Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. — TEI-tagged view

Jeffrey CummingspersName, Jacobo MintzerpersName, Henry BrodatypersName, Mary SanopersName, Sube BanerjeepersName, D.P. DevanandpersName, Serge GauthierpersName, Robert HowardpersName, Krista LanctôtpersName, Constantine G. LyketsospersName, Elaine PeskindpersName, Anton P. PorsteinssonpersName, Edgardo ReichpersName, Cristina SampaiopersName, David SteffenspersName, Marc WortmannpersName, Kate ZhongpersName (2015date). “Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition..” International Psychogeriatricstitle·j.

Object of study — agitationterm·dom in patients with cognitive disorders and how to define it

Research question — which elements a consensus definitionterm·key of agitationterm·dom in cognitive impairmentterm·key should include

Contribution — a provisional consensus clinical and research definitionterm of agitationterm·dom in cognitive disorders

Full text — tagged

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Agitationterm·dom in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definitionterm.

Abstract Agitationterm·dom is common across neuropsychiatricterm·key disorders and contributes to disability, institutionalization, and diminished quality of lifeterm for patients and their caregivers. There is no consensus definitionterm·key of agitationterm·dom and no widespread agreement on what elements should be included in the syndrome. The International Psychogeriatric Association formed an Agitation Definition Work Groupterm·dom (ADWGterm·dom) to develop a provisional consensus definitionterm·key of agitationterm·dom in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies. A consensus definitionterm·key will facilitate communication and cross-study comparison and may have regulatory applications in drug development programs.

The ADWGterm·dom developed a transparent process using a combination of electronic, face-to-face, and survey-based strategies to develop a consensus based on agreement of a majority of participants. Nine-hundred twenty-eight respondents participated in the different phases of the process.

Agitationterm·dom was defined broadly as: (1) occurring in patients with a cognitive impairmentterm·key or dementiaterm·key syndrome; (2) exhibiting behavior consistent with emotional distressterm·key; (3) manifesting excessive motor activity, verbal aggressionterm·dom, or physical aggressionterm·dom; and (4) evidencing behaviors that cause excess disabilityterm·key and are not solely attributable to another disorder (psychiatric, medical, or substance-related). A majority of the respondents rated all surveyed elements of the definitionterm as “strongly agree” or “somewhat agree” (68–88% across elements). A majority of the respondents agreed that the definitionterm is appropriate for clinical and research applications.

A provisional consensus definitionterm·key of agitationterm·dom has been developed. This definitionterm can be used to advance interventional and non-interventional research of agitationterm·dom in patients with cognitive impairmentterm·key.

Introduction Agitationterm·dom is a common clinical manifestation of many neuropsychiatricterm·key disorders. It is a frequent manifestation of Alzheimer's diseaseterm·dom (ADterm·dom), frontotemporal dementiaterm·dom (FTDterm·dom), dementiaterm·key with Lewy bodies (DLB), and other dementiaterm·key syndromes (Ballard and Corbett, 2010 ; Manoochehri and Huey, 2012 ; Bruns and Josephs, 2013 ). It occurs in schizophrenia, bipolar illness, and depression (Gonzalez et al ., 2013 ; Swann, 2013 ). While agitationterm·dom may include aggressive behaviors, it is not identical to aggressionterm·dom, and agitationterm·dom can occur without aggressionterm·dom (e.g. pacing, rocking, repetitious mannerisms). Agitationterm·dom can precipitate institutionalization (Okura et al ., 2011 ), diminishes the quality of lifeterm of patients and caregivers (Khoo et al ., 2013 ), and, when severe, may require treatment with medications (Herrmann and LanctôtpersName, 2007 ). There is an emerging biology of agitationterm·dom, and frontal lobe dysfunction is implicated in both clinical and neuroimaging studies (Senanarong et al . 2004 ; Bruen et al ., 2008 ). Treatment of agitationterm·dom – both pharmacologic and non-pharmacologic – is an unmet need in the care of patients with cognitive impairmentterm·key (Herrmann and LanctôtpersName, 2007 ; Gitlin et al ., 2012 ).

In spite of the framework of studies that have begun to increase understanding of agitationterm·dom, there is no commonly accepted consensus description of this common clinical phenomenon (Laughren, 2001 ). Lay definitionsterm of agitationterm·dom are non-specific and include states of excitement, disturbance, or worry. A consensus definitionterm·key of agitationterm·dom applicable in the setting of cognitive impairmentterm·key would facilitate a wide spectrum of research, including pharmacologic and non-pharmacologic intervention studies, epidemiologic investigations of agitationterm·dom, clinical studies, and research on the neurobiology of this behavior. A definitionterm would also provide a common framework for diagnostic nomenclatures such as the International Classification of Diseases and Related Health Problems (ICD; (World Health Organization, 2014 ) and the Diagnostic and Statistical Manual of Mental Disorders (DSM; (American Psychiatric Association, 2013 ). In addition, clinically relevant definitionsterm have important regulatory applications; when agents possibly appropriate for the treatment of agitationterm·dom are presented to the Food and Drug Administration (FDA), European Medicines Agency (EMA), or other licensing authorities, the treatment indication must be defined using language useful to clinicians caring for patients with the condition. Without a consensus definitionterm·key, it is difficult to compare studies or to know what range of behaviors were included in a study of “agitationterm·dom.”

Rating scalesterm such as the Cohen-Mansfield Agitationterm·dom Inventory (Cohen-Mansfield et al ., 1989 ), Neuropsychiatricterm·key Inventory (NPI; CummingspersName et al. , 1994 ), or Behavioral Pathology in Alzheimer's Diseaseterm·dom (BEHAVE-AD; Reisberg et al ., 1987 ; De Deyn and Wirshing, 2001 ) are often used to identify patients for clinical trials of anti-agitation agents and to measure the clinical symptoms in other descriptive and intervention studies. Rating scalesterm, however, are not definitionsterm; rather, they are means of measuring the frequency or severity of symptoms. Most clinicians do not use rating scalesterm for routine care of patients. To assist in defining populations for clinical care and research, a definitionterm that is not dependent on a particular rating scaleterm is needed.

The International Psychogeriatric Association (IPA) has an established leadership role in the field of geriatric behavioral health, including agitationterm·dom, and has led initiatives involved with this topic (Finkel et al ., 1996 ; Reisberg et al ., 1997 ; Draper, 1999 ; Finkel, 2000 ). To advance the study of agitationterm·dom by establishing a consensus definitionterm·key, the IPA formed an Agitationterm·dom Definitionterm Working Group (ADWGterm·dom) to produce a provisional consensus definitionterm·key of agitationterm·dom. The ADWGterm·dom conducted a broadly inclusive process, involving the IPA and its affiliate members, employing electronic means of participant engagement, holding a face-to-face meeting with international representation, and using survey-based methods. The ADWGterm·dom was made up of the IPA leadership and other stakeholders interested in the neuropsychiatricterm·key aspects of ADterm·dom and other disorders. The ADWGterm·dom implemented a transparent process that included nearly 1,000 survey respondents and engaged the memberships of the IPA, IPA affiliates, and other organizations involved in the care and research of neuropsychiatricterm·key disorders in patients with cognitive impairmentterm·key. Here the process is described, the definitionterm is presented, and the elements of the definitionterm are discussed.

Methods Consensus-building process Initial formulation The literature was reviewed (by Jeffrey CummingspersName), past definitionsterm of agitationterm·dom identified, and common elements of the definitionsterm reviewed. A preliminary survey of these definitionsterm and elements to be considered for inclusion was developed and presented to the IPA leadership.

Survey 1 The ADWGterm·dom was formed to guide this project. The ADWGterm·dom reviewed the proposed survey, adding or deleting elements to enhance the focus and clarity of the questions. The revised survey was sent electronically to the IPA membership and affiliate members (organizations that share the mission of advancing clinical practice, research, and education to improve the mental health of the elderly). The survey collected demographic information on the respondents, determined the preferences among five definitionsterm of agitationterm·dom used in the literature (Kong, 2005 ), asked if the definitionterm should be limited to cognitive impairmentterm·key syndromes, established key behavioral elements to be included in a definitionterm, and interrogated whether the respondents considered agitationterm·dom and anxiety to be the same and whether agitationterm·dom and aggressionterm·dom are the same.

International expert consensusterm·mth meeting Following completion and analysis of the first survey, an international expert consensusterm·mth meeting was held to develop a draft definitionterm based on a review of the literature and information derived from the survey. The members of the ADWGterm·dom present at the meeting include the authors of this paper. In this meeting a draft definitionterm was developed that represented a consensus of those present. Following the expert meeting, a preliminary draft of the definitionterm was developed and circulated to all members of the ADWGterm·dom. Through multiple electronic exchanges a final consensus was reached ( Table 1 ). Not all aspects of the consensus definitionterm·key were unanimously endorsed by all participants but a majority of stakeholders agreed on the elements. Table 1. Consensus provisional definitionterm of agitationterm·dom in cognitive disorders A. The patient meets criteria for a cognitive impairmentterm·key or dementiaterm·key syndrome (e.g. ADterm·dom, FTDterm·dom, DLB, vascular dementiaterm·key, other dementiasterm·key, a pre-dementia cognitive impairmentterm·key syndrome such as mild cognitive impairmentterm·key or other cognitive disorder). B. The patient exhibits at least one of the following behaviors that are associated with observed or inferred evidence of emotional distressterm·key (e.g. rapid changes in mood, irritability, outbursts). The behavior has been persistent or frequently recurrent for a minimum of two weeks’ and represents a change from the patient's usual behavior. (a) Excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms). (b) Verbal aggressionterm·dom (e.g. yelling, speaking in an excessively loud voice, using profanity, screaming, shouting). (c) Physical aggressionterm·dom (e.g. grabbing, shoving, pushing, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things, and destroying property). C. Behaviors are severe enough to produce excess disabilityterm·key, which in the clinician's opinion is beyond that due to the cognitive impairmentterm·key and including at least one of the following: (a) Significant impairment in interpersonal relationships. (b) Significant impairment in other aspects of social functioning. (c) Significant impairment in ability to perform or participate in daily living activities. D. While co-morbid conditions may be present, the agitationterm·dom is not attributable solely to another psychiatric disorder, suboptimal care conditions, medical condition, or the physiological effects of a substance.

To develop further consensus beyond the ADWGterm·dom, other key stakeholder groups received the provisional definitionterm for comments, including the members of the Neuropsychiatricterm·key Syndrome Professional Interest Area of ISTAART (Geda et al ., 2013 ) comprising thought leaders in the area of neuropsychiatricterm·key aspects of ADterm·dom.

Survey 2 Once an expert consensusterm·mth from the ADWGterm·dom was achieved, the IPA and affiliate members were re-contacted to provide additional input into the definitionterm and its acceptability for clinical and research studies, including prospective validation investigations. Six thousand emails were sent; there were 350 respondents (7%) in this phase of the consensus development process.

Report preparation Once the second survey was complete, this report containing a description of the consensus process, the definitionterm, and the elements of the definitionterm was prepared (Jeffrey CummingspersName) and circulated among the ADWGterm·dom members. Agreement was reached on the text describing the provisional definitionterm and the manuscript was submitted to International Psychogeriatrics for review.

Results Survey 1 Six thousand emails were sent; 557 individuals responded. The response rate from IPA members was 30.1%. Many members of the IPA and affiliate organizations are involved predominantly with mood disorders, psychosis, or other non-dementia aspects of geriatric psychiatry. Of the 557 respondents, 382 were physicians, including 292 psychiatrists. Other professional disciplines providing responses included nurses (57), psychologists (50), occupational therapists (13), social workers (14), and others/no responses (41). Three hundred eighty-eight (70%) of the respondents had been in practice for more than ten years.

This initial survey provided valuable insights from those involved in the care of agitated patients, and key elements of the definitionterm were identified. Table 2 shows the responses to five existing definitionsterm of agitationterm·dom (Kong, 2005 ). Three of the definitionsterm had relatively high acceptability (22–34% rating as the “best definitionterm”). Table 2. Five proposed definitionsterm of agitationterm·dom in dementiaterm·key and the number of respondents who ranked each of them as the best or the second-best definitionterm definitionterm percentage of respondents who ranked the definitionterm as the best percentage of respondents who ranked the definitionterm as the second best The patient has periods when he refuses to cooperate, won't let people help, or is hard to handle. 4 4 Excessive motor activity associated with a feeling of inner tension. The activity is usually non-productive and repetitious and consists of such behavior as inability to sit still, pacing, wringing of hands, and pulling at clothes. 31 19 Inappropriate verbal, vocal, or motor activity that is not explained by needs or confusion per se . It includes behaviors such as aimless wandering, pacing, cursing, screaming, biting, and fighting. 22 38 Vocal or motor behavior that is either disruptive, unsafe, or interferes with the delivery of care in a particular environment. It included four behavioral areas such as vocalization, motor disturbances, aggressiveness, and resisting care. 34 26 Those observed patient behaviors that communicate to others that the patient is experiencing an unpleasant state of excitement and which remain after interventions to reduce internal or external stimuli by managing resistiveness, alleviating aversive physical signs, and decreasing sources of accumulated stress have been carried out. 9 12 The ADWGterm·dom surveyed essential elements of the definitionterm of agitationterm·dom. The percentage of respondents identifying specific adjectives as key behavioral elements of the definitionterm included: excessive (71%), inappropriate (54%), repetitive (46%), observable (64%), dangerous (24%), and disruptive (56%) ( Table 3 ). Table 3. Proposed elements of a definitionterm of agitationterm·dom and the percentage of respondents endorsing that item as an essential element of a definitionterm of agitationterm·dom element percentage of respondents endorsing the elements as a key component of a definitionterm of agitationterm·dom Excessive 71 Inappropriate 54 Repetitive 46 Observable 64 Dangerous 24 Disruptive 56 Of the items listed as possible behaviors to be included in a definitionterm of agitationterm·dom, the following were endorsed by at least 50% of the respondents: pacing, aimless wandering, verbal aggressionterm·dom, constant unwarranted requests for attention or help, hitting others, hitting self, pushing people, throwing things, general restlessness, screaming, resistiveness, hurting self, hurting others, tearing things or destroying property, shouting, and kicking furniture ( Table 4 ). This information guided the elements included in the definitionterm by the ADWGterm·dom. Table 4. Behaviors that survey respondents indicated should be included in a definitionterm of agitationterm·dom item percentage of respondents who thought the item belonged to the definitionterm of agitationterm·dom Pacing 68 Aimless wandering 52 Spitting at meals 29 Spitting at people 40 Cursing 42 Verbal aggressionterm·dom 71 Constant unwarranted requests for attention or help 53 Repetitive questions 35 Repetitive sentences 31 Hitting others 58 Hitting self 57 Grabbing people 48 Pushing people 54 Throwing things 56 General restlessness 80 Screaming 63 Biting 49 Scratching 48 Trying to get to a different place (e.g. out of the room or building) 48 Intentional falling 16 Complaining 20 Negativism 21 Resistiveness 54 Eating/drinking inappropriate substances 15 Hurting self 54 Hurting others 53 Handling things inappropriately 26 Hiding things 11 Hoarding things 12 Tearing things or destroying property 62 Performing repetitious mannerisms 45 Making verbal sexual advances 23 Making physical sexual advances 24 Making strange noises (weird laugher or crying) 38 Stubbornness 17 Shouting 62 Slamming doors intentionally 46 Kicking furniture 52 When queried as to whether agitationterm·dom and anxiety were the same, overlapping, or distinct concepts, most of the respondents found them to be overlapping (0.3%, 61%, and 37% respectively). When asked whether agitationterm·dom and aggressionterm·dom are the same, overlapping, or distinct, 0.8%, 66%, and 32% endorsed each option.

Survey 2 Table 5 lists the questions of the survey regarding the definitionterm developed by the ADWGterm·dom and the responses of the participants. All elements of the definitionterm surveyed were rated as “strongly agree” or “somewhat agree” by a majority of the respondents (ranging from 68.2% for “the exclusion criterion is clear” to 88.8% for “the physical aggressionterm·dom components are captured appropriately in the definitionterm”). A majority agreed (strongly or somewhat) that the definitionterm is appropriate for research application. For non-interventional descriptive clinical research, 44% strongly agreed and 33.7% somewhat agreed with the appropriateness of the definitionterm (77.7% agreed); for pharmacologic interventional clinical research, 43.7% strongly agreed and 31.7% somewhat agreed (75.4% agreed); and for clinical trials 39.2% and 36% agreed strongly and somewhat respectively (75.2% agreed). Table 5. Questions of survey 2 exploring the acceptability of the draft definitionterm and the percentage of participants who responded as strongly agree or somewhat agree survey question percentage of respondents who strongly agree percentage of respondents who somewhat agree The definitionterm captures what I mean when I use the term “agitationterm·dom” to describe one of my patients. 50.8 35.1 The inclusion criteria – A, B, C – are sufficiently clear for clinical application. 51.7 31.7 The inclusion criteria – A, B, C – are sufficiently clear for research application. 35.7 37.7 The exclusion criterion – D – is sufficiently clear for clinical application. 38.5 36.8 The exclusion criterion – D – is sufficiently clear for research application. 26.0 42.2 The subjective aspects of the syndrome are captured appropriately – observed or inferred evidence of emotional distressterm·key (e.g. rapid changes in mood, irritability, outbursts). The behavior has been sustained or persistent for a minimum of two weeks in duration and represents a change from the person's usual behavior. 42.8 35.4 The physical aggressionterm·dom aspects of the syndrome are captured appropriately – grabbing, shoving, pushing, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things, and destroying property. 65.7 23.1 The verbal aspects of the syndrome are captured appropriately – yelling, speaking in an excessively loud voice, using profanity, screaming, shouting. 59.7 28.2 The definitionterm is appropriate as a means of identifying patients for non-interventional descriptive clinical research. 44.0 33.7 The definitionterm is appropriate as a means of identifying patients for non-pharmacologic interventional clinical research. 43.7 31.7 The definitionterm is appropriate as a means of identifying patients for clinical trials. 36.2 36 The definitionterm is appropriate as a foundation for validation studies of its sensitivity and specificity. 39.4 36.2 When queried whether the definitionterm should be limited to cognitive impairmentterm·key syndromes – the approach taken by the ADWGterm·dom – 67.4% said “yes.”

Discussion Elements of the consensus definitionterm·key The provisional consensus definitionterm·key uses the DSM style for defining a disorder as one that produces disability (American Psychiatric Association, 2013 ). The definitionterm is limited to patients with cognitive impairmentterm·key, requires evidence of emotional distressterm·key, requires one of the three observable types of behavior (excessive motor activity, verbal aggressionterm·dom, or physical aggressionterm·dom), specifies that the behavior causes excess disabilityterm·key, and notes that the behaviors cannot be solely attributable to a suboptimal care environment or another disorder such as psychiatric illness, medical illness, or effects of a substance.

Provisional consensus definitionterm·key The definitionterm is labeled as “provisional” because it may evolve as it is subjected to prospective validation. It represents an important starting point in a dynamic dialogue that will evolve with clinical application, research, and review. Validation studies are expected to show that some elements are better suited to clinical and research applications than others.

The definitionterm was labeled as a “consensus” because a majority of stakeholders involved in the process concurred with the current definitionterm. Not all elements were unanimously endorsed; a consensus was achieved on all aspects of the definitionterm.

Limitation to syndromes with cognitive impairmentterm·key Agitationterm·dom occurs in many disorders and is not limited to conditions with cognitive impairmentterm·key (Ballard and Corbett, 2010 ; Manoochehri and Huey, 2012 ; Bruns and Josephs, 2013 ; Gonzalez et al. , 2013 ; Swann, 2013 ). The ADWGterm·dom and the participating members of the surveys favored limiting the definitionterm to disorders with cognitive impairmentterm·key. Sixty-seven percent of Survey 2 respondents agreed with this approach.

There are currently separate definitionsterm for psychosis of ADterm·dom and psychosis in schizophrenia even though they have shared elements such as delusions and hallucinations (Jeste and Finkel, 2000 ); similarly there are definitionsterm of major depression and depression in ADterm·dom that are overlapping but not identical (Olin et al. , 2003 ). Similar considerations may apply to agitationterm·dom, and we chose to develop a definitionterm explicitly for patients with cognitive impairmentterm·key. Further research may lead to modifications of this approach.

The FDA has expressed concern about “pseudo-specificityterm·dom” of syndromes that are artificially assigned to one disorder when they represent general syndromes for which drugs are already approved (CummingspersName and Jeste, 2007 ), and the ADWGterm·dom wished to avoid constructing a definitionterm that might raise this issue. Our definitionterm applies specifically to the type of agitationterm·dom observed in patients with cognitive impairmentterm·key based on the unique relationships of agitationterm·dom with aspects of cognition (Senanarong et al ., 2004 ); a distinct pathophysiology (Bruen et al. , 2008 ; Trzepacz et al. , 2013 ); and possibly a differential response to treatment compared with syndromes such as psychosis of ADterm·dom (Schneider et al. , 2006 ).

Subjective aspect The definitionterm requires that there be observed or inferred evidence of emotional distressterm·key. Examples of behaviors indicative of emotional distressterm·key are provided, including rapid changes in mood, irritability, or emotional outbursts. The ADWGterm·dom required this subjective element because agitationterm·dom as conceived by the panel includes the concept that the patient is upset or distressed, and the agitated behavior is an expression of this emotional state. A person could exhibit purposeful aggressionterm·dom with behaviors overlapping with the definitionterm but would not be classified as “agitated” if there was no associated distress. It is also important that patients not be treated when their behavior is upsetting to someone else (a family member or caregiver) but not to the patient. Requiring the subjective element of the definitionterm makes this less likely. It is not possible to directly observe emotional states, and they must be inferred from observable behaviors. In all, 78.2% of the Survey 2 respondents strongly (42.8%) or somewhat (35.4%) agreed that this aspect of agitationterm·dom was captured appropriately by the proposed definitionterm.

Sustained A single episode or short-lived period of behavioral change would not meet the definitionterm for agitationterm·dom developed by the ADWGterm·dom. The definitionterm applies to a chronic or at least long-lasting state that has been sustained, persisted, or been frequently recurrent for at least two weeks. This aspect of the definitionterm will assist with intervention studies (pharmacologic and non-pharmacologic) where interventional groups are compared and sustained behavioral changes are required to see a difference in the study outcomes.

Change from previous behavior The ADWGterm·dom limited the definitionterm of agitationterm·dom to patients with cognitive impairmentterm·key. Behaviors that preceded the onset of the associated cognitive disorder would not be included in this definitionterm. This aspect of the consensus definitionterm·key is similar to the precedent adapted in the definitionterm of psychosis of ADterm·dom (Jeste and Finkel, 2000 ).

Observable behaviors The patient must have at least one type of observable agitated behavior. The behaviors can include excessive motor activity (such as pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms), verbal aggressionterm·dom (e.g. yelling, speaking in an excessively loud voice, using profanity, screaming, shouting), or physical aggressionterm·dom (e.g. grabbing, shoving, pushing, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things, and destroying property). These behaviors are the core aspects of the agitationterm·dom syndrome; they reflect the behaviors endorsed in Survey 1 as comprising agitationterm·dom. The ADWGterm·dom recognized that agitated patients exhibit different repertoires of behaviors and that, in the presence of emotional distressterm·key, any of the behaviors described would fulfill this criterion of the definitionterm. Clinician judgment is not prohibited by the definitionterm and behaviors other than those listed may be present in agitated patients. In all, 88.8% of the Survey 2 respondents strongly (65.7%) or somewhat (23.1%) agreed that the proposed definitionterm appropriately captured the physical aggressionterm·dom aspects of agitationterm·dom, and 87.9% strongly (59.7%) or somewhat (28.2%) agreed regarding the verbal aspects of agitationterm·dom.

Excess disabilityterm·key A disorder is defined as producing disability (American Psychiatric Association, 2013 ), and the ADWGterm·dom incorporated this aspect of the definitionterm as a measure of the clinical meaningfulness of the behavior. If the behavior produces no disability for the individual in terms of interpersonal relationships, social function, or impact on daily living activities, then it would not meet this criterion of the definitionterm. The disability must be more than can be attributed solely to the cognitive impairmentterm·key syndrome. Clinician judgment will be required to make this determination.

Necessary exclusions Agitationterm·dom has many possible causes and is seen across a broad range of neuropsychiatricterm·key illnesses (Ballard and Corbett, 2010 ; Manoochehri and Huey, 2012 ; Bruns and Josephs, 2013 ; Gonzalez et al ., 2013 ; Swann, 2013 ). The definitionterm proffered by the ADWGterm·dom requires the presence of an underlying cognitive impairmentterm·key syndrome such as ADterm·dom, FTDterm·dom, DLB, or a prodromal dementiaterm·key state. In some cases, patients with these disorders may have other psychiatric illness, medical illness, use substances, or be in suboptimal care environments that can cause agitated behaviors. The ADWGterm·dom definitionterm requires that the agitationterm·dom not be attributable solely to one of these co-existing conditions. Clinician judgment may be required to make this determination. The exclusion aspects of the definitionterm had some of the lowest endorsements on Survey 2 as 38.5% strongly agreed and 36.8% somewhat agreed that the exclusions were adequate for clinical application; 26% strongly agreed and 42.2% somewhat agreed that the exclusions were adequate for research application.

Comment on the definitionterm The ADWGterm·dom definitionterm of agitationterm·dom with cognitive impairmentterm·key is broad and assumes that agitationterm·dom is a syndrome and not a response to another disorder. An alternative approach is to define an “agitationterm·dom with psychosis,” “agitationterm·dom with depression,” etc. An extensive literature establishes that agitationterm·dom can be seen in the absence of concomitant psychopathology; neuroimaging studies suggest unique regional dysfunction that is distinct from other disorders (Bruen et al. , 2008 ; Trzepacz et al. , 2013 ); and clinical trials demonstrate that the pharmacologic response of agitationterm·dom may differ from that of other types of behavioral disturbances (Schneider et al. , 2006 ). Therapies have been approved for agitationterm·dom in multiple psychiatric settings (e.g. aripiprazole for acute treatment of agitationterm·dom with schizophrenia or bipolar I disorder), setting a precedent for viewing agitationterm·dom as a distinct syndrome. While no drug has been approved for agitationterm·dom per se (i.e. without aggressionterm·dom, depression, or psychosis), several psychosocial interventions have shown benefit in reducing agitated behavior (Low et al. , 2013 ). The ADWGterm·dom favored defining agitationterm·dom as a distinct clinically identifiable syndrome.

Using a syndromal definitionterm of clinical phenomena within neurologic disorders has a precedent in the identification of pseudo-bulbar affectterm·dom (PBAterm·dom) and the approval of dextromethorphan/quinidine for PBAterm·dom across neurologic disorders after having demonstrated efficacy in amyotrophic lateral sclerosis and multiple sclerosis. A similar strategy of showing efficacy for anti-agitation agents across several disorders could be adopted in anti-agitation drug development programs.

The relationship of agitationterm·dom to aggressionterm·dom sparked discussion. These are overlapping but not identical concepts (Cohen-Mansfield and MintzerpersName, 2005 ). Agitationterm·dom can occur in the absence of aggressionterm·dom, and predatory aggressionterm·dom can occur without agitationterm·dom; it is unlikely that aggressionterm·dom occurs without agitationterm·dom in the cognitive impairmentterm·key syndromes described by the ADWGterm·dom. Sixty-six percent of the survey respondents consider agitationterm·dom and aggressionterm·dom as overlapping concepts; 32% consider them to be distinct. Aggressionterm·dom may be a more severe form of agitationterm·dom or it may occur in differing biological or psychological circumstances. The comparative response profiles to pharmacologic or non-pharmacologic interventions of agitationterm·dom with and without aggressionterm·dom have not been comprehensively explicated. There is currently insufficient evidence to conclude that agents or interventions used for aggressive agitationterm·dom would necessarily work or be warranted in non-aggressive agitationterm·dom. The ADWGterm·dom definitionterm criterion B allows both agitationterm·dom without aggressionterm·dom (excessive motor activity) and with aggressionterm·dom (verbal aggressionterm·dom and physical aggressionterm·dom). Investigators using this definitionterm of agitationterm·dom should note which elements of criterion B were met (e.g. excessive motor activity, verbal aggressionterm·dom, or physical aggressionterm·dom). Longitudinal comparison of studies will help define the relationship between agitationterm·dom and aggressionterm·dom, and the ADWGterm·dom definitionterm will advance understanding of this aspect of agitationterm·dom.

This definitionterm will be useful in the study of psychosocial interventions and in clinical trials of anti-agitation agents. The absence of a consensus definitionterm·key may have contributed to the lack of activity in developing new therapies for agitationterm·dom with cognitive impairmentterm·key; no agent has been approved for treatment of this syndrome in spite of extensive documentation of the disability associated with agitationterm·dom. Study entry would require that the participants have agitationterm·dom as defined by the ADWGterm·dom. A minimum baseline severity level on an agitationterm·dom scale would typically be required. An outcome measure – usually an agitationterm·dom measure different from the one used to define entry severity – would be used to compare baseline with end-of-study scores for the active treatment and the placebo (or active comparator) control group. It may be useful to control for other behavioral features such as mood changes or psychosis. The ADWGterm·dom definitionterm could play a critical role in defining the patient population for such trials.

The development of a provisional definitionterm of agitationterm·dom is the first step in advancing a research agenda for the definitionterm. Validity studies using other agitationterm·dom assessments, reliability of the application of the definitionterm, usefulness in clinical trials, usefulness in non-pharmacologic research, and real-world application in clinical and healthcare settings will lead to refinements and adjustments that will enhance the definitionterm and advance the study of neuropsychiatricterm·key syndromes in cognitive impairmentterm·key disorders.

Conflict of interest declaration The sponsors, Otsuka and Avanir Pharmaceutricals, gave unrestricted education grants to help support the international meeting that was part of the definition-building process.

Dr. Jeffrey CummingspersName has provided consultation to Acadia, ADAMAS, Anavex, Avanir, Boehinger-Ingelheim, Eisai, EnVivo, GE Healthcare, Genentech, Lilly, Lundbeck, Medavante, Merck, Novartis, Otsuka, Pfizer, Prana, QR Pharma, Resverlogix, Roche, Sonexa, Suven, Takeda, and Toyoma companies. Dr. CummingspersName owns the copyright of the Neuropsychiatricterm·key Inventory.

Professor Sube BanerjeepersName has received consultancy fees, honoraria for speaking, and support in attending conferences from the makers of anti-dementia medication and other psychotropics, including Abbvie, Eisai, Pfizer, Novartis, Lilly, and Shire.

Professor Henry BrodatypersName has served as investigator for Janssen, Lilly, Medivation, Merck, Sanofi, Servier, and Tau Therapeutics, and has been on the advisory boards of Pfizer, Novartis, Janssen, Lundbeck, and Nutricia. Dr. BrodatypersName has provided consultation to Baxter, Lilly, Merck, and Nutricia.

D.P. DevanandpersName has received research support from Eli Lilly, and has provided consultation to AbbVie.

Dr. Serge GauthierpersName has been on the scientific advisory board or investigator with Abbvie, Affiris, Eisai, Lilly, Navidea, Novartis, Pfizer, Sanofi-Synthelabo, Servier, and TauRx.

Professor Robert HowardpersName reports that he has no relevant disclosures to make.

Dr. Krista LanctôtpersName has had research support and/or speaker's honoraria from Abbvie Canada, Lundbeck Canada Inc., Pfizer Canada Inc., Janssen Ortho, and Rocheand Wyeth.

Dr. Constantine LyketsospersName has received grant support (research or CME) from Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest, GlaxoSmithKline, Eisai, Pfizer, Astra-Zeneca, Lilly, Ortho-McNeil, Bristol-Myers, Novartis, National Football League, Elan, and Functional Neuromodulation. Dr. LyketsospersName has been a consultant or advisor to Astra-Zeneca, GlaxoSmithKline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, BMS, Abvie, Janssen, and Orion. Honorarium or travel support has been received from Pfizer, Forest, GlaxoSmithKline, and Health Monitor.

Dr. Jacobo MintzerpersName reports receipt of grants to his institution from Takeda Global Research and Development Center, Pfizer, Genentech, Merck, Accera, Elan, Avanir, F. Hoffmann-La Roche, Novartis, Baxter, Eli Lilly, Wyeth, and Janssen Alzheimer Initiative; and employment with NeuroQuest, and BioPharma Connex.

Dr. Elaine PeskindpersName has been on the speakers’ bureau for Forest Pharmaceuticals and on the Advisory Committee for Avanir. Dr. PeskindpersName served on the Adjudication Committee for Takeda Pharmaceuticals.

Dr. Anton PorsteinssonpersName has received a grant for his institution from Avanir, Eisai, Elan, Genentech/Roche, Janssen Alzheimer Initiative, Merck, Pfizer, and Toyama. He has provided consultation for Elan, Janssen Alzheimer Initiative, and TransTech Pharma. Dr. PorsteinssonpersName has membership on data safety and monitoring boards for Quintiles.

Dr. Edgardo ReichpersName has participated as investigator in different pharmaceutical-sponsored trials for Ely Lilly, Glaxo, Forest, Mertz. Astra Zeneca, Novartis, Roche, and Janssen. He has received travel grants from Bayer, MerckSerono, Novartis, Mertz, and Teva.

Dr. Cristina SampaiopersName has been a consultant for Abbvie, Alkermes, AstraZeneca, Avanir, Biogen, BMS, Chelsea, Genzyme, Lilly, Lundbeck, Otsuka, Pfizer, Roche, Sanofi, Servier, Takeda, and Teva.

Dr. Mary SanopersName has been on the Scientific Advisory Board for Medication and as a consultant for Bayer Schering Pharma, Bristol-Meyers Squibb, Elan, Genentech, Medivation, Medpace, Pfizer, Janssen, Takeda, and United Biosource.

Dr. David SteffenspersName is supported through grants from the National Institute of Mental Health, and he receives textbook royalties from the American Psychiatric Press.

Dr. Marc WortmannpersName reports no other salaries than from Alzheimer's Diseaseterm·dom International.

Dr. Kate ZhongpersName has provided consultation to Avanir, Pfizer, Janssen, and Wyeth Pharmaceuticals.

Description of authors’ roles J. CummingspersName, J. MintzerpersName, H. BrodatypersName, and M. SanopersName formulated the research questions, designed the study, carried out the study, analyzed the data, and wrote the paper.

S. BanerjeepersName, D. DevanandpersName, S. GauthierpersName, R. HowardpersName, K. LanctôtpersName, C. LyketsospersName, E. PeskindpersName, A. PorsteinssonpersName, E. ReichpersName, C. SampaiopersName, D. SteffenspersName, M. WortmannpersName, and K. ZhongpersName carried out the study, analyzed the data, and wrote the article.