Journal of
Personalized
Medicine
Review
Benzodiazepine Use and the Risk of Dementia in the Elderly
Population: An Umbrella Review of Meta-Analyses
Chieh-Chen Wu 1,2,† , Mao-Hung Liao 3,4,† , Chun-Hsien Su 1,5 , Tahmina Nasrin Poly 6,7
and Ming-Chin Lin 6,8, *
Citation: Wu, C.-C.; Liao, M.-H.; Su,
C.-H.; Poly, T.N.; Lin, M.-C.
Benzodiazepine Use and the Risk of
Dementia in the Elderly Population:
An Umbrella Review of Meta-Analyses.
J. Pers. Med. 2023, 13, 1485. https://
doi.org/10.3390/jpm13101485
Academic Editors: Pascale Gauthier
and Enrique Santamaria Martinez
Received: 8 August 2023
Revised: 6 September 2023
Accepted: 11 September 2023
Published: 12 October 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
J. Pers. Med. 2023, 13, 1485. https://doi.org/10.3390/jpm13101485
1 Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture
University, Taipei 111396, Taiwan; drluiswu@gmail.com (C.-C.W.); chsu@ulive.pccu.edu.tw (C.-H.S.)
2 Department of Healthcare Information and Management, School of Health Technology, Ming Chuan
University, Taipei 111, Taiwan
3 Superintendent Office, Yonghe Cardinal Tien Hospital, New Taipei City 23148, Taiwan; mhl5488@gmail.com
4 Department of Healthcare Administration, Asia Eastern University of Science and Technology, Banciao
District, New Taipei City 220303, Taiwan
5 Graduate Institute of Sport Coaching Science, College of Kinesiology and Health, Chinese Culture University,
Taipei 111396, Taiwan
6 Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical
University, Taipei 110, Taiwan; d610108004@tmu.edu.tw
7 International Center for Health Information Technology, College of Medical Science and Technology,
Taipei Medical University, Taipei 110, Taiwan
8 Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan
* Correspondence: arbiter@tmu.edu.tw
† These authors equally contributed to this study.
Abstract: The prevalence of dementia among the elderly is high, and it is the leading cause of death
globally. However, the relationship between benzodiazepine use and dementia risk has produced
inconsistent results, necessitating an updated review of the evidence. To address this, we conducted
an umbrella review of meta-analyses to summarize the available evidence on the association between
benzodiazepine use and dementia risk and evaluate its credibility. We systematically evaluated the
meta-analyses of observational studies that examined the connection between benzodiazepine use
and dementia risk. For each meta-analysis, we collected the overall effect size, heterogeneity, risk of
bias, and year of the most recent article and graded the evidence based on pre-specified criteria. We
also used AMSTAR, a measurement tool to evaluate systematic reviews, to assess the methodological
quality of each study. Our review included five meta-analyses encompassing 30 studies, and the
effect size of the association between benzodiazepine use and dementia risk ranged from 1.38 to 1.78.
Nonetheless, the evidence supporting this relationship was weak, and the methodological quality
of the studies included was low. In conclusion, our findings revealed limited evidence of a link
between benzodiazepine use and dementia risk, and more research is required to determine a causal
connection. Physicians should only prescribe benzodiazepine for appropriate indications.
Keywords: benzodiazepine; dementia; Alzheimer’s disease; meta-analysis
1. Introduction
Dementia is the most common disease among the elderly population and is the leading
cause of mortality worldwide [1]. The incidence of dementia has increased significantly
with the increasing trends of the aging population [2,3]. Currently, over 55 million indi-
viduals are living with dementia, a number that is expected to grow to 78 million in 2030
and 139 million in 2050 [4,5]. As there is no treatment available to cure dementia, it has
appeared as a major public health and economic issue. Identifying potential risk factors for
dementia is complex and challenging. Nonetheless, age, depression, diabetes, smoking, air
pollution, and head trauma have emerged as significant risk factors for dementia [6–8].
https://www.mdpi.com/journal/jpm
J. Pers. Med. 2023, 13, 1485 2 of 10

Benzodiazepine is a widely used medication to manage anxiety, depression, and in-

somnia [9]. Multiple studies indicate that benzodiazepine use is associated with numerous
severe adverse events, including falls [10], hip fractures [11], and mortality [12]. Recent
epidemiological studies have reported an elevated risk of dementia among patients using
benzodiazepines [13,14]. However, a comprehensive quantitative analysis of the available
evidence concerning dementia risk among benzodiazepine users is lacking. Despite the
numerous studies that have investigated the connection between benzodiazepine and
dementia risk [15–17], including systematic reviews and meta-analyses [18–20], a detailed
analysis is still unavailable.
To our best knowledge, no comprehensive attempt has been made to compile and
evaluate the available body of evidence. As a result, we conducted an umbrella review of
meta-analyses to provide a comprehensive overview of the reported connection between
benzodiazepine and dementia risk. The assessment of methodological quality, identifica-
tion of potential bias, and presentation of up-to-date evidence would help in the correct
interpretation of the existing data and inform clinical and policy decisions.

2. Methods
2.1. Study Protocol
An umbrella review of meta-analyses and systematic reviews reporting on the asso-
ciations between benzodiazepine use and the risk of dementia was performed according
to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
guidelines [21,22]. This study was not registered in PROSPERO.

2.2. Search Strategy

Our search strategy involved using electronic databases such as PubMed, Scopus, and
Web of Science to find relevant articles in English published between January 1990 and
January 2023. We used the following search terms: ‘(benzodiazepine) AND (dementia OR
Alzheimer’s disease) AND (meta-analysis OR systematic review)’. Our search included
meta-analyses of randomized controlled trials (RCTs) or observational studies. Articles
were reviewed by screening the titles, abstracts, and full texts to decide which ones to
include or exclude. We also searched the references of retrieved articles for relevant meta-
analyses but did not find any additional ones.

2.3. Eligibility Criteria

To be eligible for inclusion in our study, articles had to be meta-analyses or systematic
reviews of both RCTs and observational studies reporting on the association between
benzodiazepine use and the risk of dementia. We excluded review or systematic review
articles without meta-analysis, in vitro studies, and genetic studies. Additionally, we
excluded meta-analyses that lacked the necessary data to perform a reanalysis.

2.4. Data Extraction

Two authors (MMI and TNP) independently extracted the data, and any discrepancy
during the data extraction process was resolved through discussion. The following data
were extracted from eligible meta-analyses: first author, year of publication, the study
design, the number of included studies, the number of dementia patients and total partici-
pants, and overall effect size with a 95% confidence interval (CI), p-value, and I2 value.

2.5. Quality Assessment

The Measurement tool to Assess Systematic Reviews (AMSTAR-2) was used to assess
the quality of the included meta-analysis. AMSTAR-2 consists of 16 items to assess the
quality and it is recommended by Shea et al. [23]. Each item is categorized on a three-option
scale and 7 items are defined as critical to ascertain the quality of meta-analyses. The
quality of the study is considered critically low quality if it fails to achieve more than one
of these critical items, high quality if none or just one non-critical item is not addressed.
J. Pers. Med. 2023, 13, 1485 3 of 10

Any confusion in assigning quality ratings was resolved either by discussion between the
same two reviewers or by discussing with a third reviewer.

2.6. Determining the Level of Evidence

The level of evidence of each meta-analysis was classified into four different levels
of strength of the evidence of the association between benzodiazepine use and the risk
of dementia. The criteria of level of the evidence were based on effect size, p-value, and
heterogeneity between the studies [24]. The criteria were as follows:
Convincing evidence: Evidence of the association was considered convincing if the
effect size was large, calculated using a random-effect model, and p < 0.001. Moreover, no
heterogeneity was observed between studies.
Suggestive evidence: Evidence of the association was considered suggestive if the
effect size was large, calculated using a random-effect model, and p < 0.05. Moreover, no
heterogeneity was observed between studies.
Weak evidence: Evidence was considered weak if the study effect size was small,
calculated using a random-effect model, and p < 0.05. Moreover, large heterogeneity was
found between studies.
Non-significant association: If the reported effect size was not statistically significant
(p > 0.05).

3. Results
3.1. Literature Review and Study Characteristics
Electronic databases search yielded 15 systematic review and meta-analysis. Initially
10 studies were removed due to duplication. Moreover 3 studies were excluded by screen-
ing of titles and abstracts. Finally, 5 studies were selected in this umbrella review [9,25–28]
(Supplementary Figure S1).

3.2. Description of Included Studies

Table 1 shows the basic characteristics of included studies. All the meta-analysis pub-
lished between 2015 and 2019. It covers a total of eighteen years publications (2002–2018).
All the included studies searched articles in PubMed, EMBASE, and evaluated the risk of
bias using Begg’s and Egger’s test. Only one study found significant publication bias and
only one study reported that benzodiazepine use was not associated with an increased
risk of dementia due to protopathic bias. Sixteen studies were included in these five
meta-analyses and studies characteristics are given in the supplementary file.
J. Pers. Med. 2023, 13, 1485 4 of 10

Table 1. Shows the clinical characteristic of included studies.

Author, Year Study Design Search Strategy Objective Data Inclusion Period Publication Bias Findings
Quantify the association, and to Long-term benzodiazepine use is
PubMed, EMBASE, Begg’s and Egger’s
Zhong et al. 2015 [27] S&M explore a potential 2002–2013 associated with an increased risk
Cochrane library test (all p > 0.05)
dose–response pattern. of dementia
Evaluate the association Benzodiazepine use is
MEDLINE, EMBASE,
Islam et al. 2016 [9] S&M between benzodiazepine use 2002–2016 Egger’s test (p < 0.05) significantly associated
CENTRAL
and dementia risk with dementia risk
Identify whether an association
there is an association between
Lucchetta et al. 2018 PubMed, LILACS, exists between the use of GRADE rating
S&M 2011–2017 BZD use and the development of
[25] CENTRAL benzodiazepines and the system
dementia
development of dementia.
the association between
to investigate the risk of
Penninkilampi et al. PubMed, MEDLINE, benzodiazepine use and
dementia associated with the
2018 S&M EMBASE, CINAHL, 2002–2017 NR dementia incidence is not purely
use of benzodiazepines in
[26] LILACS, CENTRAL an artefact due to protopathic
elderly patients
bias
to determine the relationship Begg’s (p = 0.21) and BDZ significantly increases the
He et al. 2019 PubMed, EMBASE,
S&M between the long-term usage of 2002–2017 Egger’s (p = 0.49) risk of dementia in the elderly
[28] Cochrane library
BDZs and the risk of dementia tests population
Note: NR: Not reported, S & M: Systematic review and Meta-analysis.
J. Pers. Med. 2023, 13, 1485 5 of 10

3.3. The Effect of Benzodiazepine on Dementia Risk

The findings of each meta-analysis on the effect of benzodiazepines on dementia
risk are summarized in Table 2. All included meta-analyses showed a significant risk of
dementia among benzodiazepine users (all studies had weak evidence).

Table 2. Summary of the meta-analysis findings by pooling all the observational studies on associa-
tions of benzodiazepine use and the risk of dementia.

No of the Overall Latest

Included No of p- Heterogeneity Publication
Author, Year Total Effect Size Study Evidence
Study Study Value (I2 ) Bias
Participants (Reported) Year
Zhong et al. 1.49
Obs. 6 45,391 <0.001 35.1 2014 No Weak
2015 [27] (1.30–1.72)
Islam et al. 1.78
Obs. 8 97,091 <0.001 99 2016 Yes Weak
2016 [9] (1.33–2.38)
Lucchetta et al. 1.38
Obs. 11 980,860 <0.001 98 2017 No Weak
2018 [25] (1.07–1.77)
Penninkilampi 1.39
Obs. 14 923,632 <0.001 97.59 2017 No Weak
et al. 2018 [26] (1.21–1.59)
He et al. 2019 1.51
Obs. 10 213,964 0.002 97 2017 No Weak
[28] (1.17–1.95)
Note: Obs.: Observational.

Zhong et al. [27] examined the association between benzodiazepine and the dementia
risk using six observational studies, and explored a potential dose–response pattern. The
pooled adjusted risk ratios (RRs) for dementia were 1.49 (95% confidence interval (CI)
1.30–1.72) for long-term users compared with never users. However, the risk of dementia
was increased among recent (RR 1.55, 95% CI 1.31–1.83) and past users (RR 1.55, 95% CI
1.17–2.03). The pooled adjusted RRs were almost similar when they calculated effect size
after adjusting with anxiety and depression. The risk of dementia among benzodiazepine
users increased by 22% for a 20 defined daily dose per year increment (RR 1.22, 95% CI
1.18–1.25), and this finding showed no evidence of heterogeneity (p = 0.32; I2 = 0.0%).
Islam et al. [9] included 10 observational studies (case-control and cohort design) to
evaluate the relationship between benzodiazepine use and dementia risk. A significantly
increased dementia risk (OR, 1.78 (95% CI 1.33–2.38) was observed among benzodiazepine
users as compared to benzodiazepine non-users. The risk of dementia was almost similar
in the short half-life (≤20 h) and long half-life benzodiazepine users. Moreover, benzodi-
azepine use also significantly increased dementia risk when the effect sizes were adjusted
with insomnia, anxiety, depression, and psychiatry.
Lucchetta et al. [25] conducted a systematic review and meta-analysis of 11 observa-
tional studies, including 980,860 adults/elderly individuals. Of 11 studies, eight studies
reported an increase risk among benzodiazepine users, two studies found no association
between benzodiazepine and dementia, and one study reported a protective effect. The
overall pooled effect showed a significant association between benzodiazepine use and the
risk of dementia (OR 1.38, 95% CI: 1.07–1.77). The risk of dementia was not significantly
different among short and long-acting benzodiazepine users (RR 1.09 vs. 1.24).
Penninkilampi et al. [26] to examined the association between benzodiazepine and
the risk of dementia in elderly patients, involving 14 observational studies with 159,090
individual and tried to control protopathic bias. The risk of dementia [odds ratio (OR)
1.39, 95% confidence interval (CI) 1.21–1.59 was significantly high among benzodiazepines
users. Moreover, the magnitude of the risk of dementia was even higher among long-acting
benzodiazepines users (OR 1.21, 95% CI 0.99–1.49) than short-acting benzodiazepines users
(OR 1.13, 95% CI 1.02–1.26).
J. Pers. Med. 2023, 13, 1485 6 of 10

He et al. [28] conducted a meta-analysis to determine the association between the

long-term usage of benzodiazepine and the risk of dementia. Patients who were taking
benzodiazepine had higher risk of dementia (RR 1.51, 95% CI: 1.17–1.95) compared to non-
benzodiazepine users. The pooled RR for developing dementia was 1.16 (95% CI = 0.95–1.41,
p = 0.150) for longer half-life benzodiazepine and 1.21 (95% CI = 1.04–1.40, p = 0.016) for a
longer time.

3.4. Quality of the Included Studies

The AMSTAR-2 tool was to evaluate the quality of five systematic review and meta-
analysis (Check Supplementary File). Of five included studies, four studies were low
quality and one study was moderate quality. Table 3 shows the quality of included studies.

Table 3. Quality assessments of included meta-analysis using AMSTAR-2 tool.

AMSTAR Items
Author, Year
1 2* 3 4* 5 6 7* 8 9* 10 11 * 12 13 * 14 15 * 16 O.R.
Zhong et al.
Yes No No PY Yes yes PY Yes Yes No Yes Yes Yes Yes Yes Yes L
2015 [27]
Islam et al.
Yes No No PY Yes Yes PY Yes Yes No Yes Yes Yes Yes Yes Yes L
2016 [9]
Lucchetta et al.
Yes Yes No Yes Yes Yes PY Yes Yes No Yes Yes Yes Yes Yes Yes M
2018 [25]
Penninkilampi
Yes No No PY Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes L
et al. 2018 [26]
He et al.
Yes No No PY Yes Yes PY Yes Yes No Yes Yes Yes Yes Yes Yes L
2019 [28]
Note: PY: Partial Yes; L: Low; M: Moderate; O.R.: Overall Ratings; *: Critical domain.

4. Discussion
Main findings: This umbrella review of meta-analyses of observational studies pro-
vided an updated, comprehensive overview, and critical assessment of the association
between benzodiazepines use and the risk of dementia. Among the five included studies,
four studies had high heterogeneity and one study showed no heterogeneity. All the
included studies had weak evidence; however, the methodological quality was also low.
Updated evidence: Recently, several studies also evaluated the risk of dementia
among benzodiazepine users. However, the findings of these studies were inconsistent.
Grossi et al. [29] conducted a cohort study using data from England. They reported no
association between benzodiazepine use and the risk of developing dementia (IRR 1.06,
95% CI: 0.72–1.60). Moreover, Aldaz et al. [30] conducted a large case-control study (case:
15,212 and control: 62,397) using the Spanish database for pharmacoepidemiologic research
in primary care (BIFAP) of the Spanish Agency of Medicines and Medical Devices (AEMPS).
Benzodiazepine use was not associated with an increased risk of dementia. In fact, there
was no significant difference observed between long- and short-acting benzodiazepine use.
A retrospective study from the USA evaluated the association between benzodiazepine
exposure and the risk of developing dementia using data from 528,006 veterans (aged 65
or older patients without dementia during a 10-year baseline period) [31]. Patients with
benzodiazepine were not associated with dementia, the adjusted risk ration for dementia
were 1.06 (95% CI: 1.02–1.10), 1.05 (95% CI 1.01–1.09), and 1.05 (95% CI 1.02–1.09) for
low, medium, and high benzodiazepine users. Similarly, a prospective study from the
Netherlands included 3526 individuals aged between 70 and 78 years without dementia [32].
After two years of follow-up, no association was observed between benzodiazepine use
and the risk of dementia.
In contrary, Baek et al. [16] conducted a retrospective cohort study retrieving health
insurance claims data from the National Health Insurance Service (NHIS) database of South
J. Pers. Med. 2023, 13, 1485 7 of 10

Korea, where they included benzodiazepine users aged ≥ 55 years with no history of de-
mentia within the previous 5 years. Although, an increased risk of dementia was reported
among benzodiazepine users, the findings of the study mentioned that the association was
likely due to confounding by indication. Joyce et al. [17] conducted a case-control study
using a longitudinal Medicare claim dataset, where benzodiazepine exposure was between
approximately 8% and 13%. The risk of dementia was high among patients with benzodi-
azepine. In fact, the risk of dementia was even greater among patients with higher levels of
benzodiazepine exposure (>365 days over a 2-year period). Brieler et al. [1] endeavored to
address the prevailing limitations of previous research studies by mitigating confounding
variables. The existing body of research remains inconsistent and contentious due to the
intertwined associations of both benzodiazepines and dementia with the risk of dementia.
Consequently, it remains uncertain whether benzodiazepines, anxiety, or both are exclu-
sively responsible for the increased dementia risk. To tackle this question, a retrospective
cohort study was conducted, utilizing eight-year claim databases and implementing the
entropy balancing method to mitigate bias. Among the 72,496 patients examined, 4325
were diagnosed with anxiety. However, only a mere 3.6% of these individuals received
sustained benzodiazepine prescriptions, and 9.2% experienced dementia incidents. Upon
adjusting for confounding factors, the study revealed that both sustained benzodiazepine
use (HR 1.28, 95% CI: 1.11–1.47) and an anxiety diagnosis (HR 1.19, 95% CI: 1.06–1.33)
were independently associated with incident dementia among patients aged 65–75. No-
tably, when comparing anxiety disorder with sustained benzodiazepine use to anxiety
disorder alone, no significant association with incident dementia was observed (HR 1.18,
95% CI: 0.92–1.51) after thorough confounder control. Despite the observed link between
benzodiazepine use and increased dementia risk, the researchers suggested the need for
further investigations to ascertain the presence of a dose–response relationship. Such an
association could potentially imply that there is a specific threshold of benzodiazepine
dosage that heightens the risk of dementia, even among individuals with anxiety disorders.
Additionally, future studies should explore whether the relationship between incident
dementia and anxiolytic medications varies across different classes of these medications. In
a related study, Guo et al. [2] also delved into the connection between cognitive impairment
and the use of Z drugs. Their primary focus was on evaluating the risk of cognitive decline
associated with exposure to Z drugs among middle-aged and older patients suffering
from chronic insomnia. Conducting a case-control study design, they included patients
who met the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V)
diagnostic criteria for chronic insomnia and had a Pittsburgh Sleep Quality Index (PSQI)
score > 7. It is worth noting that the categorization of benzodiazepines in this study was
based on the World Health Organization’s Anatomical Therapeutic Chemical classification
system. To account for potential confounding factors, the researchers incorporated various
laboratory variables such as fasting blood glucose (mmol/L), triglyceride (mmol/L), total
cholesterol (mmol/L), low-density lipoprotein cholesterol (LDL-C, mmol/L), high-density
lipoprotein cholesterol (HDL-C, mmol/L), serum uric acid (µmol/L), and serum albumin
(g/L) levels into their model. The study findings indicated that benzodiazepine exposure
density emerged as an independent risk factor for cognitive impairment in middle-aged
and older patients grappling with chronic insomnia. However, no discernible correlation
was established between the use of Z drugs and cognitive impairment in this context.
What are needed to be done and Why: As the number of aging populations increases,
the prevalence of dementia is expected to rise in the near future. According to a previous
study, the proportion of people aged 60 years or older is projected to increase from 9% in 2019
to 22% in 2050 worldwide [33]. While several drugs are available to slow the progression of
the disease, none can cure it. Hence, it is vital to undertake comprehensive research to prevent
dementia as a public health priority. Older adults are more susceptible to dementia due to
the use of multiple drugs to treat chronic diseases [34]. Identifying drugs associated with
dementia is crucial for dementia prevention, improving quality of life and cognitive health.
Long-term use of certain drugs such as anticholinergic, antipsychotics, and antiepileptics
J. Pers. Med. 2023, 13, 1485 8 of 10

has been linked to an increased risk of dementia [35,36]. Recently, public attention has been
focused on the association between benzodiazepines and the risk of dementia among older
adults. However, mixed reports regarding the effect of long-term use of benzodiazepines
on dementia risk exist. Our study found weak evidence of this association. Previous study
suggested that benzodiazepines can be considered in the short-term treatment of psychiatric
disorders, as a sole or combined treatment [37]. The medium to long-term risk-benefit ratio
may generate controversy, considering the limited level of evidence available. Furthermore,
there is a lack of comprehensive information regarding the duration, dosage, and specific
types of benzodiazepines (both short- and long-acting) and their association with the risk
of dementia. Therefore, further research is necessary to explore the potential link between
benzodiazepines and the risk of dementia, taking into account varying doses and durations.
In addition to several protopathic bias, the heterogeneity due to methodological differences
among the primary studies may challenge the demonstration of a causal relationship.
It is important to note that an association between benzodiazepines and dementia
does not imply causation. Future studies should also examine the risk of dementia in older
adults who are prescribed benzodiazepines to alleviate symptoms related to depression,
anxiety, and insomnia, especially in the early stages of cognitive decline, as these symptoms
have been observed to be connected to early-stage dementia. Additionally, there is a need
for biological studies to gain a better understanding of the causal relationship between
benzodiazepine use and the increased risk of dementia in older adults.
Strengths and Limitations: Our study has both strengths and limitations. One
strength is that we included all available meta-analyses to provide an updated and com-
prehensive analysis of the evidence on benzodiazepines and dementia risk. Additionally,
we used AMSTAR-2 to evaluate the methodological quality of the included studies and
assessed the strength of the evidence. However, our study also has some limitations that
should be addressed. For example, we only included five meta-analyses, and we did
not include recently published articles or re-analyze existing data to provide the most
up-to-date evidence. Furthermore, we were unable to investigate the association between
dose and types of benzodiazepines and the incidence of dementia, as this was beyond the
scope of our study. Finally, due to data constraints, we were unable to stratify the impact of
benzodiazepines by factors such as age, gender, dosage, or treatment duration, all of which
are crucial parameters for evaluating the true nature of the association.
Recommendation on benzodiazepines use in clinical practice: While benzodiazepines
exhibit varying effects on dementia, they demonstrate effectiveness in addressing several
conditions, such as depression, anxiety, and insomnia. Although the evidence from the
studies examined in this review is somewhat limited, it is advisable to employ benzo-
diazepines judiciously to minimize the potential risks associated with long-term usage
linked to dementia, rather than discontinuing their usage altogether. Physicians should
start treatment with the lowest feasible dose of benzodiazepines for a specified treatment
duration. In cases of severe anxiety or insomnia, consideration may be given to employing
a higher dose with an extended duration [38–40].
Aging plays a significant role in the onset of dementia, and given that benzodiazepines
have been associated with cognitive impairment, mobility challenges, neuronal cell apopto-
sis, and impaired driving skills in older individuals, the short-term use of benzodiazepines
with short half-lives is generally regarded as safe and recommended for older adults [41,42].
Since prior studies have not provided conclusive evidence that short- to intermediate-term
use of benzodiazepines increases the risk of dementia, physicians should explore alterna-
tive pharmacological and behavioral approaches before resorting to benzodiazepines and
carefully assess the potential risks and benefits of their use.

5. Conclusions
This study examined the associations between benzodiazepine use and the risk of
dementia. Although all meta-analyses found significant relationships between benzo-
diazepine use and dementia risk, the strength of the evidence was weak due to the low
J. Pers. Med. 2023, 13, 1485 9 of 10

methodological quality of the included studies. Therefore, researchers and clinicians should
interpret these findings with caution. Future studies should include recent articles, evaluate
potential biases, and provide updated evidence that accounts for factors such as dose,
duration, and types of benzodiazepines.

Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/jpm13101485/s1, Figure S1: Selection Strategy.
Author Contributions: Conceptualization, C.-C.W. and T.N.P.; methodology, T.N.P.; software, C.-C.W.;
validation, M.-H.L., C.-H.S. and M.-C.L.; formal analysis, C.-C.W.; investigation, C.-H.S.; resources,
M.-H.L.; data curation, M.-C.L.; writing—original draft preparation, T.N.P.; writing—review and
editing, M.-C.L.; visualization, C.-H.S.; supervision, M.-C.L. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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