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

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.

Agitation in Alzheimer's disease: Novel outcome measures reflecting the International Psychogeriatric Association (IPA) agitation criteria

“…Information about MCID is very important for newer scales; less widely used measures, such as the NPI‐C‐A+A; as well as for the novel, IPA criteria‐informed measures. 4 Regarding MCID of NPI‐C‐A+A and NPI‐C‐IPA, follow‐up of 1 month seemed sufficient to detect the group of patients who would be very much improved by 3 months. This finding has important implications for trial design; while symptom response in clinical trials may have a different timeframe than in observational studies such as ours, what is important is that natural variation in symptoms can be observed in a short time frame (1 month) and predicts later response (3 months).…”

“…Although progress has been made in implementing randomized clinical trials (RCTs) for agitation, 3 the choice of optimal outcome measures to demonstrate treatment effectiveness is still unresolved. 4 …”

“…A shortcoming of this approach is that deriving ratings exclusively from caregiver input leads to multiple biases. 4 The NPI‐Clinician (NPI‐C) 7 version was developed to address such limitations; however, to date there is no gold standard scale rating for these trials.…”

Impact of standardizing care for agitation in dementia using an integrated care pathway on an inpatient geriatric psychiatry unit

“…First, the implementation of an interdisciplinary treatment plan defines roles of team members in carrying out assessments and interventions at specified times and helps to move the care plan forward towards the best patient outcome. Further, with clear treatment steps and decision points based on global clinical impression, the clinical team adopts measurement-based care while maximizing efficiency as recommended by guidelines and expert panels (Azermai et al, 2012, Soto et al, 2015. If replicated in larger prospective controlled studies, decreasing the LOS may help to reduce distress to the patients and caregivers and lead to cost savings (Maust et al, 2017).…”