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Effects of diazepam on the EEG in man
EUROPEAN JOURNAL OF PHARMACOLOGY 17 (1972) 167-170. NORTH-HOLLAND PUBLISHING COMPANY
Short c o m m u n i c a t i o n
EFFECTS
OF DIAZEPAM
ON THE EEG IN MAN
J.D. MONTAGU Department of Pharmacology, University College London, London WC1E 6BT, England and Runwell Hospital, Wiekford, Essex, England
Accepted 15 October 1971
Received 7 September 1971
J.D. MONTAGU, Effects ofdiazepam on the EEG in man, European J. Pharmacol. 17 (1972) 167-170. Single doses of diazepam resulted in significant decreases in theta and alpha activity and a significant increase in fast activity in the eyes-open state. Sleep patterns tended to appear soon after eye closure. Diazepam did not differ significantly from placebo in its subjective effects or in effect on the visual reaction time. Diazepam
Visual reaction time
Electroencephalogram
1. INTRODUCTION
2. MATERIALS AND METHODS
A previous communication (Montagu, 1971) reported that single doses of a benzodiazepine, nitrazepare (Mogadon), resulted in decreased activity in the EEG theta and alpha bands in the eyes-open state. These effects were in the opposite direction to those which were obtained with a barbiturate, secobarbital. It was therefore considered o f interest to investigate another benzodiazepine compound and diazepam (Valium) was selected. The results are presented in this report. It became evident in preliminary tests that diazepam had a marked tendency to induce sleep when the subject closed his eyes, even in doses which had minimal subjective sedative effects. The procedure previously adopted, which involved taking EEG recordings in the eyes-closed condition before the eyesopen state, was therefore abandoned. Instead, recordings were taken first in the eyes-open state while the subject performed a simple visual reaction time task. In addition to providing an objective measure of sedative drug action this procedure also gave confirmation that the subject's eyes were open.
The subjects were 3 male and 3 female healthy volunteers, aged 1 8 - 3 7 years. They were tested in the fasting state. Each subject received a 2.5 mg dose of diazepam orally, a 5 mg dose, and a matching placebo on different occasions in a Willeams Square design (Williams, 1949). During recording the subject was seated in a blacked-out room. Recordings were taken for 6 rain periods. For the first 3 min the room was lit. The subject was instructed to watch a 2 watt pilot light, m o u n t e d at a distance o f 2 m in his direct line of vision, and to extinguish it by pressing a microswitch as soon as the light came on. The light came on a randomized intervals ranging from 7 - 2 3 sec. At the end of 3 rain the room light was switched off and the subject was told to close his eyes and keep them closed. Recording continued for a further 3 min. Records were taken twice before medication and at 6 intervals over a period of 2½ hr afterwards. At the end o f each recording the subject rated his feelings on an 8-dimension rating battery (Norris, 1971). The EEG from an occiput-vertex derivation was recorded on a Grass Polygraph and on magnetic tape (Ampex). It was analysed by means o f three bandpass filters, the outputs of which were rectified and inte-
J.D. Montagu, EEG effects o f diazepam
168
Table 1 Analysis of the mean differences in effect between diazepam and placebo in 6 subjects.
grated (Lee-Dickens integrators). The 6 db bands were: 4 . 0 6 - 7 . 4 Hz (theta), 7 . 4 - 1 3 . 5 Hz (alpha), and 1 3 . 5 - 2 4 . 6 Hz (beta). The quantity of activity in each band was measured for the first 160 sec of each recording and for the period from 1 0 - 1 7 0 sec after eye closure. The results were expressed in terms of the change in log quantity from the pre-drug value. The subjective rating scales were quantified as in a previous investigation (Montagu, 1971).
Measure
Dose (mg)
Mean difference
S.E.M.
from
placebo
3. RESULTS The mean results for the subjective rating scales showed a peak sedative effect at 40 min after both doses, followed by complete or virtually complete recovery within the test period. However, neither dose differed significantly from placebo in total effect (table 1) or in effect at 40 min. Table 1 also shows that diazepam did not result in a significant prolongation of the visual reaction time. In contrast, the EEG results showed many significant differences between drug and placebo. In the eyes-open state the results in
Subjective rating (mm)
2.5 5
- I 7.3 -29.2
+-11.7 +-14.8
Reaction time (msec)
2.5 5
+88.2 +33.0
-+68.2 +-99.7
Theta eyes open (log quantity)
2.5 5
-35.2* -47.8*
±10.1 +-16.4
Alpha eyes open (log quantity)
2.5 5
-27.8* -43.8*
-+ 9.1 -+13.9
Beta eyes open (log quantity)
2.5 5
+17.0 +37.5*
+-12.8 +-14.6
Alpha eyes closed (log quantity)
2.5 5
-49.3 -61.7"
+-35.8 -+20.9
Each effect was calculated as the total effect in each subject by summing the changes from the pre-drug value at the 6 post-drug intervals. The mean difference in total effect between each dose and placebo was subjected to a t-test (*p < 0.05). All log values have been multiplied by 100.
+ 0-04.
Placebo 2 5 rng
0.02. >,i---
~
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,<
o © 0._J
0.02.
z
0-04
z
0-06
I u
0-08 • ...........
•
...........
•
..............
"'.......
Y
-0-10.
-2'o
8
2'0
4'0
go
9'o
MINUTES
Fig. 1. Effects o f diazepam on the quantity o f theta activity in the eyes-open condition (160 sec periods). Each point shows the mean change in log quantity from the pre-drug value at 0 rain in 6 subjects. The three curves were obtained in the same subjects or
different occasions.
J.D. Montagu, EEG effects of diazepam
169
the theta and alpha bands were similar in direction, time course, and magnitude. The mean results for the theta activity are illustrated in fig. 1. It can be seen that both doses of diazepam resulted in a sharp decrease in activity within 20 min, after which the activity remained at a lower level. There was little difference in effect between the two doses but both differed significantly from placebo. However, fig. 1 shows that there was a considerable increase in activity in the 20 rain before administration of the large dose, and it seemed possible that the pre-drug value might have been spuriously high. The initial values were therefore ignored and the log quantities after the large dose were compared with those obtained after placebo. It was found that they were significantly smaller after the drug (/9<0.02). In the beta range ( 1 3 . 5 - 2 4 . 6 Hz) both doses of diazepam resulted in increased activity in the eyesopen state by comparison with placebo. The mean curves showed a peak effect at 20 min after the small dose. This was followed by a smooth decline to the initial level at 150 min. The large dose resulted in a larger effect, with a peak at 40 rain, and the level was still raised at the end of the test period. When the individual results were examined it was seen that one subject showed decreased fast activity after both doses; another showed a negligible increase in response to the small dose. The remaining 4 subjects displayed the group dose-effect trend. In the eyes-closed condition EEG patterns indicative of drowsiness or light sleep frequently appeared soon after eye closure. This was reflected in the measurements of alpha activity. In 3 subjects there was virtually no activity in this range in one or more of the recordings taken during the first hour after administration of the large dose. In the group as a whole diazepam resulted in decreases in alpha activity which differed significantly from the effects of placebo at 40 min after the small dose and at 2 0 - 6 0 min after the large dose. The results for theta and fast activity showed considerable variations from one recording period to another with no consistent trends.
(Montagu, 1971), although more rapid in onset. In the alpha range, however, the decreases in activity as a result of diazepam were significant whereas the decreases observed with nitrazepam were not. Since diazepam tended to induce sleep soon after eye closure, it might be thought that the eyes-open results could have been influenced by drowsiness. However, the EEG effects differed markedly in time course from the subjective effects, which were not statistically significant anyway. Moreover, drowsiness would be expected to result in increased alpha activity in the eyes-open state whereas diazepam resulted in a more consistent decrease than nitrazepam. It is speculated that this difference in result with the two drugs may have been attributable, in part at any rate, to the difference in experimental procedure. The inclusion of a visual reaction time task in this investigation ensured that the subject's eyes remained open. It would also have had an alerting effect and would have tended to prevent the onset of drowsiness. In the eyes-closed condition, on the other hand, the observed effects of diazepam seemed to be largely attributable to sleepiness, in contrast to the results with nitrazepam. However, nitrazepam in the larger dose resulted in significant subjective sedation whereas diazepam did not. It would appear from this that diazepam may be a better hypnotic than nitrazepam in that it facilitates sleep under appropriate conditions in doses which have little subjective effect in the waking state. It has been reported that diazepam-induced fast activity only becomes apparent after several days of regular dosage (Towler, 1962). The present investigation has shown that an increase in fast activity can be detected in some subjects within 20 min after a single dose of the drug.
4. DISCUSSION
REFERENCES
The eyes-open EEG effects reported here are similar to those which were obtained with nitrazepam
Montagu, J.D., 1971, Effects of quinalbarbitone (secobarbital) and nitrazepam on the EEG in man: quantitative investigations, European J. Pharmacol. 14, 238.
ACKNOWLEDGEMENTS This work was supported by a grant from Roche Products Ltd. I would like to thank Professor H.O. Schild for his continued interest and encourangement.
170
J.D. Montagu, EEG effects of diazepam
Norris, H., 1971, The action of sedatives on brain stem oculomotor systems in man, Neuropharmacol. 10, 181. Towler, M.L., 1962, The clinical use of diazepam in anxiety states and depressions, J. Neuropsychiat. 3, Suppl. 1, 68.
Williams, E.J., 1949, Experimental designs balanced for the estimation of residual effects of treatment, Australian J. Sci. Res. A. 2, 149.
Short c o m m u n i c a t i o n
EFFECTS
OF DIAZEPAM
ON THE EEG IN MAN
J.D. MONTAGU Department of Pharmacology, University College London, London WC1E 6BT, England and Runwell Hospital, Wiekford, Essex, England
Accepted 15 October 1971
Received 7 September 1971
J.D. MONTAGU, Effects ofdiazepam on the EEG in man, European J. Pharmacol. 17 (1972) 167-170. Single doses of diazepam resulted in significant decreases in theta and alpha activity and a significant increase in fast activity in the eyes-open state. Sleep patterns tended to appear soon after eye closure. Diazepam did not differ significantly from placebo in its subjective effects or in effect on the visual reaction time. Diazepam
Visual reaction time
Electroencephalogram
1. INTRODUCTION
2. MATERIALS AND METHODS
A previous communication (Montagu, 1971) reported that single doses of a benzodiazepine, nitrazepare (Mogadon), resulted in decreased activity in the EEG theta and alpha bands in the eyes-open state. These effects were in the opposite direction to those which were obtained with a barbiturate, secobarbital. It was therefore considered o f interest to investigate another benzodiazepine compound and diazepam (Valium) was selected. The results are presented in this report. It became evident in preliminary tests that diazepam had a marked tendency to induce sleep when the subject closed his eyes, even in doses which had minimal subjective sedative effects. The procedure previously adopted, which involved taking EEG recordings in the eyes-closed condition before the eyesopen state, was therefore abandoned. Instead, recordings were taken first in the eyes-open state while the subject performed a simple visual reaction time task. In addition to providing an objective measure of sedative drug action this procedure also gave confirmation that the subject's eyes were open.
The subjects were 3 male and 3 female healthy volunteers, aged 1 8 - 3 7 years. They were tested in the fasting state. Each subject received a 2.5 mg dose of diazepam orally, a 5 mg dose, and a matching placebo on different occasions in a Willeams Square design (Williams, 1949). During recording the subject was seated in a blacked-out room. Recordings were taken for 6 rain periods. For the first 3 min the room was lit. The subject was instructed to watch a 2 watt pilot light, m o u n t e d at a distance o f 2 m in his direct line of vision, and to extinguish it by pressing a microswitch as soon as the light came on. The light came on a randomized intervals ranging from 7 - 2 3 sec. At the end of 3 rain the room light was switched off and the subject was told to close his eyes and keep them closed. Recording continued for a further 3 min. Records were taken twice before medication and at 6 intervals over a period of 2½ hr afterwards. At the end o f each recording the subject rated his feelings on an 8-dimension rating battery (Norris, 1971). The EEG from an occiput-vertex derivation was recorded on a Grass Polygraph and on magnetic tape (Ampex). It was analysed by means o f three bandpass filters, the outputs of which were rectified and inte-
J.D. Montagu, EEG effects o f diazepam
168
Table 1 Analysis of the mean differences in effect between diazepam and placebo in 6 subjects.
grated (Lee-Dickens integrators). The 6 db bands were: 4 . 0 6 - 7 . 4 Hz (theta), 7 . 4 - 1 3 . 5 Hz (alpha), and 1 3 . 5 - 2 4 . 6 Hz (beta). The quantity of activity in each band was measured for the first 160 sec of each recording and for the period from 1 0 - 1 7 0 sec after eye closure. The results were expressed in terms of the change in log quantity from the pre-drug value. The subjective rating scales were quantified as in a previous investigation (Montagu, 1971).
Measure
Dose (mg)
Mean difference
S.E.M.
from
placebo
3. RESULTS The mean results for the subjective rating scales showed a peak sedative effect at 40 min after both doses, followed by complete or virtually complete recovery within the test period. However, neither dose differed significantly from placebo in total effect (table 1) or in effect at 40 min. Table 1 also shows that diazepam did not result in a significant prolongation of the visual reaction time. In contrast, the EEG results showed many significant differences between drug and placebo. In the eyes-open state the results in
Subjective rating (mm)
2.5 5
- I 7.3 -29.2
+-11.7 +-14.8
Reaction time (msec)
2.5 5
+88.2 +33.0
-+68.2 +-99.7
Theta eyes open (log quantity)
2.5 5
-35.2* -47.8*
±10.1 +-16.4
Alpha eyes open (log quantity)
2.5 5
-27.8* -43.8*
-+ 9.1 -+13.9
Beta eyes open (log quantity)
2.5 5
+17.0 +37.5*
+-12.8 +-14.6
Alpha eyes closed (log quantity)
2.5 5
-49.3 -61.7"
+-35.8 -+20.9
Each effect was calculated as the total effect in each subject by summing the changes from the pre-drug value at the 6 post-drug intervals. The mean difference in total effect between each dose and placebo was subjected to a t-test (*p < 0.05). All log values have been multiplied by 100.
+ 0-04.
Placebo 2 5 rng
0.02. >,i---
~
o-
,<
o © 0._J
0.02.
z
0-04
z
0-06
I u
0-08 • ...........
•
...........
•
..............
"'.......
Y
-0-10.
-2'o
8
2'0
4'0
go
9'o
MINUTES
Fig. 1. Effects o f diazepam on the quantity o f theta activity in the eyes-open condition (160 sec periods). Each point shows the mean change in log quantity from the pre-drug value at 0 rain in 6 subjects. The three curves were obtained in the same subjects or
different occasions.
J.D. Montagu, EEG effects of diazepam
169
the theta and alpha bands were similar in direction, time course, and magnitude. The mean results for the theta activity are illustrated in fig. 1. It can be seen that both doses of diazepam resulted in a sharp decrease in activity within 20 min, after which the activity remained at a lower level. There was little difference in effect between the two doses but both differed significantly from placebo. However, fig. 1 shows that there was a considerable increase in activity in the 20 rain before administration of the large dose, and it seemed possible that the pre-drug value might have been spuriously high. The initial values were therefore ignored and the log quantities after the large dose were compared with those obtained after placebo. It was found that they were significantly smaller after the drug (/9<0.02). In the beta range ( 1 3 . 5 - 2 4 . 6 Hz) both doses of diazepam resulted in increased activity in the eyesopen state by comparison with placebo. The mean curves showed a peak effect at 20 min after the small dose. This was followed by a smooth decline to the initial level at 150 min. The large dose resulted in a larger effect, with a peak at 40 rain, and the level was still raised at the end of the test period. When the individual results were examined it was seen that one subject showed decreased fast activity after both doses; another showed a negligible increase in response to the small dose. The remaining 4 subjects displayed the group dose-effect trend. In the eyes-closed condition EEG patterns indicative of drowsiness or light sleep frequently appeared soon after eye closure. This was reflected in the measurements of alpha activity. In 3 subjects there was virtually no activity in this range in one or more of the recordings taken during the first hour after administration of the large dose. In the group as a whole diazepam resulted in decreases in alpha activity which differed significantly from the effects of placebo at 40 min after the small dose and at 2 0 - 6 0 min after the large dose. The results for theta and fast activity showed considerable variations from one recording period to another with no consistent trends.
(Montagu, 1971), although more rapid in onset. In the alpha range, however, the decreases in activity as a result of diazepam were significant whereas the decreases observed with nitrazepam were not. Since diazepam tended to induce sleep soon after eye closure, it might be thought that the eyes-open results could have been influenced by drowsiness. However, the EEG effects differed markedly in time course from the subjective effects, which were not statistically significant anyway. Moreover, drowsiness would be expected to result in increased alpha activity in the eyes-open state whereas diazepam resulted in a more consistent decrease than nitrazepam. It is speculated that this difference in result with the two drugs may have been attributable, in part at any rate, to the difference in experimental procedure. The inclusion of a visual reaction time task in this investigation ensured that the subject's eyes remained open. It would also have had an alerting effect and would have tended to prevent the onset of drowsiness. In the eyes-closed condition, on the other hand, the observed effects of diazepam seemed to be largely attributable to sleepiness, in contrast to the results with nitrazepam. However, nitrazepam in the larger dose resulted in significant subjective sedation whereas diazepam did not. It would appear from this that diazepam may be a better hypnotic than nitrazepam in that it facilitates sleep under appropriate conditions in doses which have little subjective effect in the waking state. It has been reported that diazepam-induced fast activity only becomes apparent after several days of regular dosage (Towler, 1962). The present investigation has shown that an increase in fast activity can be detected in some subjects within 20 min after a single dose of the drug.
4. DISCUSSION
REFERENCES
The eyes-open EEG effects reported here are similar to those which were obtained with nitrazepam
Montagu, J.D., 1971, Effects of quinalbarbitone (secobarbital) and nitrazepam on the EEG in man: quantitative investigations, European J. Pharmacol. 14, 238.
ACKNOWLEDGEMENTS This work was supported by a grant from Roche Products Ltd. I would like to thank Professor H.O. Schild for his continued interest and encourangement.
170
J.D. Montagu, EEG effects of diazepam
Norris, H., 1971, The action of sedatives on brain stem oculomotor systems in man, Neuropharmacol. 10, 181. Towler, M.L., 1962, The clinical use of diazepam in anxiety states and depressions, J. Neuropsychiat. 3, Suppl. 1, 68.
Williams, E.J., 1949, Experimental designs balanced for the estimation of residual effects of treatment, Australian J. Sci. Res. A. 2, 149.