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      Association between Benzodiazepine Use and Dementia: A Meta-Analysis

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          Abstract

          Background

          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.

          Methods

          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.

          Findings

          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.

          Conclusions

          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.

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          Most cited references25

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          Benzodiazepine use and risk of dementia: prospective population based study

          Objective To evaluate the association between use of benzodiazepines and incident dementia. Design Prospective, population based study. Setting PAQUID study, France. Participants 1063 men and women (mean age 78.2 years) who were free of dementia and did not start taking benzodiazepines until at least the third year of follow-up. Main outcome measures Incident dementia, confirmed by a neurologist. Results During a 15 year follow-up, 253 incident cases of dementia were confirmed. New use of benzodiazepines was associated with an increased risk of dementia (multivariable adjusted hazard ratio 1.60, 95% confidence interval 1.08 to 2.38). Sensitivity analysis considering the existence of depressive symptoms showed a similar association (hazard ratio 1.62, 1.08 to 2.43). A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia. The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46 (1.10 to 1.94). Results of a complementary nested case-control study showed that ever use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia (adjusted odds ratio 1.55, 1.24 to 1.95) compared with never users. The results were similar in past users (odds ratio 1.56, 1.23 to 1.98) and recent users (1.48, 0.83 to 2.63) but reached significance only for past users. Conclusions In this prospective population based study, new use of benzodiazepines was associated with increased risk of dementia. The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study. Considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects of this drug class in the general population, indiscriminate widespread use should be cautioned against.
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            The diagnosis and management of benzodiazepine dependence.

            H Ashton (2005)
            Despite repeated recommendations to limit benzodiazepines to short-term use (2-4 weeks), doctors worldwide are still prescribing them for months or years. This over-prescribing has resulted in large populations of long-term users who have become dependent on benzodiazepines and has also led to leakage of benzodiazepines into the illicit drug market. This review outlines the risks of long-term benzodiazepine use, gives guidelines on the management of benzodiazepine withdrawal and suggests ways in which dependence can be prevented. Recent literature shows that benzodiazepines have all the characteristics of drugs of dependence and that they are inappropriately prescribed for many patients, including those with physical and psychiatric problems, elderly residents of care homes and those with comorbid alcohol and substance abuse. Many trials have investigated methods of benzodiazepine withdrawal, of which the keystones are gradual dosage tapering and psychological support when necessary. Several studies have shown that mental and physical health and cognitive performance improve after withdrawal, especially in elderly patients taking benzodiazepine hypnotics, who comprise a large proportion of the dependent population. Benzodiazepine dependence could be prevented by adherence to recommendations for short-term prescribing (2-4 weeks only when possible). Withdrawal of benzodiazepines from dependent patients is feasible and need not be traumatic if judiciously, and often individually, managed.
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              Risk of Dementia in Patients with Insomnia and Long-term Use of Hypnotics: A Population-based Retrospective Cohort Study

              Background Hypnotics have been reported to be associated with dementia. However, the relationship between insomnia, hypnotics and dementia is still controversial. We sought to examine the risk of dementia in patients with long-term insomnia and the contribution of hypnotics. Methods Data was collected from Taiwan’s Longitudinal Health Insurance Database. The study cohort comprised all patients aged 50 years or older with a first diagnosis of insomnia from 2002 to 2007. The comparison cohort consisted of randomly selected patients matched by age and gender. Each patient was individually tracked for 3 years from their insomnia index date to identify whether the patient had a first diagnosis of dementia. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results We identified 5693 subjects with long-term insomnia and 28,465 individuals without. After adjusting for hypertension, diabetes mellitus, hyperlipidemia, and stroke, those with long-term insomnia had significantly higher risks of dementia (HR, 2.34; 95% CI, 1.92–2.85). Patients with long-term insomnia and aged 50 to 65 years had a higher increased risk of dementia (HR, 5.22; 95% CI, 2.62–10.41) than those older than 65 years (HR, 2.33; 95% CI, 1.90–2.88). The use of hypnotics with a longer half-life and at a higher prescribed dose predicted a greater increased risk of dementia. Conclusions Patients with long-term use of hypnotics have more than a 2-fold increased risk of dementia, especially those aged 50 to 65 years. In addition, the dosage and half-lives of the hypnotics used should be considered, because greater exposure to these medications leads to a higher risk of developing dementia.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 May 2015
                2015
                : 10
                : 5
                : e0127836
                Affiliations
                [1 ]The Second Student Office of Chongqing Medical University, Chongqing, China
                [2 ]School of Public Health and Management, Chongqing Medical University, Chongqing, China
                University of Groningen, NETHERLANDS
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GCZ. Performed the experiments: GCZ YW. Analyzed the data: GCZ YW. Contributed reagents/materials/analysis tools: GCZ YW Y. Zhao Y. Zhang. Wrote the paper: GCZ. Modified initial manuscript: Y. Zhao Y. Zhang.

                Article
                PONE-D-14-41634
                10.1371/journal.pone.0127836
                4446315
                26016483
                12b66e65-468a-4c8b-a5cc-016e1b1030c5
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 16 September 2014
                : 21 April 2015
                Page count
                Figures: 5, Tables: 2, Pages: 16
                Funding
                These authors have no support or funding to report.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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