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.
Keywords: 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.
Table 1.
Provisional IPA definition criteria of Agitation
| 1. The patient presents a cognitive impairment or dementia syndrome |
2. The patient exhibits at least one of the following behaviors:
|
| 3. These behaviors are associated with observed or inferred evidence of emotional distress |
| 4. The behavior has been sustained or persistent for a minimum of two weeks’ duration |
| 5. Behaviors are severe enough to produce excess disability |
| 6. The agitation is not only attributable to another psychiatric disorder, medical condition, or the physiological effects of a substance |
Adapted from Cummings et al., 2015 (12); IPA: The International Psychogeriatric Association
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.
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.
Acknowledgments
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.
*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)
Footnotes
Conflict of interests: These corporations placed no restrictions on this work.
References
- 1.Taragano FE, Allegri RF, Krupitzki H, Sarasola DR, Serrano CM, Loñ L, Lyketsos CG. Mild behavioral impairment and risk of dementia: a prospective cohort study of 358 patients. J Clin Psychiatry. 2009;70:584–592. doi: 10.4088/jcp.08m04181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Peters ME, Schwartz S, Han D, Rabins PV, Steinberg M, Tschanz JT, et al. Neuropsychiatric Symptoms as Predictors of Progression to Severe Alzheimer’s Dementia and Death: The Cache County Dementia Progression Study. Am J Psychiatry. 2015;172:460–465. doi: 10.1176/appi.ajp.2014.14040480. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Lyketsos CG, Carrillo MC, Ryan JM, Khachaturian AS, Trzepacz P, Amatniek J, Cedarbaum J, Brashear R, Miller DS. Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimers Dement. 2011;7:532–539. doi: 10.1016/j.jalz.2011.05.2410. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006;14:191–210. doi: 10.1097/01.JGP.0000200589.01396.6d. [DOI] [PubMed] [Google Scholar]
- 5.Langballe EM, Engdahl B, Nordeng H, Ballard C, Aarsland D, Selbæk G. Short-and Long-Term Mortality Risk Associated with the Use of Antipsychotics Among 26,940 Dementia Outpatients: A Population-Based Study. Am J Geriatr Psychiatry. 2014;4:321–323. doi: 10.1016/j.jagp.2013.06.007. [DOI] [PubMed] [Google Scholar]
- 6.Maust DT, Kim HM, Seyfried LS, Chiang C, Kavanagh J, Schneider LS, Kales HC. Antipsychotics, Other Psychotropics, and the Risk of Death in Patients With Dementia: Number Needed to Harm. JAMA Psychiatry. 2015;72:438–445. doi: 10.1001/jamapsychiatry.2014.3018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA. 2011;306:1359–1359. doi: 10.1001/jama.2011.1360. [DOI] [PubMed] [Google Scholar]
- 8.Soto M, Andrieu S, Nourhashemi F, Ousset PJ, Ballard C, Robert P, et al. Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design. Int Psychogeriatr. 2014;16:1–17. doi: 10.1017/S1041610214001720. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Geda YE, Schneider LS, Gitlin LN, Miller DS, Smith GS, Bell J, et al. Neuropsychiatric symptoms in Alzheimer’s disease: Past progress and anticipation of the future. Alzheimers Dement. 2013;9:602–608. doi: 10.1016/j.jalz.2012.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Robert P, Onyike CU, Leentjens AFG, Dujardin K, Aalten P, Starkstein S, et al. Proposed diagnostic criteria for apathy in AlzheimerŁs disease and other neuropsychiatric disorders. European Psychiatry. 2009:1–7. doi: 10.1016/j.eurpsy.2008.09.001. [DOI] [PubMed] [Google Scholar]
- 11.Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC, et al. Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry. 2002;10:125–128. [PubMed] [Google Scholar]
- 12.Cummings J, Mintzer J, Brodaty H, Sano M, Banerjee S, Devanand DP, et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr. 2015;27:7–17. doi: 10.1017/S1041610214001963. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Cummings JL, Mega M, Gray K, et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44:2308–2314. doi: 10.1212/wnl.44.12.2308. [DOI] [PubMed] [Google Scholar]
- 14.Porsteinsson A, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z, et al. Effect of citalopram on agitation in Alzheimer Disease; the CitAD randomized clinical trial. JAMA. 2014;311(7):682–691. doi: 10.1001/jama.2014.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Steinberg M, Lyketsos CG. Neuropsychiatric measures for cognitive disorders. In: Rush AJ, First MB, Blacker D, editors. Handbook of Psychiatric Measures. Arlington, VA: American Psychiatric Publishing; 2008. p. 864. [Google Scholar]
- 16.Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology. 1997;48: S10–S16. doi: 10.1212/wnl.48.5_suppl_6.10s. [DOI] [PubMed] [Google Scholar]
- 17.de Medeiros K, Gauthier RP, Stella F, Politis A, Leoutsakos J, Taragano F, et al. The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia, Int. Psychogeriatrics. 2010;22:984–994. doi: 10.1017/S1041610210000876. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Cohen-Mansfield J, Marx MS, Rosenthal AS. A description of agitation in a nursing home. J Gerontol. 1989;44(3):M77–M84. doi: 10.1093/geronj/44.3.m77. [DOI] [PubMed] [Google Scholar]
- 19.Levin HS, et al. The neurobehavioural rating scale: assessment of the behavioural sequelae of head injury by the clinician. Journal Neurology Neurosurgery Psychiatry. 1987;50:183–193. doi: 10.1136/jnnp.50.2.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Guy W. ECDEU Assessment Manual for Psychopharmacology, revised. Bethesda, MD: US Department of Health, Education, and Welfare; 1976. [Google Scholar]
- 21.Drye LT, Ismail Z, Porsteinsson AP, Rosenberg PB, Weintraub D, Marano C, et al. Citalopram for agitation in Alzheimer’s disease: Design and Methods. Alzheimers Dement. 2012;8:121–130. doi: 10.1016/j.jalz.2011.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Cummings J, Lyketsos C, Tariot P, et al. Dextromethorphan/quinidine (AVP-923) Efficacy and Safety for Treatment of Agitation in Alzheimer’s disease: Results from a Phase 2 Study. [Poster] 2014 American Neurological Association (ANA) 139th Annual Meeting; Baltimore MD. October 10–12, 2014; M1336WIP. [Google Scholar]
- 23.Baer L, Ivanova A. When should the sequential parallel comparison design be used in clinical trials? Clin Invest. 2013;3(9):823–833. [Google Scholar]