CLINICAL REVIEW

BENZODIAZEPINE

Benzodiazepine use and cognitive decline in the elderly

Jenna D. Picton, Pharm.D., Lahey

Hospital & Medical Center, Burlington,
MA.
Adriane Brackett Marino, Pharm.D.,
BCPS, Carolinas HealthCare System,
Lincolnton, NC.
Kimberly Lovin Nealy, Pharm.D.,
BCPS, Cabarrus Family Medicine—
Prosperity Crossing, Charlotte, NC, and
Wingate University School of Pharmacy,
Wingate, NC.
Purpose. Published evidence on the relationship between benzodiaze-
pine exposure and altered cognition in the geriatric population is reviewed.
Summary. Benzodiazepines constitute one of the most commonly pre-
scribed medication classes and are used primarily for management of anx-
iety and insomnia. Despite strong recommendations based on high-quality
evidence warning of the potential cognitive adverse effects of benzodiaz-
epine use, particularly in patients 65 years of age or older, published litera-
ture suggests that a substantial proportion of the U.S. geriatric population
use these medications in a chronic fashion. The body of evidence suggest-
ing that benzodiazepine use may be a modifiable risk factor for dementia
continues to grow. Evidence exists to suggest that benzodiazepine use in
the elderly population is associated with cognitive decline, dementia, and
Alzheimer’s disease, although evidence regarding the correlation between
benzodiazepine use and dementia is conflicting; the more recent studies
in this area have focused on eliminating causation bias. Pharmacists in a
variety of settings can educate patients and assist providers in selecting
an appropriate medication regimen for anxiety or insomnia that is tailored
to each elderly patient’s needs and takes into account the immediate and
long-term safety of the patient.

Conclusion. Investigations of the association between benzodiazepine

therapy and cognitive decline in elderly patients have yielded mixed find-
ings. Stronger links have emerged from studies examining longer- rather
than shorter-acting benzodiazepines, longer rather than shorter durations
of use, or earlier rather than later exposure. Questions remain about cau-
sality and the impact of confounders on study interpretation.

Keywords: benzodiazepines, cognition, cognitive decline, dementia, el-

derly, geriatric

Am J Health-Syst Pharm. 2018; 75:e6-12

B enzodiazepines constitute the

Address correspondence to Dr. Picton
(je.picton@wingate.edu).
Copyright © 2018, American Society of
Health-System Pharmacists, Inc. All rights
reserved. 1079-2082/18/0101-00e6.
DOI 10.2146/ajhp160381
most frequently prescribed psy-
chotropic medication class and are
used as anxiolytics, sedatives, hyp-
notics, anticonvulsants, and skeletal
muscle relaxants.1 Benzodiazepines
have also been used alone and as ad-
junctive therapy for the management
of psychological conditions. The sites
and mode of action of benzodiaz-
epines are not fully understood, but
the effects appear to be facilitated
through an inhibitory neurotransmit-
ter, gamma-aminobutyric acid. The
drugs appear to act at the limbic, tha-
lamic, and hypothalamic regions of
the central nervous system (CNS), al-
lowing for all degrees of CNS depres-
sion. While all benzodiazepines have
similar actions, there is variation re-
lated to their durations of action. Typi-
cally, short- and intermediate-acting
benzodiazepines are prescribed for
insomnia, while longer-acting benzo-
diazepines are reserved for anxiety.2
Although benzodiazepines are Food
and Drug Administration approved
as effective medications, there are
notable potential adverse effects that
warrant consideration. Undesirable
CNS effects are the most common ad-
verse effects and are an extension of

e6    AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 1 | JANUARY 1, 2018

 BENZODIAZEPINE CLINICAL REVIEW
the pharmacologic effects of benzodi-
azepines. These effects include ataxia,
fatigue, confusion, weakness, dizzi-
ness, vertigo, and syncope. Longer-
acting benzodiazepines are more
likely to cause residual sedative effects
and impair psychomotor and mental
performance. There is additional con-
cern for adverse effects in the elderly,
as the half-lives of benzodiazepines
are extended in geriatric patients due
to age-related changes in pharma-
cokinetics and pharmacodynamics,
including alterations in drug distribu-
tion and elimination. Furthermore,
the risk of adverse effects is higher
with increasing length of use. Long-
term benzodiazepine use has been
associated with increased risks of falls,
cognitive impairment, dependence,
and withdrawal symptoms. The issue
of the reversibility of benzodiazepine-
associated cognitive impairment is
controversial.3-5 Currently there is
no standard approach to help iden-
tify and monitor the cognitive adverse
effects related to benzodiazepine
therapy; as a result, the potential for
long-term consequences that might
contribute to the rising burden of cog-
nitive impairment in geriatric patients
remains unknown.
In the United States, benzodiaze-
pines remain the most commonly pre-
scribed anxiolytic medications among
the geriatric population despite their
potential to increase the risks of cogni-
tive impairment, falls, and fractures,
while benzodiazepine use in other de-
veloped countries is less common.6-11
Data from IMS Health’s longitudinal
prescription database indicate that
about 9% of the U.S. geriatric popu-
lation received at least 1 benzodiaz-
epine prescription in 2008, with about
one third of those prescriptions being
for long-term use12; elderly women
were twice as likely as elderly men to
receive benzodiazepines. A study as-
sessing controlled substance prescrib-
ing patterns in U.S. ambulatory care
clinics and emergency departments
found that benzodiazepine prescrib-
ing rates actually increased with pa-
tient age, with the highest prevalence
KEY POINTS
• Despite strong recommenda-
tions to avoid their use in the
geriatric population, benzodi-
azepines remain the most fre-
quently prescribed psychotropic
medication class.
• While pertinent studies to date
have yielded mixed findings,
longer-acting benzodiazepines
and longer durations of use are
most strongly associated with
cognitive decline in the elderly.
• Pharmacists can play an impor-
tant role in educating patients
and providers and assist in
selecting appropriate medica-
tion regimens tailored to each
elderly patient’s needs.
seen in patients 65–84 years of age.13
Another study endeavored to deter-
mine the impact of inappropriate
drug use on hospitalizations, mortal-
ity, and costs in older persons, and
the results emphasized the need for
cautious prescribing of long-acting
benzodiazepines in the geriatric
population.14 Recently, the American
Geriatrics Society (AGS) updated its
list of and criteria for potentially in-
appropriate medications for older
adults.15 The current AGS recommen-
dation is to avoid all benzodiazepines
in most adults 65 years of age or older;
in particular, benzodiazepines should
be avoided in elderly individuals with
dementia, delirium, or cognitive im-
pairment due to the increased risks or
worsening of cognitive impairment,
delirium, falls, fractures, and motor
vehicle accidents.
Furthermore, AGS recommends
avoiding benzodiazepines in elderly
patients with a history or risk of falls,
since these agents can cause ataxia,
impaired psychomotor function, and
syncope.15 If safer alternatives are not
available, AGS recommends reducing
AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 1 | JANUARY 1, 2018  e7
the use of other CNS-active medica-
tions that increase the risk of falls and
consequent fractures (i.e., anticonvul-
sants, opioid-receptor agonists, seda-
tives, and hypnotics) and implement-
ing other strategies to reduce the risk
of falls. The AGS document includes
a special mention that shorter-acting
benzodiazepines are not safer than
longer-acting ones for geriatric pa-
tients. AGS notes that longer-acting
agents may be appropriate for seizure
disorders, rapid eye movement sleep
disorders, benzodiazepine or alco-
hol withdrawal, severe generalized
anxiety disorder, and periprocedural
anesthesia. The American Psychiat-
ric Association suggests using substi-
tutes for benzodiazepines whenever
possible in the geriatric population
to avoid a higher risk of falls and frac-
tures and recommends careful moni-
toring when the use of benzodiaz-
epines is unavoidable.16 Additionally,
the National Institutes of Health has
commented on the increased risks of
residual daytime sedation, cognitive
impairment, motor incoordination,
dependence, and rebound insomnia
associated with benzodiazepine use.17
Benzodiazepine therapy, if un-
avoidable, should always be individu-
alized and monitored thoroughly, and
the need for continued therapy should
be reevaluated periodically. The pur-
pose of this article is to review the avail-
able literature in order to determine
the relationship between benzodiaz-
epine exposure and changes in cogni-
tion typically seen in geriatric patients.
An electronic search of PubMed
covering the period January 2000–
October 2015 was performed using
the following search terms: benzo-
diazepine, elderly, cognitive impair-
ment, dementia, and Alzheimer’s dis-
ease. Only literature with available
abstracts, published in English, and
regarding human subjects was includ-
ed in the search. Selected literature
was screened to identify additional
references.
Six hundred eight items were re-
turned in the search. The publica-
tions were screened to determine
 CLINICAL REVIEW BENZODIAZEPINE
their relevance to the topic of interest.
Included in the search results were
reports on randomized clinical trials,
meta-analyses, case–control studies,
cohort studies, and literature reviews
that measured benzodiazepine use in
the elderly and assessed cognition as
a function of benzodiazepine use. Sev-
enteen publications were analyzed for
the review, including reports on 9 pro-
spective trials, 8 case–control studies,
and 1 meta-analysis.18-34
Relationship between
benzodiazepine use and
dementia
While it is well known that ben-
zodiazepine use contributes to acute
cognitive and memory deficits, the
long-term effects remain less well
understood. Evidence suggests an as-
sociation between benzodiazepine
use and cognitive dysfunction in the
elderly, but evidence regarding the ex-
tent of cognitive decline varies, with
some literature suggesting no long-
term effects and other (more recent)
reports proposing an association with
Alzheimer’s disease. In a case–control
investigation of the potential asso-
ciation of benzodiazepine use and
cognitive decline, 3,777 community-
dwelling individuals at least 65 years
of age were followed for 8 years, and
those who developed dementia (n =
150) were compared with matched
controls.26 “Ever use” of benzodiaze­
pines (i.e., exposure at least once be-
fore the index date) and “former use”
(use ending at least 2 years prior to the
index date) were linked to a signifi-
cantly increased risk of dementia; the
calculated odds ratios (ORs) were 1.7
(95% confidence interval [CI], 1.2–2.4)
and 2.3 (95% CI, 1.2–4.5), respectively.
In the Caerphilly Prospective Study
(CaPS), men who had taken benzodi-
azepines regularly at 1 or more times
in their lifetime had a significantly in-
creased frequency of dementia, with
the strongest correlation seen in pa-
tients with earlier initial exposure.21 In
contrast, a prospective study assess-
ing benzodiazepine use and cognitive
decline in an elderly population with
e8    AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 1 | JANUARY 1, 2018
normal baseline cognition found that
despite poorer cognition in benzodi-
azepine users, the decline was not sta-
tistically significant.33
Additionally, a case–control study
revealed an increased risk of devel-
oping Alzheimer’s disease or vascular
dementia in patients who started tak-
ing benzodiazepines less than 3 years
prior to diagnosis of either disorder,
but the results were not statistically
significant.25
Degree of cognitive impairment
While the majority of pertinent
studies reviewed here suggest an asso-
ciation between benzodiazepine use
and cognitive impairment in the el-
derly, the degree to which cognition is
altered (if it is altered) is widely debat-
ed; some evidence indicates an accel-
erated rate of cognitive decline,28 while
other evidence indicates that cogni-
tive decline is transient.29 In addition,
results of the ”Three-city study,” which
assessed 969 subjects who used ben-
zodiazepines for 2, 4, or 7 consecutive
years, indicated that chronic benzodi-
azepine users (defined as those who
were using benzodiazepines at study
inclusion and at 2-year follow-up) had
significantly (p < 0.001) poorer cogni-
tive performance, as measured using
a set of standardized neuropsycho-
logical tests (the Mini–Mental State
Examination [MMSE], the Isaacs Set
Test, the Benton Visual Retention Test,
and the Trail Making Test), relative
to controls but did not show an ac-
celerated rate of decline over the full
7-year follow-up period.28 In contrast,
Paterniti et al.29 assessed whether the
long-term use of benzodiazepines ac-
celerated cognitive decline and found
that chronic users (defined as indi-
viduals who reported benzodiazepine
use at baseline and at 2- and 4-year
follow-up examinations) had a signifi-
cantly (p = 0.02) higher risk of decline
than both episodic and recurrent us-
ers (defined as those taking benzodi-
azepines at 1 and 2 examinations, re-
spectively). Although cognitive decline
was more evident in recurrent versus
episodic users, the difference was not
statistically significant. The investiga-
tors concluded that long-term benzo-
diazepine use is, indeed, a risk factor
for increased cognitive decline in the
elderly.
Recently published studies in-
vestigated whether there is a link be-
tween the use of benzodiazepines and
Alz­heimer’s disease. Two such studies
had conflicting results. In a retrospec-
tive case–control analysis, 26,459 indi-
viduals at least 65 years of age with a
new diagnosis of Alzheimer’s disease
or vascular dementia over a 15-year
period were matched with dementia-
free controls.25 The results indicated
that starting benzodiazepine use less
than 3 years prior to diagnosis was
not associated with a significantly in-
creased risk of developing Alzheimer’s
disease or vascular dementia. How-
ever, another case–control study, con-
ducted by Billioti de Gage et al.,18 which
had a follow-up period of 10 years,
found an increased risk of Alzheimer’s
disease in patients who took 91–180
benzodiazepine daily doses (OR, 1.32;
95% CI, 1.01–1.74) and patients who
took more than 180 daily doses (OR,
1.84; 95% CI, 1.62–2.08). The investi-
gators also found that the association
was stronger for long-acting (OR, 1.70;
95% CI, 1.46–1.98) than for short-act-
ing benzodiazepines (OR, 1.43; 95%
CI, 1.27–1.61).
In complete contrast to the find-
ings of Billioti de Gage et al.,18 3 stud-
ies did not demonstrate a significant
association between benzodiazepine
use and a change in cognition. In a
nonrandomized clinical study of el-
derly patients admitted to hospital
acute care wards, the use of benzo-
diazepines was not associated with
cognitive dysfunction (as measured
by MMSE scores), but a higher serum
concentration of temazepam correlat-
ed with a lower MMSE score.30 It is im-
portant to note that while the MMSE is
one of the most widely used tools for
cognitive dysfunction and dementia
screening, it is primarily used in non-
acutely ill patients and, therefore, may
have diminished reliability in mea-
suring cognitive function in geriatric
 BENZODIAZEPINE CLINICAL REVIEW
patients, many of whom are acutely
ill. Similarly, in a study to determine
the impact of benzodiazepine use on
cognitive decline (as measured with
the MMSE) in nursing home residents
over 1 year, the findings did not dem-
onstrate a statistically significant dif-
ference between users and nonusers.19
In a clinical study that aimed to iden-
tify differences between psychogeriat-
ric benzodiazepine users (i.e., elderly
patients using the drugs for psychiat-
ric disorders) and nonusers in terms of
performance on standardized tests of
learning and memory, executive func-
tions, and vigilance, there was no sig-
nificant difference in any test results
after Bonferroni correction.24
Influence of duration of action
and frequency of use
The majority of studies reviewed
here addressed the effects of long-
term benzodiazepine use or use of
long-acting benzodiazepines (or both)
in the elderly. The aforementioned
treatment guidelines express concerns
regarding decreased metabolism in
geriatric patients and the use of agents
with longer durations of action, so as-
sessing duration of use and the par-
ticular agent used is relevant. Stronger
correlations to cognitive decline with
both the use of benzodiazepines that
have longer durations of action and
longer durations of use of benzodiaze-
pine use have been proposed. The au-
thors of 9 reviewed studies comment-
ed only on the duration or frequency
of benzodiazepine use. In a prospec-
tive population-based study of 3,434
participants, there was a slightly
higher risk of dementia in people with
the lowest benzodiazepine exposure
(hazard ratio, 1.25; 95% CI, 1.03–1.51)
but no increased risk in those with the
highest level of exposure (equivalent
to about 1 year of daily use).22 A report
on a case–control study of 590 women
at least 65 years of age found that for-
mer users had a 50% increased risk of
cognitive decline relative to nonusers,
but this result was not found to be sig-
nificant.27 Similarly, a meta-analysis
of studies involving a total of 45,391
participants indicated that the risk of
dementia increased by 22% for every
additional 20 defined daily doses of
benzodiazepines per year (relative
risk, 1.22; 95% CI, 1.18–1.25).34
A cohort study in Finland demon-
strated that long-term use of benzodi-
azepines was more common among
24,966 individuals with Alzheimer’s
disease than among controls without
the disorder, although the associa-
tion was not statistically significant.31
Paterniti et al.29 and Mura et al.28
concluded that long-term benzodi-
azepine use is a risk factor for in-
creased cognitive decline (p = 0.02
and p < 0.001, respectively). Billioti
de Gage et al.18 concluded that as the
number of lifetime benzodiazepine
doses increases, the risk of Alzheim-
er’s increases as well (OR, 1.51; 95%
CI, 1.36–1.69). Lagnaoui et al.26 and
Gallacher et al.21 concluded that the
earlier the exposure to benzodiaz-
epines, the greater the association
with dementia (reported OR values of
2.3 [95% CI, 1.2–4.5] and 3.5 [95% CI,
1.57–7.79], respectively).
A study involving 1,754 older
Canadians focused on the issue of
benzodiazepine duration of action
in relation to effects on cognition.23
The results of the prospective study
indicated that short-acting benzo-
diazepines were not associated with
worse performance on any evaluated
cognitive measure, whereas interme-
diate- and long-acting agents were
associated with lower performance
in language comprehension and free
recall. Two studies included in this
review focused on both the duration
and frequency of benzodiazepine
use and on the issue of benzodiaz-
epine duration of action. A nested
case–control study of 779 subjects
at least 45 years old with dementia
in Taiwan found an association with
higher cumulative benzodiazepine
dose (p < 0.001), longer duration of
use (p < 0.001), and use of long-acting
agents (p = 0.003).32 Another prospec-
tive cohort study that assessed mo-
bility, instrumental activities of daily
living (IADL), and social participation
AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 1 | JANUARY 1, 2018  e9
in 6,600 participants over the age of
65 revealed that long-acting benzodi-
azepine agents were associated with
IADL limitation incidence and mobil-
ity limitation prevalence.20 In addi-
tion, chronic users were at markedly
increased risk for developing limita-
tions in all 3 outcomes.
Proposed mechanism
A common debate among several
studies assessing benzodiazepine use
and cognitive decline is whether or
not the association is due to causality
or reverse causation. Since insomnia
and anxiety are prodromal symptoms
of dementia, it is difficult to deter-
mine whether the association actually
arises from treating the early symp-
toms of dementia prior to a known
diagnosis or if the benzodiazepine is
indeed responsible for causing the
dementia.18,33 Although there are no
proven mechanisms to date, Billioti de
Gage et al.18 suggested that the limita-
tion in cognitive reserve capacity in-
duced by chronic benzodiazepine use
may weaken one’s ability to cope with
early-phase brain lesions by soliciting
accessory neuronal networks. There is
no standard laboratory test to monitor
cognition, presenting a challenge for
researchers. A recent study attempted
to account for the possibilities of re-
verse causation with a lengthy follow-
up duration of 6 years,18 and research-
ers must continue to consider this
while collecting evidence. Another re-
cent study did a commendable job of
eliminating some of the possibility of
reverse causation with regard to pro-
dromal symptoms by excluding the
most recent year of benzodiazepine
use from the lengthy 10-year cumula-
tive use follow-up.22
Studies in which a relationship
was not found attributed the poor
cognitive performance in benzodiaz-
epine users to prodromal symptoms
of dementia requiring the use of these
drugs.18,33 However, in the CaPS, ear-
lier benzodiazepine exposure corre-
lated with increased association with
dementia frequency, contradicting the
theory of reverse causation.21
 CLINICAL REVIEW BENZODIAZEPINE
Discussion
The most serious limitation of this
review is that it includes a wide vari-
ety of studies that differed in terms of
patient characteristics, trial design,
measurement tools, and outcomes.
Another intrinsic limitation involved
in evaluating the association of ben-
zodiazepine use and cognitive decline
relates to protopathic bias. Anxiety is
considered a risk factor for or prodro-
mal symptom of dementia.35 Patients
who are likely to progress to a demen-
tia diagnosis are therefore more likely
to be prescribed anxiolytic agents
than the general older population.
Among the 9 prospective clinical
trials included in this review, only 3
found a significant difference in terms
of a negative cognitive effect between
benzodiazepine users and nonusers; 5
of the 7 reviewed case–control studies
identified a significant difference. The
meta-analysis included in the review
identified an increased risk of demen-
tia with benzodiazepine use. There
are several potential explanations for
discrepancies in results of the various
studies included in this review. Sam-
ple sizes varied greatly, ranging from
131 to 26,459. The majority of studies
that did not reveal a significant asso-
ciation between benzodiazepine use
and cognitive decline involved a small
sample size and short follow-up and
did not adjust for both depression and
anxiety.
In addition, the reviewed studies
varied in design from case–controlled
to prospective investigations, and all
of the study methodologies did not
adjust for covariates. Moreover, the
reviewed studies assessed varying de-
grees of cognitive decline, from mild
impairment to Alzheimer’s disease,
and different definitions of past ben-
zodiazepine use—ranging from 2 to
12 years prior to study inclusion—
were used. In studies that yielded sig-
nificant results, follow-up was longer,
sample sizes were greater, and depres-
sion and anxiety were adjusted for.
Benzodiazepine agents continue
to be used frequently for anxiety and
insomnia despite recommendations
e10    AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 1 | JANUARY 1, 2018
to limit their use. In the EMPOWER
study, researchers endeavored to de-
crease benzodiazepine use by imple-
menting a patient education strategy
in a community pharmacy setting.36
Patients in the intervention group
received education about risks asso-
ciated with the benzodiazepine class
and were provided with a stepwise
tapering protocol; those in the inter-
vention group discontinued benzo-
diazepine use at a rate of 27%, com-
pared with only 5% of participants
in the control group. These results
indicate that increased discussions
between the patient and healthcare
team and plan provision can make a
significant difference in reducing po-
tentially unnecessary or unsafe medi-
cation use.
In addition to increased patient
education and empowerment, the use
of safer therapeutic alternatives, es-
pecially nonpharmacologic interven-
tions, in the elderly can decrease the
risk of iatrogenic cognitive decline in
this vulnerable population. The ex-
pert panel of the updated “Beers cri-
teria” for inappropriate medication
use in geriatric patients published a
companion guide with recommenda-
tions on alternatives to therapies that
should be avoided.37
Insomnia presents a challenge for
management in older adults, as nearly
all agents used for treatment of the
condition appear in the Beers criteria
(e.g., benzodiazepines, benzodiaz-
epine receptor agonists, tricyclic an-
tidepressants, antihistamines)15 and
those not on the list are still active in
the CNS (e.g., trazodone, ramelteon).
Any agent whose primary action is to
cause sedation will bring with it the
risk of falls. For this reason, psycho-
logical or behavioral therapies (e.g.,
cognitive behavioral therapy) and
good sleep hygiene should be em-
phasized. Although benzodiazepine
agents have demonstrated efficacy in
significantly improving various mea-
sures of insomnia, their clinical value
in this regard may be less significant.
A 2005 meta-analysis investigating
risks and benefits of sedative hypnot-
ics in older people determined that
sleep latency was improved and sleep
time was increased only 15 minutes
per night on average with use of those
agents.38 Added sleep time may not
equate to quality, restful sleep, as ben-
zodiazepines generally increase sleep
time only in stages 1 and 2.39
Ongoing attempts to determine
the etiology of anxiety, with manage-
ment of exacerbating factors, is recom-
mended. Patients can also be referred
for counseling, with consequent appli-
cation of behavioral or cognitive thera-
pies to help with the management of
anxiety. For chronic anxiety, buspirone,
a selective serotonin reuptake inhibi-
tor (other medications in this class
include ci­talopram and sertraline), or
a serotonin–norepinephrine reuptake
inhibitor (e.g., venlafaxine, duloxetine)
should be considered. Short-term use
of benzodiazepines for acute anxiety
during initial management is reason-
able, as the other agents take weeks to
months for efficacy to be seen. Some
patients may require longer-term use
of these agents for anxiety if they do
not derive sufficient benefit from
other anxiolytic strategies.
Potential risks associated with
benzodiazepine use discussed in this
review and elsewhere should be care-
fully weighed against the benefits for
each individual patient. There will cer-
tainly be patients in whom the use of
a benzodiazepine is appropriate; how-
ever, when possible, clinicians should
try to avoid or limit benzodiazepine
exposure. If the agents cannot be dis-
continued altogether, reduced doses
and frequency of use would likely be
beneficial.
Conclusion
Investigations of the association
between benzodiazepine therapy and
cognitive decline in elderly patients
have yielded mixed findings. Strong­
er links have emerged from stud-
ies examining longer- rather than
shorter-acting benzodiazepines, lon-
ger rather than shorter durations of
use, or earlier rather than later expo-
sure. Questions remain about causal-
 BENZODIAZEPINE CLINICAL REVIEW
ity and the impact of confounders on
study interpretation.
Disclosures
The authors have declared no potential
conflicts of interest.
References
1. Galanter M, Kleber H, Brady K, eds.
Textbook of substance abuse treat-
ment. 5th ed. Arlington, VA: American
Psychiatric Publishing; 2015.
2. Ashton H. Guidelines for the rational
use of benzodiazepines. Drugs. 1994;
48:25-40.
3. Curran HV, Collins R, Fletcher S et
al. Older adults and withdrawal from
benzodiazepine hypnotics in general
practice: effects on cognitive func-
tion, sleep, mood and quality of life.
Psychol Med. 2003; 33:1223-37.
4. McAndrews MP, Weiss RT, Sandor P
et al. Cognitive effects of long-term
benzodiazepine use in older adults.
Hum Psychopharmacol Clin Exp.
2003; 18:51-7.
5. Barker MJ, Greenwood KM, Jackson
M et al. Cognitive effects of long-term
benzodiazepine use: a meta-analysis.
CNS Drugs. 2004; 18:37-48.
6. Paulose-Ram R, Safran MA, Jonas
BS et al. Trends in psychotropic
medication use among US adults.
Pharmacoepidemiol Drug Saf. 2007;
16:560-70.
7. Hanlon JT, Horner RD, Schmader KE
et al. Benzodiazepine use and cogni-
tive function among community-
dwelling elderly. Clin Pharmacol Ther.
1998; 64:684-92.
8. Fourrier A, Letenneur L, Dartigues J et
al. Benzodiazepine use in an elderly
community-dwelling population. Eur
J Clin Pharmacol. 2001; 57:419-25.
9. Magrini N, Vaccheri A, Parma E et al.
Use of benzodiazepines in the Italian
general population: prevalence, pat-
tern of use and risk factors for use.
Eur J Clin Pharmacol. 1996; 50:19-25.
10. Tu K, Mamdani MM, Hux JE et al.
Progressive trends in the prevalence
of benzodiazepine prescribing in
older people in Ontario, Canada. J Am
Geriatr Soc. 2001; 49:1341-5.
11. Windle A, Elliot E, Duszynski K et al.
Benzodiazepine prescribing in elderly
Australian general practice patients.
Aust N Z J Public Health. 2007;
31:379-81.
12. Olfson M, King M, Schoenbaum M.
Benzodiazepine use in the United
States. JAMA Psychiatry. 2015; 72:136-
42.
13. Marra EM, Mazer-Amirshahi M,
Brooks G et al. Benzodiazepine
prescribing in older adults in U.S.
ambulatory clinics and emergency
departments (2001–10). J Am Geriatr
Soc. 2015; 63:2074-81.
14. Sköldunger A, Fastbom J, Wimo A et
al. Impact of inappropriate drug use
on hospitalizations, mortality, and
costs in older persons and persons
with dementia: findings from the
SNAC study. Drugs Aging. 2015;
32:671-8.
15. American Geriatrics Society 2015
updated Beers criteria for potentially
inappropriate medication use in
older adults. J Am Geriatr Soc. 2015;
63:2227-46.
16. American Psychiatric Association.
Practice guideline for the treatment
of patients with panic disorder.
Second edition (January 2009).
http://psychiatryonline.org/pb/
assets/raw/sitewide/practice_
guidelines/guidelines/panicdisorder.
pdf (accessed 2017 Sep 26).
17. NIH state-of-the-science conference
statement on manifestations and
management of chronic insomnia in
adults. NIH Consens State Sci State-
ments. 2005; 22(2):1-30.
18. Billioti de Gage S, Moride Y, Ducruet
T et al. Benzodiazepine use and risk
of Alzheimer’s disease: case-control
study. BMJ. 2014; 349:5205.
19. Bourgeois J, Elseviers MM, van Bortel
L et al. The impact of chronic benzo-
diazepine use on cognitive evolution
in nursing home residents. Hum
Psychopharmacol. 2015; 30:85-93.
20. Carrière I, Mura T, Pérès K et al.
Elderly benzodiazepine users at
increased risk of activity limitations:
influence of chronicity, indications,
and duration of action—the three-
city cohort. Am J Geriatr Psychiatry.
2015; 23:840-51.
21. Gallacher J, Elwood P, Pickering J et
al. Benzodiazepine use and risk of de-
mentia: evidence from the Caerphilly
Prospective Study (CaPS). J Epidemiol
Community Health. 2012; 66:869-73.
22. Gray SL, Dublin S, Yu O et al. Ben-
zodiazepine use and risk of incident
dementia or cognitive decline:
prospective population based study.
BMJ. 2016; 352:1-9.
23. Helmes E, Ostbye T. Associations be-
tween benzodiazepine use and neu-
ropsychological test scores in older
adults. Can J Aging. 2015; 34:207-14.
24. Hoiseth G, Tanum L, Tveito M et al. A
clinical study of the cognitive effects
of benzodiazepines in psychogeri-
atric patients. Pharmacopsychiatry.
2013; 46:209-13.
25. Imfeld P, Bodmer M, Jick SS, Meier
CR. Benzodiazepine use and risk
AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 1 | JANUARY 1, 2018  e11
of developing Alzheimer’s disease
or vascular dementia: a case-
control analysis. Drug Saf. 2015;
38:909-19.
26. Lagnaoui R, Bégaud B, Moore N et al.
Benzodiazepine use and risk of de-
mentia: a nested case-control study. J
Clin Epidemiol. 2002; 55:314-8.
27. Lagnaoui R, Tournier M, Moride Y et
al. The risk of cognitive impairment
in older community-dwelling women
after benzodiazepine use. Age Aging.
2009; 38:226-8.
28. Mura T, Proust-Lima C, Akbaraly T et
al. Chronic use of benzodiazepines
and latent cognitive decline in the
elderly: results from the Three-city
study. Eur Neuropsychopharmacol.
2013; 23:212-23.
29. Paterniti S, Dufouil C, Alpérovitch
A. Long-term benzodiazepine use
and cognitive decline in the elderly:
the Epidemiology of Vascular Aging
Study. J Clin Psychopharmacol. 2002;
22:285-93.
30. Puustinen J, Nurminen J, Kukola M
et al. Associations between use of
benzodiazepines or related drugs and
health, physical abilities, and cogni-
tive function; a non-randomised
clinical study in the elderly. Drugs
Aging. 2007; 24:1045-59.
31. Taipale H, Koponen M, Tanskanen
A et al. Long-term use of benzodi-
azepines and related drugs among
community-dwelling individuals
with and without Alzheimer’s disease.
Int Clin Psychopharmacol. 2015;
30:202-8.
32. Wu CS, Wang SC, Chang IS, Lin KM.
The association between dementia
and long-term use of benzodiazepine
in the elderly: nested case-control
study using claims data. Am J Geriatr
Psychiatry. 2009; 17:614-20.
33. Zhang Y, Zhou XH, Meranus DH et
al. Benzodiazepine use and cognitive
decline in elderly with normal cogni-
tion. Alzheimer Dis Assoc Disord.
2015; 30:113-7.
34. Zhong G, Wang Y, Zhang Y, Zhao Y.
Association between benzodiazepine
use and dementia: a meta-analysis.
PLoS One. 2015; 10:e0127836.
35. Gulpers B, Ramakers I, Hamel R et al.
Anxiety as a predictor for cognitive
decline and dementia: a system-
atic review and meta-analysis. Am J
Geriatr Psychiatry. 2016; 18:823-42.
36. Tannenbaum C, Martin P, Tamblyn
R et al. Reduction of inappropriate
benzodiazepine prescriptions among
older adults through direct patient
education: the EMPOWER cluster
randomized trial. JAMA Intern Med.
2014; 174:890-8.
 CLINICAL REVIEW BENZODIAZEPINE

37. Hanlon JT, Semla TP, Schmader KE.

Alternative medications for medica-
tions in the Use of High-Risk Medica-
tions in the Elderly and Potentially
Harmful Drug–Disease Interactions
in the Elderly quality measures. J Am
Geriatr Soc. 2015; 63:e8-18.
38. Glass J, Lanctot KL, Herrmann N et
al. Sedative hypnotics in older people
with insomnia: meta-analysis of risks
and benefits. BMJ. 2005; 331:1169.
39. Drugs for insomnia. Med Lett Drugs
Ther. 2015; 57:95-8.

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