Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design

Abstract

Background The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer’s disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD. Methods We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013. Results We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of “clinically significant A/A”. There was considerable heterogeneity in study desin. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials. Conclusions This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.

Sedation mediates part of Citalopram's effect on agitation in Alzheimer's disease

“…A weakness of this analysis is that the measure of sedation was relatively unsophisticated. Although review of the literature did not reveal any similar formal mediator analyses, it has long been observed that psychotropic medication with sedative effects may account for some of the benefit of such medications on agitation (Jacobson 2014; Maher et al 2011; Brodaty et al 2003; Seitz et al 2013; Soto et al 2014; Gallagher & Herrmann 2014; Tariot et al 2011). The current study appears to be the first that has statistically demonstrated that this relationship exists between antidepressants and agitation in patients with dementia.…”

A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia

“…Agitation related to dementia is frequently observed clinically (Cohen-Mansfield, 2013;Ballard et al, 2001;Lyketsos et al, 2000), and various pharmacological interventions have been employed to treat this. These treatments include the use of anxiolytic, antidepressant, antipsychotic and anticonvulsant drugs (Antonsdottir et al, 2015;Cummings et al, 2015;Panza et al, 2015;Soto et al, 2015;Kales et al, 2014;Salzman et al, 2008). The most contentious approach relates to the use of antipsychotic drugs , which have been reported to be of only modest value (Ballard et al, 2009;, and to produce adverse effects (Gitlin et al, 2012).…”

“…Overall, the currently available pharmacological treatments for agitation in dementia are of little value, and the adverse effects of antipsychotic drugs are of considerable concern (Sacchetti et al, 2012;Ma et al, 2014;Ballard, 2006;. Basically, there are no officially approved pharmacotherapies for agitation in dementia, and few if any safe and effective pharmacotherapies (Antonsdottir et al, 2015;Cummings et al, 2015;Panza et al, 2015;Soto et al, 2015;Kales et al, 2014;. Also, non-pharmaceutical approaches have been shown to be of very limited value (Ballard et al, 2016;Steinberg, 2016;Kales et al, 2014).…”

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

“…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.…”

“…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). …”