اسکالوپورام در مقابل پاروکستین برای اختلال اضطراب اجتماعی: تجزیه و تحلیل اثربخشی ابعاد مختلف علامت

Abstract Background: A previous factor analysis of pooled data demonstrated that the Liebowitz Social Anxiety Scale (LSAS) can be divided into six subscales. This paper examines data from a fixed-dose trial of escitalopram versus paroxetine, in order to determine the differential effects of these agents on symptom dimensions in social anxiety disorder (SAD). Methods: Data from a 24-week randomised, placebo-controlled, comparative study of fixed doses of escitalopram (5 mg, 10 mg, 20 mg) versus paroxetine (20 mg) in SAD were examined. The six factors identified in a previous factor analysis of baseline data from escitalopram studies on the primary efficacy scale, the LSAS, were used to compute subscale scores. These were analysed using analysis of covariance (ANCOVA), and standardised effect sizes were calculated. Results: The combined escitalopram data and the paroxetine data both demonstrated significant superiority to placebo on each of the 6 LSAS factors at week 24 (OC analysis). Escitalopram doses of 5 mg, 10 mg, and 20 mg were generally more effective than placebo for each of the factors. Escitalopram 20 mg was significantly more effective than paroxetine 20 mg on 5 of the 6 symptom dimensions. Conclusion: Factor analysis of the LSAS allows for useful secondary analyses that support and extend the primary efficacy analysis of this instrument. The analysis here indicates that different escitalopram doses are effective across the various symptom dimensions of SAD.

. Introduction Social anxiety disorder (SAD) is increasingly viewed as a prevalent, chronic, disabling, and costly medical disorder (Magee et al., 1996, Schneier et al., 1994, Dupont et al., 1996 and Mogotsi et al., 2000). When untreated, SAD is frequently complicated by the subsequent onset of comorbid disorders such as depression and substance use, and patients with such comorbidity are particularly impaired (Kessler et al., 1999). The fact that SAD continues to be underdiagnosed and undertreated further contributes to the economic costs associated with this condition (Davidson et al., 1993). There is increased understanding of the psychobiology of SAD (Stein et al., 2002b), and effective pharmacotherapies and psychotherapies for this disorder are now available (Blanco et al., 2003, Ballenger et al., 1998 and van der Linden et al., 2000). Expert consensus guidelines have advised that selective serotonin reuptake inhibitors (SSRIs) are a first-line pharmacotherapy of choice in view of their effectiveness and tolerability (Ballenger et al., 1998 and Bandelow et al., 2002), and in randomised placebo-controlled trials of these agents, 60% or more of SAD patients in the medication arm are responders. Additional progress in understanding and managing social anxiety disorder (SAD) may well depend on a deeper knowledge of the heterogeneity of this condition. There is evidence, for example, that the generalized form of SAD is more severe, and more familial than the non-generalized type (Schneier et al., 2002 and Heimberg et al., 1993). There has also been some discussion of the potential clinical importance of different symptom dimensions within SAD; for example the Liebowitz Social Anxiety Scale (LSAS), the most frequently used outcome measure in SAD medication trials, differentiates between fear and avoidance symptoms. Factor analyses of the LSAS have demonstrated that the main SAD symptom dimensions are not in fact social fear and avoidance, but rather include dimensions such as social interaction, speaking in public, eating and drinking in public, and assertiveness (Safren et al., 1999, Oakman et al., 2003 and Perugi et al., 2001). An exploratory factor analysis of the LSAS by our group yielded six underlying dimensions; and we documented distinctive associations between these symptom dimensions and different areas of disability (Stein et al., 2004). Our original exploratory factor analysis of the LSAS scale was based on baseline data from three randomised placebo-controlled clinical trials in SAD with escitalopram (Lader et al., 2004, Kasper et al., 2005 and Montgomery et al., 2003). We reported that there was no association between these symptom dimensions and the short-term (week 12) response to escitalopram in comparison to placebo in two of these trials (Lader et al., 2004 and Kasper et al., 2005) (the remaining trial was a relapse prevention study). In the current paper, we focus in more detail on data from the randomised-controlled trial of SAD, in which escitalopram, paroxetine, and placebo were compared over the medium-term (24 weeks) (Lader et al., 2004), addressing the response to individual doses of escitalopram, and to paroxetine and placebo of different SAD symptom dimensions.

3. Results The data for the main analysis consisted of 839 randomised patients, evenly distributed between the five treatment groups (Lader et al., 2004). There was an approximately equal ratio of men to women (394:445), and the mean LSAS score at baseline ranged from 92.4 to 96.0 in the different treatment groups. Efficacy scores at baseline, week 12, and week 24 for this and two other SAD studies are shown in Table 1. It should be noted that the prospectively defined primary efficacy endpoint for the Lader et al. (2004) study was at week 12 (LOCF), based on the difference in change from baseline in LSAS total score between escitalopram and placebo. At week 24, the treatment difference (OC) between escitalopram 20 mg and placebo was 17.4 (95% CI: 11.5; 23.2), with a standardised effect size of 0.77 (95% CI: 0.51; 1.03). For escitalopram 20 mg and paroxetine 20 mg, the treatment difference (OC) at week 24 was 7.7 (95% CI: 2.0; 13.4), with a standardised effect size of 0.34 (95% CI: 0.09; 0.59). Table 1. Efficacy data (observed cases) from the three clinical trials in social anxiety disorder with escitalopram Lader et al., 2004 Kasper et al., 2005 Montgomery et al., 2003 Placebo ESC20 PAR20 Placebo ESC10-20 ESC20 Patients (n) 166 170 169 177 181 517 Baseline LSAS 96.0 (14.5) 94.0 (14.0) 94.1 (14.9) 95.4 (16.4) 96.3 (17.4) 94.8 (15.3) CGI-S 4.8 (0.8) 4.8 (0.7) 4.7 (0.9) 4.8 (0.7) 4.8 (0.7) 5.0 (0.8) SDS work 6.6 (1.9) 6.8 (1.9) 7.1 (1.7) 6.7 (1.9) 6.9 (2.2) 6.8 (2.1) SDS social life 7.3 (1.6) 7.3 (1.6) 7.1 (1.7) 7.0 (1.8) 6.8 (1.9) 7.3 (1.6) SDS family 4.5 (2.5) 4.6 (2.4) 4.6 (2.3) 4.7 (2.6) 4.2 (2.4) 5.0 (2.5) MADRS total score 7.6 (4.8) 7.3 (4.7) 7.2 (4.6) 7.5 (4.4) 7.6 (4.5) 7.6 (4.5) Week 12 LSAS 60.5 (23.8) 49.8 (26.7) 51.2 (30.1) 66.3 (29.9) 57.6 (30.4) 48.3 (23.9) CGI-S 3.5 (1.1) 3.0 (1.2) 3.0 (1.3) 3.7 (1.2) 3.4 (1.2) 2.9 (1.2) SDS work 4.4 (2.4) 3.3 (2.3) 3.8 (2.7) 4.7 (2.6) 3.9 (2.7) 3.3 (2.3) SDS social life 4.3 (2.4) 3.5 (2.3) 3.6 (2.6) 4.6 (2.6) 3.8 (2.6) 3.3 (2.2) SDS family 2.5 (2.1) 2.2 (2.3) 2.3 (2.2) 2.9 (2.3) 2.5 (2.1) 2.3 (2.2) MADRS total score 4.5 (3.8) 3.9 (3.7) 4.2 (4.3) 6.6 (5.3) 4.8 (4.8) 3.8 (3.9) Week 24 LSAS 51.4 (26.2) 34.7 (25.0) 41.3 (29.8) – – – CGI-S 3.1 (1.2) 2.2 (1.1) 2.5 (1.4) – – – SDS work 3.7 (2.4) 2.0 (1.9) 2.9 (2.5) – – – SDS social life 3.8 (2.5) 2.1 (1.9) 2.8 (2.5) – – – SDS family 2.3 (2.1) 1.3 (1.7) 1.7 (2.1) – – – MADRS total score 4.1 (4.1) 2.7 (3.3) 2.9 (3.8) – – – CGI-I: Clinical Global Impression-Improvement, LSAS: Liebowitz Social Anxiety Scale, MADRS: Montgomery-Åsberg Depression Rating Scale, SDS: Sheehan Disability Scale. Scores are presented as means (standard deviation). Table options Fig. 1 shows the standardised effect sizes for each of the 6 LSAS subscales at week 24. These six symptom dimensions have been previously described (Lader et al., 2004) and are designated as follows (with LSAS item numbers in parentheses): factor 1—social interaction (5, 10, 11, 12, 19, 21), factor 2—eating and drinking in public (3, 4), factor 3—speaking in public (2, 6, 14, 15, 16, 20), factor 4—assertiveness (1, 13, 18, 22, 24), factor 5—observation fear (8, 9, 17), and factor 6—partying (7, 23). Treatment with escitalopram 5, 10, and 20 mg was more efficacious than placebo (although escitalopram 10 mg failed to reach statistical significance for subscale 1 and 3). Escitalopram 20 mg was significantly superior to paroxetine 20 mg for subscales 1, 2, 3, 5, and 6 (Fig. 2). Repeating the ANCOVAs on each item of the LSAS demonstrated that escitalopram 20 mg tended to be more effective than paroxetine 20 mg for all items, except item 18 (expressing disapproval or disagreement to someone you don't know very well) (Fig. 3). Response of SAD symptom dimensions to different doses of escitalopram and to ... Fig. 1. Response of SAD symptom dimensions to different doses of escitalopram and to paroxetine. Difference versus placebo: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. Difference versus paroxetine 20 mg/day: #p ≤ 0.05, ##p ≤ 0.01. Factor 1—social interaction (5, 10, 11, 12, 19, 21), factor 2—eating and drinking in public (3, 4), factor 3—speaking in public (2, 6, 14, 15, 16, 20), factor 4—assertiveness (1, 13, 18, 22, 24), factor 5—observation fear (8, 9, 17), and factor 6—partying (7, 23). Figure options Response of different symptom dimensions to escitalopram 20 mg/day versus ... Fig. 2. Response of different symptom dimensions to escitalopram 20 mg/day versus paroxetine 20 mg/day. Figure options Response of individual LSAS items to escitalopram 20 mg/day versus paroxetine 20 ... Fig. 3. Response of individual LSAS items to escitalopram 20 mg/day versus paroxetine 20 mg/day. The individual LSAS items are: 1. Telephoning in public; 2. Participating in small groups; 3. Eating in public places; 4. Drinking with others in public places; 5. Talking to people in authority; 6. Acting, performing or giving a talk in front of an audience; 7. Going to a party; 8. Working while being observed; 9. Writing while being observed; 10. Calling someone you don't know very well; 11. Talking with people you don't know very well; 12. Meeting strangers; 13. Urinating in a public bathroom; 14. Entering a room when others are already seated; 15. Being the centre of attention; 16. Speaking up at a meeting; 17. Taking a test; 18. Expressing disagreement or disapproval to people you don't know very well; 19. Looking people you don't know very well in the eye; 20. Giving a report to a group; 21. Trying to make someone's acquaintance; 22. Returning goods to a store; 23. Giving a party; 24. Resisting a high-pressure salesperson. Figure options The results using LOCF were very similar to the OC results. All three escitalopram treatment groups were significantly superior to placebo and escitalopram 20 mg was numerically better than paroxetine 20 mg, although the difference did not reach statistical significance.