Sleep, 15(3):252-256 © 1992 American Sleep Disorders Association and Sleep Research Society
Biperiden Administration I)uring REM Sleep Deprivation Diminished the Frequency of REM Sle1ep Attempts
*Sleep Disorders Center, Henry Ford Hospital, Detroit, Michigan, U.S.A.; and tPsychobiological Department, Mexican Psychiatric Institute, Mexico City, Mexico
Summary: Sixteen subjects were assigned to a group using either placebo or biperiden, with eight subjects in each group. Both groups were studied for one acclimatization night, one baseline night, four nights of rapid eye movement (REM) sleep deprivation and two recovery nights. All the subjects received either placebo or 4 mg biperiden I hour before sleep during the four nights of REM sleep deprivation. During the baseline and the recovery nights both groups received placebo capsules. The results showed that REM sleep time during thl~ REM sleep deprivation was reduced by 70-75% below the baseline night in both groups. The number of attempts to enter REM sleep was significantly reduced by biperiden as compared to placebo for each of the four REM sleep deprivation nights. Because the total sleep time in the biperiden group was reduced, the number of REM sleep attempts was corrected by the total sleep time. The adjusted number of REM sleep attempts was also significantly reduced in the biperiden group. REM sleep latency showed a reduction in the placebo group, whereas in the biperiden group REM sleep latency was unchanged throughout the deprivation nights. In the recovery night REM sleep time was increased in both groups, with no differences between the groups. The REM sleep latency showed a reduction in the first recovery night in both groups that persisted through the second recovery night. The above findings support the role of biperiden as a REM sleep suppressive drug. Key Words: Muscarinic receptors-REM sleep deprivation-Biperiden-Human subjects.
It has been proposed that Ml and M2 muscarinic receptors as well as nicotinic receptors are involved in the regulatory process of rapid eye movement (REM) sleep based on studies in cats (1-3) and humans (4,5). Biperiden is an anticholinergic drug with preference for Ml muscarinic receptors (6). Biperiden administration in healthy normal humans increased REM sleep latency at 4- and 6-mg doses and biperiden 6 mg reduced REM sleep time (7). In the same study, after six nights of REM sleep deprivation two groups of normal subjects received either placebo or biperiden (4 mg) on the first recovery night. The REM sleep time in the group that received placebo was increased during the recovery night, whereas the group that received biperi-
Accepted for publication November 1991. Address correspondence and reprint requests to Rafael J. SalinPascual, M.D., D.MSc., U.e.S.D. Psychiatry Dept. and San Di(:go VA Medical Center-Psychiatry SVC (116 A), 3350 La Iolla Vi11age Dr., San Diego, California 92161, U.S.A.
den did not show a significant increase in REM sleep. It was not until the follow-up night (with no active
drug administration) that REM sleep increased in the biperiden group. Another group has recently reported a dose-dependent inhibition of REM sleep in normal volunteers by biperiden; they used 2-, 4-, and 8-mg doses of biperiden and found a significant reduction even with a 4-mg dose (8). The fact that biperiden modified REM sleep both on baseline and during recovery nights from REM sleep deprivation suggests that Ml receptors are involved in REM sleep mechanisms in humans. The fact that a lower biperiden dose altered REM sleep more during deprivation recovery than on baseline nights might be explained as follows. Normally, acetylcholine is released during REM sleep as shown in the cat (9). REM sleep deprivation could modify the release of acetylcholine and change muscarinic receptor sensitivity, thereby producing the increased response to a low dose ofbiperiden and reduced REM sleep rebound. In sup-
252
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*tRafael1. Salin-Pascual, tDaniel Grandos-Fuentes, tLourdes Galicia-Polo, tEstela Nieves, *Timothy A. Roehrs and *Thomas Roth
BIPERIDEN AND REM SLEEP
tinuous minutes of sleep after lights out. Awake time was defined as the minutes awake after sleep onset. REM sleep latency was defined as the time from sleep onset to the completion of two epochs of REM sleep (1 minute) (including intermittent awakenings). A REM sleep attempt was defined as one epoch of continuous REM sleep. Overall two-way ANOYAs, using group as one variable (placebo group vs. biperiden group) and night as the second variable, were performed. Post-hoc Students' t tests for repeated measures with a correction to maintain the alpha level of significance at p < 0.05 (Bonferroni's correction) were performed when indicated. RESULTS
Results of the overall two-way ANOYAs and posthoc tests are presented in Table 1. The means and standard deviations of baseline and deprivation nights and baseline and recovery nights are presented in Tables 2 and 3, respectively. REM sleep time on deprivation nights was reduced in both groups by 70-75% below baseline, with no METHODS differences between placebo or biperiden groups. DurSixteen healthy volunteers were studied [aged: 25.2 ing the recovery nights, this variable was increased ± 2.8 years (mean ± SD)]. All the subjects were between 28 to 30% without differences between the screened by the Diagnostic Interview Schedule in a groups (ANOYA-group effects: F = 0.43, df= 1,14, reliable Spanish version (11). They had no history of p = 0.51; night effects: F = 140.4, df = 6,79, p < psychiatric disorder, sleep disturbances or serious ill- 0.00001; interactions: F= 0.255, df= 6,79, p = 0.95). ness. The subjects were nonsmokers and had,no history REM sleep latency on deprivation nights was reof alcohol or other drug abuse. duced in the placebo group (vs. baseline), whereas in The subjects were randomly assigned to one of two the biperiden group it was increased (a trend indicated groups: placebo or biperiden, with eight subjects per by the interaction, p < 0.10). During recovery nights, group. Each volunteer slept in the laboratory on one a reduction in this variable was observed in both groups, acclimatization night, one baseline night, four REM with no differences between them (ANOYA-group sleep deprivation nights and two recovery nights. All effects: F = 5.83, df= 1,14, p < 0.01; night effects: F the subjects received identical capsules with either pla- = 3.56, df = 6,79, p < 0.003; interactions: F = 1.8, df cebo or 4 mg biperiden (two commercial tablets of 2 = 6,79, p < 0.10). mg Akineton, Knoll), 1 hour before sleep during the The number of REM sleep attempts on REM sleep four nights of REM sleep deprivation. During the base- deprivation nights was significantly increased in both line and recovery nights, both groups received placebo groups. But there was a reduced number of attempts capsules. For the four nights of REM sleep deprivation in the biperiden group in comparison with the other the volunteers were immediately awakened on every group (ANOYA-group effects: F = 27.7, df = 1,14, occasion when they showed polysomnographic evi- p < 0.00001; night effects: F= 25.19, df= 6,79, p < dence of REM sleep (one epoch) by technicians who 0.00001; interactions: F = 4.4, df = 6,79, p < 0.001). did not know the treatment that the volunteers were Because the total sleep time was significantly reduced receiving. The sleep recordings started at 2200 hours in the biperiden group (ANOYA-group effects: F = and ran until 0600 hours. They were scored visually 13.03, df= 1,14, p < 0.00001; night effects: F = 27.7, according to standardized criteria (12) by one of us df = 6,79, p < 0.00001; interactions: F = 2.58, df = who was not informed of the experimental procedure 6,79, p < 0.02), the number of REM sleep attempts for each group. The subjects were not allowed to nap was corrected for the total sleep time differences (by during the day and were reminded of this restriction an index: number of REM sleep attempts/total sleep time). The resulting index was also significantly reeach morning. Sleep onset was defined as the first epoch of 8 con- duced in the biperiden group. Sleep, Vol. 15, No.3, 1992
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port of the above idea, it has been reported (10) in human volunteers that physostigmine (an indirect cholinomimetic drug) infusion after four nights of REM sleep deprivation modifies the typical REM sleep recovery. If the above is the case, the question arises as to whether the combination of REM sleep deprivation and biperiden administration might further reduce cholinergic activity by both suppressing acetylcholine release and blocking receptors, thereby leading to a lessened pressure for REM sleep during deprivation. The present study was developed to examine in normal volunteers the effects of biperiden when administered simultaneously with REM sleep deprivation. We were interested in biperiden effects during REM sleep deprivation and in the recovery period when REM sleep rebound typically occurs. The main hypotheses were that if biperiden blocks M 1 receptors and if they are involved in REM sleep, then biperiden should reduce the number of REM sleep attempts during REM sleep deprivation, and the drug also should produce a differential REM sleep rebound in comparison with the placebo group.
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R. J. SALIN·PASCUAL ET AL.
254 TABLE 1.
Overall two-way ANOVAs and post-hoc comparisonS"
Overall comparison
Baseline vs. deprived
Baseline vs. recovery
REM sleep A) B) C) REM sleep latency A) B) C)
p = 0.51 p < 0.00001 p = 0.95
P: Bsl > Depr (1-4) B: Bsl > Depr (1-4)
P: Bsl < Rec (1-2) B: Bsl < Rec (l-2)
F= 5.83 F= 3.56 F= 1.80
p < 0.01 p < 0.003 p = 0.1
P: Bsl = Depr (1-4) B: Bsl = Depr (1-4) Placebo < biperiden
P: Bsl > Rec (l-2) B: Bsl > Rec (1-2) Placebo = Biperiden
p < 0.00001 p < 0.00001 p < 0.00001
P: Bsl < Depr (1-4) B: Bsl < Depr (1-4) Placebo> biperiden
P: Bsl = Rec (1-2) B: Bsl = Rec (1-2) Placebo = Biperiden
REM sleep attempts A) F= 27.7 B) F= 25.2 C) F= 4.4 Stage I A) B) C)
F= 0.04 F= 14.81 F= 0.50
P = 0.815 P < 0.00001 p = 0.802
P: Bsl < Depr (1-4) B: Bsl < Depr (1-4)
P: Bsl = Rec (1-2) B: Bsl = Rec (1-2)
A) B) C)
F= 9.29 F= 1.83 F= 0.57
p < 0.003 p = 0.1 p = 0.75
Placebo> biperiden
Placebo> biperiden
F = 1.96 F= 1.6 F = 1.53
p = 0.16 p = 0.15 p = 0.17
F= 13.03 = 27.7 = 2.5
p < 0.0001 P < 0.00001 p < 0.02
P: Bsl > Depr (1,3,4) B: Bsl > Depr (2-4) Placebo> biperiden
P: Bsl = Rec (1-2) B: Bsl = Rec (1-2) Placebo = biperiden
Stage II
Delta sleep A) B) C) Total sleep time A) B) C)
F F
a Two-way ANOV As: A = group effects (df = 1,14); B = night effects (df = 6,79); C = interactions (df = 6,79). Numbers between parentheses are p < 0.05 vs. baseline on Students' t test with Bonferroni corrections (comparisons of each night to baseline). P = placebo group; B = biperiden group; Depr = deprivation nights; Rec = recovery nights.
TABLE 2.
Sleep variables during REM sleep deprivation a
Baseline
First
Second
Third
Fourth
111.4 (25.3) 116.0 (18.7)
27.9 (13.2) 32.6 (13.5)
29.1 (11.9) 39.22 (15.8)
40.4 (21.9) 39.6 (6.3)
36.3 (16.5) 33.1 (6.8)
87.7(29.4) 94.4 (34.6)
84.5 (31.1) 120.3 (45.4)
59.8 (14.3) 115.7 (38.6)
85.8 (33.6) 106.9 (81.1)
63.8 (15.6) 92.9 (62.4)
REM sleep attempts 4.1 (1.1) PIa Bip 4.8 (0.8)
15.2 (6.5) 8.2 (4.7)
18.5 (26.1) 8.8 (2.7)
15.5 (6.7) 12.0 (3.4)
17.6 (4.1) 10.5 (3.7)
Stage I PIa Bip
14.6 (17.1) 17.9 (12.5)
35.2 (11.9) 4J.l (23.4)
34.7 (13.6) 41.1 (14.1)
35.2 (11.4) 33.5 (11.6)
42.7(24.9) 38.0 (13.9)
Stage II Pia Bip
201.2 (39.1) 205.1 (35.4)
193.4 (46.9) 170.0 (65.8)
167.3 (53.6) 147.6 (31.2)
195.5 (39.7) 146.5 (34.8)
189.6 (15.3) 154.8 (41.8)
Delta sleep Pia Bip
97.2 (26.9) 115.5 (29.4)
126.6 (59.7) 94.5 (30.8)
141.7 (74.1) 102.5 (15.9)
98.8 (42.9) 100.7 (24.1)
115.2 (23.1) 107.8 (33.0)
Sleep variables REM sleep Pia Bip REM lat. PIa Bip
Total sleep 380.1 (49.9) 384.5 (22.0) 39D.4 (29.7) 389.7 (46.1) PIa 424.2 (47.2) 319.8 (47.1) 333.4 (51.9) Bip 348.4 (73.3) 329.8 (34.6) 455.1 (15.7) a REM lat. = REM sleep latency (minutes); REM attempts = frequency of REM sleep episodes during REM sleep deprivation is equal to the number of awakenings from REM sleep. Pia = placebo; Hip = biperiden. Stages I, II and delta (III + IV) are in minutes. All values are means ± SD. Sleep, Vol. 15, No.3, 1992
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F = 0.43 F= 140.4 F= 0.255
""'" BIPERIDEN AND REM SLEEP TABLE 3. Sleep variables after REM sleep deprivation Sleep variables
Baseline
REM sleep PIa IlIA (25.3) Bip 116.0 (IS.7)
First recovery
Second recovery
142.7 (IS.9) 150.3 (27.3)
145.6 (2504) 145.3 (2304)
S7.7 (2904) 9404 (34.6)
61.S (19.7) 43.2 (30.9)
67.06 (17.7) 60.6 (lOA)
No. REM PIa Bip
4.1 (1.1) 4.S (O.S)
9.0 (1.3) 5.2 (1.0)
5.3 (104) 5.3 (0.9)
Stage I PIa Bip
14.6 (17.1) 17.9 (12.5)
7.3 (5.2) 9.6 (6.3)
12.2 (904) 9.9 (6.S)
Stage II PIa Bip
201.2 (39.1) 205.1 (3504)
176.5 (45.6) 155.S (34.3)
190.3 (5604) 163.9 (40.6)
Delta PIa Bip
97.2 (26.9) 115.5 (2904)
140.3 (24.7) 133.2 (33.9)
121.0 (43.9) 137.6 (35.2)
Total sleep PIa 424.2 (47.2) Bip 455.1 (15.7)
461.1 (17.1) 44S.0 (32.2)
466.6 (7.2) 456.5 (1904)
a REM sleep = minutes; REM lat. = REM sleep latency (minutes); No. REM = frequency of REM sleep episodes during the night; Stages I, II and delta (III, IV) are in minutes. PIa = placebo; Bip = biperiden.
Sleep stage I was increased during REM sleep deprivation nights in both groups. During the recovery nights, there were no differences (ANOYA-group effects: F = 0.04, df = 1,14, p = 0.81; night effects: F = 14.8, df = 6,79, p < 0.00001; interactions: F = 0.5, df = 6,79, p = 0.80). Sleep stage II was reduced on deprivation nights in both groups, with significant differences between both groups. Also during the recovery nights there was a reduction of this variable in comparison with baseline nights (ANOYA-group effects: F = 9.29, df= 1,14, p < 0.003; night effect: F = 1.83, df = 6,79, p = 0.1; interactions: F = 0.57, df = 6,79, p = 0.75). Finally, delta sleep did not change significantly during deprivation and recovery nights (ANOYA group effects: F = 1.96, df = 1,14, p = 0.16; night effects: F = 1.60, df = 6,79, p = 0.15; interactions: F = 1.53, df = 6,79, p = 0.172). DISCUSSION The 4-day administration ofbiperiden during REM sleep deprivation produced a reduction in the frequency of REM sleep attempts, a reduction in the total sleep time and an inhibition of changes in the REM sleep latency typically associated with REM deprivation. On the recovery nights a similar rebound in REM
sleep time was observed in both groups with a decrease in REM sleep latency. The 4-mg dose ofbiperiden was used in the present study as it has been previously shown that 4 mg does not suppress REM sleep percentage (7). A normal REM sleep percentage is necessary to evaluate the effects of biperiden on REM sleep deprivation. The results of this study showed that although 4 mg biperiden does not suppress REM sleep, it does suppress the increased number of REM attempts associated with REM sleep deprivation. With respect to REM latency, the effects ofbiperiden and REM sleep deprivation appear to be additive. Although 4 mg biperiden alone increased REM sleep latency (7) and REM sleep deprivation decreased REM sleep latency (placebo group in this study), the combination of REM sleep deprivation and biperiden produced a REM sleep latency comparable to baseline. These two findings (i.e. suppressing increased REM sleep attempts and maintaining a normal REM sleep latency) suggest that biperiden at 4 mg is a REM sleep suppressant, when it is administered together with REM sleep deprivation. The REM sleep suppressive effect of biperiden was not seen in the recovery data. In the biperiden group that received placebo after REM sleep deprivation, the usual REM sleep rebound (in this study a reduced REM sleep latency and increased REM sleep time) was seen, and the rebound endured for both recovery nights. The effect of biperiden during chronic administration and during withdrawal should be studied in order to rule out the possibility of a rebound phenomenon as a result of the anticholinergic withdrawal as has been described previously with other antimuscarinic drugs (13). However, because biperiden is a selective M 1 antagonist a different result may be found. There were some biperiden-associated changes in the sleep continuity and in the non REM sleep architecture. Total sleep time was reduced in the biperiden group, which was related to an increase in the number of awakenings. It seems that the subjects in the biperiden group compared to the placebo group had more problems returning to sleep once they had been awakened. Biperiden with repeated administration and in the REM sleep deprivation situation may have an alerting effect. A study with repeated administration of biperiden in sleep could give some clues about the effect of chronic administration ofbiperiden in human sleep. Stage 1 sleep increased during REM sleep deprivation, whereas on the recovery nights the opposite effect was observed. With Stage 2 sleep a reduction during the REM sleep deprivation and on the recovery nights was observed in both groups. These sleep stage changes are related to the manipulation of REM sleep and the reorganization of sleep architecture. Sleep. Vol. 15. No.3. 1992
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REM lat. PIa Bip
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256
REFERENCES
Sleep, Vol. 15. No.3. 1992
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1. Velazquez-Moctezuma J, Gillin Je, Shiromani PJ. Effect of specific Ml,M2 muscarinic receptor agonist on REM sleep gen'!ration. Brain Res 1989;503:128-31. 2. Velazquez-Moctezuma J, Shalauta MD, Gillin Je, Shiromani PJ. Pontine microinjections of nicotine increase REM sleep in cats. Neurosci Lett 1989;503: 128-31. 3. Berger M, Riemann D, Hoechli D, Spiegel R. The cholinergic REM sleep induction test with RS 86: state or trai-marker of depression? Arch Gen Psychiatry 1989;46:421-8. 4. Palacios JM, Bollinger G, Closse A, Enz A, Gmelin G Malanowski J. The pharmacological assessment of RS 86 '(2-ethyl.. 8methyl-2,8-diazaspiro-[ 4,5,]-decan-l ,3-dion hydrobromide): a potent specific muscarinic acetylcholine receptor agonist. Eur J Pharmacol1986; 125:5-62. 5. Velazquez-Moctezuma J, Shalauta MD, Gillin Je, Shiromani PJ. Differential effects of cholinergic antagonist on REM sle:ep components. Psychopharmacol Bull 1990;349-53. 6. Eltze M, Figala V. Affinity and selectivity ofbiperiden enantiomers of muscarinic receptor subtypes. Eur J Pharmacol 1988; 158:11-9. 7. Salin-Pascual RJ, Granados-Fuentes D, Galicia-Polo L, Nieves
E, Echev.erry J. Biperiden administration in normal sleep and after rapid eye movement sleep deprivation in healthy volunteers. Neuropsychopharmacology 1991 ;5:97-102. Gillin Je, Sutton L, Ruiz C, Golshan S, Hirsch S Warman C Shiromani P. Dose dependent inhibition of REM' sleep in nor~ mal volunteers by biperiden, a muscarinic antagonist. Bioi Psychiatry 1991;30:151-6. Kodama T, Takahashi Y, Honda Y. Enhancement of acetylcholine release during paradoxical sleep in the dorsal tegmental field of the cat brain stem. Neurosci Lett 1990;114:277-82. Salin-Pascual RJ, Nieto-Caraveo A, Roldan-Roldan G HuertoDe!gadillo L, Granado-Fuentes D. Effects of physostigmine infuslOn on healthy volunteers deprived of rapid eye movement sleep. Sleep 1989; 12:246-53. Gonzalez-Forteza C, Caraveo Andunga J, Ramos Lira L, Sanchez JJ. Reliability of the Diagnostic Interview Schedule (DIS) in Mexican psychiatric patients. Salud Ment 1988; 11 :48-54. Rechtschaffen A, Kales A. Manual ofstandardized terminology. Techniques. and scoring systemfor the stages of human subjects. Washington, DC: U.S. Government Printing Office, 1968. Sutin EL, Shiromani PJ, Kelsoe JR, Storch Fl, Gillin J. Rapideye-movement sleep during withdrawal from chronic scopolamine treatment. Life Sci 1986;39:2419-27.
Biperiden Administration I)uring REM Sleep Deprivation Diminished the Frequency of REM Sle1ep Attempts
*Sleep Disorders Center, Henry Ford Hospital, Detroit, Michigan, U.S.A.; and tPsychobiological Department, Mexican Psychiatric Institute, Mexico City, Mexico
Summary: Sixteen subjects were assigned to a group using either placebo or biperiden, with eight subjects in each group. Both groups were studied for one acclimatization night, one baseline night, four nights of rapid eye movement (REM) sleep deprivation and two recovery nights. All the subjects received either placebo or 4 mg biperiden I hour before sleep during the four nights of REM sleep deprivation. During the baseline and the recovery nights both groups received placebo capsules. The results showed that REM sleep time during thl~ REM sleep deprivation was reduced by 70-75% below the baseline night in both groups. The number of attempts to enter REM sleep was significantly reduced by biperiden as compared to placebo for each of the four REM sleep deprivation nights. Because the total sleep time in the biperiden group was reduced, the number of REM sleep attempts was corrected by the total sleep time. The adjusted number of REM sleep attempts was also significantly reduced in the biperiden group. REM sleep latency showed a reduction in the placebo group, whereas in the biperiden group REM sleep latency was unchanged throughout the deprivation nights. In the recovery night REM sleep time was increased in both groups, with no differences between the groups. The REM sleep latency showed a reduction in the first recovery night in both groups that persisted through the second recovery night. The above findings support the role of biperiden as a REM sleep suppressive drug. Key Words: Muscarinic receptors-REM sleep deprivation-Biperiden-Human subjects.
It has been proposed that Ml and M2 muscarinic receptors as well as nicotinic receptors are involved in the regulatory process of rapid eye movement (REM) sleep based on studies in cats (1-3) and humans (4,5). Biperiden is an anticholinergic drug with preference for Ml muscarinic receptors (6). Biperiden administration in healthy normal humans increased REM sleep latency at 4- and 6-mg doses and biperiden 6 mg reduced REM sleep time (7). In the same study, after six nights of REM sleep deprivation two groups of normal subjects received either placebo or biperiden (4 mg) on the first recovery night. The REM sleep time in the group that received placebo was increased during the recovery night, whereas the group that received biperi-
Accepted for publication November 1991. Address correspondence and reprint requests to Rafael J. SalinPascual, M.D., D.MSc., U.e.S.D. Psychiatry Dept. and San Di(:go VA Medical Center-Psychiatry SVC (116 A), 3350 La Iolla Vi11age Dr., San Diego, California 92161, U.S.A.
den did not show a significant increase in REM sleep. It was not until the follow-up night (with no active
drug administration) that REM sleep increased in the biperiden group. Another group has recently reported a dose-dependent inhibition of REM sleep in normal volunteers by biperiden; they used 2-, 4-, and 8-mg doses of biperiden and found a significant reduction even with a 4-mg dose (8). The fact that biperiden modified REM sleep both on baseline and during recovery nights from REM sleep deprivation suggests that Ml receptors are involved in REM sleep mechanisms in humans. The fact that a lower biperiden dose altered REM sleep more during deprivation recovery than on baseline nights might be explained as follows. Normally, acetylcholine is released during REM sleep as shown in the cat (9). REM sleep deprivation could modify the release of acetylcholine and change muscarinic receptor sensitivity, thereby producing the increased response to a low dose ofbiperiden and reduced REM sleep rebound. In sup-
252
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*tRafael1. Salin-Pascual, tDaniel Grandos-Fuentes, tLourdes Galicia-Polo, tEstela Nieves, *Timothy A. Roehrs and *Thomas Roth
BIPERIDEN AND REM SLEEP
tinuous minutes of sleep after lights out. Awake time was defined as the minutes awake after sleep onset. REM sleep latency was defined as the time from sleep onset to the completion of two epochs of REM sleep (1 minute) (including intermittent awakenings). A REM sleep attempt was defined as one epoch of continuous REM sleep. Overall two-way ANOYAs, using group as one variable (placebo group vs. biperiden group) and night as the second variable, were performed. Post-hoc Students' t tests for repeated measures with a correction to maintain the alpha level of significance at p < 0.05 (Bonferroni's correction) were performed when indicated. RESULTS
Results of the overall two-way ANOYAs and posthoc tests are presented in Table 1. The means and standard deviations of baseline and deprivation nights and baseline and recovery nights are presented in Tables 2 and 3, respectively. REM sleep time on deprivation nights was reduced in both groups by 70-75% below baseline, with no METHODS differences between placebo or biperiden groups. DurSixteen healthy volunteers were studied [aged: 25.2 ing the recovery nights, this variable was increased ± 2.8 years (mean ± SD)]. All the subjects were between 28 to 30% without differences between the screened by the Diagnostic Interview Schedule in a groups (ANOYA-group effects: F = 0.43, df= 1,14, reliable Spanish version (11). They had no history of p = 0.51; night effects: F = 140.4, df = 6,79, p < psychiatric disorder, sleep disturbances or serious ill- 0.00001; interactions: F= 0.255, df= 6,79, p = 0.95). ness. The subjects were nonsmokers and had,no history REM sleep latency on deprivation nights was reof alcohol or other drug abuse. duced in the placebo group (vs. baseline), whereas in The subjects were randomly assigned to one of two the biperiden group it was increased (a trend indicated groups: placebo or biperiden, with eight subjects per by the interaction, p < 0.10). During recovery nights, group. Each volunteer slept in the laboratory on one a reduction in this variable was observed in both groups, acclimatization night, one baseline night, four REM with no differences between them (ANOYA-group sleep deprivation nights and two recovery nights. All effects: F = 5.83, df= 1,14, p < 0.01; night effects: F the subjects received identical capsules with either pla- = 3.56, df = 6,79, p < 0.003; interactions: F = 1.8, df cebo or 4 mg biperiden (two commercial tablets of 2 = 6,79, p < 0.10). mg Akineton, Knoll), 1 hour before sleep during the The number of REM sleep attempts on REM sleep four nights of REM sleep deprivation. During the base- deprivation nights was significantly increased in both line and recovery nights, both groups received placebo groups. But there was a reduced number of attempts capsules. For the four nights of REM sleep deprivation in the biperiden group in comparison with the other the volunteers were immediately awakened on every group (ANOYA-group effects: F = 27.7, df = 1,14, occasion when they showed polysomnographic evi- p < 0.00001; night effects: F= 25.19, df= 6,79, p < dence of REM sleep (one epoch) by technicians who 0.00001; interactions: F = 4.4, df = 6,79, p < 0.001). did not know the treatment that the volunteers were Because the total sleep time was significantly reduced receiving. The sleep recordings started at 2200 hours in the biperiden group (ANOYA-group effects: F = and ran until 0600 hours. They were scored visually 13.03, df= 1,14, p < 0.00001; night effects: F = 27.7, according to standardized criteria (12) by one of us df = 6,79, p < 0.00001; interactions: F = 2.58, df = who was not informed of the experimental procedure 6,79, p < 0.02), the number of REM sleep attempts for each group. The subjects were not allowed to nap was corrected for the total sleep time differences (by during the day and were reminded of this restriction an index: number of REM sleep attempts/total sleep time). The resulting index was also significantly reeach morning. Sleep onset was defined as the first epoch of 8 con- duced in the biperiden group. Sleep, Vol. 15, No.3, 1992
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port of the above idea, it has been reported (10) in human volunteers that physostigmine (an indirect cholinomimetic drug) infusion after four nights of REM sleep deprivation modifies the typical REM sleep recovery. If the above is the case, the question arises as to whether the combination of REM sleep deprivation and biperiden administration might further reduce cholinergic activity by both suppressing acetylcholine release and blocking receptors, thereby leading to a lessened pressure for REM sleep during deprivation. The present study was developed to examine in normal volunteers the effects of biperiden when administered simultaneously with REM sleep deprivation. We were interested in biperiden effects during REM sleep deprivation and in the recovery period when REM sleep rebound typically occurs. The main hypotheses were that if biperiden blocks M 1 receptors and if they are involved in REM sleep, then biperiden should reduce the number of REM sleep attempts during REM sleep deprivation, and the drug also should produce a differential REM sleep rebound in comparison with the placebo group.
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254 TABLE 1.
Overall two-way ANOVAs and post-hoc comparisonS"
Overall comparison
Baseline vs. deprived
Baseline vs. recovery
REM sleep A) B) C) REM sleep latency A) B) C)
p = 0.51 p < 0.00001 p = 0.95
P: Bsl > Depr (1-4) B: Bsl > Depr (1-4)
P: Bsl < Rec (1-2) B: Bsl < Rec (l-2)
F= 5.83 F= 3.56 F= 1.80
p < 0.01 p < 0.003 p = 0.1
P: Bsl = Depr (1-4) B: Bsl = Depr (1-4) Placebo < biperiden
P: Bsl > Rec (l-2) B: Bsl > Rec (1-2) Placebo = Biperiden
p < 0.00001 p < 0.00001 p < 0.00001
P: Bsl < Depr (1-4) B: Bsl < Depr (1-4) Placebo> biperiden
P: Bsl = Rec (1-2) B: Bsl = Rec (1-2) Placebo = Biperiden
REM sleep attempts A) F= 27.7 B) F= 25.2 C) F= 4.4 Stage I A) B) C)
F= 0.04 F= 14.81 F= 0.50
P = 0.815 P < 0.00001 p = 0.802
P: Bsl < Depr (1-4) B: Bsl < Depr (1-4)
P: Bsl = Rec (1-2) B: Bsl = Rec (1-2)
A) B) C)
F= 9.29 F= 1.83 F= 0.57
p < 0.003 p = 0.1 p = 0.75
Placebo> biperiden
Placebo> biperiden
F = 1.96 F= 1.6 F = 1.53
p = 0.16 p = 0.15 p = 0.17
F= 13.03 = 27.7 = 2.5
p < 0.0001 P < 0.00001 p < 0.02
P: Bsl > Depr (1,3,4) B: Bsl > Depr (2-4) Placebo> biperiden
P: Bsl = Rec (1-2) B: Bsl = Rec (1-2) Placebo = biperiden
Stage II
Delta sleep A) B) C) Total sleep time A) B) C)
F F
a Two-way ANOV As: A = group effects (df = 1,14); B = night effects (df = 6,79); C = interactions (df = 6,79). Numbers between parentheses are p < 0.05 vs. baseline on Students' t test with Bonferroni corrections (comparisons of each night to baseline). P = placebo group; B = biperiden group; Depr = deprivation nights; Rec = recovery nights.
TABLE 2.
Sleep variables during REM sleep deprivation a
Baseline
First
Second
Third
Fourth
111.4 (25.3) 116.0 (18.7)
27.9 (13.2) 32.6 (13.5)
29.1 (11.9) 39.22 (15.8)
40.4 (21.9) 39.6 (6.3)
36.3 (16.5) 33.1 (6.8)
87.7(29.4) 94.4 (34.6)
84.5 (31.1) 120.3 (45.4)
59.8 (14.3) 115.7 (38.6)
85.8 (33.6) 106.9 (81.1)
63.8 (15.6) 92.9 (62.4)
REM sleep attempts 4.1 (1.1) PIa Bip 4.8 (0.8)
15.2 (6.5) 8.2 (4.7)
18.5 (26.1) 8.8 (2.7)
15.5 (6.7) 12.0 (3.4)
17.6 (4.1) 10.5 (3.7)
Stage I PIa Bip
14.6 (17.1) 17.9 (12.5)
35.2 (11.9) 4J.l (23.4)
34.7 (13.6) 41.1 (14.1)
35.2 (11.4) 33.5 (11.6)
42.7(24.9) 38.0 (13.9)
Stage II Pia Bip
201.2 (39.1) 205.1 (35.4)
193.4 (46.9) 170.0 (65.8)
167.3 (53.6) 147.6 (31.2)
195.5 (39.7) 146.5 (34.8)
189.6 (15.3) 154.8 (41.8)
Delta sleep Pia Bip
97.2 (26.9) 115.5 (29.4)
126.6 (59.7) 94.5 (30.8)
141.7 (74.1) 102.5 (15.9)
98.8 (42.9) 100.7 (24.1)
115.2 (23.1) 107.8 (33.0)
Sleep variables REM sleep Pia Bip REM lat. PIa Bip
Total sleep 380.1 (49.9) 384.5 (22.0) 39D.4 (29.7) 389.7 (46.1) PIa 424.2 (47.2) 319.8 (47.1) 333.4 (51.9) Bip 348.4 (73.3) 329.8 (34.6) 455.1 (15.7) a REM lat. = REM sleep latency (minutes); REM attempts = frequency of REM sleep episodes during REM sleep deprivation is equal to the number of awakenings from REM sleep. Pia = placebo; Hip = biperiden. Stages I, II and delta (III + IV) are in minutes. All values are means ± SD. Sleep, Vol. 15, No.3, 1992
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F = 0.43 F= 140.4 F= 0.255
""'" BIPERIDEN AND REM SLEEP TABLE 3. Sleep variables after REM sleep deprivation Sleep variables
Baseline
REM sleep PIa IlIA (25.3) Bip 116.0 (IS.7)
First recovery
Second recovery
142.7 (IS.9) 150.3 (27.3)
145.6 (2504) 145.3 (2304)
S7.7 (2904) 9404 (34.6)
61.S (19.7) 43.2 (30.9)
67.06 (17.7) 60.6 (lOA)
No. REM PIa Bip
4.1 (1.1) 4.S (O.S)
9.0 (1.3) 5.2 (1.0)
5.3 (104) 5.3 (0.9)
Stage I PIa Bip
14.6 (17.1) 17.9 (12.5)
7.3 (5.2) 9.6 (6.3)
12.2 (904) 9.9 (6.S)
Stage II PIa Bip
201.2 (39.1) 205.1 (3504)
176.5 (45.6) 155.S (34.3)
190.3 (5604) 163.9 (40.6)
Delta PIa Bip
97.2 (26.9) 115.5 (2904)
140.3 (24.7) 133.2 (33.9)
121.0 (43.9) 137.6 (35.2)
Total sleep PIa 424.2 (47.2) Bip 455.1 (15.7)
461.1 (17.1) 44S.0 (32.2)
466.6 (7.2) 456.5 (1904)
a REM sleep = minutes; REM lat. = REM sleep latency (minutes); No. REM = frequency of REM sleep episodes during the night; Stages I, II and delta (III, IV) are in minutes. PIa = placebo; Bip = biperiden.
Sleep stage I was increased during REM sleep deprivation nights in both groups. During the recovery nights, there were no differences (ANOYA-group effects: F = 0.04, df = 1,14, p = 0.81; night effects: F = 14.8, df = 6,79, p < 0.00001; interactions: F = 0.5, df = 6,79, p = 0.80). Sleep stage II was reduced on deprivation nights in both groups, with significant differences between both groups. Also during the recovery nights there was a reduction of this variable in comparison with baseline nights (ANOYA-group effects: F = 9.29, df= 1,14, p < 0.003; night effect: F = 1.83, df = 6,79, p = 0.1; interactions: F = 0.57, df = 6,79, p = 0.75). Finally, delta sleep did not change significantly during deprivation and recovery nights (ANOYA group effects: F = 1.96, df = 1,14, p = 0.16; night effects: F = 1.60, df = 6,79, p = 0.15; interactions: F = 1.53, df = 6,79, p = 0.172). DISCUSSION The 4-day administration ofbiperiden during REM sleep deprivation produced a reduction in the frequency of REM sleep attempts, a reduction in the total sleep time and an inhibition of changes in the REM sleep latency typically associated with REM deprivation. On the recovery nights a similar rebound in REM
sleep time was observed in both groups with a decrease in REM sleep latency. The 4-mg dose ofbiperiden was used in the present study as it has been previously shown that 4 mg does not suppress REM sleep percentage (7). A normal REM sleep percentage is necessary to evaluate the effects of biperiden on REM sleep deprivation. The results of this study showed that although 4 mg biperiden does not suppress REM sleep, it does suppress the increased number of REM attempts associated with REM sleep deprivation. With respect to REM latency, the effects ofbiperiden and REM sleep deprivation appear to be additive. Although 4 mg biperiden alone increased REM sleep latency (7) and REM sleep deprivation decreased REM sleep latency (placebo group in this study), the combination of REM sleep deprivation and biperiden produced a REM sleep latency comparable to baseline. These two findings (i.e. suppressing increased REM sleep attempts and maintaining a normal REM sleep latency) suggest that biperiden at 4 mg is a REM sleep suppressant, when it is administered together with REM sleep deprivation. The REM sleep suppressive effect of biperiden was not seen in the recovery data. In the biperiden group that received placebo after REM sleep deprivation, the usual REM sleep rebound (in this study a reduced REM sleep latency and increased REM sleep time) was seen, and the rebound endured for both recovery nights. The effect of biperiden during chronic administration and during withdrawal should be studied in order to rule out the possibility of a rebound phenomenon as a result of the anticholinergic withdrawal as has been described previously with other antimuscarinic drugs (13). However, because biperiden is a selective M 1 antagonist a different result may be found. There were some biperiden-associated changes in the sleep continuity and in the non REM sleep architecture. Total sleep time was reduced in the biperiden group, which was related to an increase in the number of awakenings. It seems that the subjects in the biperiden group compared to the placebo group had more problems returning to sleep once they had been awakened. Biperiden with repeated administration and in the REM sleep deprivation situation may have an alerting effect. A study with repeated administration of biperiden in sleep could give some clues about the effect of chronic administration ofbiperiden in human sleep. Stage 1 sleep increased during REM sleep deprivation, whereas on the recovery nights the opposite effect was observed. With Stage 2 sleep a reduction during the REM sleep deprivation and on the recovery nights was observed in both groups. These sleep stage changes are related to the manipulation of REM sleep and the reorganization of sleep architecture. Sleep. Vol. 15. No.3. 1992
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REM lat. PIa Bip
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Sleep, Vol. 15. No.3. 1992
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