Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer's disease: systematic review and meta-analysis
Author(s)
Type
Journal Article
Abstract
Background Dysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimer’s disease, contributing to cognitive and neuropsychiatric symptoms in some patients. This system offers a potential therapeutic target, although noradrenergic treatments are not currently used in clinical practice.
Objective To assess the efficacy of drugs with principally noradrenergic action in improving cognitive and neuropsychiatric symptoms in Alzheimer’s disease.
Methods The MEDLINE, Embase and ClinicalTrials.gov databases were searched from 1980 to December 2021. We generated pooled estimates using random effects meta-analyses.
Results We included 19 randomised controlled trials (1811 patients), of which six were judged as ‘good’ quality, seven as ‘fair’ and six ‘poor’. Meta-analysis of 10 of these studies (1300 patients) showed a significant small positive effect of noradrenergic drugs on global cognition, measured using the Mini-Mental State Examination or Alzheimer’s Disease Assessment Scale—Cognitive Subscale (standardised mean difference (SMD): 0.14, 95% CI: 0.03 to 0.25, p=0.01; I2=0%). No significant effect was seen on measures of attention (SMD: 0.01, 95% CI: −0.17 to 0.19, p=0.91; I2=0). The apathy meta-analysis included eight trials (425 patients) and detected a large positive effect of noradrenergic drugs (SMD: 0.45, 95% CI: 0.16 to 0.73, p=0.002; I2=58%). This positive effect was still present following removal of outliers to account for heterogeneity across studies.
Discussion Repurposing of established noradrenergic drugs is most likely to offer effective treatment in Alzheimer’s disease for general cognition and apathy. However, several factors should be considered before designing future clinical trials. These include targeting of appropriate patient subgroups and understanding the dose effects of individual drugs and their interactions with other treatments to minimise risks and maximise therapeutic effects.
PROSPERO registeration number CRD42021277500.
Objective To assess the efficacy of drugs with principally noradrenergic action in improving cognitive and neuropsychiatric symptoms in Alzheimer’s disease.
Methods The MEDLINE, Embase and ClinicalTrials.gov databases were searched from 1980 to December 2021. We generated pooled estimates using random effects meta-analyses.
Results We included 19 randomised controlled trials (1811 patients), of which six were judged as ‘good’ quality, seven as ‘fair’ and six ‘poor’. Meta-analysis of 10 of these studies (1300 patients) showed a significant small positive effect of noradrenergic drugs on global cognition, measured using the Mini-Mental State Examination or Alzheimer’s Disease Assessment Scale—Cognitive Subscale (standardised mean difference (SMD): 0.14, 95% CI: 0.03 to 0.25, p=0.01; I2=0%). No significant effect was seen on measures of attention (SMD: 0.01, 95% CI: −0.17 to 0.19, p=0.91; I2=0). The apathy meta-analysis included eight trials (425 patients) and detected a large positive effect of noradrenergic drugs (SMD: 0.45, 95% CI: 0.16 to 0.73, p=0.002; I2=58%). This positive effect was still present following removal of outliers to account for heterogeneity across studies.
Discussion Repurposing of established noradrenergic drugs is most likely to offer effective treatment in Alzheimer’s disease for general cognition and apathy. However, several factors should be considered before designing future clinical trials. These include targeting of appropriate patient subgroups and understanding the dose effects of individual drugs and their interactions with other treatments to minimise risks and maximise therapeutic effects.
PROSPERO registeration number CRD42021277500.
Date Issued
2022-06-01
Date Acceptance
2022-05-19
Citation
Journal of Neurology, Neurosurgery and Psychiatry, 2022, 93 (10), pp.1080-1090
ISSN
0022-3050
Publisher
BMJ Publishing Group
Start Page
1080
End Page
1090
Journal / Book Title
Journal of Neurology, Neurosurgery and Psychiatry
Volume
93
Issue
10
Copyright Statement
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000818048100001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
Subjects
AGITATION
Alzheimer's disease
apathy
APATHY
ATOMOXETINE
ATTENTION
BEHAVIORS
Clinical Neurology
cognition
dementia
DOUBLE-BLIND
Life Sciences & Biomedicine
LOCUS-COERULEUS ACTIVITY
METHYLPHENIDATE
Neurosciences & Neurology
NORADRENALINE
psychiatry
Psychiatry
RESPONSE-INHIBITION
Science & Technology
Surgery
Publication Status
Published
Date Publish Online
2022-07-05