Association between Benzodiazepine Use and Dementia: A Meta-Analysis.

The association between long-term benzodiazepine use and risk of dementia remains controversial. Therefore, current study aimed to quantify this association, and to explore a potential dose-response pattern.We searched PubMed, Embase and the Cochrane Library through August 17, 2014. We included nested case-control or prospective cohort studies that provided risk estimates on the association of benzodiazepine use with risk of dementia, and a clear definition of status of benzodiazepine use. Overall effect size was calculated using a random-effects model.Six studies were eligible for inclusion, involving 11,891 dementia cases and 45,391 participants. Compared with never users, pooled adjusted risk ratios (RRs) for dementia were 1.49 (95% confidence interval (CI) 1.30-1.72) for ever users, 1.55 (95% CI 1.31-1.83) for recent users, and 1.55 (95% CI 1.17-2.03) for past users. The risk of dementia increased by 22% for every additional 20 defined daily dose per year (RR, 1.22, 95%CI 1.18-1.25). When we restricted our meta-analyses to unadjusted RRs, all initial significant associations persisted.Long-term benzodiazepine users have an increased risk of dementia compared with never users. However, findings from our study should be treated with caution due to limited studies and potential reverse causation. Large prospective cohort studies with long follow-up duration are warranted to confirm these findings

Smoking is associated with an increased risk of dementia: a meta-analysis of prospective cohort studies with investigation of potential effect modifiers.

Previous studies showed inconsistent results on the association of smoking with all-cause dementia and vascular dementia (VaD), and are limited by inclusion of a small number of studies and unexplained heterogeneity. Our review aimed to assess the risk of all-cause dementia, Alzheimer's disease (AD) and VaD associated with smoking, and to identify potential effect modifiers.The PubMed, Embase, Cochrane Library and Psychinfo databases were searched to identify studies that provided risk estimates on smoking and incidence of dementia. A random-effects model was used to yield pooled results. Thirty-seven studies were included. Compared with never smokers, current smokers showed an increased risk of all-cause dementia (risk ratio (RR) 1.30, 95% confidence interval (CI) 1.18-1.45), AD (RR 1.40, 95% CI 1.13-1.73) and VaD (RR 1.38, 95% CI 1.15-1.66). For all-cause dementia, the risk increased by 34% for every 20 cigarettes per day (RR 1.34, 95% CI 1.25-1.43). Former smokers did not show an increased risk of all-cause dementia (RR 1.01, 95% CI 0.96-1.06), AD (RR 1.04, 95% CI 0.96-1.13) and VaD (RR 0.97, 95% CI 0.83-1.13). Subgroup analyses indicated that (1) the significantly increased risk of AD from current smoking was seen only in apolipoprotein E ε4 noncarriers; (2) current smokers aged 65 to 75 years at baseline showed increased risk of all-cause dementia and AD compared to those aged over 75 or under 65 years; and (3) sex, race, study location and diagnostic criteria difference in risk of dementia was not found.Smokers show an increased risk of dementia, and smoking cessation decreases the risk to that of never smokers. The increased risk of AD from smoking is more pronounced in apolipoprotein E ε4 noncarriers. Survival bias and competing risk reduce the risk of dementia from smoking at extreme age

Characteristics of 6 included studies regarding benzodiazepine use and dementia.

<p>SS, sample size; BZD, benzodiazepine; ICD-9, International Classification of Diseases, Ninth Revision; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, fourth edition; DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, third edition Revised.</p><p>^aAge refers to mean age of participants at baseline.</p><p>^bFollow-up refers to maximum follow-up length.</p><p>^cUsing data of different subsets of National Health Insurance Research Database in Taiwan</p><p>^dOriginal authors defined recent use and past use as first BZD claim <15 days and last BZD claim >15 days before index date, respectively. To keep homogenous with definitions of BZD use in other studies as much as possible, we redefined recent use and past use as first BZD claim <2 years and last BZD claim >2 years before index date, respectively. In this case, we pooled initial estimates to yield required estimates for “redefined" recent and past use through a random-effects model.</p><p>Characteristics of 6 included studies regarding benzodiazepine use and dementia.</p

Meta-analysis on past use of benzodiazepines and risk of dementia.

<p>The squares represent the risk estimate for each individual study, with the area reflecting the weight assigned to the study. The horizontal line across each square represents the 95% confidence interval. The diamond represents the summary risk estimate, with width representing 95% confidence interval.</p

Sensitivity analysis: exclusion of a single study in turn.

<p>The study being cited on the left is the one being left out in each analysis. The circle represents the summary risk estimates after exclusion of a single study, and the corresponding dot line represents 95% confidence interval. The middle vertical solid line represents summary risk estimates of all included studies, and left and right vertical solid line represent lower limit and upper limit, respectively. Panel A, ever use versus never use; Panel B, recent use versus never use; Panel C, past use versus never use.</p

Meta-analysis on ever use of benzodiazepines and risk of dementia.

<p>The squares represent the risk estimate for each individual study, with the area reflecting the weight assigned to the study. The horizontal line across each square represents the 95% confidence interval. The diamond represents the summary risk estimate, with width representing 95% confidence interval.</p

The flowchart of identifying relevant studies.

<p>The flowchart of identifying relevant studies.</p

Meta-analysis on recent use of benzodiazepines and risk of dementia.

<p>The squares represent the risk estimate for each individual study, with the area reflecting the weight assigned to the study. The horizontal line across each square represents the 95% confidence interval. The diamond represents the summary risk estimate, with width representing 95% confidence interval.</p

Meta-analysis for ever smoking and risk of A) all-cause dementia, B) Alzheimer’s disease and C) vascular dementia.

<p>Meta-analysis for ever smoking and risk of A) all-cause dementia, B) Alzheimer’s disease and C) vascular dementia.</p

Characteristics of 37 included studies regarding smoking and risk of dementia.

<p>APOE ε4, apolipoprotein E ε4; NA, not available; BMI, body mass index; IGT, impaired glucose tolerance; NINCDS-ADRDA, DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, third edition Revised; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, fourth edition; NINDS-AIREN, National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences; GMS-AGECAT, Geriatric Mental State-the Automated Geriatric Examination for Computer Assisted Taxonomy; ICD-8, International Classification of Diseases, Eighth Revision; ADDTC core criteria, Alzheimer’s Disease Diagnostic and Treatment Centers core criteria.</p><p>¹ Value refers to mean age of participants at baseline.</p><p>² Value is expressed as maximum.</p><p>³ Dementia was determined by a battery of neuropsychological measures and a standardized neurological examination.</p><p>⁴ The term “other” in the “Adjustment factors” column refers to all the confounders except age, sex, education, APOE ε4, BMI, diabetes, alcohol and hypertension.</p><p>⁵ Value refers to sample size at baseline.</p><p>⁶ The risk estimates were available just for former smoking and the risk of all-cause dementia and AD.</p><p>Characteristics of 37 included studies regarding smoking and risk of dementia.</p