Eur J ClinPharmacol(1991) 40:267-271 003169709100070A © Springer-Verlag1991
Residual effects of lormetazepam on mood and performance in healthy elderly volunteers J. B. Deijen, M. L. Heemstra, and J. E Orlebeke Department of Psychology,PsychophysiologyDivision,Free University,Amsterdam,The Netherlands Received: May 19, 1989/Acceptedin revised form:July 11,1990
Summary. 45 subjects aged over 65 years were randomly assigned to treatment with lormetazepam 0.5 mg or 1 mg or placebo. Mood and performance were measured with a battery of computerized tests. Subjects were tested before and after i and 8 nights of treatment. Pre- and post-treatment scores were analysed by a multivariate covariance technique, the pre-treatment score serving as covariate. The single and repeated doses of lormetazepam resulted in impairment of performance in a memory task, and the repeated dose administration impaired performance of a perceptual task. The single administration of a low dose gave an improvement in fine motor control. No change was found in the mood states of the subjects. Key words: Lormetazepam Memory; Geriatric volunteers Residual effects Psychometry, perception, motor control Lormetazepam is a relatively new member of the benzodiazepine series, which has been marketed in The Netherlands since 1981. It is prescribed as a short-acting hypnotic based on its elimination half-life of 10-12 h. A large number of clinical trials and laboratory studies has established its sleep-inducing efficacy and its safety as assessed by physical examination and clinical laboratory tests [Nicholson and Stone 1982; Vogel 1984]. A number of studies has also been carried out to detect residual effects on daytime performance; for instance, a study [Nicholson and Stone 1982] was done to establish the residual effects on sleep, mood and performance of 0.5, 1 and 2 mg lormetazepam administered the previous night, and of i mg lormetazepam administered in the morning. In that study the subjects were young (18-27 y). Administration of 2 mg lormetazepam on the preceding night, resulted in a marked decrement in performance in a visuo-motor task and digit-symbol task. This significant fall in visuo-motor performance was still present 10.5 h after ingestion and in the digit-symbol task after 9.75 h. Immediate effects of administration in the morning of * This studywas supportedby a grant from WyethLaboratoriaB.V.
1 mg lormetazepam were evident until 3.75 h after ingestion. Heidrich et al. [1981] examined the possible residual effects of lormetazepam by subjective assessment. Subjects were healthy male and female chronic insomniacs aged 20-60 y. The treatment group ingested 2 mg lormetazepam for 2 weeks. From the daily measurements of morning freshness, ability to concentrate at work, calmness and tiredness in the evening, it was concluded that lormetazepam caused no residual effects. On the contrary, it appeared that subjects were much fresher in the morning and in the evening and were better able to concentrate at work. Beyond the possible residual side-effect of benzodiazepines, another side-effect sometimes occurs, namely amnesia. Benzodiazepines appear to exert their greatest effect in tests of long-term episodic memory ]Lister 1985], at the stage of long-term acquisition [Brown et al. 1982]. Lormetazepam 0.02 mg/kg i.v. induced anterograde amnesia for a short period [Dorow 1987]. Although much is known about the residual effects of lormetazepam in younger subjects, the possibly more serious residual effects in elderly subjects are uncertain. The present study was undertaken to assess the residual effects of lormetazepam in elderly volunteers. In order to measure sedation and amnesic effects a battery of psychometric tests was used, covering motor control, sensory analysis, central processing (including memory) and mood.
Subjects and methods
Subjects Fifty three volunteers entered the study of whom 45 subjects (35 men, 10 women) were evaluated (subjects dropped out because of poor compliance with the treatment regime or were randomly removed to balance the design).Subjectswere randomlyassignedto one of the 3 treatment groups; 15 subjects received 0.5 mg lormetazepam, 15 received lmg lormetazepam and 15 received a placebo. The mean age of the subjectswas 70 y and their weightwas
J. B. Deijen et al.: Lormetazepanr effects in the aged
268 Table 1. Subjects
mean age (y) mean IQ cups of coffee/day cups of tea/day
0.5 mg lormetazepam
i mg lormetazepam
placebo
71 111 4.1 1.7
70 113 3.2 3.0
70 115 4.3 3.4
between 50 and 80 kg. All subjects were self-reliant inhabitants of Amsterdam and surrounding area, who had responded to a written invitation to take part in the study. Although the groups were not matched, the subjects appeared to be quite comparable with respect to age and IQ. At the first test session subjects reported how many cups of coffee and tea they usually drink each day (Table 1).
Measures o f m o o d and p e r f o r m a n c e The measures were selected from the Neurobehavioral Evaluation System (NES), which is especially recommended for measurement of the behavioral effects of neurotoxic agents [Baker et al. 1985 personal communication]. The treatment effects were measured by means of a battery of tests, including a self-rating scale for mood and sensorimotor tests. The choice of the sensorimotor tests took into account three important functions of the CNS, viz. motor control, sensory analysis and central processing. Profile of mood states (POMS): The POMS is a self-reported mood questionnaire, which yields scores on 5 factor derived scales of fatigue, depression, anger, tension and vigour. Associate learning. Nine pairs of a name and an occupation are presented sequentially on the screen and then the subject is prompted 9 times with one of the names and the 9 alternative occupations. Each time a name is presented, the subject has to choose one of the alternative occupations. Three trials are given in which the subject has to learn as many paired names and occupations as possible. The number of correct responses in each trial is recorded. Continuous performance test: Every second a random letter appears on the screen. If the letter is an "S" the subject must push a reaction time button. Reaction times, omission and commission errors are recorded. Hand-eye coordination task."The subject is asked to use a joystick to trace a large sine wave pattern on the screen. A cursor moves horizontally at a constant rate, while the subject controls only the vertical motion of the cursor with the joystick. Two measures of the vertical distance of the cursor from the sine wave line are recorded. Symbol-digit substitution task: This is a modification of the digitsymbol substitution task in the Wechsler Adult Intelligence Scale [Wechsler 1955]. Nine symbols and 9 digits are paired at the top of the screen and the subject has to press the digit keys corresponding to a test set of the 9 symbols, in a different order than presented. The time required to complete each set of symbols and the number of digits incorrectly matched with the test symbols are recorded. Pattern comparison: Three character arrays are presented side by side. Two of the figures are identical and the third is similar, but with a few minor changes. For each trial the subject has to press the digit key corresponding to the unequal figure. The number of items correctly matched and the response latency for each item are recorded. Digit span: On the computer screen a series of 4 digits is presented, one each second. Afterwards the subject has to press the corresponding digits on the computer keyboard. After correctly responding a series of 5 digits is presented. If the subject responds correctly the series is lengthened to 6, and, in case of correct responses, to a maximum of 9 digits. At each span length a second trial is given if the first response is incorrect. After incorrectly responding to two trials of the same span length the forward procedure is ended.
In addition the subject has to respond to progressive longer series (3 to a maximum of 8) of digits in the reverse order from that presented on the computer screen. The 'backward' test, apart from the reverse response order, is comparable to the forward procedure. The scores recorded are the numbers of digits entered correctly both forward and backward. Memory scanning task."The subject is presented with a series of digits one at a time and must indicate by pushing a button (yes/no) whether the digit comes from a previously presented set of digits. The previously presented memory set can consist of 2, 4 or 5 digits. Recorded are the number of correct responses and the latency of each response for both positive and negative trials. By means of regression techniques the encoding time, motor processing time and memory scanning time can be assessed. Finger tapping." The subject is asked to press a button as many times as possible within a 10-s interval. There are trials with the left hand pressing one button, with the right hand pressing one button, and trials with the preferred hand alternately tapping the two buttons. The number of button presses in each response interval is recorded. Simple reaction time: In this visual reaction time test the subject has to press a button as quickly as possible when a large square appears on the screen. The inter-stimulus interval is varied at random to reduce effects of stimulus anticipation. The individual RT latencies are recorded. Associate recognition: A single trial of the 9 names to be matched with one of the 9 occupations used in the associate learning test is administered at the end of the testing session. A delay of one hour in the associate learning task allows a test for long term memory. The number of correct responses and whether each name was matched correctly or incorrectly are recorded. All the tests for mood and performance were presented on an Olivetti M 24 computer. Intelligence test: A condensed version of the Groninger Intelligence Test was administered by the investigator. Standards are provided for Dutch males and females, from 12 to 76 y.
General procedure All 53 subjects underwent a medical examination and performed the intelligence test. Only those subjects meeting the inclusion criteria and not meeting any of the exclusion criteria were randomly assigned to one of the three treatment groups. The exclusion criteria were: 1) uncooperative or unlikely to adhere to the protocol, 2) IQ less than 80, 3) using benzodiazepines or other hypnotics, major tranquilizers or antidepressants, 4)suffering from myasthenia gravis, acute glaucoma, severe cardiovascular, respiratory, hepatic or renal disorders, and 5) addiction or potential for addiction. If subjects had trouble coming to the laboratory by means of public transport, the psychometric tests were carried out at their homes. Of the 45 evaluable subjects, 4 subjects in each treatment group and 6 subjects in the placebo group were tested at home. As the presentation of the tests is computerized and the system is meant to be used at different locations, it was assumed that testing at home would not influence the results. The procedure was double-blind, i.e. neither investigator nor subject was aware of the type of treatment receiving. Treatment consisted either of 0.5 mg lormetazepam, 1 mg lormetazepam or placebo. Subjects were tested on three separate days. The first test took place before treatment commenced. The first treatment night was 1 week later, followed by the second testing day, and the third testing day was again 1 week later, after the eighth treatment night. On each testing day the subject was tested in the morning and in the afternoon. Thus, Session 1 took place in the morning and Session 2 in the afternoon before treatment commenced. Session 3 took place in the morning and Session 4 in the afternoon after the first treatment night. Session 5 took place in the morning and Session 6 in the afternoon after the eighth treatment night.
J. B. Deijen et al.: Lormetazepam effects in the aged
269
Test procedure
5.0
Subjects were examined individually in a quiet room. If a subject was tested at home, this also took place in a quiet room. The 6 test sessions consisted of 6 different versions of the same test battery, in order to minimize learning effects. The morning test session took place from 10.00-11.00 h, i.e. about 11 h after ingestion. The afternoon test session was from 14.00-15.00 h. Each task was preceded by a number of practice trials. The task only started after a preset criterion of a certain number of error-free trials had been reached.
4.5
g
-,.4 0
O
4.0
,J u
3,5
¢1 3.0
Medication
o Ila
Subjects were instructed to take the study medication each night 0.5 h before bedtime. The mean ingestion time in the 3 treatment groups was + 23.00 h, and there was no significant difference between treatment groups with respect to ingestion time. Treatment compliance was checked by the analysis of morning uring from each subject on the test days. The results reve ale d that all subjects in the treatment groups had taken the study medication on the preceding night, and placebo treated subj ects appeared not to have taken any benzodiazepines.
Data analysis Pre- and post-treatment scores were analysed by means of a multivariate covariance technique [MANCOVA; Finn 1978]. For the morning and afternoon post-treatment scores, the results of the corresponding pre-treatment morning and afternoon tests were used as covariates. The 4 post-treatment sessions were analysed separately. For the performance tests the IQ score also served as a covariate. MANCOVA analyses were run on clusters of related tests. Both 1 mg lormetazepam and 0.5 mg lormetazepam were tested against placebo.
Results
Associate recognition task Results f r o m the m o r n i n g session after the first t r e a t m e n t night (Session 3) s h o w e d a significant effect of 0.5 m g lorm e t a z e p a m on Associate Recognition, which was im-
4.5
m
4.0
~0
•
3.5
0 o
~a ilJ
m Z
2.5
-I" t Base-line
I 1 treatment
I 8
treatments
Fig.2. Number of correct associations by the 3 treatment groups in the afternoon sessions for the Associate Recognition Task. • Placebo © 0.5 mg lormetazepam • 1 mg lormetazepam paired c o m p a r e d to placebo (P
Residual effects of lormetazepam on mood and performance in healthy elderly volunteers J. B. Deijen, M. L. Heemstra, and J. E Orlebeke Department of Psychology,PsychophysiologyDivision,Free University,Amsterdam,The Netherlands Received: May 19, 1989/Acceptedin revised form:July 11,1990
Summary. 45 subjects aged over 65 years were randomly assigned to treatment with lormetazepam 0.5 mg or 1 mg or placebo. Mood and performance were measured with a battery of computerized tests. Subjects were tested before and after i and 8 nights of treatment. Pre- and post-treatment scores were analysed by a multivariate covariance technique, the pre-treatment score serving as covariate. The single and repeated doses of lormetazepam resulted in impairment of performance in a memory task, and the repeated dose administration impaired performance of a perceptual task. The single administration of a low dose gave an improvement in fine motor control. No change was found in the mood states of the subjects. Key words: Lormetazepam Memory; Geriatric volunteers Residual effects Psychometry, perception, motor control Lormetazepam is a relatively new member of the benzodiazepine series, which has been marketed in The Netherlands since 1981. It is prescribed as a short-acting hypnotic based on its elimination half-life of 10-12 h. A large number of clinical trials and laboratory studies has established its sleep-inducing efficacy and its safety as assessed by physical examination and clinical laboratory tests [Nicholson and Stone 1982; Vogel 1984]. A number of studies has also been carried out to detect residual effects on daytime performance; for instance, a study [Nicholson and Stone 1982] was done to establish the residual effects on sleep, mood and performance of 0.5, 1 and 2 mg lormetazepam administered the previous night, and of i mg lormetazepam administered in the morning. In that study the subjects were young (18-27 y). Administration of 2 mg lormetazepam on the preceding night, resulted in a marked decrement in performance in a visuo-motor task and digit-symbol task. This significant fall in visuo-motor performance was still present 10.5 h after ingestion and in the digit-symbol task after 9.75 h. Immediate effects of administration in the morning of * This studywas supportedby a grant from WyethLaboratoriaB.V.
1 mg lormetazepam were evident until 3.75 h after ingestion. Heidrich et al. [1981] examined the possible residual effects of lormetazepam by subjective assessment. Subjects were healthy male and female chronic insomniacs aged 20-60 y. The treatment group ingested 2 mg lormetazepam for 2 weeks. From the daily measurements of morning freshness, ability to concentrate at work, calmness and tiredness in the evening, it was concluded that lormetazepam caused no residual effects. On the contrary, it appeared that subjects were much fresher in the morning and in the evening and were better able to concentrate at work. Beyond the possible residual side-effect of benzodiazepines, another side-effect sometimes occurs, namely amnesia. Benzodiazepines appear to exert their greatest effect in tests of long-term episodic memory ]Lister 1985], at the stage of long-term acquisition [Brown et al. 1982]. Lormetazepam 0.02 mg/kg i.v. induced anterograde amnesia for a short period [Dorow 1987]. Although much is known about the residual effects of lormetazepam in younger subjects, the possibly more serious residual effects in elderly subjects are uncertain. The present study was undertaken to assess the residual effects of lormetazepam in elderly volunteers. In order to measure sedation and amnesic effects a battery of psychometric tests was used, covering motor control, sensory analysis, central processing (including memory) and mood.
Subjects and methods
Subjects Fifty three volunteers entered the study of whom 45 subjects (35 men, 10 women) were evaluated (subjects dropped out because of poor compliance with the treatment regime or were randomly removed to balance the design).Subjectswere randomlyassignedto one of the 3 treatment groups; 15 subjects received 0.5 mg lormetazepam, 15 received lmg lormetazepam and 15 received a placebo. The mean age of the subjectswas 70 y and their weightwas
J. B. Deijen et al.: Lormetazepanr effects in the aged
268 Table 1. Subjects
mean age (y) mean IQ cups of coffee/day cups of tea/day
0.5 mg lormetazepam
i mg lormetazepam
placebo
71 111 4.1 1.7
70 113 3.2 3.0
70 115 4.3 3.4
between 50 and 80 kg. All subjects were self-reliant inhabitants of Amsterdam and surrounding area, who had responded to a written invitation to take part in the study. Although the groups were not matched, the subjects appeared to be quite comparable with respect to age and IQ. At the first test session subjects reported how many cups of coffee and tea they usually drink each day (Table 1).
Measures o f m o o d and p e r f o r m a n c e The measures were selected from the Neurobehavioral Evaluation System (NES), which is especially recommended for measurement of the behavioral effects of neurotoxic agents [Baker et al. 1985 personal communication]. The treatment effects were measured by means of a battery of tests, including a self-rating scale for mood and sensorimotor tests. The choice of the sensorimotor tests took into account three important functions of the CNS, viz. motor control, sensory analysis and central processing. Profile of mood states (POMS): The POMS is a self-reported mood questionnaire, which yields scores on 5 factor derived scales of fatigue, depression, anger, tension and vigour. Associate learning. Nine pairs of a name and an occupation are presented sequentially on the screen and then the subject is prompted 9 times with one of the names and the 9 alternative occupations. Each time a name is presented, the subject has to choose one of the alternative occupations. Three trials are given in which the subject has to learn as many paired names and occupations as possible. The number of correct responses in each trial is recorded. Continuous performance test: Every second a random letter appears on the screen. If the letter is an "S" the subject must push a reaction time button. Reaction times, omission and commission errors are recorded. Hand-eye coordination task."The subject is asked to use a joystick to trace a large sine wave pattern on the screen. A cursor moves horizontally at a constant rate, while the subject controls only the vertical motion of the cursor with the joystick. Two measures of the vertical distance of the cursor from the sine wave line are recorded. Symbol-digit substitution task: This is a modification of the digitsymbol substitution task in the Wechsler Adult Intelligence Scale [Wechsler 1955]. Nine symbols and 9 digits are paired at the top of the screen and the subject has to press the digit keys corresponding to a test set of the 9 symbols, in a different order than presented. The time required to complete each set of symbols and the number of digits incorrectly matched with the test symbols are recorded. Pattern comparison: Three character arrays are presented side by side. Two of the figures are identical and the third is similar, but with a few minor changes. For each trial the subject has to press the digit key corresponding to the unequal figure. The number of items correctly matched and the response latency for each item are recorded. Digit span: On the computer screen a series of 4 digits is presented, one each second. Afterwards the subject has to press the corresponding digits on the computer keyboard. After correctly responding a series of 5 digits is presented. If the subject responds correctly the series is lengthened to 6, and, in case of correct responses, to a maximum of 9 digits. At each span length a second trial is given if the first response is incorrect. After incorrectly responding to two trials of the same span length the forward procedure is ended.
In addition the subject has to respond to progressive longer series (3 to a maximum of 8) of digits in the reverse order from that presented on the computer screen. The 'backward' test, apart from the reverse response order, is comparable to the forward procedure. The scores recorded are the numbers of digits entered correctly both forward and backward. Memory scanning task."The subject is presented with a series of digits one at a time and must indicate by pushing a button (yes/no) whether the digit comes from a previously presented set of digits. The previously presented memory set can consist of 2, 4 or 5 digits. Recorded are the number of correct responses and the latency of each response for both positive and negative trials. By means of regression techniques the encoding time, motor processing time and memory scanning time can be assessed. Finger tapping." The subject is asked to press a button as many times as possible within a 10-s interval. There are trials with the left hand pressing one button, with the right hand pressing one button, and trials with the preferred hand alternately tapping the two buttons. The number of button presses in each response interval is recorded. Simple reaction time: In this visual reaction time test the subject has to press a button as quickly as possible when a large square appears on the screen. The inter-stimulus interval is varied at random to reduce effects of stimulus anticipation. The individual RT latencies are recorded. Associate recognition: A single trial of the 9 names to be matched with one of the 9 occupations used in the associate learning test is administered at the end of the testing session. A delay of one hour in the associate learning task allows a test for long term memory. The number of correct responses and whether each name was matched correctly or incorrectly are recorded. All the tests for mood and performance were presented on an Olivetti M 24 computer. Intelligence test: A condensed version of the Groninger Intelligence Test was administered by the investigator. Standards are provided for Dutch males and females, from 12 to 76 y.
General procedure All 53 subjects underwent a medical examination and performed the intelligence test. Only those subjects meeting the inclusion criteria and not meeting any of the exclusion criteria were randomly assigned to one of the three treatment groups. The exclusion criteria were: 1) uncooperative or unlikely to adhere to the protocol, 2) IQ less than 80, 3) using benzodiazepines or other hypnotics, major tranquilizers or antidepressants, 4)suffering from myasthenia gravis, acute glaucoma, severe cardiovascular, respiratory, hepatic or renal disorders, and 5) addiction or potential for addiction. If subjects had trouble coming to the laboratory by means of public transport, the psychometric tests were carried out at their homes. Of the 45 evaluable subjects, 4 subjects in each treatment group and 6 subjects in the placebo group were tested at home. As the presentation of the tests is computerized and the system is meant to be used at different locations, it was assumed that testing at home would not influence the results. The procedure was double-blind, i.e. neither investigator nor subject was aware of the type of treatment receiving. Treatment consisted either of 0.5 mg lormetazepam, 1 mg lormetazepam or placebo. Subjects were tested on three separate days. The first test took place before treatment commenced. The first treatment night was 1 week later, followed by the second testing day, and the third testing day was again 1 week later, after the eighth treatment night. On each testing day the subject was tested in the morning and in the afternoon. Thus, Session 1 took place in the morning and Session 2 in the afternoon before treatment commenced. Session 3 took place in the morning and Session 4 in the afternoon after the first treatment night. Session 5 took place in the morning and Session 6 in the afternoon after the eighth treatment night.
J. B. Deijen et al.: Lormetazepam effects in the aged
269
Test procedure
5.0
Subjects were examined individually in a quiet room. If a subject was tested at home, this also took place in a quiet room. The 6 test sessions consisted of 6 different versions of the same test battery, in order to minimize learning effects. The morning test session took place from 10.00-11.00 h, i.e. about 11 h after ingestion. The afternoon test session was from 14.00-15.00 h. Each task was preceded by a number of practice trials. The task only started after a preset criterion of a certain number of error-free trials had been reached.
4.5
g
-,.4 0
O
4.0
,J u
3,5
¢1 3.0
Medication
o Ila
Subjects were instructed to take the study medication each night 0.5 h before bedtime. The mean ingestion time in the 3 treatment groups was + 23.00 h, and there was no significant difference between treatment groups with respect to ingestion time. Treatment compliance was checked by the analysis of morning uring from each subject on the test days. The results reve ale d that all subjects in the treatment groups had taken the study medication on the preceding night, and placebo treated subj ects appeared not to have taken any benzodiazepines.
Data analysis Pre- and post-treatment scores were analysed by means of a multivariate covariance technique [MANCOVA; Finn 1978]. For the morning and afternoon post-treatment scores, the results of the corresponding pre-treatment morning and afternoon tests were used as covariates. The 4 post-treatment sessions were analysed separately. For the performance tests the IQ score also served as a covariate. MANCOVA analyses were run on clusters of related tests. Both 1 mg lormetazepam and 0.5 mg lormetazepam were tested against placebo.
Results
Associate recognition task Results f r o m the m o r n i n g session after the first t r e a t m e n t night (Session 3) s h o w e d a significant effect of 0.5 m g lorm e t a z e p a m on Associate Recognition, which was im-
4.5
m
4.0
~0
•
3.5
0 o
~a ilJ
m Z
2.5
-I" t Base-line
I 1 treatment
I 8
treatments
Fig.2. Number of correct associations by the 3 treatment groups in the afternoon sessions for the Associate Recognition Task. • Placebo © 0.5 mg lormetazepam • 1 mg lormetazepam paired c o m p a r e d to placebo (P
