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

Published online by Cambridge University Press:  16 September 2014

Maria Soto ,
Sandrine Andrieu ,
Fati Nourhashemi ,
Pierre Jean Ousset ,
Clive Ballard ,
Philippe Robert ,
Bruno Vellas ,
Constantine G. Lyketsos  and
Paul B. Rosenberg
Maria Soto*
Affiliation:
Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France
Sandrine Andrieu
Affiliation:
Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France Department of Epidemiology, Toulouse University Hospital Toulouse, France
Fati Nourhashemi
Affiliation:
Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France
Pierre Jean Ousset
Affiliation:
Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France
Clive Ballard
Affiliation:
Wolfson Centre for Age-Related Diseases, King's College, London, UK
Philippe Robert
Affiliation:
EA CoBTeK / ICMRR University of Nice Sophia Antipolis -CHU, France
Bruno Vellas
Affiliation:
Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France
Constantine G. Lyketsos
Affiliation:
Department of Psychiatry, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
Paul B. Rosenberg
Affiliation:
Department of Psychiatry, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
*
Correspondence should be addressed to: Maria Soto, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, 170 avenue de Casselardit, 31059 Toulouse, Cedex 9, France. Phone: +33 5 61 77 96 65; Fax: +33 5 61 49 71 09. E-mail: soto-martin.me@chu-toulouse.fr.
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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 design. 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.

Keywords

behavioragitationaggressionAlzheimer’smeasurementtherapeuticsclinical trial
Type
Review Article
Information
International Psychogeriatrics , Volume 27 , Issue 2 , February 2015 , pp. 181 - 197
Copyright
Copyright © International Psychogeriatric Association 2014 

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