Escitalopram in the Treatment of Social Anxiety Disorder Randomised, Placebo-Controlled, Flexible-Dosage Study

BRITISH JOURNAL OF PSYCHIATRY (2005), 186, 222^226

Escitalopram in the treatment of social the Clinical Global Impression scale rating for severity (CGI–S; Guy, 1976) or no de- anxiety disorder crease in CGI–S score since baseline. The mean daily dose of escitalopram was 17.6 mg at week 12. Efficacy and tolerabil- Randomised, placebo-controlled, flexible-dosage study ity were assessed at baseline and after 1, 2, 3, 4, 6, 8 and 12 weeks of treatment. SIEGFRIED KASPER, DAN J. STEIN, HENRIK LOFT and RICO NIL

Patient population The patient population comprised female and male out-patients with a primary Background Selective serotonin Social phobia or anxiety disorder is increas- diagnosis of generalised social anxiety dis- reuptakeinhibitors are effective ininthe the ingly recognised as a highly prevalent and order established by means of a diagnostic chronic disorder with onset during the teen- interview following DSM–IV criteria treatmentof social anxietydisorderanxiety disorder and age years (Le(Lepine´pine & PePelissolo,´lissolo, 1996; (American Psychiatric Association, 1994), are currently regarded as the WittchenWittchen et aletal, 1999). Although the disor- using the Mini-International Neuropsychia- pharmacotherapy of choice. der is associated with significant disability tric Interview (MINI; Sheehan et aletal, 1998),1998) (including educational and occupational) to assist in the exclusion of disallowed co- Aims Toinvestigate the efficacy and which has a negative impact on quality morbidity. The patients were mainly tolerabilitytolerabilityof of escitalopraminescitalopraminthe the of life, it is both underdiagnosed and recruited through advertisements. At the treatmentof generalised social anxiety undertreated (Kasper, 1998). Early work screening visit, patients 18–65 years old disorder.disorder. demonstrated that monoamine oxidase were selected if they had a total score of inhibitors (e.g. phenelzine) were effective at least 70 on the Liebowitz Social Anxiety MethodMethod Patients with generalised in the treatment of the disorder, but these Scale (LSAS; Liebowitz, 1987) with exhib- agents are limited by their side-effect pro- ited fear or avoidance traits in at least four social anxiety disorder were randomised file, the need for dietary precautions, and social situations, and were otherwise to receive placebo (nn¼177) or10^20 mg drug interactions (Versiani, 2000). More healthy based on a physical examination. escitalopram (nn¼181) in a 12-week, recent work has established the efficacy of Patients were excluded if they had another double-blind trial.The primary outcome several selective serotonin reuptake inhibi- Axis I disorder that was considered the pri- measuremeasurewasthemeanchangefrom was the mean change from tors (SSRIs) (Stein et aletal, 1999; Van mary diagnosis within the previous 6 AmeringenAmeringen et aletal, 2001; Liebowitz et aletal,, months, if the investigator diagnosed a ser- baseline to last assessment in the 2002) and these agents have been ious risk of suicide or if the Montgomery– Liebowitz Social Anxiety Scale (LSAS) recommended as first-line pharmaco- AAsberg˚ sberg Depression Rating Scale (MADRS; total score. therapy (Ballenger et aletal, 1998). This study Montgomery & AAsberg,˚ sberg, 1979) total score investigates the efficacy and tolerability of was higher than 19. Patients were also ex- ResultsResults The study showed a statistically escitalopram in the treatment of generalised cluded if they had a DSM–IV diagnosis of superior therapeutic effect for social anxiety disorder. alcohol or drug misuse during the past 6 escitalopram compared with placebo on months, or if they had taken a psychoactive drug (including any type of antidepressant, theLSAStotalscore(the LSAS total score (PP¼0.005).There METHOD beta-blocker, benzodiazepine, narcotic, were significantly more responders to analgesic, antipsychotic or herbal remedy) treatmentfor escitalopramthan for Study design and dosing schedule within 2 weeks (5 weeks for fluoxetine placebo (54% vv.39%;PP550.01).The clinical This multinational study was a randomised, and 6 months for depot neuroleptics) relevance of these findings was supported parallel group, placebo-controlled trial before screening, or if the patient had a involving 41 centres in eight countries positive urine drug screen for opiates, by significant reduction in the work and (Austria, Canada, Denmark, Finland, methadone, cocaine, amphetamines or social components of the Sheehan Germany, Norway, South Africa and the benzodiazepines. The only allowed conco- Disability Scale and by the good UK). Patients who met selection criteria mitant use of a psychotropic drug during tolerabilitytolerabilityof of escitalopramtreatment. entered a 1-week, single-blind, placebo the study was chloral hydrate taken as a lead-in period before being randomised to hypnotic but not for more than three conse- Conclusions Escitalopram was 12 weeks of double-blind treatment with cutive nights. Furthermore, patients with a efficacious and welltoleratedinwelltoleratedinthe the escitalopram or matched placebo capsules. diagnosis of mania or hypomania, body Patients were contacted for a safety dysmorphic disorder, schizophrenia/other treatmentof generalised social anxiety follow-up 30 days after their last dose. psychotic disorder, eating disorders, mental disorder.disorder. The initial dosage of escitalopram was retardation or any Axis II cluster diagnosis 10 mg per day. The dosage could be in- were also excluded. Patients with a known Declaration of interest The studyThestudy creased to 20 mg per day after 4, 6 or 8 drug (including citalopram) allergy or wassponsoredby H.Lundbeck A/S.Other weeks of treatment in case of an unsatisfac- hypersensitivity or a known lack of thera- funding detailed in Acknowledgements. tory response, judged as a score above 5 on peutic response to an adequate trial with

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citalopram were also excluded. Patients Statistical analysis participating in a formal psychotherapy Efficacy analyses were based on the full programme that went beyond medical analysis set (corresponding to the intent- counselling were not included. to-treat population), which comprised all randomised patients who took double- Efficacy assessments blind study product and had at least one valid post-baseline assessment of the pri- The primary efficacy measure was the mary efficacy measure. Safety analyses mean change from baseline to the last were based on the set of all patients treated, assessment (carried forward) of the LSAS which included all patients who took at total score. This scale consists of 24 items, least one dose of double-blind study 13 describing performance situations and product.product. 11 describing social interaction situations A minimum of 135 patients per treat- (Liebowitz, 1987). Each of the items is ment arm was required to reach a power separately rated for ‘fear’ and ‘avoidance’ of 90% to detect a significant difference using a four-point categorical scale. All between treatment groups in mean change investigators attended supervised group from baseline to final assessment in LSAS sessions in order to standardise the inter- total score at the 5% significance level. A view and rating techniques. Secondary general linear model for analysis of covar- efficacy measures included: iance (ANCOVA) was applied to the (a)(a)meanmean change from baseline to each visit primary and secondary efficacy measures in the LSAS sub-scale scores for ‘fear/ with factors for treatment group and anxiety’ and ‘avoidance’; centres (all centres with fewer than four patients were collapsed into one collective (b)(b)CGI–SCGI–S score per visit and change from centre), and with baseline LSAS total baseline to visit; score as a covariate. The final CGI–S and Fig. 11Fig. Study profile. CGI–I scores were also analysed using the (c)(c)ClinicalClinical Global Impression – Improve- non-parametric Cochran–Mantel–Haenszel ment (CGI–I) score: proportion of mean score statistics. Between-group com- responders to treatment, defined as patients achieving a score of 1 (very parisons of the proportion of responders disorder, as measured by the baseline LSAS much improved) or 2 (much improved) (CGI–I score of 1 or 2) to treatment were total score and the CGI score. There was no on the CGI–I; performed using chi-squared and Fisher’s difference with respect to medical history exact tests. Descriptive statistics were used or physiological variables. Comorbidity (d)(d)SheehanSheehan Disability Scale (SDS; Sheehan, for absolute values and mean changes from with depressive symptoms was low, as 1983) score, for the three domains baseline in laboratory values, ECG para- judged by the baseline MADRS total score ‘work’, ‘social’ and ‘family’; meters, vital signs and body weight. All and the low number of patients with a diag- statistical tests were two-sided and nosis of comorbid depression or dysthymia (e)(e)changechange from baseline to each visit in were carried out at the 5% level of (Table 1). The high baseline LSAS total MADRS total score (the MADRS significance. score and the baseline SDS score between consists of ten items, each rated on a 6 and 7 (on a ten-point scale) for the work scale from 0 to 6). RESULTSRESULTS and social life items are in line with the average CGI–S score, indicating a markedly Safety and tolerability Patient baseline characteristics ill patient population. Safety assessments were based on vital signs A total of 358 patients were randomised (in a sitting position after 5 min rest), body into the study, 177 to placebo treatment weight, clinical laboratory tests (including and 181 to escitalopram treatment. Of haematology and biochemistry) and these, 5 patients did not receive double- Patient withdrawals electrocardiograms (ECGs), and were blind treatment. The full analysis set thus A total of 68 patients (19%) withdrew assessed at the screening visit and at week consisted of 177 patients in the escitalo- from the study, with no overall between- 12. Adverse events observed by the investi- pram group and 176 patients in the placebo group difference (18% in the placebo group gator, spontaneously reported by the group. A total of 290 patients (81%) com- and 20% in the escitalopram group). How- patient or reported in response to non- pleted the study, 145 in each treatment ever, numerically more patients in the leading questions were recorded at each group (Fig. 1). There were slightly more escitalopram group (8.8%) than in the visit. The investigator documented the men than women in both treatment groups. placebo group (4.5%) withdrew because relationship to treatment, onset duration Baseline characteristics were similar for the of adverse events and numerically more and intensity (mild, moderate or severe). two treatment groups with the exception of patients in the placebo group (6.2%) All adverse events were coded using the age and duration of the disorder, both of than in the escitalopram group (2.2%) included term according to the World which were slightly higher in the escitalo- withdrew because of lack of efficacy, with Health Organization Adverse Reaction pram group (Table 1). No between-group the latter difference approaching statistical Terminology. difference was seen for the severity of the significance (PP¼0.059).0.059).

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Ta b l e 1 Patient characteristics at baseline assessment also manifested in the change from baseline to week 12 (LOCF) in CGI–S score Placebo group Escitalopram group Total ((PP550.01), the mean CGI–I score at week 12 (12(PP550.001) and in the change from ((nn¼177) ((nn¼181) ((nn¼358)358) baseline to week 12 (LOCF) in the two Gender, nn (%)(%) SDS items ‘work’ (PP¼0.01) and ‘social’ Men 94 (53) 101 (56)(56)101 195 (55) ((PP¼0.02) (Table 2). Women 83 (47)(47)83 80 (44)(44)80 163 (45)(45)163 A total of 54% of escitalopram-treated patients and 39% of placebo-treated Age, years: mean (s.d.) 36 (11) 39 (11)(11)39 38 (11) patients responded to treatment (LOCF, Age at onset of SAD, years 15 (8) 15 (9)(9)15 PP550.01). The corresponding figures for Duration of SAD, years: mean (s.d.) 21 (12) 24 (13) the observed case (OC) analysis were 63% Efficacy measure baseline scores: mean (s.d.) of escitalopram-treated patients and 43% LSAS total score 95.4 (16.4) 96.3 (17.4)(17.4)96.3 of placebo-treated patients (PP550.001).0.001). CGI^S 4.8 (0.7) 4.8 (0.7) SDS work sub-scale 6.7 (1.9) 6.9 (2.2)(2.2)6.9 Safety results SDS social sub-scale 7.0 (1.8)(1.8)7.0 6.8 (1.9) Table 3 shows all treatment-emergent SDS family sub-scale 4.7 (2.6) 4.2 (2.4) adverse events with an incidence of more MADRS total score 7.5 (4.4) 7.6 (4.5) than 5% in either treatment group. No CGI^S, Clinical Global Impression ^ Severity; LSAS, Liebowitz Social Anxiety Scale; MADRS, Montgomery^—sberg clinically relevant trend was observed in Depression Rating Scale; SAD, social anxiety disorder; SDS, Sheehan Disability Scale. mean ECG or in clinical laboratory parameters. Efficacy results treatment-by-centre or treatment-by-base- Primary efficacy outcome line LSAS total score interaction effect. DISCUSSION The same was true for treatment During double-blind treatment the LSAS interactions with gender, age and duration Patient population total score decreased in the escitalopram of disorder. The typical onset of social anxiety disorder group from a baseline value of 96.3 during adolescence, with its chronic course, (s.d.(s.d.¼17.4) to 62.2 (s.d.¼30.7) at week its high level of psychiatric comorbidity Secondary efficacy measures 12 (last observation carried forward; and its low spontaneous remission rate, LOCF) and in the placebo group from The mean change from baseline to end- contributes to serious impairment of daily 95.4 (s.d.95.4(s.d.¼16.4) to 68.8 (s.d.¼29.7). The29.7).The point (LOCF) in the LSAS sub-scale scores functioning in the professional and social treatment difference of 7.3 between was statistically significant in favour of life of those with this disorder (Le(Lepine´pine & escitalopram and placebo in change escitalopram at week 12 (PP550.05) for0.05)for PePelissolo,´lissolo, 2000). These epidemiological from baseline to week 12 in favour of ‘avoidance’ and at weeks 6 and 12 characteristics were reflected among our escitalopram was statistically significant ((PP550.001) for ‘fear/anxiety’, but not for participants. The mean age of onset was (ANCOVA, PP¼0.005) (Fig. 2). Exploratory the SDS ‘family’ sub-scale (Table 2). Super- 15 years and the chronicity of the disorder analyses of potential covariates revealed no iority of escitalopram over placebo was was evident from its average duration, which was more than 20 years. Sheehan Disability Scale mean baseline scores for ‘work’ and ‘social’ items (around 7 on the ten-point sub-scales) indicate the negative impact of the disorder on daily life functioning in this group. 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 Fig. 22Fig. Mean change from baseline in Liebowitz Social Anxiety Scale (LSAS) total score (last observation a more severely ill patient population than carried forward; LOCF) by week, for the escitalopram and placebo groups (full analysis set), adjusted for that in other published clinical drug trials baseline score and centre by least squares mean analysis of covariance (**PP550.010.01 vv.placebo)..placebo). (Baldwin(Baldwin et aletal, 1999; Liebowitz et aletal, 2002).,2002).

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Ta b l e 22Tab Adjusted mean change from baseline to week12 in LSAS and SDS scores and response rate change from baseline or the percentage of responders. This is somewhat in contrast Placebo group (nn¼176)Escitalopram group (nn¼177) to other studies of this disorder, in which placebo responders were generally less Adjusted mean change in score symptomatic (Montgomery, 1998) and LSAS11 where a better separation between active Total score 7727.2 7734.5** medication and placebo was seen among Fear/anxiety sub-scale 7712.712.7 7716.9*** the more severely affected patients. The trend towards a higher response rate in Avoidance sub-scale 7714.4 7717.6* the placebo groups with increasing size of SDS11 trial, as found by Oosterbaan et aletal (2001),(2001), Work sub-scale 772.032.03 772.90*** is consistent with the substantial size of Social sub-scale 772.12 772.70* our trial.ourtrial. Family sub-scale 771.551.55 771.59 Irrespective of the placebo response Responders to treatment (%)22 39 54** size, the clinical significance of the escitalo-

LSAS, Liebowitz Social Anxiety Scale; SDS, Sheehan Disability Scale. pram treatment effects in this study was 1. Full analysis set, last observation carried forward. demonstrated by statistically significant 2. Participants achieving a score of1orof 1 or 2 on the Clinical Global Impression ^ Improvement scale. effects on the global measures of severity **PP550.05, **PP550.01, ***PP550.0010.001 vv. placebo (analysis of covariance). of illness and improvement (CGI–S and CGI–I) and, importantly, also on the two Therapeutic efficacy and placebo 1999; Baldwin et aletal, 1999). However, no Sheehan Disability Scale items ‘work’ and response other published study has reported a ‘social’. A final score on the CGI–I scale placebo response as high as 39% (LOCF) of 1 or 2 (very much or much improved) This study of the SSRI escitalopram in social anxiety disorder. A review by has commonly been used as a response confirmed the efficacy of SSRIs in the treat- Oosterbaan et aletal (2001) analysed 15 criterion in social anxiety disorder pharma- ment of generalised social anxiety disorder. placebo-controlled studies and concluded cotherapy trials. In this trial, the escitalo- Escitalopram had a significantly better that a moderate placebo response is seen pram response rate (OC) was 63% effect than placebo at the end of the 12- in this disorder which appears to be lower compared with 43% in the placebo group. week trial period on both the primary and than that in depression or panic disorder. Again, the magnitude of response of the the secondary efficacy measures, including The review found no evidence of an in- escitalopram-treated patients is consistent the two LSAS sub-scales of ‘fear/anxiety’ crease in the placebo response in studies with that reported in other studies, whereas and ‘avoidance’. The primary analysis of social anxiety over the past decade, the placebo response rate is higher than that showed a decrease in the total LSAS score although this is seen for other disorders. found previously (Liebowitz et aletal, 2002).,2002). of 34.4 points in the escitalopram group There was, however, a trend towards a and a relatively large decrease of 27.2 higher response rate in the placebo groups, Withdrawals points in the placebo group. The effect size but not in the active treatment groups, with The total withdrawal rate of 19% is clearly in the escitalopram group is comparable increasing sample size. No relation was lower than that in a recently reported fixed- with that reported in other studies of SSRIs found between the baseline severity of dose study with paroxetine (Liebowitz et aletal,, in the treatment of generalised social social anxiety disorder and improvement 2002) and somewhat lower than the aver- anxiety (Stein et aletal, 1998; Allugander, during treatment, as measured by the mean age rate of 23% based on the 15 studies reviewed by Oosterbaan et aletal (2001). The latter review further reported a positive Ta b l e 3 Treatment-emergent adverse events with an incidence greater than 5% relation between withdrawal rate and the size of the trials. The withdrawal rates varied slightly between treatment groups Placebo group Escitalopram group in our study, with borderline statistical sig- ((nn¼177) nn (%) ((nn¼181) nn (%) nificance for the higher rate of withdrawals due to lack of efficacy in the placebo group, Headache 45 (25)45(25) 46 (25)46(25) and a somewhat higher withdrawal rate Nausea 21 (12) 39 (22)(22)39 due to adverse events in the escitalopram FatigueFatigue 15 (9)(9)15 25 (14) group.group. Somnolence 9(5)9 (5) 1818(10) (10) Diarrhoea 8 (5) 17 (9)(9)17 Tolerability Insomnia 11 (6)(6)11 17 (9)(9)17 Escitalopram was well tolerated in this DizzinessDizziness 9(5)9 (5) 1313(7) (7) study, with prevalence rates of single Rhinitis 9(5)9 (5) 1313(7) (7) adverse symptoms comparable with those Sweating increased 3 (2) 11 (6)(6)11 in studies of its use in depression (Wade Ejaculation failure (men) 0 6(6)6 (6) et aletal, 2002). A favourable tolerability Libido decreased 2 (1) 10 (6)(6)10 profile is important in the pharmacotherapy of this chronic disease, for which

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lengthy treatment may be required. Head- ache was the adverse event with the highest CLINICAL IMPLICATIONS incidence, and its incidence was similar in the two treatment groups. Nausea, && Escitalopram is efficacious in the treatment of generalised social anxiety disorder. increased sweating and sexual side-effects occurred with a higher incidence during && The tolerability of escitalopram in the dosage range10^20 mg was as favourable as escitalopram treatment. Also in agreement that previously seen in the treatment of depression. with depression studies, no clinically rele- && The efficacy/tolerability profile of escitalopram and the low withdrawalratewithdrawal rate in this vant mean change in ECG variables was seen in the escitalopram group. study make escitalopram a valuable pharmacotherapeutic option in the treatment of patients with social anxiety disorder.

ACKNOWLEDGEMENTS LIMITATIONS

The authors acknowledge the valuable contributions && A high placebo response rate was found in this study. of all participating investigators in this study. Austria:: Siegfried Kasper, Hans Georg Zapotoczky, Anton && Given the chronic course of the disease, studies with a longer treatment duration ToTolk«lk, , AlbertAlb e r t Wuschitz;Wu s c hit z ; Canada:MichaelVan may be warranted to assess further potential improvements. Ameringen, Jacques Plamondon, Kevin Dwight Kjernisted, Pratap Rao Chokka, Stanley P. Kutcher, && The patient sample was selected to minimise comorbidity with other psychiatric Martin A. Katzman; DenmarkDenmark: Henrik Lublin, Eva disorders in order to investigate effects of escitalopram specifically in social anxiety Jensen, Annemarie Lund Laursen, Peter Kaare stergaard, Flemming Bjrndal, Palle Stensbk disorders. Schrder;Schrder; Finland: Hannu Juhani Koponen, Anna Eliisa Savela, Anneli Timonen, Ulla Marjatta Lepola, Riitta Helena Jokinen, Markus Pulkkinen; Germany:: Dolores Backhaus, Johannes BoBohringer,Karl«hringer, Karl Ditzler, SIEGFRIED KASPER, MD,FRCP,Department of General Psychiatry,University of Vienna,Vienna, Austria; P. Donat, Buckhard FloFlototto,«totto, Hinrich HoHornlein-«rnlein- DAN J. STEIN, PhD,FRCP,University of Stellenbosch,CapeTown, South Africa and University of Florida, Rummel, Gerhard Roth, Christoph Schenk; NorwayNorway:: Gainesville, Florida,USA; HENRIKLOFT,PhD,H. Lundbeck A/S,Copenhagen, Denmark; RICO NIL, PD, Alv A. Dahl, Fred Holsten; South Africa:DanJ.Stein, Dr.sc.nat., ETH, Lundbeck (Switzerland) Ltd,Glattbrugg, Switzerland William J. C. Verbeeck, Catherine Mary Maud, Dora Wynchank, Donald A. B.Wilson, Premakanthie CorrespCorrespondence:ondence: Professor Siegfried Kasper,Department of General PsychPsychiatry,Universityiatry,University of Vienna, R. Laban,Wally Landsberg, Chane¤Magnus; UKUK:Alan WaWahringer« hringer Gurtel18^20,1090 Gu«rtel18^20,1090 Vienna, Austria.Tel: +43140400 3568; fax: +43140400 3099; Wade. e-mail: sci-genpsy@@meduniwien.ac.at R.N. and H.L. are full-time employees of H. Lundbeck AS. S.K. has received grants or (First received 21January21 January 2004, final revision 16 September 2004, accepted 29 September, 2004) research support from Eli Lilly, Lundbeck, Bristol- Myers Squibb, GlaxoSmithKline, Organon and Guy, W. (1976) ECDEU Assessment Manual for Sheehan, D.V., Lecrubier,Y., Sheehan, K. H., et aletal Servier.He works or has worked as a consultant or Psychopharmacology. Revised DHEW Pub. (ADM). (19 9 8) The Mini-International Neuropsychiatric on an advisory board for AstraZeneca, Bristol- Rockville, MD: National Institute of Mental Health. Interview (MINI): the development and validation of a Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, structured diagnostic interview for DSM^IV and ICD^ Kasper, S. 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