Psychopharmacology (1991) 105:428-432

003331589100228S

Psychopharmacology
Springer-Verlag 1991

Alprazolam versus buspirone in the treatment

of outpatients with generalized anxiety disorder
Rainer Enkelmann
Heerstrasse 114, W-5401 St. Goar, Federal Republic of Germany
Received July 19, 1990 / Final version December 3, 1990

Abstract. The efficacy and safety of alprazolam and buspirone for treating generalized anxiety disorder (GAD)
were compared in a 6-week, double-blind, randomized,
placebo-controlled study of 94 outpatients. Mean daily
doses at the end of the study were 1.9 mg atprazolam and
18.7 mg buspirone. As judged by the Hamilton Anxiety
Rating Scale, Hamilton Depression Rating Scale, Physician's Global Improvement Scale, and other efficacy
scales, alprazolam and buspirone were similar in efficacy,
but more effective than placebo, for treating anxiety and
depression symptoms in these patients. Clinically important differences were noted between drugs in the onset of
effect, with alprazolam producing rapid and sustained
improvement within the first week of treatment and buspirone producing more gradual, continuous improvement throughout the study. Significantly more buspirone-treated than alprazolam-treated patients failed to
complete the study, primarily because of side effects or
inefficacy. No clinically important differences were noted
between alprazolam and buspirone in side effects, vital
signs, or laboratory test results. Alprazolam-treated patients most frequently reported central nervous systemrelated side effects (drowsiness and sedation), while buspirone-treated patients most frequently reported gastrointestinal system-related side effects (appetite disturbances and abdominal complaints).
Key words" Alprazolam - Buspirone Generalized anxiety disorder

In recent years, nonbenzodiazepine anxiolytics have

joined benzodiazepines in the anxiolytic marketplace.
One such agent is buspirone, a member of a group of
heterocyclic compounds, the azospirodecanediones,
which are structurally unrelated to the benzodiazepines
and which do not interact with benzodiazepine receptors.
Clinical studies have shown that buspirone is comparable
to diazepam in anxiolytic effect (Feighner et al. 1982),
that it has antidepressant effects (Goldberg and Finnerty
1982), and that it causes fewer and milder side effects
than benzodiazepines (Cohn and Wilcox 1986; Goa and
Ward 1986). Moreover, studies have shown that buspirone does not potentiate alcohol's effects and that it has
no dependence potential (Goa and Ward 1986).
The purpose of this double-blind, placebo-controlled
study was to compare the efficacy and safety of buspirone for treating generalized anxiety disorder (GAD)
in outpatients with those of alprazolam, a triazolobenzodiazepine that is effective for treating anxiety disorders
(Chouinard et al. 1982; Cohn and Wilcox 1984; Vaisanen and Jalkanaen 1987; Rickels et al. 1987), panicrelated disorders (Ballenger et al. 1988), depression (Imlah 1985; Rickels et al. 1987), and depression associated
with anxiety (Cropper et al. 1987; Werner 1987; Lesser
et al. t988) and that is reported to cause fewer side effects
than the classical 1,4-benzodiazepines (Fabre and
McLendon 1979; Cohn 1982; Rickels et al. 1983).

Placebo Materials and methods

Though benzodiazepines have traditionally been regarded as the drugs of choice for treating anxiety disorders, controversy exists about their long-term efficacy as
well as about their potential for abuse and for producing
psychologic and physiologic dependence (Marks 1978;
Gorman 1987). These issues, combined with increasing
public and media criticism of benzodiazepines, have led
to a certain reluctance on the part of practitioners to
prescribe them.

Patient selection criteria. Patients of either sex aged 18-65 years

with a DSM-III (American Psychiatric Association 1980) diagnosis

of G A D and with total scores of at least 18 on the Hamilton Anxiety
Rating Scale ( H A M - A ; Hamilton 1959), at least 7 on the Covi
Anxiety Scale (Lipman and Covi 1976), and no more than 7 on the
Raskin Depression Scale (Raskin et al. 1970) were eligible for the
study. Patients with endogenous depression, psychosis, convulsive
disorders, serious personality disorders, or mixed anxiety/depression in which depression predominated were excluded from the
study, as well those with a history of or existing dependence on
alcohol or drugs. Other exclusion criteria included severe cardiovas-

429
cular, liver, or kidney disease; metabolic disorders; known hypersensitivity to benzodiazepines; pregnancy; nursing; and concomitant use of 13-blockers or centrally acting substances.
Patients underwent a screening examination to ensure study
eligibility. This examination included medical and psychiatric histones; physical examination; laboratory tests; and completion of
the HAM-A, the 21-item Hamilton Depression Rating Scale
(HAM-D; Hamilton 1960), the Raskin Depression Scale, the Covi
Anxiety Scale, and a Symptoms Checklist-90 Global Index and
Factor Scale (SCL-90). Informed consent was obtained from all
patients in accordance with the Declaration of Helsinki.

Study design and procedures. This was a 6-week, double-blind,

placebo-controlled, parallel-group comparison of the efficacy and
safety of alprazolam and buspirone for treating outpatients with
GAD. A 3-7-day washout period (week-l) during which patients
took one placebo capsule daily preceded the treatment period. At
the end of the washout period (baseline evaluation), the HAM-A,
HAM-D, Raskin Depression Scale, Covi Anxiety Scale, and
SCL-90 were completed. Patients who experienced a 50% decrease
in the HAM-A or Covi Anxiety total score during the washout were
considered placebo responders and were not enrolled in the treatment period of the study.
Patients who successfully completed the washout period were
randomized to receive treatment for up to 6 weeks with alprazolam
0.5 rag, buspirone 5 nag, or placebo capsules, all of which were
identical in appearance. The initial dosage of one capsule daily was
increased to one capsule 3 times daily by day 4. Thereafter, the
dosage was adjusted as necessary and at the investigator's discretion
until anxiety symptoms became adequately controlled. The minimum allowable dosage was three capsules daily (1.5 mg alprazolam
or 15 mg buspirone); the maximum was eight capsules daily (4 mg
alprazolam or 40 mg buspirone). Patients were gradually tapered to
zero dose whenever they left the study.
Patients were evaluated weekly. At each visit, a physical examination was performed; vital signs (blood pressure, pulse rate, basal
temperature) were determined; the HAM-A, SCL-90, Physician's
Global Improvement Scale (0 =very bad, could not be worse to
10 = major improvement, back to normal), and a 41-item symptoms
and side-effects checklist were completed; and patients were questioned about the occurrence of intercurrent illnesses and adverse
drug reactions. The HAM-D was completed after weeks 2, 4, and
6; the Raskin Depression Scale and Covi Anxiety Scale were completed after week 6. If patients left the study early, all evaluations
were performed at that time. Compliance was assessed by pill count
at each visit.
Patients were instructed not to use alcohol and not to take
nonstudy psychotropic drugs. Patients were also warned that the
study medications could impair their ability to drive and to operate
dangerous equipment.
Statistical methods. Baseline comparisons among treatment groups
were analyzed by Chi-square test (qualitative variables) or by analysis of variance (ANOVA) techniques (quantitative variables). Differences among treatment groups at weeks 2, 4, and 6 were analyzed
by ANOVA techniques, with only data from patients still in the
study at the time point (week 2, 4, or 6) included in the analyses.
Safety analyses were performed for all patients who received study
medication. Statistically significant differences were defined as
P-<0.05; marginally significant differences were defined as
0.05< P<0.10. If the overall difference among treatment groups
was significant (ANOVA), the Bonferroni Test was used to compare
means among the groups.
Results

Table 1. Number of dropouts by Reason

ALP
N=32

BUS
N=31

PBO
N=31

Side effects
Inefficacy
Side effects and inefficacy
Lost to follow-up
Improvement
Refused treatment
Other

1
0
0
1
0
t
I

3
4
2
2
0
0
0

2
7
0
4
2
5
1

Total

11

21

nosis o f G A D , w h o we referred to the investigator by

general practitioners or w h o came for treatment o f their
o w n accord, were enrolled in the study. D u r a t i o n o f the
present illness was 90 days or less for 21% o f patients,
3 m o n t h s to 1 year for 44% o f patients, and 1 year or
longer for 35 % o f patients. Thirty-one (33 %) patients had
previously received outpatient psychiatric treatment, and
17 (18%) h a d previously received p s y c h o t r o p i c d r u g
treatment.
N o statistically significant prestudy differences were
noted a m o n g treatment g r o u p s in d e m o g r a p h i c variables, and few significant prestudy differences were noted
in psychiatric illness variables. However, significantly
m o r e placebo-treated patients (t5) t h a n alprazolamtreated or buspirone-treated patients (3 and 9, respectively) were receiving outpatient psychiatric treatment at
screen ( P = 0.0003). N o patient was receiving p s y c h o t r o pic drug t h e r a p y at screen.
Twenty-eight o f 32 patients r a n d o m i z e d to alprazolam, 20 o f 31 patients r a n d o m i z e d to buspirone, and
10 o f 31 patients r a n d o m i z e d to placebo completed the
study. Analysis o f the n u m b e r o f patients w h o d r o p p e d
out o f the study reveals that significantly m o r e placebotreated patients t h a n alprazolam-treated or buspironetreated patients ( P = 0 . 0 0 0 1 and P = 0 . 0 1 , respectively)
and significantly m o r e buspirone-treated patients t h a n
alprazolam-treated patients ( P = 0.03) failed to complete
the study. The reasons patients d r o p p e d out o f the study
are summarized in Table 1.

Dosage data
There were no significant differences a m o n g treatment
g r o u p s in the n u m b e r o f capsules taken daily at a n y time
during the study. M e a n daily n u m b e r o f capsules during
week 6 was 3.8 capsules (1.9rag) o f alprazolam,
3.7 capsules (18.7 rag) o f buspirone, and 3.9 capsules o f
placebo.

Effi'eacy data

Patient data
N i n e t y - f o u r patients (48 m e n and 46 w o m e n ) o f m e a n
age 35 years (range, 19-65 years) with a D S M - I I I diag-

As j u d g e d by decreases in the m e a n H A M - A total score,

both active treatments p r o d u c e d i m p r o v e m e n t in anxiety
s y m p t o m s t h r o u g h o u t the study, while placebo p r o d u c e d

430
3O
M

M
E
A 25
N

E
N 20:
T
O
T

T
O 20T
A
L 15~

15-

C
OR 10-

R
E

C
O lo

5-

r . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

-1

,
5

F-6

* --

-1

........

...........

WEEK

-r'

-r"-

WEEK

Fig. 1. M e a n Hamilton Anxiety Rating Scale total scores at

screen (week-l), baseline (week 0), and study weeks 1 through 6.
--- []
Alprazolam;
....I... buspirone;
* ........ placebo. ** Treatment is significantly different from placebo ( P < 0.05)

Fig. 2. Mean Hamilton Depression Rating Scale total scores at

screen (week-l), baseline (week 0), and study weeks 1 through 6.
[]
Alprazolam; --4----- buspirone; ...... *--- placebo.
** Treatment is significantly from placebo ( P < 0.05)

variable improvement (Fig. 1). Improvement in symptoms was rapid (within the first week) and sustained in
the alprazolam group and gradual and continuous in the
buspirone group. By study-end, the mean total H A M - A
score was similar in the alprazolam and buspirone groups
and significantly lower in both active-treatment groups
than in the placebo group.
Examination of the mean H A M - A psychic and somatic factor scores revealed patterns of improvement
similar to those observed for the total score: Alprazolam
produced rapid (week 1) and sustained improvement,
buspirone produced gradual (beginning at week 2) and
continuous improvement, and placebo produced variable improvement in the psychic and somatic factor
scores. Significant differences in the mean psychic factor
score, favoring greater efficacy for alprazotam than for
placebo, were noted at weeks 2, 4, and 6, and significant
differences in the mean somatic factor score, again favoring greater efficacy tbr alprazolam than for placebo, were
noted at weeks 2 and 6. Significant differences in these
scores, favoring greater efficacy for buspirone than for
placebo, were noted at weeks 2 and 6. Mean scores for
these factors did not differ significantly between the alprazolam and buspirone groups at weeks 2, 4, or 6.
As judged by the mean H A M - D total score, alprazolam and buspirone produced similar improvement in
depression symptoms during the study (Fig. 2). Mean
H A M - D total scores were consistently lower, though not
significantly so, in the alprazolam group than in the
buspirone group.
The mean Physician's Global Improvement Score was
consistently higher (indicative of greater improvement),
but not significantly so, in the alprazolam group than in
the buspirone group (Table 2). The mean Physician's
Global Improvement score was significantly higher for
the alprazolam and buspirone groups than for the placebo group at weeks 2 and 6.
Patterns of improvement similar to those described
for the H A M - A and H A M - D total scores were observed
for the mean Raskin Depression Scale, Covi Anxiety
Scale, and SCL-90 total scores as welt as for the mean

Table 2. Physician's global improvement scale d (mean score =1:standard deviation)

Evaluation

Alprazolam

Buspirone

Placebo

Baseline
Week 2
Week 4
Week 6

4.63 + 1.34
7.20 1.77 b
7.374- 1.67
8.28=1:1.17 b

4.7i i 1.53
6.17+2.15 b
7.09=1:2.02
7.60=1:1.47 b

5.10=1:1.49
5.29=1:2.07
6.38=t:2.40
6.00:t:2.54

a Scale: 0 = very bad, could not be worse; 5 = unchanged; 10 = major improvement, back to normal
b Significantly different from placebo (P < 0.05)

SCL-90 somatization, obsessive-compulsive, interpersonM sensitivity, depression, anger-hostility, phobic anxiety, paranoid ideation, and psychotism subfactor scores.
Alprazolam produced rapid and sustained improvement
in these subfactor scores, buspirone produced gradual
and continuous improvement, and placebo produced
variable improvement. Scores were significantly better
for both active treatments than for placebo, but similar
between active treatments, at study-end.

Safety data
There were no significant differences among treatment
groups in the number of patients who reported side
effects (13 alprazolam-treated, 16 buspirone-treated, and
8 placebo-treated patients). Side effects in both treatment
groups were mild in intensity and consistent with the
known side-effect profiles of the drugs, with alprazolamtreated patients most frequently reporting drowsiness,
sedation, dizziness, insomnia, and appetite disturbances
and buspirone-treated patients most frequently reporting
appetite disturbances, abdominal complaints, tiredness,
tremor, irritability, and insomnia.
One alprazolam-treated patient, five buspironetreated patients, and two placebo-treated patients
dropped out of the study because of side effects. Reasons
for dropout in the alprazolam group included nausea,

431
insomnia, nervousness, and tiredness; reasons for dropout in the buspirone group included nausea, vomiting,
dizziness, vertigo, tremor, ataxia, restlessness, insomnia,
fatigue, and weakness.
Blood pressure, pulse rate, basal temperature, and
laboratory test results did not differ significantly among
treatment groups.
Discussion

In this double-blind, randomized study, alprazolam and

buspirone were similar in efficacy, but more effective
than placebo, for treating anxiety and depression symptoms in patients with a DSM-III diagnosis of GAD.
Alprazolam produced rapid and sustained improvement
in symptoms, reducing baseline efficacy scores for anxiety and depression by > 50% within the first week of
treatment, while buspirone produced gradual, continuous improvement in symptoms throughout the
study, reaching about the same level of improvement as
in the alprazotam group by the fifth or sixth study week.
The later onset of buspirone's effect relative to alprazolam suggests that persistence may be needed by both
the therapist and patient to continue treatment with
buspirone until maximal therapeutic effect is achieved.
The fact that the efficacy analyses were performed
using only data from patients still in the study at a time
point (completer analysis) should be considered when
interpreting the efficacy results. Because significantly
more buspirone-treated patients than alprazolam-treated
patients failed to complete the study (11 versus 4), any
greater ett]cacy of alprazolam over buspirone, particularly at study-end, could have been masked by this analysis,
since efficacy data for the buspirone-treated patients who
inadequately responded to treatment were excluded.
No clinically important differences in safety were
noted between alprazolam and buspirone. Side effects in
both treatment groups were mild in intensity and consistent with the known side-effect profiles of the drugs, with
alprazolam-treated patients most frequently reporting
central nervous system-related events and buspironetreated patients most frequently reporting gastrointestinal system-related events. More buspirone-treated patients than alprazolam-treated patients dropped out of
the study because of side effects (3 versus 1) and because
of side effects/inefficacy (2 versus 0).
All treatment groups had relatively high mean H A M - D
total scores (_>20; 21-item scale) at screen and at
baseline. These findings are thought to be related to the
scale itself since, because many symptoms of anxiety are
also symptoms of depression (and, thus, included in the
HAM-D), it is possible for anxious patients to achieve
appreciable H A M - D total scores even if they score low
on some scale items. All patients in this study had a
DSM-III diagnosis of GAD, and none exclusively displayed depressive symptomatology.
Greater efficacy may have been achieved with higher
doses of the medications. However, the doses of alprazolam and buspirone were generally adequate and
equivalent to each other. It was interesting that patients

frequently refused dosage increases, often expressing

concern about increased side effects with higher doses
even though there was no apparent cause for such concern. This may have been a study peculiarity, since the
study was conducted in outpatients who were without the
immediate support of a hospital setting. Additionally,
most of the patients were working during the study and
may have been concerned that drug-related side effects
would impair their work performance.
In future studies, it may be interesting to classify
patients according to an "agitation" or "apathy" parameter to see if alprazolam, which has a greater sedative
effect, is more effective in the agitated, anxious patient,
and buspirone, which has no sedative effect, is more
effective in the apathetic, withdrawn, anxious patient.
Information such as this would provide therapists with
a better understanding of which anxious patients would
respond better to alprazolam and which would respond
better to buspirone, similar to the way in which the
"Kielholz scheme" (Kielholz 1977) defines the patients
who respond to certain antidepressant medications.
In conclusion, this 6-week, double-blind, randomized,
placebo-controlled study demonstrates that alprazolam
and buspirone are similar in efficacy, but more effective
than placebo, for treating anxiety and depression symptoms in patients with GAD. Clinically important differences were noted between drugs in the onset of effect,
with alprazolam producing rapid and sustained improvement within the first week of treatment and buspirone
producing more gradual, continuous improvement
throughout the study. No clinically important differences
in safety were noted between the alprazolam and buspirone groups.

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