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The study of sleep effect in the night and the next morning of triazolam and brotizolam on the polysomnography and subjective sleep rating scale
International Congress Series 1232 (2002) 837 – 841
The study of sleep effect in the night and the next morning of triazolam and brotizolam on the polysomnography and subjective sleep rating scale H. Yamadera *, H. Suzuki, Y. Kudo, K. Asayama, T. Ito, S. Endo Department of Neuropsychiatry, Nippon Medical School, Tama Nagayama Hospital, 1-7-1 Nagayama, Tmama, Tokyo 206-8512, Japan
Abstract We studied the sleep effect, the carry over effect (sleepiness) on polysomnography (PSG), the sleep propensity test (SPT), the subjective sleep rating scale for the ultra short acting hypnotics triazolam and short acting hypnotics brotizolam. Ten healthy male volunteers were used for double blind crossover design by randomized allocation with a single oral administration. Informed consent was obtained from all subjects. Placebo (PL), triazolam (TL, 0.125 mg), triazolam (TH, 0.25 mg) and brotizolam (BR, 0.25 mg) were administered at 11 p.m. PSG was recorded from 11 p.m. to 7 a.m. in the next morning. Then, Stanford Sleepiness Scale (SSS) and Kwansei Gakuin Sleepiness Scale (KSS) were checked before 8 a.m., and SPT was recorded at 8:00 – 8:20 a.m. In PSG of total sleep, TH decreased the frequency of stage shifts significantly ( p<0.05) compared to PL. TH and BR increased the percentage of stage 1 combined with stage 2 sleep significantly ( p<0.01) and decreased the percentage of REM sleep significantly ( p<0.01) compared to PL. However, all the drugs had no effect on the percentage of slow wave sleep compared to PL. Although all drugs had no effect on the subjective feeling of sleepiness in SSS and KSS, BR decreased sleep latency significantly ( p<0.05) compared to PL in SPT. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Triazolam; Brotizolam; Carry over effect; PSG; MSLT
1. Introduction We usually use the ultra short acting hypnotics triazolam and short acting hypnotics brotizolam as drugs that cause fast sleep onset and awake in the early morning. However, the half time of these drugs is different. It is well known that generally, hypnotic drugs of *
Corresponding author. Tel.: +81-42-371-2111; fax: +81-42-389-1178. E-mail address: [email protected] (H. Yamadera).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 8 3 0 - 5
838
H. Yamadera et al. / International Congress Series 1232 (2002) 837–841
benzodiazepine caused some side effects—carry over effect, reduction of muscle tension, rebound insomnia, paradoxical reaction, etc. 2. Object We conducted this study to examine the sleep effect and the carry over effect (sleepiness just after awakening in the morning), the effect on polysomnography (PSG), and the subjective sleepiness rating scale for ultra short acting hypnotics triazolam and short acting hypnotics brotizolam. 3. Methods 3.1. Subjects Ten healthy young male volunteers were used. Mean age was 23.8F2.4 years old. We conducted this study under the permission of Nippon Medical School ethical committee. 3.2. Measure items Polysomnography (PSG), Stanford Sleepiness Scale (SSS) [1], Kwansei Gakuin Sleepiness Scale (KSS) [2] and sleep latency test (SLT) were done. SSS and KSS were subjective sleepiness self-rating scales. Sleep stage was classified with Rechtshaffen and Kales criteria [3]. 3.3. Drugs Triazolam (TL, 0.125 mg), triazolam (TH, 0.25 mg), brotizolam (BR, 0.25 mg) and the inactive drug placebo (PL) were administered. Triazolam is an ultra short acting drug (half time; 1.5 –3 h) and brotizolam is a short acting drug (half time; 7 h).
Table 1 PSG (total sleep), n=10, mean (FSD)
SOL (min) NOSS(time) SEI (%) REML (min) Wake (%) REM (%) St (1+2) SWS (%)
Placebo
Triazolam, 0.125 mg
Triazolam, 0.25 mg
Brotizolam, 0.25 mg
24.3 (15.6) 138 (35) 91.5 (4.0) 82.4 (40.3) 4.8 (2.9) 23.4 (3.9) 50.5 (7.8) 22.5 (8.8)
18.8 (8.5) 126 (41) 94.4 (3.2) 93.3 (34.1) 2.9 (2.4) 19.9 (3.7) 55.9 (6.4) 22.5 (7.3)
23.7 (21.3) 120 (30)* 93.2 (4.1) 122.4 (40.9) 2.9 (1.9) 18.7 (2.6)** 57.2 (5.8)** 22.2 (6.1)
24.9 (14.2) 130 (36) 93.1 (3.2) 104.3 (46.7) 3.5 (1.9) 20.0 (3.3)** 55.5 (6.9)** 22.4 (7.0)
SOL: sleep onset latency, NOSS: number of stage shift, SEI: sleep efficiency index, REML: REM latency, St (1+2); stage 1 combined with stage 2, SWS: slow wave sleep paired t-test. * p<0.05 (vs. placebo). ** p<0.01 (vs. placebo).
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Table 2 PSG parameters divided into three duration of the total sleep, n=10, mean (FSD) Placebo
Triazolam, 0.125 mg
Triazolam, 0.25 mg
Brotizolam, 0.25 mg
3.5 10.5 44.4 41.6
(2.2) (5.7) (9.6) (10.9)
1.6 4.4 44.9 9.1
(1.8)* (2.7)* (11.2) (11.5)*
2.2 4.3 45.6 47.9
3.7 6.0 46.7 43.5
(3.9) (4.2)* (12.5) (15.5)
The second 1/3 Wake (%) 4.9 (5.5) REM (%) 28.7 (7.3) St (1+2) 51.7 (15.4) SWS (%) 14.8 (11.7)
3.4 26.0 62.2 8.5
(3.1) (7.9) (9.3) (9.5)*
3.3 (2.8) 20.5 (5.9)* 64.9 (12.3)* 11.3 (10.6)
2.9 25.7 56.7 14.7
(3.0) (5.8) (11.7) (11.5)
The third 1/3 Wake (%) REM (%) St (1+2) SWS (%)
4.7 26.9 60.6 7.3
(4.6) (10.8) (10.0) (9.1)
3.1 31.5 58.1 7.3
3.8 28.5 59.1 8.8
(2.8) (6.3) (9.5)* (9.7)
The first 1/3 Wake (%) REM (%) St (1+2) SWS (%)
5.2 (3.5) 31.2 (9.6) 52.3 (13.3) 11.3 (11.5)
(1.9) (4.5)* (13.1) (14.8)
(2.2) (9.2) (12.4) (9.1)*
St (1+2): stage 1 combined with stage 2, SWS: slow wave sleep paired t-test. * p<0.05 (vs. placebo).
3.4. Study schedule This study consists of four sessions. In the first session, we recorded three PSG nights consecutively and SSS and KSS were checked before 8 a.m., then SLT was recorded from 8:00 to 8:20 a.m. after the second and the third PSG night. In the 2nd, 3rd and 4th sessions, we recorded two PSG nights and the next morning we conducted the same procedure, as mentioned. PSG was recorded from 11 p.m to 7 a.m. in the next morning. SLT is a modified Multiple Sleepiness Latency Test (MSLT) [4], recording the resting EEG for 20 min. The drugs were administered with double blind trial using randomized allocation by single oral administration at 11 p.m. in the third night (the 1st session) and the second night (the 2nd, 3rd and 4th session).
4. Results Table 1 shows the changes of PSG parameters of total sleep, TH decreased significantly the number of stage shift ( p<0.05), the percentage of REM sleep ( p<0.001) and increased the percentage of stage 1 combined with stage 2 ( p<0.001) compared to the PL administration. BR decreased significantly the percentage of REM sleep ( p<0.001) and increased the percentage of stage 1 combined with stage 2 ( p<0.001) compared to the PL administration. We divided the total sleep into three durations to observe the more detailed changes of PSG parameters. Table 2 shows the changes of PSG parameters of three divided sleep durations. TL decreased significantly the percentage of wake ( p<0.05) and the percentage
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H. Yamadera et al. / International Congress Series 1232 (2002) 837–841
Table 3 The result of SLT, SSS, KSS, n=10, mean (FSD)
SLT SSS KSS
Placebo
Triazolam, 0.125 mg
Triazolam, 0.25 mg
Brotizolam, 0.25 mg
13.8 (5.9) 3.3 (0.7) 3.8 (2.6)
10.6 (4.1) 3.4 (1.0) 4.0 (0.6)
10.1 (5.7) 2.8 (1.0) 3.4 (1.0)
7.1 (5.5)* 3.0 (1.2) 3.9 (1.2)
SLT: sleep latency test, SSS: Stanford Sleep Latency Test, KSS: Kwansei Gakuin Sleepiness Scale. * p<0.05 paired t-test (vs. placebo).
of REM sleep ( p<0.05) at the first 1/3 duration and the percentage of slow wave sleep ( p<0.05) at the first and the second 1/3 duration. TH decreased statistically significantly the percentage of REM sleep ( p<0.05) at the first 1/3 duration, decreased the percentage of REM sleep ( p<0.05) and increased the percentage of stage 1 combined with stage 2 ( p<0.05) at the second 1/3 duration, and decreased the percentage of slow wave sleep ( p<0.05) at the third 1/3 duration. BR decreased the percentage of REM sleep ( p<0.05) at the first 1/3 duration and increased the percentage of stage 1 combined with stage 2 ( p<0.05) at the third 1/3 duration. Table 3 shows the result of SLT, SSS and KSS in the morning. BR decreased sleep latency time significantly ( p<0.05) compared to the PL administration. There was no statistical significance in SSS and KSS.
5. Discussion 5.1. The effect on PSG of TL, TH and BR This study suggested that TL almost had no effect on PSG of total sleep. TH and BR increased the percentage of stage 1 combined with stage 2, and decreased the percentage of REM sleep. These findings of TL, TH and BR were supported by other papers [5 –9]. Also in this study, the decrease of slow wave sleep, which is usually seen in benzodiazepines, was not obtained. It seemed to be a good result. We divided a PSG into three durations and analyzed the sleep parameters to observe the drug effect with time course. Most of the changes were seen at the first 1/3 and second 1/3 durations. Interestingly, TL increased the percentage of slow wave sleep at the first 1/3 and the second 1/3 duration. However, in the total PSG, TL did not increase the percentage of slow wave sleep. The reason for this finding might be due to the decrease in the percentage of slow wave sleep at the third 1/3 duration. The effect seen in the first 1/3 and the second 1/3 duration mainly seemed to be caused by the short half time of TL, TH and BR. 5.2. The effect on sleepiness in the morning of TL, TH and BR Although Thorphy [10] evaluated the validity of SSS, he reported that sleepiness was not always realized and self-evaluation of sleepiness contained some problems. Utumi et al. [11] reported that the clinical psychopharmacological utility of SSS was lower than MSLT in the study of zolpidem and nitrazepam.
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Parino et al. [9] reviewed the previous literatures and noted that there were no reports in which triazolam showed the carry over effects. On the other hand, Ogura et al. [5] reported that triazolam prolonged the sleepiness in the afternoon but not in the morning compared with the placebo administration. Mamelak et al. [12] reported that brotizolam showed the carry over effect in the 1st day after administration in the comparison study with flurazepam. Our study supported these findings. Generally, the carry over effect was considered to be less in the short half time drug. Therefore, our study’s result seemed to be caused by the difference of the half time between triazolam (1.5 –3 h) and brotizolam (7 h). However, Enomoto et al. [13] reported that no drug showed any changes of MSLT in the comparison study of ultra short acting hypnotics triazolam, zolpidem and intermediate acting hypnotics nitrazepam. Therefore, it might be that MSLT did not always show the carry over effect due to the difference of half time. Furthermore, we have to clarify the carry over effect in the morning of ultra short acting hypnotics and short acting hypnotics in future studies. References [1] E. Hoddes, V. Zarcone, H. Smythe, R. Phillips, W.C. Dement, Quantification of sleepiness: a new approach, Psychophysiology 10 (1973) 431 – 436. [2] K. Ishihara, A. Miyashita, M. Inugami, Sleep rating scale and its experimental discussion, Shinrigaku Kenkyu 52 (1982) 362 – 365 (In Japanese). [3] A. Rechtshaffen, A. Kales, A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stage of Human Subjects, Public Health Services, UCLA Brain Information Service Institute, Los Angeles, 1968. [4] M.A. Carkadon, Guideline for the Multiple Latency Test (MSLT): a standard measure of sleepiness, Sleep 9 (1986) 519 – 524. [5] C. Ogura, K. Nakazawa, K. Majima, K. Nakamura, H. Ueda, Y. Umezawa, W.M. Wardell, Residual effects of hypnotics: triazolam, flurazepam, and nitrazepam, Psychopharmacology 68 (1980) 61 – 65. [6] A.N. Nicholson, B.M. Stone, P.A. Pascoe, Studies on sleep and performance with a triazololo-1,4-thienodiazepine(brotizolam), Br. J. Pharmacol. 10 (1980) 75 – 81. [7] T. Okawa, Y. Nakazawa, T. Kotorii, H. Sakurada, K. Nonaka, K. Tainoson, T. Sakamoto, H. Oshima, H. Matunaga, The effect of brotizolam, a thionotriazolodiazepine, derivative, on sleep of normal healthy subjects—investigation using polysomnography, Rinsho Seishinigaku 13 (1984) 749 – 760 (Japanese with English abstract). [8] O. Kanno, H. Watanabe, K. Nakagome, I. Ichikawa, R. Iyo, T. Suzuki, H. Kazamaturi, Effects of zolpidem and triazolam on sleep and daytime activities in normal young volunteers—a polysomnographic study, Shinkei Seishin Yakuri 16 (1994) 45 – 56 (In Japanese). [9] L. Parino, M.G. Terzano, Polysomnographic effects of hypnotic drugs a review, Psychopharmacology 126 (1996) 1 – 16. [10] M.J. Thorphy, Report from the American sleep disorder association. The clinical use of the multiple sleep latency test, Sleep 15 (1992) 268 – 276. [11] M. Utumi, T. Sugiyama, M. Suzuki, M. Murasaki, Effects of a single dose of zolpidem, triazolam and nitrazepam on daytime sleepiness, Shinkei Seishin Yakuri 16 (1994) 45 – 56 (in Japanese with English abstract). [12] M. Mamelak, A. Csima, L. Buck, V. Price, A comparative study on the effects of brotizolam and flurazepam on sleep and performance in elderly, J. Clin. Psychopharmacol. 9 (1989) 260 – 267. [13] T. Enomoto, J. Urata, M. Uchiyama, S. Shirakawa, M. Iyo, The time course of effects of triazolam on both event-related (ERP) and subjective mental and emotional state, Nouha to Kindenzu 22 (1994) 30 – 37 (In Japanese with English abstract).
The study of sleep effect in the night and the next morning of triazolam and brotizolam on the polysomnography and subjective sleep rating scale H. Yamadera *, H. Suzuki, Y. Kudo, K. Asayama, T. Ito, S. Endo Department of Neuropsychiatry, Nippon Medical School, Tama Nagayama Hospital, 1-7-1 Nagayama, Tmama, Tokyo 206-8512, Japan
Abstract We studied the sleep effect, the carry over effect (sleepiness) on polysomnography (PSG), the sleep propensity test (SPT), the subjective sleep rating scale for the ultra short acting hypnotics triazolam and short acting hypnotics brotizolam. Ten healthy male volunteers were used for double blind crossover design by randomized allocation with a single oral administration. Informed consent was obtained from all subjects. Placebo (PL), triazolam (TL, 0.125 mg), triazolam (TH, 0.25 mg) and brotizolam (BR, 0.25 mg) were administered at 11 p.m. PSG was recorded from 11 p.m. to 7 a.m. in the next morning. Then, Stanford Sleepiness Scale (SSS) and Kwansei Gakuin Sleepiness Scale (KSS) were checked before 8 a.m., and SPT was recorded at 8:00 – 8:20 a.m. In PSG of total sleep, TH decreased the frequency of stage shifts significantly ( p<0.05) compared to PL. TH and BR increased the percentage of stage 1 combined with stage 2 sleep significantly ( p<0.01) and decreased the percentage of REM sleep significantly ( p<0.01) compared to PL. However, all the drugs had no effect on the percentage of slow wave sleep compared to PL. Although all drugs had no effect on the subjective feeling of sleepiness in SSS and KSS, BR decreased sleep latency significantly ( p<0.05) compared to PL in SPT. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Triazolam; Brotizolam; Carry over effect; PSG; MSLT
1. Introduction We usually use the ultra short acting hypnotics triazolam and short acting hypnotics brotizolam as drugs that cause fast sleep onset and awake in the early morning. However, the half time of these drugs is different. It is well known that generally, hypnotic drugs of *
Corresponding author. Tel.: +81-42-371-2111; fax: +81-42-389-1178. E-mail address: [email protected] (H. Yamadera).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 8 3 0 - 5
838
H. Yamadera et al. / International Congress Series 1232 (2002) 837–841
benzodiazepine caused some side effects—carry over effect, reduction of muscle tension, rebound insomnia, paradoxical reaction, etc. 2. Object We conducted this study to examine the sleep effect and the carry over effect (sleepiness just after awakening in the morning), the effect on polysomnography (PSG), and the subjective sleepiness rating scale for ultra short acting hypnotics triazolam and short acting hypnotics brotizolam. 3. Methods 3.1. Subjects Ten healthy young male volunteers were used. Mean age was 23.8F2.4 years old. We conducted this study under the permission of Nippon Medical School ethical committee. 3.2. Measure items Polysomnography (PSG), Stanford Sleepiness Scale (SSS) [1], Kwansei Gakuin Sleepiness Scale (KSS) [2] and sleep latency test (SLT) were done. SSS and KSS were subjective sleepiness self-rating scales. Sleep stage was classified with Rechtshaffen and Kales criteria [3]. 3.3. Drugs Triazolam (TL, 0.125 mg), triazolam (TH, 0.25 mg), brotizolam (BR, 0.25 mg) and the inactive drug placebo (PL) were administered. Triazolam is an ultra short acting drug (half time; 1.5 –3 h) and brotizolam is a short acting drug (half time; 7 h).
Table 1 PSG (total sleep), n=10, mean (FSD)
SOL (min) NOSS(time) SEI (%) REML (min) Wake (%) REM (%) St (1+2) SWS (%)
Placebo
Triazolam, 0.125 mg
Triazolam, 0.25 mg
Brotizolam, 0.25 mg
24.3 (15.6) 138 (35) 91.5 (4.0) 82.4 (40.3) 4.8 (2.9) 23.4 (3.9) 50.5 (7.8) 22.5 (8.8)
18.8 (8.5) 126 (41) 94.4 (3.2) 93.3 (34.1) 2.9 (2.4) 19.9 (3.7) 55.9 (6.4) 22.5 (7.3)
23.7 (21.3) 120 (30)* 93.2 (4.1) 122.4 (40.9) 2.9 (1.9) 18.7 (2.6)** 57.2 (5.8)** 22.2 (6.1)
24.9 (14.2) 130 (36) 93.1 (3.2) 104.3 (46.7) 3.5 (1.9) 20.0 (3.3)** 55.5 (6.9)** 22.4 (7.0)
SOL: sleep onset latency, NOSS: number of stage shift, SEI: sleep efficiency index, REML: REM latency, St (1+2); stage 1 combined with stage 2, SWS: slow wave sleep paired t-test. * p<0.05 (vs. placebo). ** p<0.01 (vs. placebo).
H. Yamadera et al. / International Congress Series 1232 (2002) 837–841
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Table 2 PSG parameters divided into three duration of the total sleep, n=10, mean (FSD) Placebo
Triazolam, 0.125 mg
Triazolam, 0.25 mg
Brotizolam, 0.25 mg
3.5 10.5 44.4 41.6
(2.2) (5.7) (9.6) (10.9)
1.6 4.4 44.9 9.1
(1.8)* (2.7)* (11.2) (11.5)*
2.2 4.3 45.6 47.9
3.7 6.0 46.7 43.5
(3.9) (4.2)* (12.5) (15.5)
The second 1/3 Wake (%) 4.9 (5.5) REM (%) 28.7 (7.3) St (1+2) 51.7 (15.4) SWS (%) 14.8 (11.7)
3.4 26.0 62.2 8.5
(3.1) (7.9) (9.3) (9.5)*
3.3 (2.8) 20.5 (5.9)* 64.9 (12.3)* 11.3 (10.6)
2.9 25.7 56.7 14.7
(3.0) (5.8) (11.7) (11.5)
The third 1/3 Wake (%) REM (%) St (1+2) SWS (%)
4.7 26.9 60.6 7.3
(4.6) (10.8) (10.0) (9.1)
3.1 31.5 58.1 7.3
3.8 28.5 59.1 8.8
(2.8) (6.3) (9.5)* (9.7)
The first 1/3 Wake (%) REM (%) St (1+2) SWS (%)
5.2 (3.5) 31.2 (9.6) 52.3 (13.3) 11.3 (11.5)
(1.9) (4.5)* (13.1) (14.8)
(2.2) (9.2) (12.4) (9.1)*
St (1+2): stage 1 combined with stage 2, SWS: slow wave sleep paired t-test. * p<0.05 (vs. placebo).
3.4. Study schedule This study consists of four sessions. In the first session, we recorded three PSG nights consecutively and SSS and KSS were checked before 8 a.m., then SLT was recorded from 8:00 to 8:20 a.m. after the second and the third PSG night. In the 2nd, 3rd and 4th sessions, we recorded two PSG nights and the next morning we conducted the same procedure, as mentioned. PSG was recorded from 11 p.m to 7 a.m. in the next morning. SLT is a modified Multiple Sleepiness Latency Test (MSLT) [4], recording the resting EEG for 20 min. The drugs were administered with double blind trial using randomized allocation by single oral administration at 11 p.m. in the third night (the 1st session) and the second night (the 2nd, 3rd and 4th session).
4. Results Table 1 shows the changes of PSG parameters of total sleep, TH decreased significantly the number of stage shift ( p<0.05), the percentage of REM sleep ( p<0.001) and increased the percentage of stage 1 combined with stage 2 ( p<0.001) compared to the PL administration. BR decreased significantly the percentage of REM sleep ( p<0.001) and increased the percentage of stage 1 combined with stage 2 ( p<0.001) compared to the PL administration. We divided the total sleep into three durations to observe the more detailed changes of PSG parameters. Table 2 shows the changes of PSG parameters of three divided sleep durations. TL decreased significantly the percentage of wake ( p<0.05) and the percentage
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H. Yamadera et al. / International Congress Series 1232 (2002) 837–841
Table 3 The result of SLT, SSS, KSS, n=10, mean (FSD)
SLT SSS KSS
Placebo
Triazolam, 0.125 mg
Triazolam, 0.25 mg
Brotizolam, 0.25 mg
13.8 (5.9) 3.3 (0.7) 3.8 (2.6)
10.6 (4.1) 3.4 (1.0) 4.0 (0.6)
10.1 (5.7) 2.8 (1.0) 3.4 (1.0)
7.1 (5.5)* 3.0 (1.2) 3.9 (1.2)
SLT: sleep latency test, SSS: Stanford Sleep Latency Test, KSS: Kwansei Gakuin Sleepiness Scale. * p<0.05 paired t-test (vs. placebo).
of REM sleep ( p<0.05) at the first 1/3 duration and the percentage of slow wave sleep ( p<0.05) at the first and the second 1/3 duration. TH decreased statistically significantly the percentage of REM sleep ( p<0.05) at the first 1/3 duration, decreased the percentage of REM sleep ( p<0.05) and increased the percentage of stage 1 combined with stage 2 ( p<0.05) at the second 1/3 duration, and decreased the percentage of slow wave sleep ( p<0.05) at the third 1/3 duration. BR decreased the percentage of REM sleep ( p<0.05) at the first 1/3 duration and increased the percentage of stage 1 combined with stage 2 ( p<0.05) at the third 1/3 duration. Table 3 shows the result of SLT, SSS and KSS in the morning. BR decreased sleep latency time significantly ( p<0.05) compared to the PL administration. There was no statistical significance in SSS and KSS.
5. Discussion 5.1. The effect on PSG of TL, TH and BR This study suggested that TL almost had no effect on PSG of total sleep. TH and BR increased the percentage of stage 1 combined with stage 2, and decreased the percentage of REM sleep. These findings of TL, TH and BR were supported by other papers [5 –9]. Also in this study, the decrease of slow wave sleep, which is usually seen in benzodiazepines, was not obtained. It seemed to be a good result. We divided a PSG into three durations and analyzed the sleep parameters to observe the drug effect with time course. Most of the changes were seen at the first 1/3 and second 1/3 durations. Interestingly, TL increased the percentage of slow wave sleep at the first 1/3 and the second 1/3 duration. However, in the total PSG, TL did not increase the percentage of slow wave sleep. The reason for this finding might be due to the decrease in the percentage of slow wave sleep at the third 1/3 duration. The effect seen in the first 1/3 and the second 1/3 duration mainly seemed to be caused by the short half time of TL, TH and BR. 5.2. The effect on sleepiness in the morning of TL, TH and BR Although Thorphy [10] evaluated the validity of SSS, he reported that sleepiness was not always realized and self-evaluation of sleepiness contained some problems. Utumi et al. [11] reported that the clinical psychopharmacological utility of SSS was lower than MSLT in the study of zolpidem and nitrazepam.
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Parino et al. [9] reviewed the previous literatures and noted that there were no reports in which triazolam showed the carry over effects. On the other hand, Ogura et al. [5] reported that triazolam prolonged the sleepiness in the afternoon but not in the morning compared with the placebo administration. Mamelak et al. [12] reported that brotizolam showed the carry over effect in the 1st day after administration in the comparison study with flurazepam. Our study supported these findings. Generally, the carry over effect was considered to be less in the short half time drug. Therefore, our study’s result seemed to be caused by the difference of the half time between triazolam (1.5 –3 h) and brotizolam (7 h). However, Enomoto et al. [13] reported that no drug showed any changes of MSLT in the comparison study of ultra short acting hypnotics triazolam, zolpidem and intermediate acting hypnotics nitrazepam. Therefore, it might be that MSLT did not always show the carry over effect due to the difference of half time. Furthermore, we have to clarify the carry over effect in the morning of ultra short acting hypnotics and short acting hypnotics in future studies. References [1] E. Hoddes, V. Zarcone, H. Smythe, R. Phillips, W.C. Dement, Quantification of sleepiness: a new approach, Psychophysiology 10 (1973) 431 – 436. [2] K. Ishihara, A. Miyashita, M. Inugami, Sleep rating scale and its experimental discussion, Shinrigaku Kenkyu 52 (1982) 362 – 365 (In Japanese). [3] A. Rechtshaffen, A. Kales, A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stage of Human Subjects, Public Health Services, UCLA Brain Information Service Institute, Los Angeles, 1968. [4] M.A. Carkadon, Guideline for the Multiple Latency Test (MSLT): a standard measure of sleepiness, Sleep 9 (1986) 519 – 524. [5] C. Ogura, K. Nakazawa, K. Majima, K. Nakamura, H. Ueda, Y. Umezawa, W.M. Wardell, Residual effects of hypnotics: triazolam, flurazepam, and nitrazepam, Psychopharmacology 68 (1980) 61 – 65. [6] A.N. Nicholson, B.M. Stone, P.A. Pascoe, Studies on sleep and performance with a triazololo-1,4-thienodiazepine(brotizolam), Br. J. Pharmacol. 10 (1980) 75 – 81. [7] T. Okawa, Y. Nakazawa, T. Kotorii, H. Sakurada, K. Nonaka, K. Tainoson, T. Sakamoto, H. Oshima, H. Matunaga, The effect of brotizolam, a thionotriazolodiazepine, derivative, on sleep of normal healthy subjects—investigation using polysomnography, Rinsho Seishinigaku 13 (1984) 749 – 760 (Japanese with English abstract). [8] O. Kanno, H. Watanabe, K. Nakagome, I. Ichikawa, R. Iyo, T. Suzuki, H. Kazamaturi, Effects of zolpidem and triazolam on sleep and daytime activities in normal young volunteers—a polysomnographic study, Shinkei Seishin Yakuri 16 (1994) 45 – 56 (In Japanese). [9] L. Parino, M.G. Terzano, Polysomnographic effects of hypnotic drugs a review, Psychopharmacology 126 (1996) 1 – 16. [10] M.J. Thorphy, Report from the American sleep disorder association. The clinical use of the multiple sleep latency test, Sleep 15 (1992) 268 – 276. [11] M. Utumi, T. Sugiyama, M. Suzuki, M. Murasaki, Effects of a single dose of zolpidem, triazolam and nitrazepam on daytime sleepiness, Shinkei Seishin Yakuri 16 (1994) 45 – 56 (in Japanese with English abstract). [12] M. Mamelak, A. Csima, L. Buck, V. Price, A comparative study on the effects of brotizolam and flurazepam on sleep and performance in elderly, J. Clin. Psychopharmacol. 9 (1989) 260 – 267. [13] T. Enomoto, J. Urata, M. Uchiyama, S. Shirakawa, M. Iyo, The time course of effects of triazolam on both event-related (ERP) and subjective mental and emotional state, Nouha to Kindenzu 22 (1994) 30 – 37 (In Japanese with English abstract).