Department of General Psychiatry, University of Vienna, Vienna, Austria
University of Stellenbosch, Cape Town, South Africa and University of Florida, Gainesville, Florida, USA
H. Lundbeck A/S, Copenhagen, Denmark
Lundbeck (Switzerland) Ltd, Glattbrugg, Switzerland
Correspondence: Professor Siegfried Kasper, Department of General Psychiatry, University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Tel: +43 1 40400 3568; fax: +43 1 40400 3099; e-mail: sci-genpsy{at}meduniwien.ac.at
Declaration of interest The study was sponsoredby H. Lundbeck A/S. Other funding detailed in Acknowledgements.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aims To investigate the efficacy and tolerability of escitalopram in the treatment of generalised social anxiety disorder.
Method Patients with generalised social anxiety disorder were randomised to receive placebo (n=177) or 10-20 mg escitalopram (n=181) in a 12-week, double-blind trial. The primary outcome measure was the mean change from baseline to last assessment in the Liebowitz Social Anxiety Scale (LSAS) total score.
Results The study showed a statistically superior therapeutic effect for escitalopram compared with placebo on the LSAS total score (P=0.005). There were significantly more responders to treatment for escitalopram than for placebo (54% v. 39%; P<0.01). The clinical relevance of these findings was supported by significant reduction in the work and social components of the Sheehan Disability Scale and by the good tolerability of escitalopram treatment.
Conclusions Escitalopram was efficacious and well tolerated in the treatment of generalised social anxiety disorder.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
METHOD |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patient population
The patient population comprised female and male out-patients with a
primary diagnosis of generalised social anxiety disorder established by means
of a diagnostic interview following DSMIV criteria
(American Psychiatric Association,
1994), using the Mini-International Neuropsychiatric Interview
(MINI; Sheehan et al,
1998) to assist in the exclusion of disallowed comorbidity. The
patients were mainly recruited through advertisements. At the screening visit,
patients 1865 years old were selected if they had a total score of at
least 70 on the Liebowitz Social Anxiety Scale (LSAS;
Liebowitz, 1987) with exhibited
fear or avoidance traits in at least four social situations, and were
otherwise healthy based on a physical examination. Patients were excluded if
they had another Axis I disorder that was considered the primary diagnosis
within the previous 6 months, if the investigator diagnosed a serious risk of
suicide or if the MontgomeryÅsberg Depression Rating Scale
(MADRS; Montgomery & Åsberg,
1979) total score was higher than 19. Patients were also excluded
if they had a DSMIV diagnosis of alcohol or drug misuse during the past
6 months, or if they had taken a psychoactive drug (including any type of
antidepressant, beta-blocker, benzodiazepine, narcotic, analgesic,
antipsychotic or herbal remedy) within 2 weeks (5 weeks for fluoxetine and 6
months for depot neuroleptics) before screening, or if the patient had a
positive urine drug screen for opiates, methadone, cocaine, amphetamines or
benzodiazepines. The only allowed concomitant use of a psychotropic drug
during the study was chloral hydrate taken as a hypnotic but not for more than
three consecutive nights. Furthermore, patients with a diagnosis of mania or
hypomania, body dysmorphic disorder, schizophrenia/other psychotic disorder,
eating disorders, mental retardation or any Axis II cluster diagnosis were
also excluded. Patients with a known drug (including citalopram) allergy or
hypersensitivity or a known lack of therapeutic response to an adequate trial
with citalopram were also excluded. Patients participating in a formal
psychotherapy programme that went beyond medical counselling were not
included.
Efficacy assessments
The primary efficacy measure was the mean change from baseline to the last
assessment (carried forward) of the LSAS total score. This scale consists of
24 items, 13 describing performance situations and 11 describing social
interaction situations (Liebowitz,
1987). Each of the items is separately rated for
fear and avoidance using a four-point categorical
scale. All investigators attended supervised group sessions in order to
standardise the interview and rating techniques. Secondary efficacy measures
included:
Safety and tolerability
Safety assessments were based on vital signs (in a sitting position after 5
min rest), body weight, clinical laboratory tests (including haematology and
biochemistry) and electrocardiograms (ECGs), and were assessed at the
screening visit and at week 12. Adverse events observed by the investigator,
spontaneously reported by the patient or reported in response to nonleading
questions were recorded at each visit. The investigator documented the
relationship to treatment, onset duration and intensity (mild, moderate or
severe). All adverse events were coded using the included term according to
the World Health Organization Adverse Reaction Terminology.
Statistical analysis
Efficacy analyses were based on the full analysis set (corresponding to the
intent-to-treat population), which comprised all randomised patients who took
double-blind study product and had at least one valid post-baseline assessment
of the primary efficacy measure. Safety analyses were based on the set of all
patients treated, which included all patients who took at least one dose of
double-blind study product.
A minimum of 135 patients per treatment arm was required to reach a power of 90% to detect a significant difference between treatment groups in mean change from baseline to final assessment in LSAS total score at the 5% significance level. A general linear model for analysis of covariance (ANCOVA) was applied to the primary and secondary efficacy measures with factors for treatment group and centres (all centres with fewer than four patients were collapsed into one collective centre), and with baseline LSAS total score as a covariate. The final CGIS and CGII scores were also analysed using the non-parametric CochranMantelHaenszel mean score statistics. Between-group comparisons of the proportion of responders (CGII score of 1 or 2) to treatment were performed using chi-squared and Fishers exact tests. Descriptive statistics were used for absolute values and mean changes from baseline in laboratory values, ECG parameters, vital signs and body weight. All statistical tests were two-sided and were carried out at the 5% level of significance.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Patient withdrawals
A total of 68 patients (19%) withdrew from the study, with no overall
between-group difference (18% in the placebo group and 20% in the escitalopram
group). However, numerically more patients in the escitalopram group (8.8%)
than in the placebo group (4.5%) withdrew because of adverse events and
numerically more patients in the placebo group (6.2%) than in the escitalopram
group (2.2%) withdrew because of lack of efficacy, with the latter difference
approaching statistical significance (P=0.059).
Efficacy results
Primary efficacy outcome
During double-blind treatment the LSAS total score decreased in the
escitalopram group from a baseline value of 96.3 (s.d.=17.4) to 62.2
(s.d.=30.7) at week 12 (last observation carried forward; LOCF) and in the
placebo group from 95.4 (s.d.=16.4) to 68.8 (s.d.=29.7). The treatment
difference of 7.3 between escitalopram and placebo in change from baseline to
week 12 in favour of escitalopram was statistically significant (ANCOVA,
P=0.005) (Fig. 2).
Exploratory analyses of potential covariates revealed no treatment-by-centre
or treatment-by-baseline LSAS total score interaction effect. The same was
true for treatment interactions with gender, age and duration of disorder.
|
Secondary efficacy measures
The mean change from baseline to end-point (LOCF) in the LSAS sub-scale
scores was statistically significant in favour of escitalopram at week 12
(P<0.05) for avoidance and at weeks 6 and 12
(P<0.001) for fear/anxiety, but not for the SDS
family sub-scale (Table
2). Superiority of escitalopram over placebo was also manifested
in the change from baseline to week 12 (LOCF) in CGIS score
(P<0.01), the mean CGII score at week 12
(P<0.001) and in the change from baseline to week 12 (LOCF) in the
two SDS items work (P=0.01) and social
(P=0.02) (Table
2).
|
A total of 54% of escitalopram-treated patients and 39% of placebo-treated patients responded to treatment (LOCF, P<0.01). The corresponding figures for the observed case (OC) analysis were 63% of escitalopram-treated patients and 43% of placebo-treated patients (P<0.001).
Safety results
Table 3 shows all
treatment-emergent adverse events with an incidence of more than 5% in either
treatment group. No clinically relevant trend was observed in mean ECG or in
clinical laboratory parameters.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In order to investigate the specific efficacy of escitalopram in the treatment of social anxiety disorder, the study selected a somewhat atypical patient population with a low level of comorbidity. The average MADRS total score of 7.5 indicates the absence of significant depressive symptoms. It can thus be concluded that the patient population in this study represents patients with relatively pure, generalised social anxiety disorder. The average LSAS total score at baseline of over 95 indicates a more severely ill patient population than that in other published clinical drug trials (Baldwin et al, 1999; Liebowitz et al, 2002).
Therapeutic efficacy and placebo response
This study of the SSRI escitalopram confirmed the efficacy of SSRIs in the
treatment of generalised social anxiety disorder. Escitalopram had a
significantly better effect than placebo at the end of the 12-week trial
period on both the primary and the secondary efficacy measures, including the
two LSAS sub-scales of fear/anxiety and avoidance.
The primary analysis showed a decrease in the total LSAS score of 34.4 points
in the escitalopram group and a relatively large decrease of 27.2 points in
the placebo group. The effect size in the escitalopram group is comparable
with that reported in other studies of SSRIs in the treatment of generalised
social anxiety (Stein et al,
1998; Allugander,
1999; Baldwin et al,
1999). However, no other published study has reported a placebo
response as high as 39% (LOCF) in social anxiety disorder. A review by
Oosterbaan et al
(2001) analysed 15
placebo-controlled studies and concluded that a moderate placebo response is
seen in this disorder which appears to be lower than that in depression or
panic disorder. The review found no evidence of an increase in the placebo
response in studies of social anxiety over the past decade, although this is
seen for other disorders. There was, however, a trend towards a higher
response rate in the placebo groups, but not in the active treatment groups,
with increasing sample size. No relation was found between the baseline
severity of social anxiety disorder and improvement during treatment, as
measured by the mean change from baseline or the percentage of responders.
This is somewhat in contrast to other studies of this disorder, in which
placebo responders were generally less symptomatic
(Montgomery, 1998) and where a
better separation between active medication and placebo was seen among the
more severely affected patients. The trend towards a higher response rate in
the placebo groups with increasing size of trial, as found by Oosterbaan
et al (2001), is
consistent with the substantial size of our trial.
Irrespective of the placebo response size, the clinical significance of the escitalopram treatment effects in this study was demonstrated by statistically significant effects on the global measures of severity of illness and improvement (CGIS and CGII) and, importantly, also on the two Sheehan Disability Scale items work and social. A final score on the CGII scale of 1 or 2 (very much or much improved) has commonly been used as a response criterion in social anxiety disorder pharmacotherapy trials. In this trial, the escitalopram response rate (OC) was 63% compared with 43% in the placebo group. Again, the magnitude of response of the escitalopram-treated patients is consistent with that reported in other studies, whereas the placebo response rate is higher than that found previously (Liebowitz et al, 2002).
Withdrawals
The total withdrawal rate of 19% is clearly lower than that in a recently
reported fixed-dose study with paroxetine
(Liebowitz et al,
2002) and somewhat lower than the average rate of 23% based on the
15 studies reviewed by Oosterbaan et al
(2001). The latter review
further reported a positive relation between withdrawal rate and the size of
the trials. The withdrawal rates varied slightly between treatment groups in
our study, with borderline statistical significance for the higher rate of
withdrawals due to lack of efficacy in the placebo group, and a somewhat
higher withdrawal rate due to adverse events in the escitalopram group.
Tolerability
Escitalopram was well tolerated in this study, with prevalence rates of
single adverse symptoms comparable with those in studies of its use in
depression (Wade et al,
2002). A favourable tolerability profile is important in the
pharmacotherapy of this chronic disease, for which lengthy treatment may be
required. Headache was the adverse event with the highest incidence, and its
incidence was similar in the two treatment groups. Nausea, increased sweating
and sexual side-effects occurred with a higher incidence during escitalopram
treatment. Also in agreement with depression studies, no clinically relevant
mean change in ECG variables was seen in the escitalopram group.
![]() |
Clinical Implications and Limitations |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
ACKNOWLEDGMENTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
R.N. and H.L. are full-time employees of H. Lundbeck AS. S.K. has received grants or research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon and Servier. He works or has worked as a consultant or on an advisory board for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Janssen Pharmaceutica and Novartis. His speakers bureaux include AstraZeneca, Eli Lilly, Lundbeck and Janssen Pharmaceutica. D.S. has received research grants and/or consultancy honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo and Wyeth.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
American Psychiatric Associaton (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). Washington, DC: APA.
Baldwin, D., Bobes, J., Stein, D. J., et al (1999) Paroxetine in social phobia/social anxiety disorder. Randomised, double-blind, placebo-controlled study. Paroxetine Study Group. British Journal of Psychiatry, 175, 120 -126.[Abstract]
Ballenger, J. C., Davidson, J. R. T., Lecrubier, Y., et al (1998) Consensus statement on social anxiety disorder from the International Consensus Group on Depression and Anxiety. Journal of Clinical Psychiatry, 59 (suppl. 17), 54 -60.[Medline]
Guy, W. (1976) ECDEU Assessment Manual for Psychopharmacology. Revised DHEW Pub. (ADM). Rockville, MD: National Institute of Mental Health.
Kasper, S. (1998) Social phobia: the nature of the disorder. Journal of Affective Disorders, 50, S3-S9.[CrossRef][Medline]
Lépine, J. P. & Pélissolo, A. (1996) Comorbidity and social phobia: clinical and epidemiological issues. International Clinical Psychopharmacology, 11 (suppl. 3), 35 -41.
Lépine, J. P. & Pélissolo, A. (2000) Why take social anxiety disorder seriously? Depression and Anxiety, 11, 87-92.[CrossRef][Medline]
Liebowitz, M. R. (1987) Social phobia. Modern Problems in Pharmacopsychiatry, 22, 141 -173.
Liebowitz, M. R., Stein, M. B., Tancer, M., et al (2002) A randomised, double-blind, fixed-dose comparison of paroxetine and placebo in the treatment of generalised social anxiety disorder. Journal of Clinical Psychiatry, 63, 66-74.[Medline]
Montgomery, S. A. (1998) Implication of the severity of social phobia. Journal of Affective Disorders, 50, S17 -S22.[CrossRef][Medline]
Montgomery, S. A. & Åsberg, M. (1979) A new depression scale designed to be sensitive to change. British Journal of Psychiatry, 134, 382 -389.[Abstract]
Oosterbaan, D. B., van Balkom, A. J. L. M., Spinhoven, P., et al (2001) The placebo response in social phobia. Journal of Psychopharmacology, 15, 199 -203.[Medline]
Sheehan, D. V. (1983) The Anxiety Disease. New York: Scribner.
Sheehan, D. V., Lecrubier, Y., Sheehan, K. H., et al (1998) The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry, 59 (suppl. 20), 22 -33.[Medline]
Stein, M. B., Liebowitz, M. R., Lydiard, R. B., et al (1998) Paroxetine treatment of generalised social phobia (social anxiety disorder) - a randomised controlled trial. JAMA, 26, 707 -713.[CrossRef]
Stein, M. B., Fyer, A. J., Davidson, J. R., et al
(1999) Fluvoxamine treatment of social phobia (social anxiety
disorder): a double-blind, placebo-controlled study. American
Journal of Psychiatry, 156, 756
-760.
Van Ameringen, M. A., Lane, R. M., Walker, J. R., et al
(2001) Sertraline treatment of generalised social phobia: a
20-week, double-blind, placebo-controlled study. American Journal
of Psychiatry, 158, 275
-281.
Versiani, M. (2000) A review of 19 double-blind placebo-controlled studies in social anxiety disorder (social phobia). World Journal of Biological Psychiatry, 1, 27-33.[Medline]
Wade, A., Lemming, O. M. & Hedegaard, K. B. (2002) Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. International Clinical Psychopharmacology, 17, 95-102.[Medline]
Wittchen, H. U., Stein, M. B. & Kessler, R. C. (1999) Social fears and social phobia in a community sample of adolescents and young adults: prevalence, risk factors and co-morbidity. Psychological Medicine, 29, 309 -323.[CrossRef][Medline]
Received for publication January 21, 2004. Revision received September 16, 2004. Accepted for publication September 29, 2004.