Social adjustment in generalised anxiety disorder: a long-term placebo-controlled study of venlafaxine extended release

European Psychiatry 19 (2004) 272–279 www.elsevier.com/locate/eurpsy

Original article

Social adjustment in generalised anxiety disorder: a long-term placebo-controlled study of venlafaxine extended release Patrice Boyer a,*, Vincent Mahé b, David Hackett c a

CNRS UMR 7593, Hôpital de la Pitié-Salpêtrière, 47, Boulevard de L’Hôpital, 75651 Paris, France b Service de Psychiatrie, Hôpital General de Meaux, France c Wyeth Research, Paris, France

Abstract The objective of this analysis was to evaluate the short- (8 weeks) and long-term (24 weeks) efficacy of three fixed doses of venlafaxine extended release (ER) and placebo on the social adjustment of patients with generalised anxiety disorder (GAD). We analysed data from 544 outpatients who participated in a 24-week, double-blind, multicentre, parallel-group, placebo-controlled study conducted at 55 centres in five countries. All patients meet the DSM-IV criteria for GAD and were randomly assigned to receive venlafaxine ER 37.5, 75, and 150 mg or matched placebo administered orally once daily. Social adjustment was measured using the Social Adjustment Scale-Self Report, which explores social adaptation in the areas of work, social and leisure, extended family, primary relationship (marital), parental, and family unit. At baseline, the GAD patients had a high level of social dysfunction. Venlafaxine ER showed a dose-related improvement in social impairment during short-term treatment and in sustaining this improvement over the long-term. In the most severely socially impaired subgroup, placebo remission rates on the HAM-A were low, and the magnitude of the venlafaxine-placebo difference on the mean HAM-A total score was high, reaching more than 7 points. The benefits of venlafaxine ER treatment of GAD extend beyond that of improvement of anxiety symptoms to a significant improvement in the impairment of functioning that is associated with the illness. © 2004 Published by Elsevier SAS. Keywords: Generalised anxiety disorder; Social impairment; Venlafaxine

1. Introduction Generalised anxiety disorder (GAD) is one of the most common anxiety disorders [13]. The current prevalence of GAD in the general population is estimated to be 1.6% [32] with lifetime prevalence affecting 1.9–5.4% of the general population [7,28]. GAD has a chronic course [3,22] and can persist over many years or even decades [23,20,5,33], and may be either constant or fluctuating with spontaneous improvement and relapse [19,17]. In the fourth edition [2] (1994) of the DSM, the disorder is characterised by excessive and chronic anxiety or worry, which is difficult to control, and involves various anxiety symptoms such as restlessness, tension, fatigability, concentration difficulties, irritability, muscle tension, and sleep disturbances. Additionally, the anxiety, worry, or physical symptoms must be the cause of clinically significant distress or impairment in social, occu* Corresponding author. © 2004 Published by Elsevier SAS. doi:10.1016/j.eurpsy.2004.05.010

pational, or other important areas of functioning in order to be diagnosed as GAD. Contrary to the traditional view that GAD is a mild disorder, the majority of people with GAD report substantial interference with their life and a high degree of professional help-seeking [32]. It is associated with impairment in social adjustment to the normal aspects of daily life [15], increased disability and dysfunction [32,26], and loss of productivity [24,12]. The efficacy of pharmacologic treatment on social adjustment in these patients has only rarely [18] been systematically evaluated with a standard instrument. Previous studies have shown venlafaxine ER to be effective in the treatment of GAD [6,8,21]. A recently published study [1] that investigated the efficacy and safety of venlafaxine ER in nondepressed patients diagnosed with GAD (DSM-IV) included an assessment of social functioning using the Social Adjustment rating Scale-Self Report (SAS-SR). In 1976, Weissman and Bothwell [30] developed the Social Adjustment rating Scale (SAS), which was designed to evaluate social adjustment in different populations of psychiatric patients. A self-rating

P. Boyer et al. / European Psychiatry 19 (2004) 272–279

version of this questionnaire (SAS-SR) [31] was validated in the general population. The construct of social adjustment used to develop this scale was defined as the interplay between the individual and his or her social environment. It refers to an individual’s ability to adapt and derive satisfaction from his or her social roles, which are defined as the specific ways of behaving in a broad range of everyday social contexts including interactions with co-workers, friends, extended family, spouses, and others. Using this scale in a general community sample, a mean and S.D. of 1.59 ± 0.33 were observed [31], in comparison with a mean score of 2.53 (±0.46) for acutely depressed patients, 2.22 (±0.61) for alcoholic patients, and 1.95 (±0.62) for schizophrenic patients. The data from the venlafaxine ER study are here analysed and interpreted to determine the extent of social impairment in a clinical trial sample of GAD patients, the impact of different levels of social impairment on the efficacy of venlafaxine ER, and the relationship of improvement of social adjustment with improvement of the symptoms of anxiety.

2. Methods 2.1. Patients and study design The study of population and methodology has been described previously [1]. Briefly, men or women outpatients at least 18 years of age who had a DSM-IV diagnosis of GAD were eligible to enter the study. Patients had to have a minimum screening and baseline HAM-A total score of 20 and scores of at least two on HAM-A item 1 (anxious mood) and item 2 (tension). Patients also had to demonstrate a Covi Anxiety Scale total score higher than their Raskin Depression Scale total score, and a Raskin Depression Scale total score of less than nine. Exclusion criteria included major depressive disorder or having received venlafaxine ER in the last 6 months. One of the main objectives of these criteria was to exclude patients with significant depressive symptoms or syndrome in order to test the anxiolytic potential of venlafaxine ER independently of antidepressant efficacy. A total of 544 outpatients were enrolled in the study from 55 centres in Sweden (2), Finland (5), Belgium (4), France (23), and the United Kingdom (21). After a 4–7 days screening period, patients were randomly assigned to receive fixed doses of venlafaxine ER 37.5, 75 or 150 mg, or matched placebo. In this study, the primary observer rating scales were the HAM-A [10] and the Clinical Global Impression (CGI) scores [9]. Self-report assessments included the SAS-SR and the Hospital Anxiety and Depression Scale (HADS) [34]. The SAS-SR is a comprehensive scale of 54 questions that measures overall social adjustment performance as well as role performance within six key areas of social functioning. These are work (either paid, unpaid homemaker, or student), social and leisure activities, relationships with extended family, role as marital partner, parental role, and role within

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family unit. Each question is rated from 1 (normal) to 5 (most impaired), such that the “best” possible score on each item is 1. The scores of items within each role are summed and a mean for each role is obtained together with an overall mean score. The overall mean score may, therefore, range from 1 to 5. In a recent methodological development [29], overall mean scores are converted into T scores (mean and S.D. 50 ± 10). Based upon the overall T score, subjects have been categorised according to their severity of social impairment. The categories were defined using normative data from the community sample and from psychiatric patients with depression, schizophrenia or alcoholism [31]. For the purpose of this analysis, a primary two-way split of baseline severity was made between categories representing “no/minimal social impairment” (T score ≤ 60) and “social impairment” (T score > 60). An additional subgroup of patients with “marked social impairment” was defined as those with a baseline T score > 70. Assuming that T scores have a normal distribution, 84.1% of the general community sample studied by Weissman et al. [31] may be calculated as having had no/minimal social impairment. 2.2. Statistical methods The SAS-SR was scheduled for completion in each patient at baseline, week 8, and month 6. The efficacy analyses were conducted on a modified intent-to-treat population, i.e., patients who had at least one baseline evaluation of the SAS-SR and at least one on-therapy value of the SAS-SR. If the questionnaire was not completed at or before week 8, the data for the week 8 time point were not imputed. However, if data on the SAS-SR at month 6 were missing, the week 8 value, if available, was carried forward (last observation carried forward [LOCF]). Since only 15% of the patients remaining in the study at week 8 discontinued after this time point, the use of LOCF was considered to provide a conservative level of imputation of the missing data over the longerterm part of this study. The comparisons of primary interest were between each dose of venlafaxine ER and placebo after 8 weeks (shortterm) and 24 weeks (long-term) treatment. The demographic variables at baseline were analysed using a two-way analysis of variance (ANOVA) with treatment group and social impairment category as factors and their interaction in the model. The HAM-A total score was analysed for each assessment time, using an analysis of covariance (ANCOVA) with treatment, level of social impairment at baseline, and treatment by level of social impairment interaction as factors in the model and baseline as a covariate. The adjusted means and the pairwise comparisons of placebo adjusted means vs. venlafaxine ER adjusted means with their 95% confidence limits were also computed. Response was defined as patients showing a 50% or greater decrease from baseline in HAM-A total score. Remission was defined as HAM-A total score ≤7. Both responder and remission rates at each time point were compared using the Fisher exact test or logistic regression.

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3. Results 3.1. Demography There were no differences among treatment groups in baseline demographic characteristics. The mean patient age was the mid-40s and they reported having suffered from GAD for approximately 10 years. There were no significant differences among treatment groups for level of social impairment at baseline. At entry, the mean and S.D. of the overall adjusted mean score were 2.2 ± 0.2. This overall mean score corresponds to a T score of 67 for women and 70 for men (Table 1).

The distribution of patients with “no/minimal impairment” and “impairment” was similar among the treatment groups. Each of the four groups contributed approximately one quarter of the patients in either category. However, the SAS-SR categories of impairment differed significantly for age, sex, body weight, and all measures of anxiety severity (HAM-A total score, HAM-A psychic factor, HADS anxiety factor, and CGI severity). The impaired patients were, on average, younger, relatively more likely to be male, had a higher body weight and had higher anxiety scores than the no/minimally impaired patients. 3.4. Percent of patients with no/minimal social impairment following treatment

3.2. Effect of venlafaxine ER on SAS-SR mean scores The level of social adjustment of patients with GAD was first expressed using mean scores. We compared the efficacy of venlafaxine ER and placebo on the overall mean score, as well as on the area scores. Data on mean scores are displayed in Table 2. For the overall mean social adjustment score, patients treated with venlafaxine ER 75 and 150 mg showed significantly greater improvement than those treated with placebo at week 8 and at month 6 in the LOCF analysis. Certain role areas of social adaptation appeared to be more sensitive than others. For example, the social and leisure area score showed significantly greater improvement in both the 75 and 150 mg venlafaxine ER dose groups than in the placebo group at week 8 and month 6. 3.3. Distribution of patients into categories of impairment A total of 357 (68%) of 525 patients were determined to have impairment of social functioning at baseline (T score > 60). The remaining 168 patients with a T score ≤ 60 were considered to have no/minimal social impairment. The key baseline characteristics of the study population by category of impairment are shown in Table 3.

By the month 6, 62%, 72%, and 80% of the patients in the venlafaxine ER 37.5, 75 and 150 mg groups, respectively, were not socially impaired, compared with 56% of the patients in the placebo group (Table 4). 3.5. Patients with marked social impairment Socially impaired patients with a T score > 70 were categorised as having marked social impairment and were identified for further study. The demographic characteristics of this subgroup are shown in Table 5. Outcome in these patients with marked social impairment was examined by determining their status at week 8 and at month 6 according to one of the following: • No change, i.e., patients remained in the markedly impaired category at endpoint. • Improved, i.e., patients shifted out of the markedly impaired category but did not achieve a T score of ≤60. • Recovered, i.e., patients who shifted from the markedly impaired category to the no/minimally socially impaired category. By month 6 of treatment, 50% of the placebo-treated patients with marked social impairment at baseline remained so, while only 24% had improved and 26% had shown

Table 1 Demographic characteristics at baseline All patients N % Men/women Mean age (min–max) Duration of current episode (Mean weeks) HAM-A total score Mean (±S.D.) HAM-A psychic anxiety factor score Mean (±S.D.) HADS anxiety subscale score Mean (±S.D.) SAS-SR overall score Mean (±S.D.)

Placebo 130 58/42 46 (18–86)

Ven 37.5 (mg) 138 58/42 45 (19–79) 568.2

491.6

Ven 75 (mg) 130 61/39 44 (18–75)

Ven 150 (mg) 131 65/35 45 (20–82)

463.6

428.6

26.7 (5.5)

26.6 (5.0)

26.3 (4.9)

26.3 (4.1)

14.6 (3.2)

14.7 (2.7)

14.7 (3.0)

14.6 (2.5)

14.6 (3.4)

14.7 (3.5)

14.7 (3.6)

14.6 (3.4)

2.2 (0.5)

2.2 (0.5)

2.2 (0.5)

2.2 (0.5)

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Table 2 SAS-SR adjusted mean change from baseline (95% CI): LOCF analysis Area (mean)

Overall Baseline Week 8 Month 6 Role Baseline Week 8 Month 6 Social and leisure Baseline Week 8 Month 6 Extended family Baseline Week 8 Month 6 Parental Baseline Week 8 Month 6 Family unit Baseline Week 8 Month 6 a b

Placebo N

Adj. mean (95% CI)

Venlafaxine ER37.5 (mg) N Adj. mean (95% CI)

128 93 111

2.2 2.0 (1.9, 2.1) 1.9 (1.9, 2.0)

138 98 125

2.2 2.0 (1.9, 2.0) 1.9 (1.8, 2.0)

128 91 115

2.2 1.9 (1.8, 1.9) a,b 1.8 (1.7, 1.9) a

131 107 118

2.2 1.8 (1.7, 1.9) a,b 1.7 (1.7, 1.8) a,b

123 85 103

2.1 2.0 (1.8, 2.1) 1.8 (1.7, 2.0)

133 89 118

2.1 1.8 (1.7, 2.0) 1.8 (1.7, 1.9)

126 88 111

2.1 1.7 (1.6, 1.9) a 1.7 (1.6, 1.8)

125 98 113

2.1 1.7 (1.6, 1.8) a 1.6 (1.4, 1.7) a,b

128 93 111

2.6 2.3 (2.2, 2.5) 2.3 (2.2, 2.4)

138 98 124

2.6 2.2 (2.1, 2.4) 2.2 (2.1, 2.3)

128 91 115

2.6 2.2 (2.0, 2.3) a 2.1 (2.0, 2.2) a

131 106 118

2.6 2.0 (1.9, 2.1) a,b 2.0 (1.9, 2.1) a,b

126 90 108

1.9 1.7 (1.6, 1.8) 1.7 (1.6, 1.8)

137 96 123

1.9 1.8 (1.7, 1.9) 1.7 (1.6, 1.7)

128 90 115

1.9 1.6 (1.5, 1.7) b 1.5 (1.5, 1.6) a

128 105 116

1.9 1.6 (1.5, 1.7) b 1.5 (1.5, 1.6) a

59 35 48

1.8 1.8 (1.6, 1.9) 1.7 (1.6, 1.8)

80 46 65

1.8 1.5 (1.4, 1.6) a 1.5 (1.4, 1.6)

62 41 55

1.8 1.5 (1.4, 1.7) a 1.5 (1.4, 1.7)

73 55 61

1.8 1.5 (1.4, 1.6) a 1.5 (1.4, 1.6)

98 63 80

2.1 2.0 (1.8, 2.1) 1.8 (1.6, 1.9)

101 71 93

2.1 1.8 (1.7, 1.9) 1.8 (1.7, 1.9)

93 66 84

2.1 1.7 (1.6, 1.9) a 1.6 (1.5, 1.7)

104 84 92

2.1 1.7 (1.6, 1.9) a 1.6 (1.5, 1.7) a,b

75 (mg) N Adj mean (95% CI)

150 (mg) N Adj. mean (95% CI)

Significantly different (P # 0.05) from placebo, on the two-way ANCOVA. Significantly different (P # 0.05) from venlafaxine ER 37.5 mg on the two-way ANCOVA comme ca?

Table 3 Baseline demographic characteristics: intent-to-treat patients a by impairment status

N % Women/men Mean age (min–max) Weight (kg) mean (±S.D.) Duration current episode (mean weeks) HAM-A total mean (±S.D.) HAM-A psychic anxiety factor mean (±S.D.) HADS-a anxiety subscale mean (±S.D.) CGI severity mean (±S.D.) SAS-SR total mean (±S.D.) Placebo N (%) 37.5 mg ven ER N (%) 75 mg ven ER N (%) 150 mg ven ER N (%)

No/minimal impairment (T score ≤ 60) 168 67/33 47.3 (18–82) 69 (12.9) 516 25.2 (4.6) 14.0 (2.8) 12.1 (3.5) 4.3 (0.7) 1.7 (0.2) 39 (23) 43 (26) 45 (27) 41 (24)

Impairment (T score > 60) 357 57/43 43.9 (19–86) 73 (15.7) 481 27.1 (4.9) 15.0 (2.8) 13.8 (3.3) 4.6 (0.8) 2.1 (0.1) 89 (25) 95 (27) 83 (23) 90 (25)

P-value

0.045 0.005 0.006 N.S. <0.001 <0.001 <0.001 <0.001 <0.001 N.S. N.S. N.S. N.S.

Note: There were no significant treatment effects or treatment by subgroup effects. a Four patients did not have a SAS-SR rating at baseline, so 525 patients form the SAS-SR intent-to-treat population.

recovery of their social adjustment. In contrast, a substantially higher percent of patients treated with venlafaxine ER showed improvement. Less than 23% at the highest dose level showed no change, while 60% showed recovery of social adjustment (Fig. 1).

3.6. Impact of social impairment on improvement of anxiety Improvement in the HAM-A total score tended to increase at the higher doses of venlafaxine ER compared with placebo, irrespective of the level of impairment at baseline

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Table 4 No/minimally impaired patients (%) at week 8 and month 6

Placebo Ven a 37.5 (mg) Ven 75 (mg) Ven 150 (mg) a

Week 8 N Not socially impaired 94 47 (50) 98 59 (60) 91 61 (67) 107 73 (68)

Month 6 N Not socially impaired 111 63 (56) 125 78 (62) 115 83 (72) 118 94 (80)

Venlafaxine.

Table 5 Baseline demographic characteristics: patients with marked social impairment (T score > 70) N % Women/men Mean age (min–max) Weight (kg) mean ± S.D. Duration current episode (mean no. weeks) HAM-A total (mean ± S.D.) HAM-A psychic anxiety factor score (mean ± S.D.) HADS-a subscale (mean ± S.D.) CGI severity (mean ± S.D.) SAS-SR total (mean ± S.D.) N (%) placebo N (%) 37.5 mg ven ER N (%) 75 mg ven ER N (%) 150 mg ven ER

217 57/43 42.7 (19–86) 72.6 (16.4) 397 27.8 (4.9) 15.4 (2.8) 14.4 (3.0) 4.7 (0.7) 2.7 (0.3) 52 (24) 57 (26) 56 (26) 52 (24)

No change (SAS-SR T score > 70)

70

Improvement (SAS-SR T score 61 - 70) Recovered (SAS-SR T Score <= 60)

60 50 40 % 30 20 10 0 Placebo

Ven ER 37.5 mg

Ven ER 75 mg

Ven ER 150 mg

Fig. 1. Social adjustment in GAD. Status at month 6 of patients who were markedly socially impaired (T score > 70) at baseline by treatment group (LOCF analysis).

(Table 6). The efficacy of the lowest (37.5 mg) dose appeared to be less in patients with social impairment than in patients with no/minimal social impairment and particularly less in those patients who were markedly socially impaired. In contrast, the efficacy of the highest dose of venlafaxine ER increased in comparison with that of placebo in the markedly impaired category of social impairment. Thus at 6 months, there was an adjusted mean difference of over 7 points in the HAM-A between venlafaxine ER and placebo in the markedly socially impaired subgroup (Table 6).

Response rates as measured using the HAM-A were similar between impaired and no/minimally impaired patients. Remission rates, however, tended to be lower in the impaired groups compared with the no/minimally impaired group for the placebo group and the lower venlafaxine ER dose groups. Remission rates were similar for the higher venlafaxine ER dose group (150 mg/day) regardless of baseline level of social impairment. This resulted in a greater difference in rates of remission between placebo and the highest dose of venlafaxine ER in the markedly impaired subgroup (Table 7). HAM-A scores were tested against impairment status from the SAS-SR, regardless of treatment administered. Among the patients who achieved remission (HAM-A score ≤7) at month 6, 87% showed no/minimal social impairment. In contrast, 67% of patients achieving a response but not remission showed no/minimal impairment, and only 41% of nonresponders did so (Fig. 2). 3.7. Discontinuation from study Safety and tolerability of venlafaxine ER for this study has previously been reported [1]. There was no clear influence of the baseline level of social impairment upon the rate of discontinuation from the study.

4. Discussion The majority of people with GAD report substantial interference with their life and a high degree of professional help-seeking [32]. Compared with other psychiatric disorders, there has been far less appreciation of the burden that GAD places on healthcare services and the negative impact that the disorder has on achievement and functioning. Kessler and Frank [12] have shown that on average 1.4 days are lost from work and that patients show work impairment for 3.1 days per month. The majority of clinical studies, whether in depression or anxiety, have concentrated on the effects of an intervention on psychiatric symptomatology, but very few have sought to determine the effects on a detailed analysis of social adjustment. The adverse impact of GAD on overall functioning, such as completion of education or fulfillment of potential in the work and social spheres, has received far less recognition than, for example, the deficits associated with major depressive illness [2]. In this study, the effect of three fixed doses of the serotonergic and noradrenergic reuptake inhibitor venlafaxine ER was assessed. At least two-third of the patients with GAD recruited to this study self-rated themselves as suffering from a measurable degree of social impairment and over half of these could be categorised as suffering from a marked degree of impairment. At entry, the mean and S.D. of the overall mean SAS-SR score in our sample of patients were 2.2 ± 0.2. This is substantially higher than the mean score reported for a gen-

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Table 6 HAM-A total score: adjusted mean difference (95% CI) vs. placebo by baseline social impairment category Visit

Ven ER (mg/day)

Week 8

37.5 75 150 37.5 75 150

Month 6

Mean (95% CI) No/minimal impairment 2.9 (–0.7, 6.4) 2.9 (–0.6, 6.4) 3.7 (0.1, 7.3) 4.7 (0.8, 8.6) 5.5 (1.7, 9.4) 4.5 (0.6, 8.4)

Impaired 0.9 (–2.8, 4.6) 3.3 (–0.8, 7.3) 4.0 (0.2, 7.7) 1.8 (–2.2, 5.9) 3.3 (–1.1, 7.8) 5.7 (1.6, 9.8)

Marked impairment 2.8 (–0.2, 5.9) 5.3 (2.2, 8.4) 6.0 (2.9, 9.1) 2.3 (–1.1, 5.7) 6.2 (2.8, 9.6) 7.1 (3.6, 10.5)

Table 7 HAM-A total score: response and remissions rates (%) by baseline social impairment category

Placebo Ven ER 37.5 (mg/day) Ven ER 75 (mg/day) Ven ER 150 (mg/day)

Minimal social impairment Response Remission 44 28 65 46 73 * 57 * 72 * 54 *

Impaired Response 47 59 68 ** 75 ***

Remission 22 37 * 43 ** 54 ***

Marked impairment Response 43 53 70 ** 76 ***

Remission 20 36 42 * 55 ***

* Significantly different from placebo at P ≤ 0.05 (logistic regression). ** Significantly different from placebo at P ≤ 0.01 (logistic regression). *** Significantly different from placebo at P ≤ 0.001 (logistic regression). 100 90 80

Week 8

Month 6

70 60 % 50 40 30 20 10 0 Non Response

Response only

Remission

Fig. 2. Social adjustment in GAD. Rates of no/minimal social impairment according to achieved anxiety status at week 8 and month 6 (all treatment groups combined).

eral community sample (1.59) and similar to or greater than that reported for depressed, alcoholic and/or schizophrenic subgroups [31]. Even our subgroup of patients categorised as having no/minimal impairment showed a mean score (1.7) higher than that of Weissman’s general community sample. There were significant differences between the subgroups of patients defined according to social impairment. The patients with the greatest functional impairment had the more pronounced symptoms of anxiety, as reflected in higher scores on the anxiety scales. It is also interesting to note that the patients with marked impairment had a somewhat shorter duration of illness. This suggests that patients with longer duration of illness may achieve a degree of adaptation to their condition, or may come to rate themselves as having normal levels of social adjustment. Venlafaxine ER administered at the doses of 75 and 150 mg/day improved social impairment in these GAD patients and was efficacious in improving the most markedly

socially impaired patients defined according to the most severe of the Weissman categories. Due to the infrequency of measurement, it is not possible from this study to analyse fully the time at which improvement in social impairment begins or what is its temporal relationship with changes in scores of anxiety. However, the percentage of patients with no/minimal social impairment was greater at month 6 than at week 8 in both the venlafaxine ER 75- and 150-mg groups. By the month 6, 72% and 80% of the patients (LOCF analysis) in the venlafaxine ER 75- and 150-mg groups, respectively, were in this category, compared with 56% of the patients in the placebo group. There are two important observations here. The first is that after 6 months of treatment the distribution of patients in the venlafaxine ER group, especially those in the 150-mg group, between the categories of impaired and no/minimally impaired was similar to that of the participants in the community sample cited by Weissman et al. [31]. When compared with HAM-A remission rates of around 55% at this dose level, it suggests that social functioning normalises in some patients who still have to reach full remission from their symptoms of anxiety. Efficacy of venlafaxine ER at a dose level of 75 or 150 mg/day is not attenuated in the most severely socially impaired patients. Indeed, the difference in HAM-A anxiety scores between placebo treatment and venlafaxine ER treatment at these doses becomes more evident as the baseline severity of social impairment increases. Response and particularly remission rates on the HAM-A in the more severely impaired subgroups treated with placebo are very low, while these rates are higher and similar regardless of baseline severity for patients treated with venlafaxine ER. Thus, the magnitude of effect on the HAM-A for venlafaxine ER (the difference between the mean changes seen with placebo and venlafaxine ER at endpoints) is highly clinically meaningful

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in the most severely ill subgroup, reaching values exceeding 7 points on the HAM-A. Inclusion of patients according to the severity of their social impairment, therefore, appears to provide additional and compelling evidence in favour of the efficacy of venlafaxine ER and may assist in separating true efficacy of active compared with inactive treatments. Venlafaxine ER showed a dose response for the improvement in adjusted mean difference in SAS-SR total regardless of the baseline category of impairment; i.e., the higher the dose of venlafaxine ER, the greater the improvement. Venlafaxine is an antidepressant drug that inhibits the reuptake of serotonin and norepinephrine with different potencies [4] that may explain its dose–response efficacy in the treatment of depression [14]. However, it is difficult in the present study to know whether the better efficacy of venlafaxine at higher doses in improving social impairment is a direct property of its effect on noradrenergic mechanisms or whether it is a reflection of a dose response in improving anxiety symptoms in general. Anxiety symptoms also showed a dose–response efficacy in this study [1], although not all studies of venlafaxine ER in GAD have shown such a dose response [6]. There have long been suggestions that efficacy based upon a noradrenergic effect would have a different profile from that based upon a serotoninergic effect, e.g., it has been proposed that antidepressants with predominantly noradrenergic effect would have primary effects on drive and motivation while serotoninergic activity would be associated with mood regulation [27]. More recently in investigations with reboxetine, a noradrenergic specific reuptake inhibitor, some studies [25,11], though not others [16], point to the possibility that the noradrenergic mechanism may offer better efficacy compared with the serotonin mechanism in improving patient motivation and self-perception and social interaction in both patients and in volunteer settings. The possibility exists therefore that while serotonin mechanisms may account for efficacy in the treatment of the anxiety symptoms of GAD, noradrenergic mechanisms may be beneficial in improving social adjustment through a beneficial effect on motivation and drive. The fact that the most severely impaired patients in this study were those that showed the greatest drug–placebo difference may be an indication of this dual action. Future studies in the treatment of GAD therefore need to consider not only outcomes relating to anxiety symptoms but also how this translates into improved functioning. Such studies would benefit from being of longer duration than those that consider efficacy in terms of symptomatic relief alone.

compared with placebo in patients with marked social impairment. The placebo remission rates on the HAM-A in the most severely impaired subgroups are low, and the magnitude of effect on the HAM-A for venlafaxine ER is increased in this subgroup. The benefits of venlafaxine ER treatment of GAD extend beyond that of improvement of anxiety symptoms to a significant improvement in the impairment of functioning that is associated with this disorder.

5. Conclusions

[14]

Patients with GAD have a high level of social dysfunction as self-rated on the SAS-SR. Venlafaxine ER at 75 and 150 mg improves social impairment in patients with GAD and significantly improves response and remission rates

[15]

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