Drugs Aging 2012; 29 (8): 639-658

SYSTEMATIC REVIEW 1170-229X/12/0008-0639/$49.95/0

Adis ª 2012 Springer International Publishing AG. All rights reserved.

A Systematic Review of Amnestic

and Non-Amnestic Mild Cognitive
Impairment Induced by Anticholinergic,
Antihistamine, GABAergic and
Opioid Drugs
Cara Tannenbaum,1,2 Amélie Paquette,2 Sarah Hilmer,3 Jayna Holroyd-Leduc4
and Ryan Carnahan5
1 Faculties of Pharmacy and Medicine, Université de Montréal, Montreal, QC, Canada
2 Centre de Recherche de l’Institut universitaire de gériatrie de Montréal, Montreal, QC, Canada
3 Sydney Medical School, Faculty of Medicine, University of Sydney, Royal North Shore Hospital, , Sydney,
NSW, Australia
4 Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, AB, Canada
5 Department of Epidemiology, The University of Iowa College of Public Health, Iowa City, IA, USA

Abstract Background: Mild cognitive deficits are experienced by 18% of community-

dwelling older adults, many of whom do not progress to dementia. The effect
of commonly used medication on subtle impairments in cognitive function
may be under-recognized.
Objective: The aim of the review was to examine the evidence attributing
amnestic or non-amnestic cognitive impairment to the use of medication with
anticholinergic, antihistamine, GABAergic or opioid effects.
Methods: MEDLINE and EMBASE were searched for randomized, double-
blind, placebo-controlled trials of adults without underlying central nervous
system disorders who underwent detailed neuropsychological testing prior to
and after oral administration of drugs affecting cholinergic, histaminergic,
GABAergic or opioid receptor pathways. Seventy-eight studies were identified,
reporting 162 trials testing medication from the four targeted drug classes. Two
investigators independently appraised study quality and extracted relevant data
on the occurrence of amnestic, non-amnestic or combined cognitive deficits
induced by each drug class. Only trials using validated neuropsychological tests
were included. Quality of the evidence for each drug class was assessed based on
consistency of results across trials and the presence of a dose-response gradient.
Results: In studies of short-, intermediate- and long-acting benzodiazepine
drugs (n = 68 trials), these drugs consistently induced both amnestic and non-
amnestic cognitive impairments, with evidence of a dose-response relation-
ship. H1-antihistamine agents (n = 12) and tricyclic antidepressants (n = 15)
640 Tannenbaum et al.

induced non-amnestic deficits in attention and information processing. Non-

benzodiazepine derivatives (n = 29) also produced combined deficits, but less
consistently than benzodiazepine drugs. The evidence was inconclusive for
the type of cognitive impairment induced by different bladder relaxant anti-
muscarinics (n = 9) as well as for narcotic agents (n = 5) and antipsychotics
(n = 5). Among healthy volunteers >60 years of age, low doses of commonly
used medications such as lorazepam 0.5 mg, oxybutynin immediate release
5 mg and oxycodone 10 mg produced combined deficits.
Conclusion: Non-amnestic mild cognitive deficits are consistently induced by
first-generation antihistamines and tricyclic antidepressants, while benzo-
diazepines provoke combined amnestic and non-amnestic impairments. Risk-
benefit considerations should be discussed with patients in order to enable an
informed choice about drug discontinuation or substitution to potentially
reverse cognitive adverse effects.

1. Introduction language or executive function. Single-domain MCI

The impact of pharmaceutical substances on
the cognitive function of older adults is of increas-
ing concern to both patients and their healthcare
providers. Ninety percent of persons aged 65 years
and older take at least one prescription med-
ication, and of these, almost half consume five
drugs or more.[1,2] At the same time, up to 18% of
community-dwelling adults aged 65 years and
older report memory impairment or have objec-
tively demonstrable cognitive deficits that are
greater than expected for their age but do not
significantly interfere with function.[3-5] Mild cogni-
tive impairment (MCI) is a relatively new concept
that has been introduced over the past 10 years to
classify memory impairment that falls in the grey
zone between normality and dementia.[3] Alter-
natively coined ‘benign senescent forgetfulness,’
‘age-associated memory impairment’ or ‘cognitive
impairment, no dementia,’[6-8] current guidelines
divide these mild cognitive deficits into amnestic
or non-amnestic subtypes, with each category sub-
divided according to whether the objective cog-
nitive deficits are identified within a single or
multiple cognitive domain.[3,9] Amnestic MCI
predominantly affects short-term and/or long-
term memory, whereas non-amnestic MCI is char-
acterized by disturbances of attention/concentration,
information processing and psychomotor speed,
is more frequent than multiple-domain MCI,
with non-amnestic and amnestic subtypes occur-
ring with equal frequency.[9,10]
Population-based studies suggest that up to
40% of persons who show initial deficits on neu-
ropsychological testing revert to normal at 5-year
follow-up, with only 15% per year going on to
develop dementia.[3,11-13] The effects of an under-
lying disease, depression, resolving delirium, stress
or anxiety, and other conditions that can indepen-
dently elicit subjective and/or objective cognitive
impairments may partially account for the fluctu-
ating nature of neuropsychological test scores over
time.[14,15] Consumption of medication that can neg-
atively affect cognition is an alternate explanation
that may be under-recognized because of its infre-
quent assessment in otherwise healthy individuals.
Pharmacological interference has the potential
to disrupt normal neurotransmission in areas of
the brain responsible for both amnestic and non-
amnestic cognitive functioning.[16,17] The cholinergic
system projects to the cortex and hippocampus,
and is predominantly involved with memory stor-
age and retrieval, as well as arousal, percep-
tion and attention.[18,19] Blockade of histamine H1
receptors can produce sedation, diminished atten-
tion and reduced psychomotor speed.[20] The in-
hibitory amino acid g-aminobutyric acid (GABA)
and certain opioid peptides may also play a role in

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Drug-Induced Cognitive Impairment 641

modulating cognitive performance.[21-23] Although
other neurotransmitters exist, the cholinergic,
histaminergic, GABAergic and opioid receptor
pathways are hypothesized to be most commonly
implicated in modulation of learning, memory,
attention and executive function (figure 1).[16,17]
The purpose of this review was to systematically
examine the evidence attributing objectively mea-
sured amnestic or non-amnestic cognitive deficits
to the use of medication acting on cholinergic,
histaminergic, GABAergic and opioid receptor
pathways in otherwise healthy adults.
2. Methods
2.1 Data Sources and Searches
MEDLINE (OvidSP) was searched from 1948
to October 2011. EMBASE (OvidSP) was searched
from 1980 to October 2011. The search strategy
employed an exploded search option that com-
bined drug terms with selected terms for cognitive
impairment. In MEDLINE, the MeSH drug terms
used were ‘hypnotics and sedatives’, ‘narcotics’,
‘antipsychotic agents’, ‘cholinergic antagonists’,
‘GABA agonists’, ‘histamine H1 antagonists’,
‘opiate alkaloids’, ‘anticonvulsants’, ‘antidepressive
agents’, ‘anti-anxiety agents’, ‘antiparkinson agents’
and ‘bronchodilator agents’. The MeSH terms
for cognitive impairment that were used with the
subheadings ‘chemically induced’, ‘drug effects’,
and ‘etiology’ when available included ‘amnesia’,
‘cognition disorders’, ‘dementia’, ‘memory dis-
orders’, ‘cognition’ or ‘memory’. A search in natural
language in all fields was added for the terms
‘cognitive impairment’, ‘cognitive dysfunction’,
‘memory loss’, ‘cognitive decline’, ‘memory decline’,
‘memory deficits’ and ‘cognitive effects’. Exclusions
were imposed for the exploded terms of ‘delirium’
and ‘encephalopathy’. In EMBASE, exploded
subject heading drug terms were ‘hypnotic agent’,
‘sedative agent’, ‘narcotic agent’, ‘atypical anti-
psychotic agent’, ‘neuroleptic agent’, ‘cholinergic
receptor blocking agent’, ‘4-aminobutyric acid re-
ceptor stimulating agent’, ‘benzodiazepine receptor
affecting agent’, ‘histamine H1 receptor antagonist’,

Pathways
Cholinergic
Histaminergic
GABAergic
Opioid
Frontal cortex
Attention

Cingulum

Striatum
Memory Thalamus
Corpus callorum
Memory
Alertness
Pre-frontal cortex
Memory
Executive function
Visual cortex

Amygdala
Memory
Cerebellum
Memory
Hypothalamus
Alertness
Arousal
Alertness
Hippocampus
Memory
Attention

Fig. 1. Cholinergic, histaminergic, GABAergic and opioid receptor pathways mediating cognitive function. GABA = g-aminobutyric acid.

Adis ª 2012 Springer International Publishing AG. All rights reserved. Drugs Aging 2012; 29 (8)
642 Tannenbaum et al.

‘opiate’, ‘anticonvulsive agent’, ‘antidepressant
agent’, ‘anxiolytic agent’, ‘antiparkinson agent’
and ‘bronchodilating agent’. Exploded subject
headings terms for cognitive impairment included
‘memory disorder’, ‘cognitive defect’, ‘confusion’,
‘memory’, ‘cognition’ and ‘amnesia’. Studies were
limited to humans and adults 18 years and older,
and conservative limits were imposed for study
type (all phases of clinical trials, randomized
controlled trials, controlled clinical trials, multi-
centre studies, evaluation studies and case re-
ports) and language (English only). Additional
articles were identified from manually searching
the bibliographies of retrieved articles. A flow-
chart of the identification, screening, eligibility
and inclusion process is depicted in figure 2.
2.2 Study Screening
Two reviewers independently screened the ti-
tles and abstracts of each of the articles identified
in the search process according to the following

8062 records identified through

database searching:
3153 MEDLINE
4909 EMBASE

7118 records after duplicates removed

6746 records excluded

Population with dementia or other
underlying central nervous system
7118 records screened disorders, mixed nursing home population,
no evidence of neuropsychological testing,
co-administration of drugs, intravenous
use, non-experimental study design

311 full-text articles excluded

• Condition that affects central nervous system (103)
• Drug combination or duplicate study (20)
• Not orally administered (37)
372 full-text articles assessed
• No validated cognitive measures (18)
for eligibility
• Wrong drug class (28)
• Not a randomized, placebo-controlled study (73)
• Not healthy volunteers, excessive dose (7)
• Lack of documentation of concomitant drug use (18)

17 additional records identified

through hand or reference
searching
78 studies included in this review

GABA GABA Anticholinergic Anticholinergic

benzodiazepines non-benzodiazepines bladder relaxant drugs tricyclic antidepressants
63 single-dose trials 27 single-dose trials 3 single-dose trials 10 single-dose trials
5 repeated-dose trials 2 repeated-dose trials 6 repeated-dose trials 5 repeated-dose trials

H1 antihistamines H1 antihistamines Mixed

first generation
11 single-dose trials
2 repeated-dose trials
Opioids
second generation mechanisms
5 single-dose trials
14 single-dose trials 3 single-dose trials
0 repeated-dose trials
4 repeated-dose trials 2 repeated-dose trials

Fig. 2. Flowchart of study identification, screening, eligibility and inclusion. GABA = g-aminobutyric acid.

Adis ª 2012 Springer International Publishing AG. All rights reserved. Drugs Aging 2012; 29 (8)
Drug-Induced Cognitive Impairment
criteria: (i) study of human adults aged 18 years
and older; (ii) medication use affecting choliner-
gic, histaminergic, GABAergic (benzodiazepine
or non-benzodiazepine) or opioid receptor path-
ways; (iii) measurement of cognitive outcomes;
(iv) community-dwelling persons; and (v) absence
of schizophrenia, psychosis or other mental health
disorders such as established dementia or delir-
ium. Only studies in volunteers without under-
lying disorders affecting cognition were included,
as the intent was to study the impact of drug ad-
ministration on repeat cognitive performance,
independent of potential effects of an underly-
ing disease. Studies conducted in nursing home
residents were excluded, as it was impossible
to distinguish cognitive test results from in-
dividuals with and without established cogni-
tive dysfunction (e.g. dementia). Discrepancies
were resolved by a third reviewer or by consensus
discussion.
2.3 Study Selection
Full-text articles that passed the screening pro-
cess were assessed by two independent reviewers
for eligiblity for inclusion in the systematic re-
view. In order to exclude studies with biased re-
sults, methods for handling confounding, such as
randomization, allocation concealment, restric-
tion of participants to healthy volunteers, exclu-
sion of persons with underlying conditions that
could affect cognition, and documentation that
no other central nervous system-active medica-
tions were being taken, were considered during
the study selection process. Studies that satisfied
the following criteria were included: (i) use of oral
medication; (ii) no drug combinations; (iii) medica-
tions exerting pronounced anticholinergic, anti-
histamine, GABAergic or opiate effects; (iv) clear
documentation of cognitive outcomes, using de-
tailed validated neuropsychological tests (use
of the Mini-Mental State Examination alone was
excluded); (v) healthy volunteer participants who
were without seizure disorders, stroke, Parkinson’s
disease, major depression, anxiety, insomnia,
chronic pain or other conditions that could affect
performance on cognitive test batteries; (vi) clear
documentation that study participants were not
Adis ª 2012 Springer International Publishing AG. All rights reserved.
643
taking other central nervous system medications
at the time of testing; and (vii) use of a random-
ized, double-blind, placebo-controlled trial de-
sign. Medications were included if they could be
classified as having anticholinergic, antihistamine,
GABAergic or opiate effects according to the
CPS 2010 (Compendium of Pharmaceuticals and
Specialities from the Canadian Pharmacists As-
sociation)[24] or Lexi-Comp’s Drug Information
Handbook.[25] Neuropsychological tests measur-
ing amnestic or non-amnestic cognitive domains
that were described and referenced in a published
compendium of neuropsychological assessment
techniques were considered to be valid methods
of cognitive outcome assessment.[26] Driving eval-
uations and physical function examinations (e.g.
body sway, balance tests) were not included.
Validated neuropsychological tests assessing am-
nestic domains, namely short-term memory and/
or delayed recall included Buschke’s selective re-
minding test, word list recall, story or paragraph
recall, digit span test, hidden objects and item
recognition tasks. Validated tests assessing non-
amnestic domains included those assessing reaction
time/attention and concentration, specifically choice
reaction time, simple reaction time, discriminant
reaction time, d2 task, critical fusion flicker test,
finger tapping, memory scanning speed, the digit-
symbol substitution test, digit-digit coding, digit
vigilance task, visual search tasks, tests of divided
attention, and the continuous performance test.
Non-amnestic psychomotor/executive functions
were evaluated using validated tasks including
the Stroop, complex figure tests, Groton maze
and the pegboard task.
2.4 Data Extraction
Data extraction was performed for each eligi-
ble study by two reviewers using a standardized
data extraction sheet. The data extraction sheet
queried details of the population studied, in-
cluding the sample size and age of the partici-
pants, the study design, the molecule tested, the
dose and duration of medication use (single use
or repeated dosing), the timing of administration
of the neuropsychological assessments, the type
of cognitive tests, and the results of the cognitive
Drugs Aging 2012; 29 (8)
644
tests. Many studies reported more than one trial
arm, often with different drugs or drug doses.
Data for each trial arm were extracted separately.
For articles that reported the evaluation of
multiple drugs from the same or different classes
of medication, data were only extracted for
those drugs with anticholinergic, antihistamine,
GABAergic, or opioid receptor effects. Documen-
tation of patients lost to follow-up was recorded.
To evaluate whether a given drug caused cogni-
tive impairment in each individual trial, a change
in the results of the neuropsychological tests from
baseline to study endpoint was compared be-
tween treatment and placebo arms. A drug was
considered to cause impairment if the mean group
change in score on a cognitive task was reported
as being significantly worse (p < 0.05) in the drug
treatment arm compared with in the placebo arm.
In many but not all studies, adjustments were
made for multiple comparisons.
2.5 Data Analysis
Descriptive statistics were used to characterize
the trials that were retained for qualitative synthe-
sis. Cognitive impairments were grouped under
amnestic or non-amnestic subtypes. The quality
of evidence for each drug class was rated accord-
ing to the recommended Grading of Recommen-
dations Assessment, Development and Evaluation
(GRADE) approach,[27,28] where judgements re-
flect the extent of confidence that specific drug
classes can provoke amnestic or non-amnestic
cognitive deficits. Judgements were assessed based
on consistency of the results across trials, whether
a dose-response gradient was present, or if het-
erogeneous results could be explained by plau-
sible confounding, such as an age effect.[27] A
rating of ‘high quality’ was assigned if the data
was consistent and a dose-response relationship
was present. Ratings of ‘moderate quality’ were
assigned when the findings were relatively con-
stant across studies and discrepancies could be
explained by an age or drug effect. ‘Low quality’
evidence ratings were assigned when the results of
different studies were mixed, if the studies were
few or had small sample sizes, if the drug doses
that were tested were excessively high, or if no
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Tannenbaum et al.
firm conclusions could be drawn. Whenever pos-
sible, differences between young adults and those
over age 60 years were compared. The results
from single-dose studies were compared with
those from steady-state studies to try to ascertain
whether tolerance to cognitive effects developed
over time. To calculate an effect size for each
drug class, we recorded the magnitude of dif-
ference in test scores between each agent and
placebo, and the standard deviation/standard
error within each group. In 31 of 78 publications
(39.7%), the means with or without standard de-
viations were only graphically represented in a
figure over multiple time points, or only p-values
were indicated in the figures or embedded within
the text to describe whether differences were sig-
nificant or not. Of the remaining 47 publications
where actual test scores and standard deviations/
standard errors of the test scores from the placebo
and drug groups were explicitly listed in a table or
within the text, there was wide variability in the
different drugs, doses and time windows being test-
ed within the same drug class. For this reason, the
quality of the data was judged insufficient to quan-
tify effect sizes for the different drug classes as a
group. Short-acting benzodiazepines were defined
as those having a median half-life of 1–12 hours
according to Lexi-Comp’s Drug Information Hand-
book.[25] Intermediate-acting benzodiazepines were
classified as having a median half-life of 12–40
hours, and long-acting benzodiazepines as having
median half-lives of 40–250 hours.
3. Results
The primary search identified 8062 citations.
We considered 7118 citations after duplicates
were removed. A total of 372 articles were retrieved
for full text review. A further 17 articles were
added from searching the reference lists of re-
trieved articles or through expert recommenda-
tion. Seventy-eight publications met inclusion
criteria for qualitative synthesis. A flowchart of the
identification, screening, eligibility and inclusion
process is depicted in figure 2. A total of 162 trials
of different drugs and doses were reported in the
78 publications retained for qualitative synthesis.
Twenty percent of trials used a parallel group
Drugs Aging 2012; 29 (8)
Drug-Induced Cognitive Impairment
design. The remainder used a crossover trial de-
sign, generally with a 1-week washout period be-
tween drugs. Eighty percent tested single doses of
each medication and evaluated cognitive func-
tions immediately before and within 2–24 hours
post-administration of each pharmaceutical
agent. Less than one-third of trials specifically
studied persons aged 60 years and older, or strat-
ified the results by age group. Half of all studies
had very small sample sizes (n £ 12), as is typical
with medication challenge experiments.
3.1 GABAergic Medication
GABAergic medication was analysed in two
groups: benzodiazepine derivatives (classical
sedative-hypnotic agents such as lorazepam, flu-
mazepam) and non-benzodiazepine derivatives
(newer hypnotic medication such as zolpidem,
zopiclone and zaleplon) [table I]. Short-acting
benzodiazepines consistently induced decrements
on both amnestic and non-amnestic cognitive
function tests, with evidence of a dose-response
gradient.[29-42] Collie et al.[29] calculated a number
needed to harm of 2 for midazolam 1.75 mg, and
close to 1 for the higher 5.25 mg dose, even in
patients who did not report subjective impair-
ment. A similar profile of evidence implicated
intermediate-acting benzodiazepines.[39,41-61] Con-
sistent findings predominantly affecting memory
storage, but also impacting attention, reaction
time and specific psychomotor functions, char-
acterized single- and repeated-dose studies, without
development of complete tolerance over 3 weeks
administration.[58] Adults aged 60 years and older
were more sensitive to low doses of benzodia-
zepines such as 0.5 mg of lorazepam than younger
adults.[43,44] The evidence implicating long-acting
benzodiazepines was of slightly lower quality,
with inconsistencies that could only partially be
explained by an age effect: younger adults show-
ing fewer impairments than older adults on tests
of delayed recall, concentration, reaction time
and tracking ability.[24,34,48,62-68]
Evidence implicating the non-benzodiazepine
GABAergic derivatives was only of moderate
quality, as only half of all studies reported sig-
nificant amnestic and/or non-amnestic cognitive
Adis ª 2012 Springer International Publishing AG. All rights reserved.
645
deficits.[30,32,33,37,38,66,68-76] One 7-day study with
zolpidem showed no residual deficits.[75] Hetero-
geneity across studies could not be explained by
different drugs, doses, the type of neuropsycho-
logical test, the analysis method or the age of the
participants.
3.2 Anticholinergic Medication
Two classes of anticholinergic agents were
studied: antimuscarinic agents used for the treat-
ment of overactive bladder and the tricyclic anti-
depressants (table II). Three single-dose studies
and six steady-state trials of antimuscarinic agents
showed inconsistent effects, with impairments
predominantly attributable to the use of oxy-
butynin.[77-80] Amnestic and non-amnestic defi-
cits varied widely across different drugs, doses
and durations of administration, with the most
consistent effects seen during tests of divided at-
tention and reaction time. All participants were
aged 60 years or older, so heterogeneity could not
be attributed to age. Two long-term studies re-
ported significant loss to follow-up.[79,80] The
quality of evidence could only be judged as low-
to-moderate. The tricyclic antidepressants pro-
vided more robust evidence that anticholinergic
activity deleteriously affects non-amnestic func-
tions, with deficits in attention and reaction time
induced in all single-dose studies.[81-87,93] Amnes-
tic impairments occurred rarely and only at higher
doses. Steady-state trials provided evidence of
diminishing effects on non-amnestic function over
time, with potential development of tolerance,
particularly in younger individuals.[88-92]
3.3 H1 Antihistamines
Consumption of first-generation H1 receptor
blockers produced consistent decrements in non-
amnestic tasks requiring attention and vigilance
after single-dose use in ten studies, with only one
single-dose study of 25 mg showing no effect
(table III).[44,77,94-100] Repeated use over 5 days
led to tolerance in one group of young adults,
while only partial tolerance developed in another
group of slightly older adults 51 years or younger,
although doses of diphenhydramine were high
in the latter study (25 mg four times daily), and
Drugs Aging 2012; 29 (8)
 Table I. Data of included studies for GABAergic benzodiazepine and non-benzodiazepine derivatives
Drugs and doses (mg)
[tested in the elderly]a
GABAergic benzodiazepines
Midazolam
1.75, 5.25[29]
Triazolam
0.125,[30,31] 0.25,[30-37]
0.5[30,32]
[0.125,[30,31] 0.25[35,36]]
Temazepam
7.5[34,38]
[7.5[38]]
Oxazepam
15,[39] 30[39-42]
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Lorazepam
0.5,[43,44] 1,[39,43,45,46]
1.5,[44,47] 2,[39,41,42,48-54]
2.5,[55,56] 3,[47] 5[48]
[0.5,[43] 1[39]]
Lorazepam
2[57]
Lorazepam
0.5 bid, 1.0 bid[58]
[0.5 bid, 1.0 bid[58]]
Alprazolam
0.25, 0.5, 0.75,[59] 1[54,60]
Alprazolam
0.5 bid, 1.0 bid[58]
[0.5 bid, 1.0 bid[58]]
Drugs Aging 2012; 29 (8)
646
Sample size (n) Duration Neuropsychological tests Amnestic Non-amnestic impairments
impairments
28[29] Single dose Delayed recall, Groton maze, Delayed recall, Groton maze at 5.25 mg
recognition task recognition at both
doses
18,[30,37] 23,[32] Single dose Word lists, recognition, delayed recall, All tasks, all doses, DSST at 0.125 mg and 0.25 mg in 5/6 studies,
24,[33,35] 47,[31] verbal fluency, DS, DSST, CPT, CRT 7/7 studies 0.5 mg in 2/2 studies, CRT in 1/1 studies at
52,[34] 61[36] 0.5 mg
12,[38] 52[34] Single dose CFF, CRT, d2 test of attention, word No CRT, CFF
lists, DS, trail making test, story recall,
DSST
9,[39] 30,[40] 10,[41] Single dose Word lists, TT, DSST, DS, word stem Delayed recall, word DSST impaired in 3/4 studies at both doses
10[42] completion task stem completion, all
studies, both doses
6,[49] 7,[47] 9,[39,55] Single dose CFF, SRT, TT, CPT, DS, DSST, Delayed recall in 1/2 TT, DSST, SRT, CRT, CFF, Groton maze,
10,[37,41,42] memory scanning, word stem studies at 0.5 mg, and Stroop impaired in all 15 studies where non-
12,[44-46,50,51] 18,[43] completion task, word lists, story and in all 20 other studies amnestic tasks were measured
20,[56] 36,[52] 39,[54] paragraph recall, Groton maze, Stroop at all doses
55[53]
12[57] 3 days CRT, DS, word lists, picture recall Delayed recall CRT
16[58] 3 weeks Buschke, discriminant reaction Delayed recall at both CFF only at 1 mg bid
time, CFF doses
12,[59,60] 39[54] Single dose Story recall, SRT, DSST, and word lists Delayed recall in 4/4 DSST and SRT in all studies
studies, all doses
16[58] 3 weeks Buschke, discriminant reaction Delayed recall CFF only at 1 mg bid
time, CFF
Continued next page
Tannenbaum et al.
 Table I. Contd
Drugs and doses (mg) Sample size (n) Duration Neuropsychological tests Amnestic Non-amnestic impairments
[tested in the elderly]a impairments
Clonazapam 10[61] Single dose CFF, CRT Not assessed CFF, CRT
2[61]

Diazepam 10,[48] 11,[63] Single dose Buschke, DSST, card sorting, word Delayed recall in 4/7 DSST, card sorting, PG, TT impaired in all
2,[62,63] 2.5,[64] 5,[48,63,64] 12[62,64,65] lists, CPT, TT, PG, complex figures, studies across all studies where tested, except in 1 study at 2 mg
10[48,63,65] picture recognition doses
[2.5,[64] 10[65]]

Flurazepam 52,[34] 18,[66] Single dose CFF, CRT, DSST, TT, memory recall, Delayed recall in 3/4 CFF, CRT, tracking test impaired in 3/3 studies,
15,[34] 30[66-68] 24,[68] 25[67] word lists, tracking test studies but not DSST in 2/4 studies
Drug-Induced Cognitive Impairment

[30[66,67]]

Clorazepate 10[48] Single dose Word list, CPT, TT No Not reported

7.5, 15[48]

GABAergic non-benzodiazepine derivatives

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Zolpidem 12,[69] 36,[70] Single dose DSST, word lists, picture recognition, Delayed recall in 4/6 In a variety of non-amnestic tests (TT, PG, CPT,
7.5,[69] 10,[30,32,70-74] 18,[30,37] 10,[72,74] DS, SRT, CRT, TT, story, PG, CPT studies testing 10 mg DS, DSST, CRT), 1 study showed impairment at
20[30,32,33,37,73,74] 23,[32] 30,[73] 24,[33] and in 4/4 with 20 mg 7.5 mg, 5/8 studies showed impairments with
[10[70]] 70[71] 10 mg, and 3/4 with 20 mg

Zolpidem 24[75] 7 days CRT, CFF, memory scanning task, No No

5,[75] 10[24,75] word recognition task, tracking test
[5,[75] 10[24]]

Zolpidem MR 18,[66] 24,[68] 70[71] Single dose CFF, CRT, DSST, memory recall, No deficits at either Impairment in tracking time in 1/1 study and
12.5,[66,68,71] 25[68] tracking test dose in 3/3 studies DSST in 1/2 studies at 12.5 mg
[12.5,[68] 25[68]]

Zopiclone 30,[76] 36,[70] 12[38] Single dose DSST, CFF, CRT, SRT, word lists, DS, Delayed recall at SRT, tracking time and DSST impaired in 1/2
7.5,[70,76] 10[38] trail making test, tracking time, divided 7.5 mg in 1/3 studies studies, CRT, trail making, CFF impaired only at
[7.5,[70] 10[38]] attention, story recall and at 10 mg 10 mg

Zaleplon 10,[74] 24,[33] 30[73] Single dose Word list, DS, DSST, picture Delayed recall in 2/3 DSST in 1/3 studies at 10 and 20 mg
10,[33,73,74] 20[33,73,74] recognition, divided attention, TT studies of 10 mg, 2/3
at 20 mg
a Doses in square brackets were tested in groups of healthy volunteers aged 60 years and older in the referenced study.
bid = twice daily; CFF = critical flicker fusion; CPT = continuous performance task; CRT = choice reaction time; DS = digit span; DSST = digit-symbol substitution task; GABA = g-aminobutyric
acid; MR = modified release; PG = pegboard; SRT = simple reaction time; TT = tapping test.

Drugs Aging 2012; 29 (8)

647
648 Tannenbaum et al.

Table II. Data of included studies for anticholinergic drugs

Drugs and doses (mg) Sample Duration Neuropsychological tests Amnestic impairments Non-amnestic
[tested in the elderly]a size (n) impairments
Anticholinergic bladder relaxant drugs
Oxybutynin IR 12,[77] Single dose Buschke, DS, trail making, Delayed recall in 1 study at DSST, DS, trail making
5,[77] 10[77,78] 12[78] verbal fluency, DSST, TT, 5 mg and in 1/2 studies at and reaction times
[5,[77] 10[77]] reaction time, CPT, SRT, 10 mg impaired at both doses
CRT, DS
Oxybutynin ER 50[79] 3 weeks Name-face recognition, Delayed recall with 10, 15 mg Divided attention with
10, 15, 20[79] hidden objects, divided 15 mg only
[10, 15, 20[79]] attention, CRT,
discriminant reaction time
Darifenacin CR 129[80] 2 weeks SRT, CRT, word lists, item No Reaction time for 3.75 mg
3.75, 7.5, 15[80] recognition only
[15[80]]
Darifenacin IR 50,[79] 3 weeks Name-face recognition, No Divided attention only in
7.5,[79] 15[79,80] 129[80] hidden objects, divided 1/2 studies with 15 mg
[7.5,[79] 15[80]] attention, CRT,
discriminant reaction time
Solifenacin 12[78] Single dose SRT, CRT, DS, word and No No
10[78] picture recall
[10[78]]
Anticholinergic tricyclic antidepressants
Amitriptyline 6,[81] Single dose CPT, digit-digit coding, item No impairment in 1 study at CPT, reaction time and
25,[81-83] 37.5,[39] 15,[84,87] recognition and word lists, 25 mg, in 2/4 at 50 mg and in 1 DSST impaired at all
50,[84-87] 70[39] 9,[39,82] Buschke, DS, DSST, CRT, at 37.5 mg; delayed recall doses in all studies tested
[25,[81] 50[84,86]] 17,[85] CFF impaired in 1 study testing
12,[86] 70 mg
13[83]
Amitriptyline 10,[88] 7 days–2 CRT, CFF, memory Recall not reported in 1 study, CRT, CFF, tracking test
25,[88] 37.5,[89] 12,[89,91] weeks scanning task, word not assessed in 1 study, impaired in 3/5 studies;
70,[89] 75[90,91] 24[90] recognition task, tracking impaired at 37.5 and 70 mg effects diminish over
[25[88]] test, word lists, block test, time, becoming
DSST, CPT insignificant
Imipramine 24[92] 7 days 3 different CRT Not assessed Impairment in 1/3 CRT
50 bid[92] tests
[50 bid[92]]
a Doses in square brackets were tested in groups of healthy volunteers aged 60 years and older in the referenced study.
CFF = critical flicker fusion; CPT = continuous performance task; CR = controlled release; CRT = choice reaction time; DS = digit span;
DSST = digit-symbol substitution task; ER = extended release; IR = immediate release; SRT = simple reaction time; TT = tapping test.

memory function was not assessed.[101,102] Second-
generation H1-blocking agents do not appear to
affect any cognitive domain over the short or long
term, with only one of 14 single-dose studies show-
ing changes in attention and memory with deslor-
atadine compared with placebo.[95-98,100-103]
3.4 Opioid Receptor-Binding Agents
Five single-dose, randomized, crossover de-
sign trials testing the impact of opioid agents on
cognition in healthy volunteers were identified
(table III).[22,46,51] One study of oxycodone 10 mg
induced significant impairments in both memory
and attention in both older and middle-aged par-
ticipants, as did 10 and 15 mg of morphine. Low-
dose dextropropoxyphene failed to elicit deficits in
a small sample of middle-aged adults, although
the 200 mg dose affected attention and reaction
time. No studies were found that evaluated the
extent to which tolerance alleviated the adverse
cognitive effects.

Adis ª 2012 Springer International Publishing AG. All rights reserved. Drugs Aging 2012; 29 (8)
Drug-Induced Cognitive Impairment 649

Table III. Data of included studies for antihistamine, opioid and antipsychotic drugs
Drugs and doses Sample Duration Neuropsychological tests Amnestic impairments Non-amnestic
(mg) [tested in the size (n) impairments
elderly]a
First-generation histamine H1 antagonists
Hydroxyzine 18[94] Single dose, Tracking test, divided Not assessed Tracking test, divided
50 mg[94] crossover attention, SRT attention, SRT
Promethazine 24,[95,98] Single dose CFF, CRT, TT, tracking, Not assessed in 3 studies, CFF, CRT, tracking
25,[93,95,96] 30[97] 9,[96] word recall word recall impaired in 1 impaired in all studies
20[97] study at 25 mg
Diphenhydramine 12,[44,77] Single dose Buschke, DS, trail making, No effect on recall in 4 DSST unimpaired at
25,[99] 50,[44,77,100] 37,[99] verbal fluency, DSST, TT, lower-dose studies, not 25 mg; DSST, DS,
75,[44] 100[44] 42[100] reaction time, CPT, CRT assessed in 1, impaired at reaction time, CPT
[25,[99] 50[77]] 100 mg impaired in all other
studies
Diphenhydramine 32[101] 5 days SRT, CPT, DS, DSST, Not assessed Only the number of errors
100[101] divided attention task, on the tracking test
discriminant reaction time increased
Triprolidine 10[102] 5 days CFF, CRT, memory Not assessed No
10[102] scanning
Second-generation histamine H1 antagonists
Cetirizine 9,[96] Single dose CFF, CRT, CPT, tracking Only assessed in 1 study No impairment in 13/14
2.5,[95] 5,[95,97] 10[95] 16,[103] time, DSST, recall where delayed recall was studies; CRT impaired
Levocetirizine 20,[97] found to be impaired with only for desloratadine
10[97] 24,[95,98] desloratadine 5 mg 5 mg
Loratadine 42[100]
10,[95,97] 20,[95] 40[95]
Desloratadine
5[96]
Fexofenadine
25,[103] 60,[98]
120,[98] 180[100]
Ebastine 10,[102] 5 days CFF, CRT, memory Not assessed No
10, 20, 30[102] 33[101] scanning, DS, DSST, SRT
Loratadine
7.5[101]
Opioids
Oxycodone 71[22] Single dose SRT, CRT, DSST, DS, Delayed recall SRT, sustained attention
10[22] word list recall, d2 task of
[10[22]] sustained attention
Morphine 12[46] Single dose SRT, CRT, CFF, memory Delayed recall and picture CFF
10,[46] 15[46] scanning, item recognition, recognition at both doses
recall
Dextropropoxyphene 12[51] Single dose SRT, CRT, number No Only CFF impaired at
100,[51] 200[51] vigilance, memory 200 mg
scanning, word recall, word
and picture recognition,
CFF
Mixed mechanism antipsychotics
Chlorpromazine 12[104] Single dose DS, DSST, face No No
50[104] recognition, story and
word recall

Continued next page

Adis ª 2012 Springer International Publishing AG. All rights reserved. Drugs Aging 2012; 29 (8)
650
Table III. Contd
Drugs and doses Sample Duration
(mg) [tested in the size (n)
elderly]a
Risperidone 12[45] Single dose
0.25,[45] 0.5[45]
[0.25,[45] 0.5[45]]
Haloperidol 14[105] 4 days
3[105]
Olanzapine
3[105]
a Doses in square brackets were tested in groups of healthy volunteers aged 60 years and older in the referenced study.
CFF = critical flicker fusion; CPT = continuous performance task; CRT = choice reaction time; DS = digit span; DSST = digit-symbol substitution
task; SRT = simple reaction time; TT = tapping test.
3.5 Antipsychotics: Mixed Anticholinergic and
Antihistamine Effects
Five small trials using typical and atypical
antipsychotics were included in the qualitative
synthesis, three single-dose and two repeated-
dose studies.[45,104,105] A 3 mg dose of haloperidol
impaired recall and reaction time, while 0.25 and
0.5 mg of risperidone only affected psychomotor
speed. Chlopromazine and olanzapine did not
elicit deficits. Unexplained heterogeneity resulted
in a low-quality evidence rating, precluding con-
fident conclusions about the cognitive safety of
these agents.
Table IV summarizes the findings and quality
of the evidence for each drug class according to
the GRADE criteria.
4. Discussion
Results of this systematic review of randomized
controlled experiments assessing the attribution of
amnestic or non-amnestic cognitive deficits to the
use of GABAergic, histaminergic, anticholinergic
and opioid medication in adults without under-
lying central nervous system disorders reveal a
strong potential for several commonly used drugs
to induce symptoms of forgetfulness and/or diffi-
culty concentrating. Data on the short- and inter-
mediate-acting benzodiazepine GABAergic drugs
suggest that a combined pattern of amnestic and
non-amnestic cognitive deficits consistently emerges
with use of these agents. First-generation H1 anti-
histamine and tricyclic antidepressant drugs evoke
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Tannenbaum et al.
Neuropsychological tests Amnestic impairments Non-amnestic
impairments
CFF, SRT, TT, CPT, DS, No TT, DSST
DSST memory scanning
test, word lists
SRT, CRT, CFF, DS, word Only haloperidol impaired Only haloperidol
and picture recognition recall impaired reaction time
non-amnestic impairments. Findings for the other
drug classes were contradictory or of lesser quality
and did not permit sound conclusions to be drawn
about their specificity for affecting different cog-
nitive domains.
Large, population-based, epidemiological stud-
ies querying the association between medication
consumption and cognitive performance support
the findings from this review. Data from 2765
persons participating in the Duke Established
Population for Epidemiologic Studies of the Elderly
showed that short-, intermediate- and long-acting
benzodiazepine users made a significantly greater
number of errors on memory testing compared with
non-users, with sub-analyses examining increasing
dose and cumulative exposure over time suggest-
ing a dose-response relationship.[106] An increased
occurrence of both amnestic and non-amnestic
cognitive deficits among benzodiazepine users was
also confirmed by 2105 respondents from the Lon-
gitudinal Aging Study Amsterdam in the Nether-
lands,[107] over 9000 participants from the Canadian
Study of Health and Aging[108] and 1389 people
aged 60–70 years recruited for the Epidemiology
of Vascular Aging study in Nantes.[109] Only the
smaller Eugeria Longitudinal Study of Cerebral
Aging (n = 372) failed to detect an effect of ben-
zodiazepines on cognition.[110] Regarding anti-
cholinergic medication, multiple cross-sectional,
population-based studies have shown consistent
associations between drug intake and non-amnestic
cognitive impairments as well as other measures
of global cognitive function, although most studies
simultaneously examined the cumulative effect of
Drugs Aging 2012; 29 (8)
Drug-Induced Cognitive Impairment 651

drugs with any anticholinergic properties rather retrospective analysis showed no effects of anti-
than by drug class alone.[13,111-118] One study of cholinergic agents on cognition.[119,120] For H1
tricyclic antidepressants and data from a small receptor antagonists, only one study has been

Table IV. Summary of findings/Grading of Recommendations Assessment, Development and Evaluation (GRADE) quality rating
Mechanism Class effect No. of single-dose Summary of the evidence Level of
trials/no. at evidence quality
steady state
GABAergic Short-acting 20 single dose Fairly consistent impairments occur across a range of Moderate-high
benzodiazepines cognitive functions, including attention, psychomotor speed,
strategy use and problem solving, learning and delayed recall
up to 8 hours after use. Dose-response gradient present. No
data on repeated use.
Intermediate-acting 28 single dose/5 Impairment mainly in the ability to learn new information, i.e. High
benzodiazepines steady state the transfer of data from short-term memory to longer-term
storage up to 8 hours post-dose. Reduced
attention/concentration and slower reaction times may also
occur at higher doses. Consistent evidence of a dose-response
gradient across studies. Repeated-dose studies at steady state
show only partial tolerance to these effects with chronic use.
Long-acting 15 single dose Heterogeneity across studies can be explained by the age of Moderate
benzodiazepines the participants. Consistent and marked effects on cognitive
performance were evident in older adults across multiple
domains, but were absent at low doses in young adults.
Inconsistent dose-response effect.
Non- 27 single dose/2 Unexplained heterogeneity across studies unrelated to dose, Low
benzodiazepine steady state drug, type of test or age of the participants. Half the studies
derivatives show significant impairment in attention and memory recall,
while the other half shows no effect. One study at steady state
induced no cognitive deficits. Inconsistent evidence for a
dose-response gradient.
Anticholinergic Bladder 3 single dose/6 Inconsistent deficits on memory and attention tasks. Low-moderate
antimuscarinics steady state Heterogeneity across studies partially explained by different
batteries of neuropsychological tests, drug effects and dose,
with greater impairments consistently induced by single and
repeated high doses of oxybutynin.
Tricyclic 10 single dose/5 Significant effects on vigilance and attention, inconsistently on Moderate-high
antidepressants steady state memory. Evidence of a dose-response effect. Younger
individuals may develop tolerance with repeated use.
Histamine H1 First generation 11 single dose/2 Decreased alertness produces disturbances in attention and Moderate-high
antagonists steady state vigilance for up to 8 hours after single-dose use. Partial
tolerance developed in one study and complete tolerance
developed in another study of 5 days’ duration. Unclear dose-
response relationship.
Second generation 14 single dose/4 Only one small (n = 9) single-dose study with desloratadine High
steady state produced impairments in memory and reaction time. Other
drugs exhibited no effects on cognition during single and
repeated use.
Opioids Oxycodone, 5 single dose Single-use, high-dose consumption of oral opioid drugs elicits Low-moderate
morphine, impairments in concentration and memory storage. Slight age
dextropropoxyphene effect may be present, worse in older adults. Insufficient
evidence on low doses, repeated use or dose-response effect.
Mixed Antipsychotics 3 single dose/2 Unexplained heterogeneity across studies unrelated to age, Low
mechanisms steady state duration of use or typical vs atypical compounds.
Small studies.
GABA = g-aminobutyric acid.

Adis ª 2012 Springer International Publishing AG. All rights reserved. Drugs Aging 2012; 29 (8)
652
conducted, which found an association between
impaired cognition and diphenhydramine use,
but cognition was not specifically modelled as the
outcome variable, so results can only be inter-
preted cautiously.[121] Opioid consumption was
investigated in relation to cognitive performance
in a Canadian, cross-sectional, population-based
study of 2035 older adults, of whom 1.5% used
narcotic agents and performed significantly worse
on a neuropsychological test of attention com-
pared with non-users.[108] Of note, none of these
observational studies were inception cohort stud-
ies with participants who were treatment-naive
at baseline, so the results are less robust for de-
termining causality than data from randomized
placebo-controlled trials, where baseline cognitive
measures are collected prior to drug adminis-
tration. Among the longitudinal trials that ex-
ist,[111,122-124] data are conflicting and address the
question of whether continuous drug use can lead
to a progressive decline in cognitive status, which
is separate from the topic targeted in this review.
While it is clear that benzodiazepines and first-
generation H1 antihistamines provoke cognitive
deficits, inconclusive findings for the non-benzo-
diazepine derivatives and bladder antimuscarinic
drugs warrant comment. Scrutiny of the results
for individual drugs within these classes points to
the possibility that some agents may preferentially
induce deficits due to their specific formulations,
physicochemical properties or receptor selectivity
while others may not. If this is the case, then
caution should be taken in lumping class effects
with effects unique to individual pharmacolog-
ical molecules, as they may have overlapping but
differential properties. Within the anticholinergic
drug class, for example, amitriptyline possesses
H1 antagonist properties while solifenacin does
not. On the other hand, discrepant results could
also be explained by a lack of standardization in
the neuropsychological test batteries administered
by the different studies and the diverse statistical
approaches employed to ascertain whether cog-
nitive effects occurred among participants. Some
studies, particularly within the first-generation
H1 antihistamine class, exclusively evaluated non-
amnestic functions, others used auto-administered
computerized test batteries, and many failed to
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Tannenbaum et al.
correct for multiple comparisons in their analysis.
An alternate explanation relates to the age of the
participants. While age per se may not discrim-
inate between drug effects, age-related physio-
logical alteration may amplify the potential for
cognitive impairments to occur via changes in
receptor density and pharmacodynamics, redis-
tribution of body composition, diminished he-
patic and renal clearance, or a more permissively
penetrable blood-brain barrier. Finally, the small
sample sizes used in many of these studies may
have rendered the achievement of statistical sig-
nificance difficult, especially in the face of trivial
impairments or a reduced sensitivity of the cho-
sen tests to detect impairments.
Because of the aforementioned considerations,
our systematic review was unable to include a
valid meta-analysis for calculating the magnitude
of effect or the frequency with which cognitive
impairment could be expected to occur with each
drug class. The studies included in this review
tended to report significant changes in group means
on various neuropsychological tests instead of
the frequency with which individuals performed
poorly on amnestic or non-amnestic tasks. The
omission of actual test scores and/or standard
deviations of the test scores from the results in
almost 40% of the 78 studies retained for the re-
view made it impossible to combine data from
different studies. The inability to conduct a meta-
analysis encourages reflection on the type of in-
formation that is needed to better counsel patients
on the prevention and reversal of drug-induced
amnestic or non-amnestic cognitive deficits. Even
if valid effect sizes could be calculated, without
data on the number of individuals in whom im-
pairments are expected to occur, patients will be
unable to gauge their personal risk of adverse
cognitive effects when choosing between phar-
maceutical therapies. To ascertain causality with
certainty, it would be ideal to conduct neuro-
psychological tests in an n-of-1 trial before and
after initiation of each agent; however, this is neither
practical nor feasible in a busy outpatient setting.
Furthermore, few studies evaluated whether tol-
erance to deleterious cognitive effects develops
over time with steady-state concentration of each
drug. The results from the single-dose studies in-
Drugs Aging 2012; 29 (8)
Drug-Induced Cognitive Impairment
cluded in this review can therefore only be ap-
plied to medications such as benzodiazepines,
antihistamines and narcotic agents that are used
episodically on an as needed basis for the treat-
ment of insomnia, anxiety, allergic symptoms,
itchiness or pain, respectively.
This review is limited by the search engines’
strategy for identifying relevant articles; articles
that did not list the selected keywords in their
titles or abstracts would have been missed by the
search strategy and excluded from this analysis.
While great measures were taken to search the
references of pertinent articles, it is likely that
older papers may not have been captured,[125] as
well as studies that tested a multitude of phar-
macodynamic parameters and those that used
benzodiazepines as positive controls to test the
cognitive effects of other agents. As the effects of
benzodiazepines tend to be consistent, it is un-
likely that the inclusion of extra articles would
have altered the findings. An additional caveat is
that because the trials reviewed in this analysis
were all conducted in adults without underlying
central nervous system disorders, they do not
provide information regarding the full extent
of cognitive effects in individuals with chronic
diseases taking multiple medications over several
years, which is becoming increasingly common
for the aging population. Vulnerable older adults
may be more susceptible to drug-induced cognitive
deficits, especially in the presence of polyphar-
macy, which increases the risk of drug-drug inter-
actions and elevated plasma levels of certain agents
over time. This review did not establish whether
cognitive disturbances elicited by GABAergic, an-
tihistamine, anticholinergic or opioid medication
have important repercussions on activities of daily
living, especially as it appears that some degree of
tolerance may develop over time. Nor did the study
address whether interference with attention and
other executive functions increases the risk of
postural instability, falls, driving impairment or
automobile accidents.
5. Conclusions
Patients are increasingly concerned with per-
ceived memory and attention deficits that may
Adis ª 2012 Springer International Publishing AG. All rights reserved.
653
signal early dementia. As a result, more patients
are undergoing neuropsychological testing and
are being diagnosed and monitored for amnestic
or non-amnestic MCI. The impact of medications
on cognitive function and their ability to affect
the results of neuropsychological test scores during
the clinical assessment of memory complaints is
undervalued. This review provides a synthesis of
the evidence on the role medications can play
during the assessment of mild cognitive impair-
ment. There is a consistent body of evidence sug-
gesting that drug-induced MCI can occur with
episodic use of medication for insomnia, anxiety,
pruritus or allergic symptoms. Combined amnes-
tic and non-amnestic deficits occur with the use of
benzodiazepine agents and may partially underlie
older adults’ frequent complaints of forgetfulness
or difficulty concentrating. The interpretation of
neuropsychological tests in patients being screened
for cognitive impairment needs to take into account
the effect of exogenous centrally active pharmaco-
logical substances.
The trade-off between the risks and benefits of
pharmacological therapy needs to be made on an
individual basis in accordance with each patient’s
circumstances. Despite the known risks, some
patients may be better off taking certain drugs
when they need them than if the underlying dis-
order were left untreated. Each patient has the
right to an informed choice, with safer pharma-
cological or non-pharmacological alternatives of-
fered whenever possible and the risks and benefits
weighed in accordance with patient preferences.
Future studies aimed at clarifying the extent and
type of impairment that can be expected with use
of various medications should employ standard-
ized and easily reproducible neuropsychological
test batteries, with greater attention paid to pop-
ulation homogeneity and estimation of the num-
ber-needed-to-harm statistic.
Acknowledgements
We gratefully acknowledge the assistance of Audrey Attia,
Marion Guillemont, Jean-Francois Cabana, Thomas Jubault
and Don Sheppard in the preparation of this manuscript.
This work was sponsored by The Michel Saucier Endowed
Chair in Geriatric Pharmacology, Health and Aging, from the
Faculty of Pharmacy, Université de Montréal. The sponsors
Drugs Aging 2012; 29 (8)
654
had no role in the design and conduct of the study; collection,
management, analysis and interpretation of the data; and
preparation, review and approval of the manuscript.
The financial disclosures for the authors are as follows:
Cara Tannenbaum was supported by The Michel Saucier
Endowed Chair in Geriatric Pharmacology, Health and
Aging, from the Faculty of Pharmacy, Université de Montréal
and by a junior researcher award from the Fondation de Re-
cherche en Santé du Québec. She declares having received
honoraria and/or consulting fees from Allergan Inc., Astellas,
Ferring and Pfizer during the past 3 years. Amélie Paquette
was supported by the Canadian Institutes of Health grant
108262. Ryan Carnahan was supported by an Agency for
Healthcare Research and Quality (AHRQ) Centers for Edu-
cation and Research on Therapeutics cooperative agreement
#5 U18 HSO16094 (the Iowa Older Adults CERT). He has
previously received research support from Eli Lilly and Co.,
Forest Laboratories, Wyeth and Boehringer Ingelheim. All
other authors declare that they have received no support from
any organization for the submitted work, have no financial
relationships with any organizations that might have an in-
terest in the submitted work in the previous 3 years and have
no other relationships or activities that could appear to have
influenced the submitted work.
Contributions: Cara Tannenbaum had full access to all of
the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis. Cara
Tannenbaum, Amélie Paquette and Ryan Carnahan con-
tributed to the design of the study. All authors contributed to
the data collection, management, analysis and interpretation
of the data, and the preparation and review of the manuscript.
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Correspondence: Dr Cara Tannenbaum, Faculties of Phar-
macy and Medicine, Université de Montréal, 4565 Queen
Mary Road, Montreal, Québec, Canada H3W 1W5.
E-mail: cara.tannenbaum@umontreal.ca
Drugs Aging 2012; 29 (8)