Buspirone: Rocco L. Manfredi, Edward 0. Bixler,
Objective: continued parameters, ascertain drug. and/or
the
drug
and
sleep
had
not
laboratory
(there
by lesser infrequent.
above
used
protocol.
administration
difficulty
M.D., M.D.,
of this study were on sleep induction
Six insomniac subjects who asleep and who were in good
buspirone, Wake time
were
Anthony Kales, Melda A. Isaac,
objectives of buspirone
on which Results:
creased
or Stimulant
Effect?
Alexandros and Charles
N. Vgontzas, M. Falcone,
degrees Following baseline.
any
had chronic complaints physical health, were
medication The
for at least
protocol
consisted
a marked
and
significant
the
last
and to of the
falling asleep from any major
month
participated
of 4 placebo-baseline
in
nights,
and 5 placebo-withdrawal during the first 3 nights
increase
on
with
continued drug administration. Overall, drug termination, there was a delayed and Conclusions: These data not only confirm that
tive effects but also suggest that the drug may suggest that buspirone has limited usefulness
side effects, withdrawal
ofdifficulty not suffering
1 0 mg at bedtime, was administered, after sleep onset increased moderately was
M.D., M.D.
to evaluate the effects of initial and and maintenance and sleep stage
to determine the presence or absence of any drug-induced presence or absence of sleep disturbances following abrupt
disorders,
a 1 6-night nights nights.
M.D., Ph.D.,
The primary administration
Method: staying
mental
Sedative
have stimulant properties. in anxious patients with
the first
night)
and
7 of in-
reports ofside effects mild increase in sleep buspirone lacks sedaFurther, these findings concomitant sleep dif-
ficulties. (AmJ
Psychiatry
1991;
148:1213-1217)
B
uspimone is an antianxiety agent with a molecular formula of 8-[4-[4-(2-pynimidinyl)-1-piperazinyll butylj-8-azaspiro[4.S]decane-7,9-dione monohydrochloride. Its chemical structure and clinical pharmacology are uniquely different from the other anxiolytic agents, including benzodiazepines and barbiturates (1). Buspinone does not bind to benzodiazepine receptors or directly or indirectly to raminobutynic acid receptors (2, 3). It appears to have a strong affinity for dopamine receptors and for serotonin type 1 receptors located pnimanly in the hippocampus (3). Also, buspinone differs from other anxiolytics in that it lacks the anticonvulsant action, muscle relaxant effects, and sedative properties typical of benzodiazepines (1). Because anxiety occurs in many medical and psychiatnic disorders, an anxiolytic drug that is effective but does not impair psychomotor and cognitive functioning is highly desirable. Studies of healthy volunteers which
Presented in part at the 143rd annual meeting ofthe American Psychiatric Association, New York, May 12-17, 1990. Received Aug. 7, 1990; revision received Jan. 25, 1991; accepted Feb. 15, 1991. From the Sleep Research and Treatment Center and the Department of Psychiatry, Pennsylvania State University College of Medicine. Address reprint requests to Dr. Manfredi, Department of Psychiatry, Pennsyl-
vania
State University
College
of Medicine,
shey, PA 17033. Copyright © 1991
American
Psychiatric
Am
]
Psychiatry
148:9,
September
500 University Association.
1991
Drive,
Her-
have
funcskills, including simulated driving, have shown that impairments, if present, are less severe than those following equivalent doses of diazepam and tend to improve with continued administration of the drug (4-7). Also, when combined with alcohol, buspimone, in contrast to benzodiazepines, does not produce an additive effect in terms of impairing psychomotor functioning (8, 9). Use of buspinone has not been shown to lead to either abuse (2, 10, 1 1) or physical and psychological dependence (1, 12, 13). In addition, the investigators in one study (14) reported that patients treated for 6 months with buspirone did not show significant rebound anxiety on withdrawal symptoms (15, 16) when rapidly switched to placebo. However, one report (13) suggested that buspirone may not be entirely free of the potential for dependence. Buspirone has been associated with adverse effects such as headache, nervousness, dizziness, lightheadedness, and, to a lesser degree, drowsiness, weakness, nausea, and insomnia (17, 18). The presence and sevenity of drug-induced insomnia is of particular importance, since the majority of patients who use anxiolytics suffer also from sleep disturbances. Thus, the primary objectives of this study were to evaluate the effects on sleep of initial and continued administration of 10 mg tioning,
assessed
eye-hand
buspirone’s
coordination,
effects
on psychomotor
and
reactive
1213
BUSPIRONE:
SEDATIVE
OR
STIMULANT
EFFECT?
TABLE 1. Effects of 10 mg of Buspirone on Sleep Induction and Maintenance Baseline (nights 2-4) Variable Sleep
latency
Wake
time
Total
wake
Sleep
time
Number Wake First
(mm) after
sleep
time
(mm)
(%) of awakenings
time
Third
(mm)
SD
22.0
14.9
35.4
13.5
57.4
18.8
88.0
3.9
Nights
Nights
9-1
1 SD
Nights
12-14
Nights
15-16
Mean
22.3
16.0
21.7
10.2
16.4
49.3
37.3
45.0
45.6
37.9
30.4
45.4
45.0
71.6
34.1
66.7
41.4
54.3
32.9
64.7
42.0
85.1
7.1
86.1
8.6
88.7
6.9
86.5
3.1
6.7
2.6
6.6
4.0
6.7
third third
of night of night
4.7
1.8
6.8
6.5
5.5
3.9
6.5
4.0
8.5
2.0
4.3
2.4
ofnight
12.1
4.9
16.8
23.9
19.5
26.7
of buspirone at bedtime to insomniac subjects, to determine the presence or absence of any drug-induced side effects, and to ascertain the presence or absence of sleep disturbances following abrupt withdrawal of the drug.
METHOD Six insomniac subjects (four women and two men), 26-61 years of age (mean±SD=41.7±1S.7 years), were selected to participate in the study. The subjects were in good physical health and had not used any medication for at least the past month. The subjects demonstrated mild degrees of anxiety and depression but did not have mental disorders (for example, psychoses or major affective disorders) that would require psychopharmacologic treatment or that would prevent them from adheming to the study guidelines and requirements. Each subject had at least a 6-month history of difficulty falling asleep, staying asleep, or both. To qualify for the study, subjects had to report a history of taking an estimated 30 minutes to fall asleep and/or obtaining fewer than 6.5 hours of total sleep time. Throughout the study the subjects were instructed not to nap, not to alter their level of daily activity significantly, and not to use any medication. Each subject was fully informed of the nature of the experiment, gave his or her written consent, and was paid for participation in the study. The experimental protocol included 1 6 consecutive nights, which were divided into 4 placebo-baseline nights followed by 7 nights of drug administration and S placebo-withdrawal nights. The first placebo-baseline night allowed for adaptation to the new sleeping environment, and nights 2-4 were used to obtain baseline measurements. Buspirone’s effects on sleep efficiency variables and on sleep stages were evaluated during nights 5-1 1 . The effects of drug withdrawal were determined on nights 12-16, when matching placebo was again administered. On each night of the study, the subjects were continuously monitored for 8 hours by EEG, electromyogram, and electro-oculogram. Subsequently, all sleep recordings were scored according to standardized criteria (19). Variables assessed from the sleep recordings in-
1214
5-7
Withdrawal
SD
7.0
Mean
Administration
Mean
SD
9.5
Mean 19.3
SD 8.3
8.8
3.2
7.2
3.5
4.4
3.3
4.1
3.1
8.5
10.0
6.4
11.7
7.9
19.0
(%)
third
Second
onset
Mean
in Six Insomniac Subjects Drug
.
5.4 24.0
cluded sleep induction (sleep latency), sleep maintenance (wake time after sleep onset), sleep induction and sleep maintenance (total wake time), and percentage of sleep time. We also assessed sleep stage variables (including REM sleep and stages 1-4), number of REM periods, interval from sleep onset to the first REM penod (REM latency), and percentage of slow wave (stages 3 and 4) sleep. In addition, the distribution of wakefulness and sleep throughout the night was exammed by thirds of the night. Thirds of the night were established by subtracting sleep latency from the total amount of laboratory time (480 minutes) and then dividing the remaining time into equal thirds. Throughout the study, upon awakening in the morning, the subjects completed a questionnaire on which they estimated the time it had taken to fall asleep, the number of awakenings during the night, total sleep time, the soundness and quality of sleep, and morning sleepiness. They also completed an adjective checklist that used a 9-point scale for assessing tension, anxiety, and other mood factors. Tension and anxiety were also assessed on a separate 7-point scale and on a 10-cm analog scale that ranged from “extremely calm” to “cxtremely agitated.” Each night before going to sleep, the subjects completed a questionnaire in which they estimated their sleepiness and tension/anxiety during the day and their degree of sleepiness at bedtime. They also rated their presleep levels ofanxiety on the 10-cm analog scale and the State section of the State-Trait Anxiety Inventory (20). Side effects on each of the 1 6 nights of the study were recorded from information on the questionnaires cornpleted by the subjects each morning and evening and from subjects’ spontaneous reports of side effects to laboratory personnel. In addition, when the subjects meturned home after completion of the withdrawal penod, they were instructed to call if they had any subsequent adverse effects or difficulties. Data
Analysis
All of the sleep records were scored according to standardized criteria (19) independent of any knowledge of the experimental conditions. In order to correct
Am
]
Psychiatry
1 48:9,
September
1991
MANFREDI,
TABLE 2. EffeCts of 10 mg of Buspirone on Sleep Stage Variables Baseline (nights Variable
Mean
Sleep
time
Drug
SD
24.2 5.2
3.7 1.1
Stage
67.6
3.9
2
Stage3 4
Slowwave REM sleep First
time
third
Second
REM
third latency
Number
REM
Significantly Significantly
21.3 6.6 69.5 2.6
3.3 3.0 4.4 2.1
23.5 6.5 67.7 2.3
4.7 1.2 5.6 2.2
Mean
12-14 SD
Nights Mean
15-16 SD
26.3 6.4 63.9 3.4
3.9 2.0 4.8 3.8
25.9 5.5 65.8 2.8
7.2 1.5 6.8 2.3
2.7 0.2
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
3.0
2.7
2.6
2.0
2.3
2.2
3.4
3.8
2.8
2.3
7.9
54
10#{149}3b
6.2
17.3
4.9
17.3
7.3
26.3
5.3
25.8
4.1
29.8
8.9
26.8
9.1
of night
32.8
4.0
28.4
7.8
36.5
9.4
32.3
4.7
33.8
11.9
(mm)
81.2
18.0
104.8
69.5
19.5
60.2
4.2
0.6
4.4
0.8
periods period
sleep
(mm)
(mm)
different different
from from
baseline baseline
8.Oa
3.8
on Sleep
Induction
Psychiatry
I 48:9,
September
0.8
94.5 3.7
5.4
24.6
9.0
27.2
102.6
16.7
86.6
13.7
97.7
(t=4.71, (t=2.87,
and
39.7
24.8
df=70, df=70,
Sleep
Maintenance
1991
48.5 0.5
6.5 22.7
4.6
6.3
5.9 0.5
26.5
6.9
24.4
8.9
112.5
21.1
109.4
37.1
p
Objective: continued parameters, ascertain drug. and/or
the
drug
and
sleep
had
not
laboratory
(there
by lesser infrequent.
above
used
protocol.
administration
difficulty
M.D., M.D.,
of this study were on sleep induction
Six insomniac subjects who asleep and who were in good
buspirone, Wake time
were
Anthony Kales, Melda A. Isaac,
objectives of buspirone
on which Results:
creased
or Stimulant
Effect?
Alexandros and Charles
N. Vgontzas, M. Falcone,
degrees Following baseline.
any
had chronic complaints physical health, were
medication The
for at least
protocol
consisted
a marked
and
significant
the
last
and to of the
falling asleep from any major
month
participated
of 4 placebo-baseline
in
nights,
and 5 placebo-withdrawal during the first 3 nights
increase
on
with
continued drug administration. Overall, drug termination, there was a delayed and Conclusions: These data not only confirm that
tive effects but also suggest that the drug may suggest that buspirone has limited usefulness
side effects, withdrawal
ofdifficulty not suffering
1 0 mg at bedtime, was administered, after sleep onset increased moderately was
M.D., M.D.
to evaluate the effects of initial and and maintenance and sleep stage
to determine the presence or absence of any drug-induced presence or absence of sleep disturbances following abrupt
disorders,
a 1 6-night nights nights.
M.D., Ph.D.,
The primary administration
Method: staying
mental
Sedative
have stimulant properties. in anxious patients with
the first
night)
and
7 of in-
reports ofside effects mild increase in sleep buspirone lacks sedaFurther, these findings concomitant sleep dif-
ficulties. (AmJ
Psychiatry
1991;
148:1213-1217)
B
uspimone is an antianxiety agent with a molecular formula of 8-[4-[4-(2-pynimidinyl)-1-piperazinyll butylj-8-azaspiro[4.S]decane-7,9-dione monohydrochloride. Its chemical structure and clinical pharmacology are uniquely different from the other anxiolytic agents, including benzodiazepines and barbiturates (1). Buspinone does not bind to benzodiazepine receptors or directly or indirectly to raminobutynic acid receptors (2, 3). It appears to have a strong affinity for dopamine receptors and for serotonin type 1 receptors located pnimanly in the hippocampus (3). Also, buspinone differs from other anxiolytics in that it lacks the anticonvulsant action, muscle relaxant effects, and sedative properties typical of benzodiazepines (1). Because anxiety occurs in many medical and psychiatnic disorders, an anxiolytic drug that is effective but does not impair psychomotor and cognitive functioning is highly desirable. Studies of healthy volunteers which
Presented in part at the 143rd annual meeting ofthe American Psychiatric Association, New York, May 12-17, 1990. Received Aug. 7, 1990; revision received Jan. 25, 1991; accepted Feb. 15, 1991. From the Sleep Research and Treatment Center and the Department of Psychiatry, Pennsylvania State University College of Medicine. Address reprint requests to Dr. Manfredi, Department of Psychiatry, Pennsyl-
vania
State University
College
of Medicine,
shey, PA 17033. Copyright © 1991
American
Psychiatric
Am
]
Psychiatry
148:9,
September
500 University Association.
1991
Drive,
Her-
have
funcskills, including simulated driving, have shown that impairments, if present, are less severe than those following equivalent doses of diazepam and tend to improve with continued administration of the drug (4-7). Also, when combined with alcohol, buspimone, in contrast to benzodiazepines, does not produce an additive effect in terms of impairing psychomotor functioning (8, 9). Use of buspinone has not been shown to lead to either abuse (2, 10, 1 1) or physical and psychological dependence (1, 12, 13). In addition, the investigators in one study (14) reported that patients treated for 6 months with buspirone did not show significant rebound anxiety on withdrawal symptoms (15, 16) when rapidly switched to placebo. However, one report (13) suggested that buspirone may not be entirely free of the potential for dependence. Buspirone has been associated with adverse effects such as headache, nervousness, dizziness, lightheadedness, and, to a lesser degree, drowsiness, weakness, nausea, and insomnia (17, 18). The presence and sevenity of drug-induced insomnia is of particular importance, since the majority of patients who use anxiolytics suffer also from sleep disturbances. Thus, the primary objectives of this study were to evaluate the effects on sleep of initial and continued administration of 10 mg tioning,
assessed
eye-hand
buspirone’s
coordination,
effects
on psychomotor
and
reactive
1213
BUSPIRONE:
SEDATIVE
OR
STIMULANT
EFFECT?
TABLE 1. Effects of 10 mg of Buspirone on Sleep Induction and Maintenance Baseline (nights 2-4) Variable Sleep
latency
Wake
time
Total
wake
Sleep
time
Number Wake First
(mm) after
sleep
time
(mm)
(%) of awakenings
time
Third
(mm)
SD
22.0
14.9
35.4
13.5
57.4
18.8
88.0
3.9
Nights
Nights
9-1
1 SD
Nights
12-14
Nights
15-16
Mean
22.3
16.0
21.7
10.2
16.4
49.3
37.3
45.0
45.6
37.9
30.4
45.4
45.0
71.6
34.1
66.7
41.4
54.3
32.9
64.7
42.0
85.1
7.1
86.1
8.6
88.7
6.9
86.5
3.1
6.7
2.6
6.6
4.0
6.7
third third
of night of night
4.7
1.8
6.8
6.5
5.5
3.9
6.5
4.0
8.5
2.0
4.3
2.4
ofnight
12.1
4.9
16.8
23.9
19.5
26.7
of buspirone at bedtime to insomniac subjects, to determine the presence or absence of any drug-induced side effects, and to ascertain the presence or absence of sleep disturbances following abrupt withdrawal of the drug.
METHOD Six insomniac subjects (four women and two men), 26-61 years of age (mean±SD=41.7±1S.7 years), were selected to participate in the study. The subjects were in good physical health and had not used any medication for at least the past month. The subjects demonstrated mild degrees of anxiety and depression but did not have mental disorders (for example, psychoses or major affective disorders) that would require psychopharmacologic treatment or that would prevent them from adheming to the study guidelines and requirements. Each subject had at least a 6-month history of difficulty falling asleep, staying asleep, or both. To qualify for the study, subjects had to report a history of taking an estimated 30 minutes to fall asleep and/or obtaining fewer than 6.5 hours of total sleep time. Throughout the study the subjects were instructed not to nap, not to alter their level of daily activity significantly, and not to use any medication. Each subject was fully informed of the nature of the experiment, gave his or her written consent, and was paid for participation in the study. The experimental protocol included 1 6 consecutive nights, which were divided into 4 placebo-baseline nights followed by 7 nights of drug administration and S placebo-withdrawal nights. The first placebo-baseline night allowed for adaptation to the new sleeping environment, and nights 2-4 were used to obtain baseline measurements. Buspirone’s effects on sleep efficiency variables and on sleep stages were evaluated during nights 5-1 1 . The effects of drug withdrawal were determined on nights 12-16, when matching placebo was again administered. On each night of the study, the subjects were continuously monitored for 8 hours by EEG, electromyogram, and electro-oculogram. Subsequently, all sleep recordings were scored according to standardized criteria (19). Variables assessed from the sleep recordings in-
1214
5-7
Withdrawal
SD
7.0
Mean
Administration
Mean
SD
9.5
Mean 19.3
SD 8.3
8.8
3.2
7.2
3.5
4.4
3.3
4.1
3.1
8.5
10.0
6.4
11.7
7.9
19.0
(%)
third
Second
onset
Mean
in Six Insomniac Subjects Drug
.
5.4 24.0
cluded sleep induction (sleep latency), sleep maintenance (wake time after sleep onset), sleep induction and sleep maintenance (total wake time), and percentage of sleep time. We also assessed sleep stage variables (including REM sleep and stages 1-4), number of REM periods, interval from sleep onset to the first REM penod (REM latency), and percentage of slow wave (stages 3 and 4) sleep. In addition, the distribution of wakefulness and sleep throughout the night was exammed by thirds of the night. Thirds of the night were established by subtracting sleep latency from the total amount of laboratory time (480 minutes) and then dividing the remaining time into equal thirds. Throughout the study, upon awakening in the morning, the subjects completed a questionnaire on which they estimated the time it had taken to fall asleep, the number of awakenings during the night, total sleep time, the soundness and quality of sleep, and morning sleepiness. They also completed an adjective checklist that used a 9-point scale for assessing tension, anxiety, and other mood factors. Tension and anxiety were also assessed on a separate 7-point scale and on a 10-cm analog scale that ranged from “extremely calm” to “cxtremely agitated.” Each night before going to sleep, the subjects completed a questionnaire in which they estimated their sleepiness and tension/anxiety during the day and their degree of sleepiness at bedtime. They also rated their presleep levels ofanxiety on the 10-cm analog scale and the State section of the State-Trait Anxiety Inventory (20). Side effects on each of the 1 6 nights of the study were recorded from information on the questionnaires cornpleted by the subjects each morning and evening and from subjects’ spontaneous reports of side effects to laboratory personnel. In addition, when the subjects meturned home after completion of the withdrawal penod, they were instructed to call if they had any subsequent adverse effects or difficulties. Data
Analysis
All of the sleep records were scored according to standardized criteria (19) independent of any knowledge of the experimental conditions. In order to correct
Am
]
Psychiatry
1 48:9,
September
1991
MANFREDI,
TABLE 2. EffeCts of 10 mg of Buspirone on Sleep Stage Variables Baseline (nights Variable
Mean
Sleep
time
Drug
SD
24.2 5.2
3.7 1.1
Stage
67.6
3.9
2
Stage3 4
Slowwave REM sleep First
time
third
Second
REM
third latency
Number
REM
Significantly Significantly
21.3 6.6 69.5 2.6
3.3 3.0 4.4 2.1
23.5 6.5 67.7 2.3
4.7 1.2 5.6 2.2
Mean
12-14 SD
Nights Mean
15-16 SD
26.3 6.4 63.9 3.4
3.9 2.0 4.8 3.8
25.9 5.5 65.8 2.8
7.2 1.5 6.8 2.3
2.7 0.2
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
3.0
2.7
2.6
2.0
2.3
2.2
3.4
3.8
2.8
2.3
7.9
54
10#{149}3b
6.2
17.3
4.9
17.3
7.3
26.3
5.3
25.8
4.1
29.8
8.9
26.8
9.1
of night
32.8
4.0
28.4
7.8
36.5
9.4
32.3
4.7
33.8
11.9
(mm)
81.2
18.0
104.8
69.5
19.5
60.2
4.2
0.6
4.4
0.8
periods period
sleep
(mm)
(mm)
different different
from from
baseline baseline
8.Oa
3.8
on Sleep
Induction
Psychiatry
I 48:9,
September
0.8
94.5 3.7
5.4
24.6
9.0
27.2
102.6
16.7
86.6
13.7
97.7
(t=4.71, (t=2.87,
and
39.7
24.8
df=70, df=70,
Sleep
Maintenance
1991
48.5 0.5
6.5 22.7
4.6
6.3
5.9 0.5
26.5
6.9
24.4
8.9
112.5
21.1
109.4
37.1
p
