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2015 ; 27
(2
): 181-197
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Medication development for agitation and aggression in Alzheimer disease: review
and discussion of recent randomized clinical trial design
#MMPMID25226218
Soto M
; Andrieu S
; Nourhashemi F
; Ousset PJ
; Ballard C
; Robert P
; Vellas B
; Lyketsos CG
; Rosenberg PB
Int Psychogeriatr
2015[Feb]; 27
(2
): 181-197
PMID25226218
show ga
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.