Agitation in cognitive disorders: Progress in the International Psychogeriatric Association consensus clinical and research definition

Sano, Mary; Cummings, Jeffrey L.; Auer, Stefanie; Bergh, Sverre; Fischer, Corinne E.; Gerritsen, Debby L.; Grossberg, George T.; Ismail, Zahinoor; Lanctôt, Krista L.; Lapid, Maria I.; Mintzer, Jacobo; Palm, Rebecca; Rosenberg, Paul B.; Splaine, Michael; Zhong, Kate; Zhu, Carolyn W.

doi:10.1017/s1041610222001041

Cited by 25 publications

(29 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The trial reported here differed from the previous 2 trials in that it required patients to meet the International Psychogeriatric Association definition of agitation at entry, which was not available at the time of the previous trials . Furthermore, a post hoc analysis of the first 2 trials indicated that patients who did not meet the CMAI factor 1 (aggressive behavior) positivity criterion at baseline had insufficient baseline agitation severity to show measurable change over time .…”

Section: Discussionmentioning

confidence: 92%

“…Patients (a volunteer sample) were enrolled by investigators at 123 Alzheimer disease clinical trial sites in Europe (Bulgaria, Hungary, Serbia, Slovakia, Spain, Ukraine) and the United States. Key inclusion criteria were age 55 to 90 years; diagnosis of probable Alzheimer disease, defined by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria; Mini-Mental State Examination (MMSE) score of 5 to 22 at screening and baseline; previous computed tomography or magnetic resonance imaging scan of the brain with findings consistent with a diagnosis of Alzheimer disease; a diagnosis of agitation that meets the International Psychogeriatric Association definition (which was a provisional definition at the time); onset of agitation at least 2 weeks prior to screening; Neuropsychiatric Inventory (NPI) or NPI–Nursing Home version (NPI-NH) Agitation/Aggression domain score (frequency × severity) of 4 or greater at screening and baseline; requiring pharmacotherapy for the treatment of agitation in the investigator’s judgment after an evaluation for reversible factors (eg, pain, infection, polypharmacy) and a trial of nonpharmacological interventions (eg, redirecting behavior, group activities, music therapy); living in a care facility or community-based setting (not living alone); and having an identified caregiver who has sufficient contact to describe the patient’s symptoms and behavior. An additional required inclusion criterion based on positivity for Cohen-Mansfield Agitation Inventory (CMAI) factor 1 (aggressive behavior [12 items: hitting, kicking, scratching, grabbing, pushing, hurting self or others, throwing things, cursing or verbal aggression, spitting, tearing things or destroying property, screaming, and biting]) was blinded to patients, caregivers, and investigators .…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia

Lee,

Slomkowski,

Hefting

et al. 2023

JAMA Neurol

View full text Add to dashboard Cite

ImportanceAgitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment.ObjectiveTo confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia.Design, Setting, and ParticipantsThis randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted.InterventionsIn this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio.Main Outcomes and MeasuresThe primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events.ResultsA total of 345 patients were randomized to receive brexpiprazole (n = 228) or placebo (n = 117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n = 225), demonstrated statistically significantly greater improvement than those taking placebo (n = 116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, −22.6; placebo baseline, 79.2, mean change, −17.3; least-squares mean difference, −5.32; 95% CI, −8.77 to −1.87; P = .003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo.Conclusions and RelevanceIn this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population.Trial RegistrationClinicalTrials.gov Identifier: NCT03548584

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia

Lee,

Slomkowski,

Hefting

et al. 2023

JAMA Neurol

View full text Add to dashboard Cite

show abstract

“…Agitation is a very troublesome behavioral problem in AD with major impacts, including costs and caregiver burden. 62,63 In a community-dwelling study involving older adults with a range of cognitive impairments, the prevalence of agitation ranged from 8.3% to 48.9%. 64 Agitation increases with dementia severity, and even higher rates (> 50%) are observed in nursing homes.…”

Section: Agitationmentioning

confidence: 99%

“…Two different types of aggression – reactive and proactive – have been recognized. 62 The former seems to be more frequent in the context of dementia, while the second is mainly associated with psychotic phenomena. In line with this difference, it is worth noticing that agitation and psychosis usually do not load on the same behavioral domains (see above: Assessment and management of behavioral symptoms of AD).…”

Section: Agitationmentioning

confidence: 99%

Behavioral or neuropsychiatric symptoms of Alzheimer's disease: from psychopathology to pharmacological management

Teixeira,

Rocha,

Gatchel

2023

Arq Neuropsiquiatr

View full text Add to dashboard Cite

Neuropsychiatric or behavioral symptoms of dementia encompass a series of disorders, such as anxiety, depression, apathy, psychosis, and agitation, all commonly present in individuals living with dementia. While they are not required for the diagnosis of Alzheimer's disease (AD), they are ubiquitously present in all stages of the disease, contributing to negative clinical outcomes, including cognitive decline, functional disability, and caregiver burden. Neuropsychiatric symptoms have been conceptualized not only as risk factors but as clinical markers of decline along the AD spectrum. The concept of “mild behavioral impairment”, the behavioral correlate of mild cognitive impairment, has been proposed within this framework. The first steps in the management of behavioral symptoms in AD involve defining the target and investigating potential causes and/or aggravating factors. Once these factors are addressed, non-pharmacological approaches are preferred as first-line interventions. Following the optimization of anticholinesterase treatments, specific pharmacological approaches (e.g., antidepressants, antipsychotics) can be considered weighing potential side effects.

show abstract

“…Among NPS, agitation has gained the most attention because of its adverse clinical and prognostic impact and the lack of effective treatments for this condition. The International Psychogeriatric Association developed provisional criteria for agitation in 2014 with an update in 2023 [8,9 ▪ ]. These criteria require the presence of cognitive impairment or dementia, emotional distress accompanying behavioral changes, excessive motor activity or verbal or physical aggression, and symptoms causing excess disability that are not solely attributable to other psychiatric, medical, or substance-related disorders.…”

Section: Introductionmentioning

confidence: 99%

Management of neuropsychiatric symptoms in dementia

Devanand

2023

Current Opinion in Neurology

View full text Add to dashboard Cite

Purpose of review The purpose is to review the results and clinical implications of recent studies of neuropathology in relation to neuropsychiatric symptoms (NPS) in Alzheimer's disease and related dementias, and discuss new therapeutic approaches based on evidence from clinical trials. Recent findings In a large autopsy series from a national consortium, multiple neuropathologies of dementia subtypes were common and increased severity of specific NPS during life was associated with greater severity of neuropathology across diagnoses. Based on three clinical trials, brexpiprazole, which is an antipsychotic with dopamine and serotonin receptor partial agonism properties, was recently approved for the treatment of agitation in Alzheimer's dementia by the U.S. Food and Drug Administration (FDA). Its therapeutic profile indicates modest efficacy with high safety. Brexpiprazole has not been compared to other antipsychotics that are commonly prescribed to treat agitation in dementia, though none of them have been approved for this indication. Other drugs that showed positive results in Phase 2 trials are being tested in Phase 3 trials. These include cannabinoids and drug combinations that inhibit dextromethorphan metabolism peripherally, thereby increasing its bioavailability in the brain. Apathy is common in several types of dementia, and there is initial evidence that treatment with methylphenidate, a psychostimulant, may be efficacious with good tolerability. Summary Greater understanding of the associations between NPS and dementia subtypes can improve clinical management of these disorders. In addition to the approval of brexpiprazole to treat agitation in Alzheimer's dementia, there is optimism about other medications based on ongoing clinical trials. Along with short-term improvement, altering the adverse impact on NPS on long-term prognosis remains an important challenge for the field.

show abstract

Agitation in cognitive disorders: Progress in the International Psychogeriatric Association consensus clinical and research definition

Cited by 25 publications

References 51 publications

Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia

Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia

Behavioral or neuropsychiatric symptoms of Alzheimer's disease: from psychopathology to pharmacological management

Management of neuropsychiatric symptoms in dementia

Contact Info

Product

Resources

About