original version (13)) or 12 (in a later version (16)).

The NPI provides a comprehensive assessment of NPS in dementia, and has been widely used in epidemiological and treatment trials. It is familiar to most AD clinicians and simple to administer. The NPI is based on caregiver input obtained during a clinical interview and does not include clinician judgment as part of the assessment. Recently, the Neuropsychiatric Inventory Clinician (NPI-C) Rating was developed based on the NPI (17). The NPI-C further increased the number of assessed NPS (or domains) from 12 to 14, and included clinician assessment as the basis for scoring overall NPS severity. A trained clinician provides an overall rating based on both patient and caregiver interviews, direct observation, and additional chart or other information. The NPI-C adds additional details to the profile of some NPI domains behaviors, for example the agitation and aggression domains are assessed separately by 13 and 8 questions/items (total 21) versus 8 on the NPI-A/A domain. The NPI-C development has followed the LED standard (longitudinal, expert, all data), and has shown a better reliability and concurrent validity than the NPI in a validation study (17).  NPI-C is a versatile measure that can be used as a broad-spectrum or as a narrow spectrum measure of a particular domain, such as agitation or aggression. The main limitations of NPI-C are the longer administration time if the full Inventory is used, the requirement of expert clinician raters and the lack of data from longitudinal or interventional studies. Anticipated data from the 12-week HARMONY-AD trial population will allow describing NPS based on the NPI-C. Another widely used measure, specific to A/A, is the Cohen-Mansfield Agitation Inventory (CMAI), which was originally developed for use in institutionalized patients (18). It is also based on caregiver ratings and does not include a clinician assessment. The Neurobehavioral Rating Scale (NBRS) is a 28-item observer-clinician rater instrument derived from the Brief Psychiatric Rating Scale (19). The agitation sub-scale of the NBRS (NBRS-A) combines subscores of agitation, disinhibition/aggression and hostility/uncooperativeness. The NBRS-A was used as co-primary outcome in CitAD trial.

In order to complement NPS ratings based on caregiver report, clinical global ratings are used. Their strength is their being derived from experienced clinicians (20). Several versions allow global ratings in agitation specific domains (or other NPS) over time by study clinicians masked to treatment assignment. These scales have been used in recent and on-going trials, as key secondary or co-primary outcomes.

In summary, there are 3 types of outcome measures to assess NPS: 1) those based on structured caregiver interviews, 2) those based on structured clinician (global) ratings, and 3) those that utilize a combination of these approaches such as the NPI-C. Recent trials have used a combination of these measures as primary outcome measures. Recent positive data from two A/A completed trials (AVP-923 and CitAD) indicate that these scales are sensitive to drug effects.

Other Issues Discussed

Participation of caregivers 

A key question in this kind of RCTs is the role and participation of the caregiver. First, a standard definition of caregiver (family, formal/professional caregiver, how much time spent with the patient…) is needed. Second, caregivers are essential in efficacy assessment since they are the closest to the patient and observe frequency and severity of NPS closely, especially episodic and fluctuant NPS. However, as previously mentioned, a potential drawback is the inexperience of caregivers in performing efficacy assessments and their lack of objectivity—which could partly contribute to the high placebo effect observed in RCTs. Therefore, it is crucial to train caregivers (informal and professional) in identifying and rating NPS, since their information is precious.  Thus, innovative approaches that include training and support of caregivers (including psychosocial interventions) are needed to support trial engagement.

Study length 

Almost all RCTs for NPS were designed with a treatment duration of 9 to 12 weeks. However, for drugs that show efficacy, it will be important to evaluate the persistence of efficacy over a longer period. Time to relapse can be assessed in discontinuation phases of trials.

Allowed rescue medication to treat NPS

As a minimum, trials should allow for rescue medications for acute exacerbation of symptoms during the trial and to decrease patient dropout.  The requirement for rescue medications can serve as a proxy measure of the efficacy of the intervention.

Use of concomitant medications 

Some trials have allowed continuation of use of concomitant medications for agitation/aggression (AVP-923, 12-AVR-131 study) whereas others excluded patients taking other medications or required patients “wash out” their medications prior to study entry (CitAD). Like in other areas of CNS research (e.g. pain, depression), polymedication is not uncommon and therefore testing adjunctive therapy is important. Drug interactions (both pharmacokinetics and pharmacodynamics) can potentially confound assessment of efficacy and/or safety. Assessment of new treatments as monotherapy is important and can provide a clearer picture of specific drug effects, but monotherapy trials limit the pool of study participants in terms of symptom severity and use of medications and may limit generalizability of results with respect with prescription patterns in clinical practice.

Design Experience of Recent Completed Trials

A well designed and executed model trial evaluating the antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI), for agitation in patients with AD without major depression recently reported its findings (CitAD). The study evaluated the effect of up to 30 mg daily of citalopram on patient functioning, caregiver distress, and safety parameters, (14).  In CitAD a psychosocial intervention was used to ensure that patients and caregivers received appropriate « enhanced usual care » in both groups. This was expressly designed to be practical and easily standardized for a research setting (21). CitAD results suggested that citalopram led to a significant reduction on the agitation domain of the NBRS-A, with a meaningful clinically relevant response in 40% on citalopram (vs 26% on placebo) on the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change scale (mADCS-CGIC).

More recently, a 10-week phase 2 clinical trial of AVP-923 for agitation in AD (study 12-AVR-131; NCT 01584440) reported efficacy for dextromethorphan combined with quinidine. Results were presented at the American Neurological Association Meeting on October 13, 2014 (22). The study enrolled 220 patients. The study employed a sequential parallel comparison design (SPCD) to reduce the impact of a potential placebo response on the ability to detect a treatment effect (23). The NPI A/A domain was the primary efficacy endpoint. AVP-923 was associated with a clinically meaningful and statistically significant improvement in agitation on the primary endpoint and also in key secondary endpoints (patient/caregiver and clinician global measures and NPI-4 domain agitation clusters). Analysis of clinical characteristics of study participants will provide insights to help plan future studies.

Conclusion

In summary, treatment development for NPS, including agitation and aggression, has accelerated in the last few years with the promise of more effective novel treatments on the immediate horizon. Despite potential heterogeneity in clinical manifestations and neurobiology, agitation and aggression seems to be accepted as an entity for drug development. The field appears to be reaching a consensus in using both agitation and aggression (or other NPS)-specific quantitative measures (such as relevant domains of NPI/NPI-C) plus a global rating of change for agitation outcomes based on clinician judgment as the main outcomes.

In parallel with the considerable efforts in crafting appropriate designs for RCTs of therapeutic agents for NPS, in particular A/A, EU-US Task Force members expressed the urgent need to gain more clarity regarding the underlying neurobiology and affected circuitry of NPS in AD. This better understanding of the neuropathogenesis may offer the opportunity to develop better targeted drug treatments, as well as biomarkers as intermediate outcomes or endpoints to measure treatment efficacy.

Conflict of interests: Dr. Soto has received grants from the National French Projet Hospitalier de Recherche Clinique (PHRC N° 13 7031 08), the European Commission (FP7-HEALTH-F3-2010-242153) and Ethypharm, and has served as a consultant/advisor to Ethypharm. Dr Lyketsos Grant has received support (research or CME) from the NIMH, NIA, Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest, Glaxo-Smith-Kline, Eisai, Pfizer, Astra-Zeneca, Lilly, Ortho-McNeil, Bristol-Myers, Novartis, National Football League, Elan and Functional Neuromodulation. He has served as a consultant/advisor to Astra-Zeneca, Glaxo-Smith Kline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, BMS, Abvie, Janssen, Orion, Otsuka, Servier, Astellas. He has received honorarium or travel support from Pfizer, Forest, Glaxo-Smith Kline and Health Monitor. Dr Abushakra is a full time employee and hold stocks and stock options of Transition Therapeutics, San Mateo, California, USA. Dr Joao Siffert is a full time employee of Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA. The Gérontopôle (chair  Pr Vellas) has received grant support from the PHRC, ANR, European Comission as well as: Abbvie, Affiris, Avid, BMS,  Eisai,  Elan, Envivo, Exhonit, Genentech, GSK, Ipsen, Lilly, Lundbeck, Médivation, MSD, Nutricia, Otsuka, Pharnext, Pfizer, Pierre-Fabre, Régénéron, Roche, Sanofi, Servier, TauRx Therapeutics, Wyeth. Dr Vellas has served as consultant/advisor to Biogen, GSK,  Lilly, Lundbeck, Medivation, MSD, Nestlé, Nutricia,  Pfizer, Roche, Sanofi, Servier, TauRx Therapeutics, Novartis. Dr Robert has received grants from European commission (projet FP7 VERVe). He has received honorarium from Roche, Servier and Lilly. Dr. Cummings has provided consultation to Abbvie, Acadia, ADAMAS, Alzheon, Anavex, Avanir, Biogen-Idec, Biotie, Boehinger-Ingelheim, Chase, Eisai, Forum, Genentech, Grifols, Intracellular Therapies, Lilly, Lundbeck, Merck, Neurotrope, Novartis, Nutricia, Otsuka, QR Pharma, Resverlogix, Roche, Suven, Takeda, and Toyoma companies.  Dr. Cummings owns stock in ADAMAS, Prana, Sonexa, MedAvante, Neurotrax, and Neurokos.  Dr. Cummings owns the copyright of the Neuropsychiatric Inventory. The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work.

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NEW IPA CRITERIA FOR AGITATION IN COGNITIVE IMPAIRMENT

J. Cummings

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA

Corresponding Author: Jeffrey Cummings, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA, cumminj@ccf.org

J Prev Alz Dis 2015;2(3):160-162
Published online May 12, 2015, http://dx.doi.org/10.14283/jpad.2015.65


Agitation and aggression are common neuropsychiatric symptoms (NPS) across all stages of Alzheimer’s disease (AD) (1), becoming more commun as the disease progresses and causing substantial disruption to the lives of both patients and caregivers (2). Despite the importance of these and other NPS to patient management, there are currently no drugs approved specifically for their treatment (3). Indeed, many trials of drugs for behavioral disorders specifically exclude patients with dementia.           

While agitation and other behavioral and psychological symptoms of dementia (BPSD) are widely recognized as important therapeutic targets (4), an incomplete understanding of their underlying neurobiological, psychological, behavioral, and environmental correlates has complicated the development of effective treatments. The absence of a consensus definition hinders further basic and clinical research. A consensus definition is needed to facilitate a wide range of studies, including non-interventional, non-pharmaceutical, and pharmaceutical trials; it would enable construction of research populations, conduct of clinical trials, and comparison of data across multiple studies.

Recognizing the need for a consensus definition, the International Psychogeriatric Association (IPA) formed an Agitation Definition Working Group (ADWG), comprising a multidisciplinary and multinational group of experts in neuropsychiatric aspects of AD. Following a transparent process that included two surveys and responses from nearly 1,000 IPA members and affiliate members, the ADWG published in January 2015 a provisional consensus clinical and research definition of agitation in cognitive impairment (5).

Defining agitation in cognitive impairment

As a first step in developing this consensus definition, a review of the literature extracted common elements from existing definitions. A survey prepared from these common elements and definitions was then sent to a broad range of stakeholders for their input. An expert consensus meeting was built on the survey feedback and led to development of a draft definition. The draft was then distributed to ADWG members who, through an iterative process, reached consensus on the draft definition.  This proposed definition was then circulated to the larger group for further comment in a second survey. A final product was arrived at and published (5) (Table 1).

Table 1. Consensus provisional definition of agitation in cognitive disorders (5)

The proposed consensus definition applies only to patients with cognitive impairment and defines the disorder as severe enough to produce disability. One or more of the three behaviors must be observed and inferred to cause distress: excessive motor activity, verbal aggression, and physical aggression. These behaviors must be persistent or recurrent for at least two weeks and represent a change from the individual’s behavior prior to the onset of cognitive impairment.  Comorbid conditions, delirium, or other aggravating circumstances should not entirely account for the behavior.  Shorter episodes of agitation might be noted as “acute agitation” and would not be included in the proposed definition.

Drug development for agitation in cognitive impairment

Pharmacologic treatment of agitation has typically been limited to off-label use of antipsychotics such as haloperidol or second generation antipsychotics such as olanzapine, quetiapine, or risperidone, which produce modest benefits but substantial side effects (6). There is limited evidence to support their efficacy in reducing agitation or other NPS (7). Non-pharmacologic treatments — such as behavioral approaches, exercise, music, massage, aromatherapy, and environmental modifications —  which target behaviors rather than underlying neurobiologic disease mechanisms (8) have some advantages and may be offered as first-line treatment. They generally are associated with fewer adverse effects, although in some cases have resulted in increased agitation or aggression. In addition, their efficacy is limited (9) and data informing the target symptoms, course or response, durability of response, and required exposure are incomplete.

Identifying effective treatments for agitation thus represents an urgent unmet need for patients and families living with dementia. Establishing a consensus definition of agitation is the first step towards eliminating barriers to drug development. The consensus definition will enable identification of appropriate subjects to include in trials in conjunction with rating scales that determine symptom severity. Several existing rating scales for agitation exist, including the multi-symptom Neuropsychiatric Inventory (NPI) (10), the Cohen-Mansfield Agitation Inventory (CMAI) (11); and the Agitated Behavior Dementia Scale (ABID) (12). These scales may be used to establish minimum baseline severity as an entry criterion for a trial for patients who meet the criteria of the new definition. An outcome measure different from the one used to determine eligibility for the trial is typically used.  The NPI, for example, may be used to define baseline severity and the CMAI may be used an outcome measure to establish change from baseline in the drug and placebo group.

Several drugs are currently in trials for the treatment of agitation associated with cognitive impairment and/or AD. These include ELND005 (scylloinositol), Nuedexta (a combination of dextromethorphan and quinidine), the atypical antipsychotic brexpiprazole, the selective serotonin reuptake inhibitor (SSRI) citalopram, the NMDA agonist memantine, lithium, and others.

Discussion

This definition assumes that agitation is a distinct, clinically identifiable syndrome, rather than a complication of another condition such as psychosis or depression. Consistent with this approach, recent research has begun to characterize an underlying biology of agitation. For example, agitation in dementia has been linked to elevated levels of tau pathology in the brain, suggesting that neurofibrillary tangles may play a role in the biology of agitation (13). In addition, Banno et al used single photon emission tomography (SPECT) to show that different agitated behaviors are associated with distinct neural networks (14).   

The absence of approved therapies for agitation and the serious adverse effects associated with antipsychotics commonly used to treat agitation represent substantial barriers to clinical care of cognitively impaired patients with NPS.  The absence of a consensus definition of agitation has limited drug development in this area.  The US Food and Drug Administration (FDA) and other regulatory bodies require that patients meet criteria for a generally recognized clinical syndrome for trial entry.  Rating scales are then used to determine the severity of the symptoms and to identify a level of severity necessary for trial participation.  The basic step of having a definition to define a trial population was lacking and challenged proper execution of trials.  The IPA ADWG definition responds to this need.  It had input from most major stakeholders, was developed through a transparent process, had input from many members and affiliate members, and was informed by individuals with experience with NPS in dementia syndromes.  Pharmaceutical and biotechnology companies, federal agencies, and academic investigators can use this definition to construct clinical trial populations and assess treatment effects.  Populations can be compared across trials and neurobiological studies of patients meeting the criteria will further inform drug discovery and development.  The creation of this definition removes one hurdle to drug development for these important and disabling symptoms.

The ADWG emphasized the provisional nature of this definition, noting that not all of the elements incorporated into it were unanimously endorsed. Topics for further discussion include the application of this definition to other psychiatric disorders, the appropriate terminology for periods of agitation lasting less than 2 weeks, and mechanisms for prospective validation of the proposed criteria.  The relationship of agitation to aggression also requires clarification.  With publication of the consensus definition, the IPA ADWG hopes to stimulate increased discussion and research on these issues, as well as facilitate the conduct of future validation studies to confirm or revise the definition.

Disclosures:  Dr. Cummings has provided consultation to Abbott, Acadia, Adamas, Anavex, Astellas, Avanir, Eisai, Forum, Genentech, Lundbeck, Neuronetrix, Novartis, Otsuka, Pfizer, Takeda and Toyama pharmaceutical companies.  Dr. Cummings owns the copyright of the Neuropsychiatric Inventory.  Dr. Cummings has stock options in Prana, Neurokos, ADAMAS, MedAvante, QR pharma. 

Acknowledgments: None

Ethical standards: This was done internal to the IPA with their permission.

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