J Clin Neurol.  2019 Jan;15(1):9-19. 10.3988/jcn.2019.15.1.9.

Risk of Dementia in Long-Term Benzodiazepine Users: Evidence from a Meta-Analysis of Observational Studies

• He Q
• Chen X
• Wu T
• Li L
• Fei X

• KMID: 2451140
• DOI: http://doi.org/10.3988/jcn.2019.15.1.9

Abstract

BACKGROUND AND PURPOSE
There is conflicting evidence in the literature on the association between benzodiazepines (BDZs) and the risk of dementia. This meta-analysis aimed to determine the relationship between the long-term usage of BDZs and the risk of dementia.
METHODS
The PubMed and Embase databases were systematically searched for relevant publications up to September 2017. The literature search focused on observational studies that analyzed the relationship between the long-term use of BDZs and the risk of dementia. Pooled rate ratios (RRs) with 95% confidence interval (CI) were assessed using a random-effects model. The robustness of the results was checked by performing subgroup and sensitivity analyses.
RESULTS
Ten studies were included: six case-control and four cohort studies. The pooled RR for developing dementia was 1.51 (95% CI=1.17-1.95, p=0.002) in patients taking BDZ. The risk of dementia was higher in patients taking BDZs with a longer half-life (RR=1.16, 95% CI=0.95-1.41, p=0.150) and for a longer time (RR=1.21, 95% CI=1.04-1.40, p=0.016).
CONCLUSIONS
This meta-analysis that pooled ten studies has shown that BDZ significantly increases the risk of dementia in the elderly population. The risk is higher in patients taking BDZ with a longer half-life (>20 hours) and for a longer duration (>3 years).

Keyword

dementia; benzodiazepines; meta-analysis

MeSH Terms

Aged
Benzodiazepines*
Cohort Studies
Dementia*
Half-Life
Humans
Benzodiazepines

Figure

• 

  Fig. 1 PRISMA flow diagram of the study selection process. Flow chart shows the number of citations retrieved by database search and criteria used to include or exclude a citation. Number of citations excluded are given in rectangular box along with the reason for exclusion. A total of 3,030 citations were screened and out of which 10 citations were finally included for pooled analysis. BDZ: benzodiazepine, n: number of studies.

• 

  Fig. 2 Forest plot of RR of ever BDZ users compared to never BDZ users. There is an increased risk of dementia in ever BDZ users compared to never BDZ users. Forest plot representing RR estimates with 95% CIs of each study and combined RR based on 10 studies (6 case-control and 4 cohort studies). Squares indicate RR in each study. The square size is proportional to the weight of the corresponding study in the meta-analysis; the length of horizontal lines represents the 95% CI. The diamond indicates the pooled RR and 95% CI (random-effects model). BDZ: benzodiazepines, CI: confidence interval, RR: relative risk.

• 

  Fig. 3 Forest plot of subgroup-analysis for ever BDZ users vs. never BDZ users accrding to study quality (low and medium study quality). No significant difference in RR found among the subgroups according to medium (n=8) and low (n=2) quality studies. Both indicating an increased risk of dementia in ever BDZ users compared to never BDZ users. Results of each subgroup is shown at the end of each subgroup in diamond shape. Squares indicate RR in each study. The square size is proportional to the weight of the corresponding study in the meta-analysis; the length of horizontal lines represents the 95% CI. BDZ: benzodiazepines, CI: confidence interval, n: number of studies, RR: relative risk.

• 

  Fig. 4 Forest plot of subgroup-analysis for ever BDZ users vs. never BDZ users accrding to study design (case-control and cohort). No significant difference in RR found among the subgroups according to cohort (n=4) and case-control (n=6) studies. Both indicating an increased risk of dementia in ever BDZ users compared to never BDZ users. Forest plot representing pooled (random-effects model) results (RR and 95% CIs) of subgroup-analysis according to study design i.e. Results of each subgroup is shown at the end of each subgroup in diamond shape and could be inferred as increased risk of dementia in BDZ users across the study design. Squares indicate RR in each study. The square size is proportional to the weight of the corresponding study in the meta-analysis; the length of horizontal lines represents the 95% CI. BDZ: benzodiazepines, CC: case-control, CI: confidence interval, COH: Cohort, n: number of studies, RR: relative risk.

• 

  Fig. 5 Forest plot of secondary-analysis for long term BDZ users compared to short term BDZ users. Long term BDZ users have significantly higher risk of dementia compared to short term BDZ users. Forest plot representing pooled estimate of RR and 95% CIs based duration of BDZ use. Squares indicate RR in each study. The square size is proportional to the weight of the corresponding study in the meta-analysis; the length of horizontal lines represents the 95% CI. The diamond indicates the pooled RR and 95% CI (random-effects model). BDZ: benzodiazepines, CI: confidence interval, RR: relative risk.

• 

  Fig. 6 Forest plot of secondary-analysis for long acting BDZ users compared to short/medium acting BDZ users. Long acting BDZ users have non significantly higher risk of dementia compared to short acting BDZ users. Forest plot representing pooled estimate of RR and 95% CIs based half-life of BDZ. Squares indicate RR in each study. The square size is proportional to the weight of the corresponding study in the meta-analysis; the length of horizontal lines represents the 95% CI. The diamond indicates the pooled RR and 95% CI (random-effects model). BDZ: benzodiazepines, CI: confidence interval, RR: relative risk.

• 

  Fig. 7 Funnel plot representing publication bias. Funnel plot does not have any asymmetry representing no significant publication bias in the study. Rate ratios are displayed on a logarithmic scale. Circles represent studies included in the meta-analysis.

• 

  Fig. 8 Sensitivity analysis forest plot. There is no significant impact of single study on pooled effect estimate. Sensitivity analysis plot representing impact on pooled effect estimate if individual studies are removed one by one based on ascending order of difference between the effect size and the pooled estimate. Square and length of horizontal lines beside each study represents pooled effect estimate and its 95% CI of all included studies except the study beside the square. The diamond indicates the pooled RR and 95% CI (random-effects model). BDZ: benzodiazepines, CI: confidence interval, RR: relative risk.

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