Mexazolam and Alprazolam in the Treatment of Generalised Anxiety Disorder
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
CLINICAL USE Clin Drug Invest 2001; 21 (4): 257-263
1173-2563/01/0004-0257/$22.00/0
© Adis International Limited. All rights reserved.
Mexazolam and Alprazolam in the Treatment
of Generalised Anxiety Disorder
A Double-Blind, Randomised Clinical Trial
Adriano Vaz-Serra,1 Maria Luisa Figueira,2 Alberto Bessa-Peixoto,3 Horatio
Firmino,2 Rodolfo Albuquerque2 Cristina Paz,3 Ana Dolgner,4 Manuel Vaz-
Silva4 and Luis Almeida4
1 Department of Psychiatry, Hospital of the University of Coimbra, Coimbra, Portugal
2 Department of Psychiatry, Hospital Santa Maria/Faculty of Medicine, Lisbon, Portugal
3 Department of Psychiatry, Hospital S. Marcos, Braga, Portugal
4 Department of Research & Development, Bial, S. Mamede do Coronado, Portugal
Abstract Objective: To compare the anxiolytic effects of mexazolam with those of
alprazolam in patients with generalised anxiety disorder (GAD).
Methods: Multicentre, randomised, double-blind, parallel-group clinical trial in
64 outpatients with GAD (DSM-IV criteria). Patients were assigned to
mexazolam 1mg three times daily (n = 32) or alprazolam 0.5mg three times daily
(n = 32) during 1 week, followed sequentially by a period of 2 weeks of reducing
dosage according to therapeutic response and by 1-week taper and 1-week treat-
ment-free periods. The Hamilton Anxiety Rating Scale (HAM-A), the Clinical
Global Impression (CGI), and the Snaith & Zigmund anxiety and depression
self-rating scale (SZS) were used to evaluate the patient's clinical status.
Results: Both treatment groups showed a statistically significant anxiolytic
effect: a decrease of mean HAM-A score of 16.28 with mexazolam (p < 0.0001
vs baseline) and 14.2 with alprazolam (p< 0.0001) and a reduction in CGI-disease
severity score of 2.66 (p < 0.0001) with mexazolam and 2.44 with alprazolam
(p < 0.0001). Although a higher absolute rate of responders was observed in the
mexazolam group, there were no statistically significant differences in the
between-group comparisons (80% vs 70% in HAM-A and 96.7% vs 86.7% in
CGI evaluations). Five mexazolam and nine alprazolam recipients reported mild
adverse events.
Conclusion: Both mexazolam and alprazolam showed a significant anxiolytic
effect and were well tolerated in the treatment of GAD, making it an effective
pharmacotherapeutic alternative in the treatment of GAD.258 Vaz-Serra et al.
Generalised anxiety disorder (GAD) is a com- score ≥21 in the Hamilton Anxiety Rating Scale
mon condition estimated to have a 1-year preva- (HAM-A) and a scoreMexazolam and Alprazolam in GAD 259
Table I. Disposition of patients included in the studya
Alprazolam Mexazolam Total
No. of patients enrolled (entry, day 0) 32 32 64
Evaluable at visit 2 (day 7) 30 31 61
Evaluable at visits 3 and 4 (days 21 and 28) 30 30 60
Evaluable at visit 5 (day 35) 29 29 58
a Patients who dropped out were lost to follow-up.
investigator could reduce the daily dose according carried forward). Proportions of responders were
to the clinical response. This adjusted daily dose compared by Chi-square test. The assessments at
was maintained from visit 2 up to visit 3 (day 21). visit 1 were considered as baselines. The within-
At visit 3 the investigator implemented a 1 -week group analyses were evaluated by the non-
therapy discontinuation (taper) period. At visit 4 parametric Friedman test. Statistically significant
(day 28) a treatment-free follow-up period started, differences were defined as p < 0.05. For tolerabil-
lasting for 1 week up to visit 5 (day 35). ity parameters descriptive statistics were used.
Data cleaning occurred before the breaking of
Assessment Procedure the randomisation code. The treatments were
coded ('treatment A' vs 'treatment B') for the
The patient's clinical status was evaluated at purposes of blinding for statistical analysis. The
each visit by using the HAM-A scale, the Clinical SPSS statistical package was used.
Global Impression (CGI) and a self-rating scale
(SZS). Primary efficacy variables were HAM-A
mean global scores, proportion of HAM-A Results
responders (>50% decrease in the HAM-A global
scores), CGI disease severity and global improve- Patient Disposition
ment rating by the investigator and proportion of
CGI responders ('highly improved' or 'moderately A total of 64 patients were enrolled: 32 were
improved'). SZS score was the secondary efficacy randomly assigned to the mexazolam group and 32
variable. At each visit, a physical examination was to the alprazolam group (table I).
performed and patients were questioned about At the end of the fixed-dose period (visit 2),
adverse events. Compliance was assessed by tablet three patients were lost to follow-up and 61
counting at each visit. patients were available for both efficacy and toler-
ability analyses (alprazolam: n = 30; mexazolam:
Statistics n = 31). At the end of the period of dosage adjust-
ment (visit 3), one additional patient from the
Baseline comparisons between treatment mexazolam group was lost to follow-up. No pre-
groups were analysed by the Chi-square test mature withdrawal was attributable to adverse
(qualitative variables) or by one-way analysis of events and no major protocol violation was ob-
variance (ANOVA) with the Bonferroni correction served. Thus, all the available patients at every
for multiple comparisons (quantitative variables). follow-up visit were evaluable (table I).
For the continuous variables, differences between Demographic data are presented in table II. The
treatment groups were analysed by one-way between-groups comparison showed no statisti-
ANOVA with Bonferroni alpha adjustment. In cally significant differences in the demographic
patients who dropped out prematurely but took parameters. There were no statistically significant
part for at least two visits, the missing values were differences between treatment groups with regard
replaced by the last valid value (last observation to baseline clinical parameters such as mean
© Adis International Limited. All rights reserved. Clin Drug Invest 2001; 21 (4)260 Vaz-Serra et al.
Table II. Demographic and clinical data of patients available for analysis
Alprazolam Mexazolam p-Value
Age (y) [mean ± SD (range)] 38.7±12.1 (19-65) 36.9±10.8(21-64) NSa
Gender (n) [male/female] 6/26 9/23 NSb
Race (n) [Caucasian/other] 32/0 32/0
Height (cm) [mean ± SD (range)] 161.5 ±9.5 (148-186) 161.9 ± 7.9(150-182) NSa
Weight (kg) [mean ± SD (range)] 67.8 ±13.3 (47-96) 63.3 ±10.8 (44-90) NSa
HAM-A score (mean ± SD) 26.4 ± 3.15 26.45 ± 3.48 NSa
CGI score (mean ± SD) 4.07 ± 0.64 4.13 ± 0.68 NSa
SZS score (mean + SD) 1.74 ±0.35 1.99 ± 0.35 NSa
a ANOVA with Bonferroni correction.
b Chi-square test.
CGI = clinical global improvement; HAM-A = Hamilton Anxiety Rating scale; NS = between groups difference not statistically significant
(p > 0.05); SD = standard deviation; SZS = Snaith & Zigmund anxiety and depression self-rating scale. ___________
HAM-A scores, mean CGI-disease severity score with no differences between the treatment groups
and mean SZS scores (table II). (fig. 3). CGI-DSS decreased by 2.66 (p < 0.0001)
Although the protocol had specified that at with mexazolam and by 2.44 with alprazolam (p <
visit 2 the investigator could reduce the daily dose 0.0001). As with the HAM-A score, mexazolam
according to the clinical response, the dose was showed a higher percentage of responders accord-
decreased in only eight patients from the mexazo- ing to the CGI-global improvement score (CGI-
lam group and six patients from the alprazolam GIS) than alprazolam at the end of the first and
group. third weeks of treatment (54.8% vs 46.7%, and
Efficacy Data
Analysis of the mean HAM-A global scores at
the different visits showed a rapid and pronounced
effect for both mexazolam and alprazolam. For
both treatment groups, the reduction in the HAM-A
score from baseline was statistically significant
(p = 0.0001) from visit 2 onwards (fig. 1). Mean
HAM-A scores decreased by 16.28 with mexazo-
lam (p < 0.0001 vs baseline) and by 14.2 with
alprazolam (p < 0.0001).
After 1 week of therapy, the proportion of
HAM-A responders was 35.5% with mexazolam
and 23.3% with alprazolam; after 3 weeks of treat-
ment, the values increased to 80.0% and 70.0%,
respectively. Although the absolute results
obtained were higher with mexazolam than with
alprazolam, these differences failed to show statis-
tical significance (p > 0.05) [fig. 2].
Fig. 1. Hamilton Rating Scale for Anxiety (HAM-A) mean score
The mean CGI-disease severity score (CGI- variation from baseline (within-group analysis: p < 0.0001,
DSS) reduction from baseline was statistically Friedman non-parametric test; between-groups comparison:
significant in both treatment groups (p< 0.00001), D > 0.05. ANOVA)Mexazolam and Alprazolam in GAD 261
patients in each group; dizziness was reported by
one patient with mexazolam and by two patients
with alprazolam; blurred vision was reported by
one patient with mexazolam; weight gain, nausea,
initial insomnia and asthenia were other events
reported with alprazolam (one patient each).
During the 1-week taper and 1-week treatment-
free periods, five patients in the mexazolam group
and one in the alprazolam group reported mild
initial insomnia, two patients receiving
mexazolam and one receiving alprazolam re-
ported mild irritability, and one patient receiving
mexazolam mentioned increased dreams.
Discussion
Benzodiazepines are largely accepted as being
the first pharmacotherapeutic approach in the treat-
Fig. 2. Hamilton Rating Scale for Anxiety (HAM-A) - percentage ment of GAD. Lader[16] stated that for short-term
of responders (>50% reduction in the HAM-A total score from
baseline) [between-groups comparison: p > 0.05, Chi-square treatment up to 4 weeks, the benzodiazepines are
test]. an invaluable symptomatic treatment, assuaging
anxiety and tension, lessening physical symptoms
and inducing a state of well-being.
96.7% vs 86.7%, respectively). Again these differ-
In this double-blind, randomised study,
ences did not achieve statistical significance (fig. 4).
mexazolam and alprazolam showed similar effi-
The beneficial anxiolytic effect of both mexazo-
lam and alprazolam persisted during the tapering
and withdrawal periods (fig. 3).
Analysis of the SZS global scores also did not
show significant differences between alprazolam
and mexazolam, and the effect of both drugs
persisted until the end of the follow-up period.
Tolerability Data
All the adverse events were mild to moderate in
intensity and no serious adverse events were re-
ported. There were no premature withdrawals re-
sulting from adverse events. The adverse events
observed with each drug were consistent with the
profile known for benzodiazepines, mostly con-
sisting of CNS-related symptoms.
In the 3-week treatment period, a total of 14
patients (five patients in the mexazolam group and Fig. 3. Clinical global impression - disease severity score
(CGI-DSS): mean score variation from baseline (within-group
nine patients in the alprazolam group) reported analysis: p < 0.0001, Friedman non-parametric test; between-
adverse events. Drowsiness was reported by three groups comparison: p > 0.05, ANOVA).
© Adis International Limited. All rights reserved. Clin Drug Invest 2001 : 21(4)262 Vaz-Serra et al.
the trial, including the tapering and treatment-free
follow-up periods. This short latency of the anxio-
lytic effect has clinical relevance since it allows
the rapid and consistent control of symptoms. In
terms of percentage of patients with a reduction of
>50% from baseline in the total HAM-A score,
mexazolam and alprazolam achieved similar and
significant anxiety control throughout the entire
clinical trial. Although in absolute values
mexazolam appeared to obtain somewhat superior
results compared with alprazolam in the proportion
of responders, both in HAM-A scores and on the
CGI-GIS, the difference did not achieve statistical
significance. Similar results were obtained for
alprazolam in a study reported by Figueira.[5]
A possible limitation of this study is the lack of
a placebo group, which would exclude the possi-
bility that improvement would have occurred in
Fig. 4. Clinical global impression - global improvement score time, irrespective of the intervention.
(CGl-GIS): percentage of responders (patients highly improved
or moderately improved) [between-groups comparison: p > Benzodiazepines seem to obtain more rapid
0.05, Chi-square test]. anxiety control than the 5-HT1A agonist buspirone,
as shown in several studies.[4,17,18] There are also
reports comparing the onset of action of anti-
cacy in treating anxiety in patients with GAD, depressants and benzodiazepines in the treatment
the effect being evident as early as 1 week after of GAD. In a 6-week double-blind, randomised
initiating treatment. A similar efficacy, short study, Hoehn-Saric et al.[8] showed that both
latency and sustained effect was also reported alprazolam and imipramine produced significant
with mexazolam in 206 outpatients with GAD in improvements in patients with GAD. Rickels et
an open-label study.[10] In that study mexazolam al.[19] demonstrated a slower onset of action of
showed good efficacy and tolerability in control- imipramine or trazodone compared with diazepam.
ling anxiety associated with diverse causes (e.g. Different types of benzodiazepines at equiva-
post-traumatic stress disorder and depressive syn- lent doses appear to be equally effective for GAD,
dromes). and the agent used should be chosen on the basis
To our knowledge, ours was the first compara- of potency, half-life and adverse effect profile.
tive study between mexazolam and alprazolam. Al- Fabre and McLendon[9] and Anden and Thein[20]
prazolam was chosen as the reference drug'because found optimal therapeutic doses of l.8mg and
of its widespread use in the treatment of anxiety 1.5mg per day, respectively, for alprazolam for
disorders. As in the studies by Enkelmann[4] (al- the control of anxiety. In our study the dose of
prazolam vs buspirone) and Figueira[5] (alprazolam mexazolam used (1mg three times daily) seemed to
vs bromazepam), the present study showed that be equipotent with alprazolam 0.5mg three times
alprazolam produced a rapid and sustained reduc- daily.
tion in parameters related to anxiety. Mexazolam In this study, no clinically important differences
had a similar efficacy profile, i.e. a fast onset of in tolerability were noted between mexazolam and
action (significant reduction in anxiety scores in alprazolam. Adverse reactions in both treatment
the first week) and a sustained effect throughout groups were mild in intensity and consistent withMexazolam and Alprazolam in GAD 263
the well-known adverse effect profile of benzo- 5. Figueira ML. Alprazolam extended release in the management
of anxiety. Curr Ther Res 1995; 56: 57-65
diazepines. The most commonly reported effect 6. Klein E, Zinger O, Colin V, et al. Clinical similarity and biolog-
was drowsiness (9.7% with mexazolam and 10.0% ical diversity in the response to alprazolam in patients with
with alprazolam). The frequency of adverse re- panic disorder and generalized anxiety disorder. Acta Psy-
chiatrScand 1995; 92: 399-408
actions with alprazolam was similar to that re- 7. Cohn JB, Wilcox CS. Low-sedation potential of buspirone
ported in other comparative studies. Enkelmann[4] compared with alprazolam and lorazepam in the treatment of
found adverse reactions in 13 out of 32 patients anxious patients: a double-blind study. J Clin Psychiatry
1986; 47:409-12
with GAD treated with alprazolam. Also, Figueira[5] 8. Hoehn-Saric R, McLeod DR, Zimmerli WD. Differential ef-
found 32.2% of GAD patients reporting at least one fects of alprazolam and imipramine in generalized anxiety
disorder: somatic versus psychic symptoms. J Clin Psychiatry
adverse event with alprazolam. In the present 1998; 49: 293-301
study, 16.1% of patients treated with mexazolam 9. Fabre LF, McLendon D. A double-blind study comparing the
reported adverse events. The frequency of daytime efficacy and safety of alprazolam with diazepam and placebo
in anxious outpatients. Curr Ther Res 1979; 25:519-26
sedation (9.7%) found with the use of mexazolam 10. Vieira-Coelho MA, Garret J. Mexazolam in anxiety disorders:
was similar to that observed in the study published results of a multicenter trial. Adv Ther 1997; 14:125-33
by Vieira-Coelho and Garret[10] (7.5%). 11. Katsunuma H, Shimoto Y, Senba K, et al. Clinical trials of the
anti-anxiety drug CS-386 (mexazolam) in the field of geriat-
rics. Geriatr Med 1981; 19: 126-34
Conclusion 12. Ohara K, Suzuki Y, Kawaguchi K. Clinical evaluation of
mexazolam in neuroses. Jpn J Clin Exp Med 1987; 64: 263-6
This double-blind, randomised study showed 13. Vaz-Serra A, Firmino H. Double-blind randomized clinical trial
that mexazolam can be considered to be as effec- comparing mexazolam versus bromazepam [in Portuguese].
Psiquiatria Clinica 1993; 14:77-84
tive and well tolerated as alprazolam in the treat- 14. Hamilton M. The assessment of anxiety states by rating. B J
ment of patients with GAD, making it an effective Med Psychol 1959; 32: 50-5
pharmacotherapeutic alternative in the treatment 15. Zigmund AS, Snaith RP. The hospital anxiety and depression
scale. Acta Psychiatr 1983; 67 (6): 361-70
of GAD. 16. Lader MH. The nature and duration of treatment for GAD. Acta
Psychiatr Scand 1998; 98 (393 Suppl.): 109-17
Acknowledgements 17. Ansseau M, Papart P, Gerard MA, et al. Controlled comparison
of buspirone and oxazepam in generalized anxiety. Neuro-
This study was supported by a grant from Laboratories psychobiology 1990; 24: 74-8
Bial, Portugal. 18. Rickels K, Schweizer E, Csanalosi I, et al. Long-term treatment
of anxiety and risk of withdrawal. Prospective comparison of
clorazepate and buspirone. Arch Gen Psychiatry 1988; 45:
References 444-50
1. Kaplan HI, Sadock BJ. Generalized anxiety disorder. In: 1.9. Rickels K, Downing R, Schweizer E, et al. Antidepressants for
Kaplan HI, Sadock BJ, editors. Synopsis of psychiatry: the treatment of generalized anxiety disorder: a placebo-con-
behavioural sciences, clinical psychiatry. 8th ed. Phila- trolled comparison of imipramine, trazodone and diazepam.
delphia: Lippincott Williams & Wilkins, 1998: 623-8 Arch Gen Psychiatry 1993; 50: 884-95
2. Uhlenhuth EH, Baiter MB, Ban TA, et al. International study of 20. Anden GC, Thein SG. Alprazolam compared to diazepam and
expert judgement on therapeutic use of benzodiazepines and placebo in the treatment of anxiety. J Clin Psychiatry 1980;
other psychotherapeutic medications: VI. Trends in recom- 41: 245-8
mendations for the pharmacotherapy of anxiety disorders,
1992-1997. Depress Anxiety 1999; 9: 107-16
3. Elie R, Lamontagne Y. Alprazolam and diazepam in the treat-
ment of generalized anxiety. J Clin Psychopharmacol 1984;
4: 125-9 Correspondence and offprints: Dr Luis Almeida, R & D
4. Enkelmann R. Alprazolam versus buspirone in the treatment of Department, Laboratórios BIAL, 4745-457 S. Mamede do
outpatients with generalized anxiety disorder. Psycho- Coronado, Portugal. E-mail: luis.almeida@bial.com
pharmacology 1991; 105: 428-32
© Adis International Limited. All rights reserved. Clin Drug Invest 2001; 21 (4)You can also read
