Zolpidem and triazolam do not affect the nocturnal sleep-induced memory improvement.

Abstract

It is widely accepted that sleep facilitates memory consolidation. Hypnotics (e.g., benzodiazepines), which reportedly increase sleep efficiency but also modify sleep architecture, could affect memory improvement that occurs during sleep.
The present study examined the effects of single doses of two short half-life hypnotics, zolpidem and triazolam, on sleep-induced improvement of memory.
Twenty-two healthy volunteers participated in this randomized, double-blind, crossover study. All subjects received a single oral dose of zolpidem (10 mg), triazolam (0.25 mg) or placebo at 9 P.M.: and slept for 7.5+/-0.2 h. The effect of sleep on memory was investigated by comparing the performance of this group of volunteers with a group of 21 subjects in wakefulness condition. Declarative memory was evaluated by using a free-recall test of ten standard word and seven nonword lists. Subjects memorized the word and nonword lists 1 h before dosing and they were asked to recall the memorized lists 10 h after dosing. Digit symbol substitution test (DSST) and forward and backward digit tests were also given 1 h before and 10 h after dosing.
Subjects who slept remembered more nonwords than those in wakefulness condition, but they did not recall significantly more standard words. Neither zolpidem nor triazolam affected the enhanced nonword recall observed after sleep. Finally, none of the hypnotics affected the improvement in the DSST performance of subjects who slept.
The hypnotics tested did not interfere with the nocturnal sleep-induced improvement of memory.

Full text

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Psychopharmacology (2005) 181: 21–26
DOI 10.1007/s00213-005-2228-0
ORIGINAL INVESTIGATION
Jaime Meléndez.Irina Galli.Katica Boric.
Alonso Ortega.Leonardo Zuñiga.
Carlos F. Henríquez-Roldán.Ana M. Cárdenas
Zolpidem and triazolam do not affect the nocturnal
sleep-induced memory improvement
Received: 24 June 2004 / Accepted: 5 February 2005 / Published online: 14 April 2005
# Springer-Verlag 2005
Abstract Rationale: It is widely accepted that sleep facil-
itates memory consolidation. Hypnotics (e.g., benzodiaze-
pines), which reportedly increase sleep efficiency but also
modify sleep architecture, could affect memory improve-
ment that occurs during sleep. Objectives: The present
study examined the effects of single doses of two short
half-life hypnotics, zolpidem and triazolam, on sleep-in-
duced improvement of memory. Methods: Twenty-two
healthy volunteers participated in this randomized, double-
blind, crossover study. All subjects received a single oral
dose of zolpidem (10 mg), triazolam (0.25 mg) or placebo
at 9 P.M. and slept for 7.5±0.2 h. The effect of sleep on
memory was investigated by comparing the performance of
this group of volunteers with a group of 21 subjects in
wakefulness condition. Declarative memory was evaluated
by using a free-recall test of ten standard word and seven
nonword lists. Subjects memorized the word and nonword
lists 1 h before dosing and they were asked to recall the
memorized lists 10 h after dosing. Digit symbol substitu-
tion test (DSST) and forward and backward digit tests
were also given 1 h before and 10 h after dosing. Results:
Subjects who slept remembered more nonwords than those
in wakefulness condition, but they did not recall signifi-
cantly more standard words. Neither zolpidem nor triazo-
lam affected the enhanced nonword recall observed after
sleep. Finally, none of the hypnotics affected the improve-
ment in the DSST performance of subjects who slept.
Conclusions: The hypnotics tested did not interfere with
the nocturnal sleep-induced improvement of memory.
Keywords Zolpidem.Triazolam.Memory
consolidation.Sleep.Hypnotics
Introduction
The idea that sleep is necessary for memory consolidation
has been supported for a long time (Smith 1996). In both
animals and humans, sleep deprivation after training in a
new task impairs its subsequent performance (Karni et al.
1994;SmithandRose1997;PlihalandBorn1999;Stickgold
et al. 2000a). Memory consolidation resulting from sleep
has also been observed as an improvement in perceptual
skillandverballearning (Plihaletal.1999;Gaisetal.2000;
Maquet et al. 2003).
The contribution of sleep in memory consolidation was
also supported by electrophysiological and functional brain
activity studies. Electrophysiological recordings of rat hip-
pocampal neurons and positron emission tomography in
humans demonstrated that neuronal populations of rat hip-
pocampus or human cortex activated by a learning expe-
rience are reactivated during post-training sleep (Wilson
and McNaughton 1994; Skaggs and McNaughton 1996;
Maquet et al. 2000; Lee and Wilson 2002). These reac-
tivations would allow the strengthening of synapses and
the incorporation of a new experience into long-term mem-
ory (Maquet 2001; Maquet et al. 2003).
In relation to the contribution of slow wave sleep (SWS)
and rapid eye movement (REM) stages to the sleep-depen-
dent consolidation, recent findings support the idea that
both stages are required for memory processes during sleep
(Giuditta et al. 1995; Stickgold et al. 2000b; Ficca et al.
2000; Ficca and Salzarulo 2004).
In view of the role of the sleep on memory consolidation,
sleep disorders such as insomnia could have a detrimental
J. Meléndez.I. Galli.K. Boric.A. Ortega.L. Zuñiga
Escuela de Psicología, Universidad de Valparaíso,
Valparaíso, Chile
K. Boric.A. M. Cárdenas (*)
Centro de Neurociencia de Valparaíso,
Universidad de Valparaíso,
Gran Bretaña 1111, Playa Ancha,
Valparaíso, Chile
e-mail: ana.cardenas@uv.cl
Tel.: +56-32-508052
Fax: +56-32-283320
C. F. Henríquez-Roldán
Departamento de Estadística,
Instituto de Matemáticas y Física,
Universidad de Valparaíso,
Valparaíso, Chile

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impact on cognitive functions. In fact, insomnia reportedly
produced cognitive dysfunctions including memory im-
pairments (Roth et al. 2001). On the other hand, drugs that
improve sleep efficiency could be beneficial on cognitive
dysfunctions observed in insomniac patients.
Benzodiazepines and nonbenzodiazepine hypnotics, zo-
piclone and zolpidem, are the most commonly prescribed
drugs in the treatment of insomnia (Roth and Roehrs 1992).
These drugs reduce sleep latency and increase total sleep
time and sleep efficiency, but they alter sleep architecture
(Lancel 1999). These hypnotics tend to reduce the time
period spent in REM and increase the total amount of
SWS, but all hypnotic drugs do not exhibit those effects
(Kanno et al. 1993; Aeschbach et al. 1994; Feinberg et al.
2000; Kanno et al. 2000; Nakajima et al. 2000; Tan et al.
2003). In this regard, hypnotic agents could either improve
or deteriorate the consolidation of memory that occurs
duringsleep.Thememoryconsolidationimprovementcould
be a consequence of an increase in sleep efficiency, while
the negative effect could be a consequence of the reported
altered sleep architecture.
Although it is well known that benzodiazepines produce
anterograde amnesia (Ghoneim and Mewaldt 1990) and
retrograde facilitation of memory (Ghoneim and Mewaldt
1990; Coenen and van Luijtelaar 1997), the effect of these
hypnotic drugs on the memory process during sleep has not
been sufficiently studied. Therefore in the present study
we evaluated the effects of two short-acting hypnotic drugs
—a benzodiazepine, triazolam, and a nonbenzodiazepine
hypnotic, zolpidem—on memory storage during sleep in
healthy volunteers. Both drugs have short half-life of ap-
proximately 2–3 h (Friedman et al. 1986; Greenblatt et al.
1998; Drover et al. 2000), but exhibit different selectivity
for benzodiazepine receptors: while triazolam binds to type
I and type II benzodiazepine receptors, zolpidem seems to
bind with relative selectivity to type I benzodiazepine re-
ceptors (Byrnes et al. 1992; Itier et al. 1996; Sanna et al.
2002). However, the clinical consequences of the pharma-
codynamic property of zolpidem have not been well estab-
lished (Lobo and Greene 1997; Nowell et al. 1997).
To establish the effect of sleep on memory, we compared
the declarative memory of subjects who slept with subjects
who remained awake. A comparison group kept in wake-
fulness condition was also necessary to determine whether
triazolam and zolpidem have different effects on memory
storage during sleep or wakefulness. Subjects who slept
received a nighttime dose of zolpidem, triazolam or pla-
cebo (“sleep condition”), while volunteers in “wakeful-
ness condition” received a morning dose of the drugs or
placebo, and remained awake during the entire day. We did
not include a group of awake subjects during the night
because sleep deprivation not onlyimpairs memory consol-
idation but also affects other different cognitive perfor-
mances that can also cause recall impairment (Harrison and
Horne 1997, 1998; Drummond et al. 2000).
Declarative memory was evaluated by using a free-recall
test of lists of standard words (common nouns) and non-
words. Recall of standard words has been used in the past
to measure the effects of either drugs or sleep on declar-
ative memory (Greenblatt et al. 1988; Mazzoni et al. 1999;
Plihal et al. 1999; Silva et al. 2003). We included a non-
word recall test to measure the subjects’ memory of
unamiliar materials having a minimal representation in
long-term lexical knowledge (Hulme et al. 1991). Con-
sidering that these hypnotic drugs reportedly produce
anterograde amnesia as aconsequenceofimpairmentinthe
abilitytolearnnewinformation(Warotetal.1987;Ghoneim
and Mewaldt 1990; Berlin et al. 1993), subjects memorized
thewordandnonword lists 1 h before dosing and they were
asked to remember them 10 h after dosing. Thus the effect
of drugs on acquisition was excluded. We also applied the
digit symbol substitution test (DSST) and the forward and
backward digit tests to measure attention and short-term
memory.
In summary, our aim was to demonstrate that triazolam
and zolpidem could affect the memory improvement that
occurs during sleep. This study may contribute to a better
understanding of the mnemonic effects of hypnotic drugs
during nocturnal sleep.
Materials and methods
Subjects
A total of 43 healthy young volunteers (20 men and 23
women, aged 18 to 25 years) participated in this study.
The subjects were university undergraduate students; none
had a history of medical disease, mental illness, drug abuse,
sleep disturbance or pathological anxiety, as determined by
physical examination (including measuring blood pressure
and heart rate), a health questionnaire, and psychological
evaluation. The Minnesota Multiphasic Personality Inven-
tory (MMPI) adapted for the Chilean population (Risetti et
al. 1989) and Rey–Osterrieth Complex Figure test (Osterrieth
1944) were also administered to exclude subjects with per-
sonality alteration and/or visuospatial memory dysfunc-
tion. All selected volunteers gave their written informed
consent and were allowed to leave the trial at any time.
The study was approved by the Ethics Committee of the
University of Valparaíso.
None of the participants were receiving other medica-
tions, including contraceptives for women. Concurrent
medication,tobacco,alcoholandcaffeinecontainingdrinks
were prohibited on experimental days.
General procedures
According to a double-blind, randomized, three-way cross-
over design, on three different occasions each participant
received a single oral dose of 10 mg zolpidem, 0.25 mg
triazolam or placebo, with at least 1-week washout between
treatments. The dosage forms were identically packaged in
gelatin capsules and orally administered with water.
Subjects were informed that during their participation in
the trial they would receive two different hypnotic drugs
and a placebo. In addition to this general information, sub-
22

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jects were blind to the type of drug administered. Subjects
were told that the aim of the trial was to see how differ-
ent drugs affect memory performance. Also, they were in-
structed to abstain from alcohol or caffeine-containing
drinks, tobacco, and any other medications, 24 h before
and 24 h after dosing.
One hour before dosing, subjects memorized the ten-
word and seven-nonword lists. Also, we administered the
digit forward and backward tests and DSST.
At 9 A.M., half of the volunteers (21) received a single
dose of zolpidem, triazolam or placebo and they remained
awake during the whole day (“wakefulness condition”).
The other 22 volunteers received a single dose at 9 P.M. and
slept for approximately 8 h (“sleep condition”).
After dosing, the subjects who remained awake con-
tinued with their daily activities at the university, but they
were always under supervision. These volunteers had a
standard lunch in the University cafeteria. The subjects in
“sleep condition” were taken to their homes by car. They
were instructed to have a light dinner and then go to bed.
They also were instructed to have a light breakfast for next
morning.
All subjects were instructed to return to the laboratory 10
h after dosing for evaluations. Immediately upon arrival,
subjects were required to answer a questionnaire. They had
to answer how their sleep was, how many hours they slept
and if they had complied with the instructions given.
After responding to the questionnaire, the subjects were
asked to recall the words and nonwords memorized. In
addition, they had to perform digit forward and backward
tests and DSST again.
Tests
Digit forward and backward tests, adapted from Wechsler
Adult Intelligence Scale (Wechsler 1988), essentially mea-
sure attention/concentration and short-term memory. A
series of numbers were read to the subjects, who were then
asked to repeat the entire series either forward or back-
ward. The digits forward test consisted of number lists that
progressively increased from three to nine digits. On the
digits backward test, the numbers progressively increased
from two to eight digits. The score is determined by the
amount of numbers of the longest digit series remembered.
DSST adapted from Wechsler Adult Intelligence Scale
(Wechsler 1988) consisted of matching symbols with num-
bers. The score was determined by the total number of
correct responses completed in a 90-s test period.
Three versions of digit forward and backward tests and
DSST were administered, one for each drug administra-
tion. However, the same version of the tests was used be-
fore and after the dosing of each drug. Subjects did not
practice these tests before the trial.
The standard word recall test consisted of a list of ten
standard words (two- to four-syllable common nouns from
different semantic categories) that were verbally presented
to the participants. The subjects were asked to repeat orally
the words in any order until they were capable of mem-
orizing the whole list. Ten hours after dosing, subjects were
asked to recall as many words as possible from the list. The
score was given on the number of correct words recalled.
The nonword recall test consisted of a list of 7 three-
syllable nonwords without semantic meaning in English or
Latin languages, taken from Condemarin and Blonquist
(1970). Some examples of nonwords are ifjuti, alledo and
renajto. The subjects were asked to repeat the nonwords
verbally in any order until they were capable of memoriz-
ing the complete list. Ten hours after dosing, subjects were
asked to recall as many nonwords as possible from the
list. The score was determined by the number of correct
nonwords recalled.
Three versions of word and nonword lists were used.
Subjects did not practice these tests before the trial.
Statistical analysis
Statistical comparisons of the mean scores in the cognitive
tests were made using linear mixed models, as described
by Verbeke and Molenberghs (1997, 2000), Twisk (2003)
and Dupont (2002). This statistical model is adequate for a
three-way crossover design, in which each participant re-
ceived triazolam, zolpidem and placebo on three different
occasions (Dean and Voss 1999). The Wald test was used
to check the significant dependence of the cognitive test
scores on gender, wakefulness/sleep conditions, or drug
treatments. The Wald test was also used to check the in-
teraction between drug treatments and wakefulness/sleep
conditions. The Bonferroni multiple comparison procedure
with adjusted P values was used to check if the effects of
triazolam, zolpidem or both, are different from that of the
control group (placebo). The analysis was performed with
the StataCorp (2003) statistical software.
Results
Twenty-one volunteers (11 women and ten men) were ran-
domly assigned to a “wakefulness condition” and 22 vol-
unteerswereassignedtoa“sleepcondition”(11womenand
11 men). Both groups did not differ in age (19.5±0.38 and
19.8±0.35 years; P=0.62), education level (all them were
college undergraduate students) and body mass index (22±
0.6 and 21±0.5 kg/m2; P=0.12). Volunteers in “sleep con-
dition” slept for 7.5±0.3, 7.6±0.3 and 7.4±0.2 h after the
dose of placebo, triazolam or zolpidem, respectively. Sub-
jects in “wakefulness condition” slept for 7.3±0.3, 7.4±0.2,
7.2±0.2 h the day before the treatment with placebo, tri-
azolam or zolpidem, respectively.
In the first evaluation, both groups had similar scores in
digit forward and digit backward tests and DSST (P>0.05;
Table 1). Statistical analysis showed that performance in
these tests was independent of gender (P>0.05). Interest-
ingly, linear mixed model analysis indicated that sleep
improved both the DSST performance (P=0.002) and the
nonword recall (P<0.0001). The performance in DSST 1 h
before and 10 h after the administration of a placebo dos-
23

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age to subjects of wakefulness and sleep condition groups
is shown in Table 2. The word and nonword recall by sub-
jects who remained awake or who slept after a placebo
dosage is shown in Table 3.
Table 2 shows the performance in digit forward, digit
backward tests and DSST of subjects who slept after the
administration of a dose of triazolam, placebo or zolpidem
in sleep condition. The tests were applied 1 h before and 10
h after dosing. Data analysis with the linear mixed model
demonstrated that performances in these tests were inde-
pendent of drug treatments (P>0.05).
Table3shows therecall ofstandard wordsandnonwords
by subjects who slept after the administration of triazolam,
placebo or zolpidem. Data analysis with the linear mixed
modeldemonstratedthatrecallofbothwordsandnonwords
was not dependent on drug treatments (P>0.05).
In agreement with previous results of Greenblatt et al.
(2000), we observed no effects of triazolam and zolpidem
on the performance of digit forward and digit backward
tests and DSST 10 h after dosing in subjects of wakefulness
condition. Also, the drugs did not affect the recall of word
and nonword lists (data not shown).
Discussion
The main finding of this paper is that neither triazolam nor
zolpidem affected the sleep-induced memory improvement
of nonword recall.
It is noteworthy that the statistical analysis of our results
showed that sleep improved the recall of nonwords, but it
did not significantly increase the recall of standard words.
Contrary to standard words, nonwords have minimal long-
termlexicalrepresentations(Hulmeetal.1991,1995;Saint-
Aubin and Poirier 2000). Jenkins and Dallenbach (1924)
demonstratedforthefirsttimethatsleepenhancedtherecall
of nonwords, suggesting that sleep plays an important role
intheconsolidationprocessofunfamiliarinformation.More
recently, Stickgold (1998) proposed that sleep can integrate
new information into associative networks. In particular,
REM sleep, which is characterized by hyperassociative
dreams, seems to enhance the activation of weak associa-
tion (Stickgold et al. 1999). In this regard, it is tempting
to speculate that weak associations of the nonwords with
long-term semantic memory would be strengthened during
sleep, improving the recall of nonwords in the morning.
The recall of standard words, which have representations
in the long-term lexical knowledge, would be less affected
by sleep.
As previously mentioned, one of our hypothesis was that
hypnotic agents could deteriorate the memory improve-
ment induced by sleep as a consequence of the reported al-
teration of sleep architecture caused by hypnotics. To test
this hypothesis, we designed a protocol that excluded the
sedative and anterograde amnesia effects of these drugs:
(1) subjects memorized the word and nonword lists before
dosing (therefore the drugs’ effect on acquisition was ex-
cluded); (2) subjects were asked to recall the memorized
lists 10 h after dosing, when the plasma levels of both tri-
azolam and zolpidem are reportedly minimum and their
sedative effects are indistinguishable from those of pla-
cebo (Greenblatt et al. 2000). Thus, in accordance with the
results of Greenblatt et al. (2000), our results show that
10 h after dosing the performance in the digit tests are not
Table 1 Data show the performance on digit forward and digit
backward tests and digit symbol substitution test (DSTT), in the first
evaluation of subjects assigned to wakefulness or sleep condition
group
Wakefulness condition
group
Sleep condition
group
P
value
Digit forward
test
Digit backward
test
DSST
6.7±0.246.6±0.29 0.84
4.9±0.255.4±0.25 0.26
59.1±1.9 60.8±1.4 0.44
Data are means±SE
Table 3 Recall of standard words and nonwords
Number of
words recalled
Number of
nonwords recalled
Wakefulness condition
Placebo
Sleep condition
Placebo
Triazolam
Zolpidem
5.6±0.612.0±0.4
6.6±0.46
6.6±0.49
6.6±0.46
3.2±0.33a
3.3±0.38
3.6±0.32
Data shown are means±SE
aLinear mixed model analysis indicate that sleep improved the
nonword recall (P<0.0001)
Table 2 Data (means±SE) show the performance of subjects on
digit forward and digit backward tests and DSST 1 h before and 10 h
after dosing
Digit forward
test
Digit backward
test
DSST
Wakefulness condition
Placebo
Before dosing
10 h after dosing
Sleep condition
Placebo
Before dosing
10 h after dosing
Triazolam
Before dosing
10 h after dosing
Zolpidem
Before dosing
10 h after dosing
6.8±0.28
6.4±0.40
5.3±0.30
5.4±0.43
60.3±1.9
64.3±1.9
6.8±0.25
7.1±0.32
5.5±0.22
5.4±0.28
61.4±2.2
70.1±1.9a
7.0±0.25
6.9±0.28
5.3±0.22
5.6±0.33
63.8±2.0
69.3±2.2
6.7±0.27
6.9±0.26
5.1±0.27
5.5±0.23
61.5±1.7
70.5±2.0
aLinear mixed model analysis indicate that sleep improved the
subjects’ DSST performance (P=0.002)
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significantly different from that of the placebo, by both
sleep and wakefulness condition groups.
Under the experimental conditions used in this paper, we
observed that the sleep-induced improvement of the non-
word recall was not affected by both zolpidem and tri-
azolam. Our results also showed that neither zolpidem nor
triazolam affected the recall of standard words. Thus, these
findings suggest that the effects of these hypnotic agents
on sleep architecture are not sufficient to impair the sleep-
induced memory improvement. In this regard, it was re-
ported that both triazolam and zolpidem reduce delta activ-
ity and increase sigma and beta activity during non-REM
sleep, but they do not significantly affect the total REM
sleep time (Feinberg et al. 2000).
Data analysis with the linear mixed model showed that
sleep improved the performance of DSST. Since this test
assesses psychomotor performance and visual perception
(Friedman et al. 1992), improvement in the DSST perfor-
mance after sleep could be a consequence of the reported
sleep-dependent consolidation of visuomotor skill learning
(Maquet et al. 2003), which depends on both SWS and
REM stages (Stickgold et al. 2000b; Mednick et al. 2003).
However, it must be mentioned that DSST is a multifacto-
rial test that also measures other cognitive abilities like at-
tention, concentration and focus (Friedman et al. 1992).
Statistical analysis of DSST scores showed no interac-
tion between wakefulness/sleep conditions and drug treat-
ments, suggesting that the sleep-induced improvement of
DSST performance was not affected by either zolpidem or
triazolam. However, additional studies, featuring more se-
lective paradigms, are required to determine the effect of
hypnotic agents on the sleep-induced improvement of pro-
cedural memory.
We cannot discard a possible circadian influence on
memory improvement for the subjects who slept. In fact,
althoughdaytimesleepcanbeasefficientasnocturnalsleep
in improving memory (Mednick et al. 2003), some authors
have proposed that the effect of sleep on memory consol-
idation (Nescaand Koulack 1994; Koulack 1997) and learn-
ing (Cajochen et al. 2004) may be partially due to circadian
rhythms.
In summary, zolpidem and triazolam do not seem to alter
the effect of nocturnal sleep on memories, since they did
not affect the improvement on nonword recall and DSST
performance. These findings could be of clinical relevance,
considering that these drugs are administered in the treat-
ment of insomnia. Sleep disorders such as insomnia could
have a deleterious effect on memory consolidation. There-
fore the use of drugs that improve sleep efficiency could
prevent cognition impairments in insomniac subjects. This
could be particularly advantageous for short-acting hyp-
notics that do not exhibit hangover effects. Nevertheless,
the present results do not establish that neither triazolam
nor zolpidem influence other type of memory processes
during sleep. Since cognition during sleep is qualitatively
distinct from that of wakefulness (Stickgold 1998), addi-
tional clinical studies are necessary to know more about
other mnemonic effects of hypnotics agents during sleep.
Acknowledgements
mento de Estadística de la Facultad de Ciencias, Universidad de Val-
paraíso), Sergio Jiménez and Javier Díaz (medical students, Escuela
de Medicina, Universidad de Valparaíso), and David Memmott for
their invaluable help. This project was supported by DIPUV 07/2002
(Universidad de Valparaíso.)
We thank Professor Alberto Caro (Departa-
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