Greist, John H.a; Liu-Dumaw, Mariab; Schweizer, Edwardc; Feltner, Douglasd
With the exception of specific phobias, social anxiety disorder (SAD) is the most common anxiety disorder, with a lifetime prevalence estimated to be 12.1% in the USA (Kessler and Wang, 2008). The 1-year US prevalence has been estimated to be 6.8%, with 30% of current cases associated with a significant work-related disability (Kessler and Wang, 2008). The course of illness of SAD is notable for its early onset and high degree of chronicity. The median age of onset is 13 years, and less than 10% of individuals have an onset of SAD after the age of 23 years (Kessler et al., 2005). The mean duration of illness of SAD is over 10 years, with more than 50% of individuals reporting persistent illness at 10-year follow-up (Bruce et al., 2005; Beard et al., 2010). Among individuals who do recover, at least one-third suffer a subsequent relapse (Bruce et al., 2005). Owing to its chronicity and the disabling effect of severe social anxiety, SAD has been reported to be one of the top medical or psychiatric disorders in terms of impairment in functioning and quality of life (Stein and Kean, 2000; Alonso et al., 2004; Saarni et al., 2007; Ruscio et al., 2008). In the National Comorbidity Survey Replication Study, 30% of individuals were unable to work or had substantial limitations in their ability to work because of their SAD (Kessler et al., 2005).
Currently, recommended first-line treatments for SAD, with category A evidence from two or more placebo-controlled, randomized clinical trials, include sertraline, paroxetine, escitalopram, fluvoxamine, and venlafaxine-extended release (Bandelow et al., 2008). Cognitive-behavioral therapy also has demonstrated significant efficacy in treating SAD (Heimberg, 2002; Rodebaugh et al., 2004).
Despite the high degree of chronicity in SAD, relatively few double-blind, placebo-controlled trials are available that evaluate the efficacy of long-term (≥6 months) treatment for preventing relapse (Walker et al., 2000; Stein et al., 2002; Stein et al., 2003; Montgomery et al., 2005). Owing to differences in outcome measures and relapse criteria, rates of relapse on active drug varied widely in previously reported trials.
Pregabalin has demonstrated significant efficacy in the short-term (Montgomery, 2006) and long-term (Feltner et al., 2008) treatment of generalized anxiety disorder (GAD) based on multiple randomized, double-blind, placebo-controlled trials. Pregabalin is a novel anxiolytic that acts by binding to the α2δ protein (Bian et al., 2006; Taylor et al., 2007). In the acute treatment of SAD, the efficacy of pregabalin is limited to the 600 mg per day dose, with lower doses not demonstrating a significant effect relative to placebo (Pande et al., 2004; Feltner et al., 2011).
The aim of this study was to evaluate the efficacy and safety of long-term (26 weeks) treatment with pregabalin in preventing relapse among patients with SAD, who initially responded to open-label pregabalin.
This was a multicenter, relapse-prevention study of pregabalin that consisted of four phases: a 1-week screening phase; a 10-week open-label phase; a 26-week randomized, double-blind, placebo-controlled, parallel-group phase; and a 2-week follow-up phase.
The study was conducted at 25 centers in the USA between 4 October 1999 and 15 March 2001. The study was funded and administered by Pfizer Inc., the study sponsor. The protocol, consent documents, and protocol amendments were approved by the Institutional Review Boards of the participating institutions, and the study was conducted according to the guidelines of the Declaration of Helsinki and its amendments. After an explanation of the risks and benefits of study participation, written consent was obtained from all patients before entry into the study. Each study center received a prespecified block of patient numbers, which were sequentially assigned to each patient at the screening visit after the informed consent was signed. The sponsor supplied study medication as identical-appearing capsules.
After completion of 1 week of screening, all patients began 10 weeks of open-label treatment with pregabalin (300 mg/day; in three divided doses) for 3 days. Pregabalin was then increased to 450 mg per day for the duration of the open-label phase. A dosage of 450 mg/day was chosen because, at the time the study was designed, this dose was considered to have a high likelihood of being both effective and well tolerated. Patients were eligible to enter the 26-week double-blind maintenance phase if they met the following response criteria at the end of the open-label phase: (a) Clinical Global Impression Improvement (CGI-I) score of less than or equal to 2 (‘much’ or ‘very much improved’); and (b) a reduction from open-label baseline in the Liebowitz Social Anxiety Scale (LSAS) total score of more than or equal to 25%. Patients not meeting the response criteria were discontinued from the study. Responders were randomly assigned, double blind, to either continue treatment with pregabalin (450 mg/day) or to receive placebo (after completing a double-blind 3-day taper on 300 mg/day).
Patients continued treatment in the double-blind maintenance phase, unless they met one of the following criteria: (a) relapse criteria at two consecutive visits, defined as a CGI-I score more than or equal to 6 (‘much’ or ‘very much worse’) compared with double-blind baseline and a Clinical Global impression Severity (CGI-S) score that was more than or equal to the CGI-S score at an open-label baseline; or (b) worsening of social phobia symptom severity that, in the investigator's judgment, required immediate clinical intervention. Upon completion of the double-blind maintenance phase, all patients entered a 2-week follow-up phase during which study medication was discontinued abruptly after a 3-day dose reduction to 300 mg.
Patients were eligible for enrollment if they were outpatients aged 18 years or older and met the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for SAD, generalized subtype, confirmed using the Mini International Neuropsychiatric Interview (Sheehan et al., 1998), with an LSAS score of more than or equal to 50 at both screening and open-label baseline. Women were enrolled if they were using a hormonal or barrier method of contraception, or were menopausal or surgically sterilized, had a negative pregnancy test at the screening visit, and were not lactating. Patients were excluded from the study if they had a current history, in the previous 6 months, of alcohol or substance abuse or dependence, major depressive disorder, or had a Hamilton Depression Rating Scale (HAM-D) item 1 (depressed mood) score of more than or equal to 3 at screening. Patients also were excluded if they met the criteria for any other Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) Axis I disorder, currently or in the past, with the exception of a dysthymia, depression not otherwise specified, simple phobia, somatization, or premenstrual dysphoric disorder. A past history of major depressive disorder also was not a reason for exclusion. Patients also were excluded if they currently had any clinically significant cardiovascular, renal, hepatic, gastrointestinal, retinal, pulmonary, endocrine, metabolic, or hematological disorders or laboratory tests that were outside normal ranges. Patients with seizure disorder or requiring treatment with anticonvulsants for any indication also were excluded.
Patients were evaluated at the screening and open-label baseline visits, and at weeks 1, 2, 4, 6, 8, 10, 11, 12, 13, 14, 16, 18, 20, 24, 28, 32, 36, 37, and 38. Weeks 1–8 were during the open-label phase; the week 10 visit was at the end of the open-label phase and was the baseline of the double-blind maintenance phase; weeks 10–36 were during the double-blind maintenance phase; and the week 36 visit was at the end of the double-blind phase and at the beginning of the follow-up phase that included weeks 37 and 38.
Efficacy outcomes consisted of the LSAS total score and fear and avoidance subscale scores (Heimberg et al., 1999), the Marks Fear Questionnaire (MFQ) total phobia and social phobia subscale scores (Marks and Mathews, 1979), the Hamilton Anxiety Rating Scale (HAM-A) total score (Hamilton, 1959), the 17-item HAM-D total score (Hamilton, 1960), the CGI-S and CGI-I scores (Guy, 1976), and the Sheehan Disability Scale (SDS) total and social, work, and family/home life subscale scores (Leon et al., 1992).
Safety assessments included the evaluation of spontaneously reported adverse events and measurement of vital signs at each study visit. Physical examination, laboratory testing, and electrocardiograms were performed at the screening visit, at the end of the open-label phase and at the end of the double-blind maintenance treatment phase. The 20-item Physician Withdrawal Checklist was administered at the week 36 visit and at the two follow-up visits to evaluate the severity of medication-discontinuation symptoms (Rickels et al., 1990).
It was estimated that a total sample size of 146 patients randomized in the double-blind maintenance phase were needed to provide 90% power to detect a 30% between-group difference in relapse rates at 6 months as significant at an α level of 0.05 (two sided), assuming a premature discontinuation rate of 20% (Marubini and Valsecchi, 1995; Elashoff, 1999).
Efficacy analyses were performed using the intent-to-treat sample, defined as all patients who were randomized in the double-blind phase and who received at least one dose of study medication after randomization, and for whom at least one post randomization assessment was available. The safety sample was defined as all patients who received at least one dose of study medication during any phase. The primary a-priori efficacy analysis was a comparison of the time to relapse between treatment groups using Kaplan–Meier time-to-event methods and the log-rank test for significance. Analyses of secondary outcomes (i.e. LSAS subscales, CGI-S, CGI-I, HAM-A, HAM-D, MFQ, and SDS) were performed using analysis of covariance with last observation carried forward (LOCF) endpoint scores as the dependent variable. Models included effects for treatment and center, with the respective double-blind phase baseline score used as a covariate. Evaluations of categorical outcomes were made using a Cochran–Mantel–Haenszel χ2-analysis. All analyses were performed using SAS 6.0 (SAS Institute, 1989).
In total, 487 patients were screened, of whom 348 entered the open-label phase. Of these, 153 were randomized to 26 weeks of double-blind treatment with either a fixed dose of pregabalin (450 mg/day) after 3 days at 300 mg/day (n=80) or placebo (n=73). Patient characteristics at open-label baseline and double-blind baseline are summarized in Table 1. The majority were male patients between the ages of 25 and 45 years, who reported the onset of SAD in their early teenage years. The mean LSAS score was 91.2 at open-label baseline and improved by more than 60% to a mean of 34.6 among those who were randomized to double-blind treatment. At double-blind baseline (Table 1), patients randomized to pregabalin and placebo were comparable on the LSAS total score and on secondary measures such as the HAM-A and HAM-D. There was a greater percentage of Hispanics in the pregabalin group than in the placebo group (15 vs. 3%, respectively).
The disposition of patients during the study is summarized in Fig. 1. Fifty-one percent of the intent-to-treat sample withdrew during the double-blind phase, 56% of the pregabalin group and 45% of the placebo group. The study was closed early by the sponsor (Pfizer) for administrative reasons relating to the overall drug development program that had nothing to do with the dosing, design, or open-label results of this study. All patients had been enrolled and had completed the open-label phase when the sponsor closed the study; however, 19 patients in pregabalin group (24%) and 16 patients in the placebo group (22%) were discontinued prematurely due to study closure. Nonstudy closure-related early discontinuations were somewhat higher with pregabalin (32.5%) compared with placebo (23.3%; Fig. 1). It should be noted that patients, who discontinued from the study because they met relapse criteria (see below), were counted as study completers and were not included in the early discontinuation category.
Treatment with pregabalin was significantly superior to placebo in delaying relapse of SAD symptoms (log rank P=0.035; Fig. 2). On the basis of Kaplan–Meier estimates of time to event, it took 49 days for 25% of the pregabalin-treated patients to relapse compared with 25% of the placebo-treated patients who took 28 days. Relapse based on either CGI-I/CGI-S criteria or based on the investigator judgment of symptomatic worsening requiring treatment, occurred in 22 (27.5%) of pregabalin-treated patients and 32 (43.8%) of placebo-treated patients (P=0.024). Relapse based on CGI-I and CGI-S criteria alone occurred in 16.3% of pregabalin-treated patients and 34.2% of placebo-treated patients (P=0.009). An analysis excluding patients who discontinued prematurely due to study closure found a relapse rate, based on either CGI-I/CGI-S criteria or on the investigator judgment of symptomatic worsening requiring treatment, of 36.1% for pregabalin-treated patients and of 56.1% for placebo-treated patients (P=0.022). Relapse rates based on CGI-I and CGI-S criteria alone were 21.3% for pregabalin-treated patients and 43.9% for placebo-treated patients (P=0.011). The odds ratio (OR) of relapse occurring during pregabalin treatment relative to placebo was similar for the total sample, and for the subgroup with administratively discontinued patients excluded, using either CGI-I and CGI-S criteria alone (OR: 0.33 vs. 0.29) or combined with investigator judgment (OR: 0.43 vs. 0.37).
The treatment with pregabalin was associated with a significantly lower LSAS total score at LOCF endpoint when compared with placebo [mean difference score (95% confidence interval): −11.4 (−20.2 to −2.5); P=0.012; Table 2 and Fig. 3]. The treatment with pregabalin also was associated with significantly more sustained improvement at LOCF endpoint on many of the secondary efficacy measures (Table 2), including the LSAS total fear and total avoidance subscales (P=0.007 and 0.022, respectively), and the MFQ total phobia (P=0.010), social phobia (P=0.014), main phobia (P=0.045), and global phobia (P=0.009) scales. The SDS total score suggested that improvement in functioning was more sustained among patients treated with pregabalin, but the difference from placebo was not significant (P=0.060; Table 2).
The most frequently occurring adverse events during the open-label phase were somnolence, dizziness, and headache (Table 3). During the double-blind phase, the most frequently reported adverse events were insomnia, infection, and headache. Insomnia occurred with similar frequency in the placebo and pregabalin groups, headache was more prevalent in the placebo group, and infection was more prevalent in the pregabalin group. The incidence of adverse events, which started during the double-blind phase and were rated as severe, was relatively low in both the pregabalin and placebo treatment groups, respectively (6.3 and 12.3%; Table 3).
Twenty-five (10.6%) patients treated with pregabalin during the open-label phase experienced a weight gain of more than or equal to 7%. During 26 weeks of double-blind treatment, two (2.6%) pregabalin-treated patients and no placebo-treated patients experienced a weight gain of more than or equal to 7%; four (5.1%) pregabalin-treated patients experienced a weight loss of more than or equal to 7%, whereas no placebo-treated patients experienced a weight loss of more than or equal to 7%. There were no clinically important changes in laboratory, vital signs, or other physical examination findings.
After 36 weeks of overall (open label+double blind) treatment, pregabalin was abruptly discontinued (after a 3-day dose reduction to 300 mg/day). Withdrawal symptoms, as measured by the change scores from the Physician Withdrawal Checklist for pregabalin, were not significantly different for pregabalin-treated patients compared with placebo-treated patients during follow-up at either week 1 (P=0.074) or week 2 (P=0.076).
The results of this 26-week, double-blind, placebo-controlled study found that pregablin, in a fixed daily dosage of 450 mg/day, had significant relapse-prevention efficacy among patients presenting with severely symptomatic SAD that was highly chronic, with a mean duration of 22 years. Protocol-defined relapse, based on a-priori CGI-I and CGI-S criteria, occurred in 16.4% of pregabalin-treated patients and 34.2% of placebo-treated patients. Overall relapse, based on either CGI-I/CGI-S criteria or symptomatic worsening requiring treatment, occurred in 27.5% of pregabalin-treated patients and 43.8% of placebo-treated patients.
At open-label baseline, patients had a level of severity (mean LSAS total score >90) that was in the top quartile of previously reported controlled clinical trials (Ipser et al., 2008). Ten weeks of open-label treatment with pregabalin (450 mg/day) resulted in a 56-point (62%) reduction in the LSAS total score for patients who continued into the double-blind treatment phase. This is in contrast to the results of a previous short-term trial, in which significant efficacy was only demonstrated for the 600-mg dose, with only inconsistent efficacy demonstrated for the 450-mg dose on secondary analyses (Feltner et al., 2011).
In addition to significantly delaying time to relapse, treatment with pregabalin was associated with a significantly greater ability to sustain improvement compared with placebo across a range of symptom-severity measures, including LSAS total and subscale scores, the MFQ total phobia, social phobia, main phobia, and global phobia scores, as well as the CGI-I. However, treatment with pregabalin was not associated with significant improvement from double-blind baseline-to-endpoint, in mean CGI-S, HAM-A total, or MFQ-anxiety subscale scores. In addition, although the LSAS change scores were significantly less in the pregabalin group, these scores did not show a reduction in mean symptom severity. This may be due to the a-priori LOCF endpoint analysis, in which the scores of the subgroup of patients who were discontinued due to clinical worsening (27.5% in the pregabalin group) were carried forward.
The long-term efficacy of pregabalin in SAD is difficult to compare with results from the few previously reported relapse-prevention studies, in part because definitions of relapse vary between studies. In a 24-week, double-blind, relapse-prevention study, treatment with sertraline was associated with a significant reduction in relapse rates compared with placebo [4 vs. 36%; absolute risk reduction, 32%; number needed to treat (NNT)=3.1; Walker et al., 2000]. However, the sample size in the study was small (N=50), and relapse criteria were not specified. The low relapse rates might also reflect the unusually long (20-week) open-label treatment with sertraline. In another 24-week relapse-prevention study (Montgomery et al., 2005), treatment with escitalopram was associated with a significant reduction in relapse rates compared with placebo (22 vs. 50%; absolute risk reduction, 28%; NNT=3.6). The relapse criteria used in this study were either an increase of more than or equal to 10 points on the LSAS total score or withdrawal because of lack of efficacy as judged by the investigator. A study by Stein et al. 2002, with a similar duration and design to this study and using similar relapse criteria, reported significantly lower relapse rates for paroxetine versus placebo (14 vs. 39%; absolute risk reduction, 25%; NNT=4.0). The relapse rates, as assessed by objective CGI-I/CGI-S criteria, for pregabalin versus placebo in this study (16 vs. 34%; absolute risk reduction, 18%; NNT=5.6) were at the lower end of the range of previously reported trials in terms of absolute risk reduction. The effect of early study termination on the relapse rates for pregabalin versus placebo is uncertain; however, the ORs of relapse occurring during pregabalin treatment relative to placebo was similar for the total sample and for the subgroup with administratively discontinued patients excluded.
In general, pregabalin was well tolerated, with an adverse event profile that was similar to what has been reported in previous studies of both SAD (Pande et al., 2004) and GAD (Montgomery, 2006). Long-term treatment was not associated with any clinically important changes in laboratory, vital signs, or other physical examination findings, with the exception of weight gain. Approximately one in 10 patients receiving pregabalin during the open-label treatment phase experienced a weight gain of more than or equal to 7%. However, during 6 months of continued treatment, 5.1% of pregabalin-treated patients experienced a weight loss of more than or equal to 7%, whereas a smaller proportion of pregabalin-treated patients (2.6%) experienced a clinically significant weight gain. The proportion of patients with clinically significant weight loss in this study was higher than the 0.5–1% rate reported in previous 6-month trials of fibromyalgia and GAD (Crofford et al., 2008; Feltner et al., 2008). One additional finding is that rapid discontinuation of pregabalin (after a 3-day reduction to 300 mg/day) after 36 weeks of overall (open label+double blind) treatment was not associated with a clinically relevant withdrawal syndrome. This result is similar to what has previously been reported in a 6-month relapse-prevention study in GAD (Feltner et al., 2008) and is different from the withdrawal symptoms typically observed when chronically administered benzodiazepines are discontinued (Rickels et al., 1990). However, it should be noted that withdrawal symptoms upon discontinuation were not reported in a 6-month study of clonazepam in SAD (Connor et al., 1998), which may be attributable to the long elimination half-life of clonazepam, or to the taper schedule used in the study. An intriguing alternative explanation is that patients with a diagnosis of SAD have less anxiety sensitivity than patients with panic or patients with GAD, and thus are less withdrawal prone (Rickels et al., 1990; Connor et al., 1998).
An important limitation of this study was the decision of the sponsor (Pfizer Inc.) to close the study early for administrative reasons unrelated to study conduct. As a consequence, 23% of randomized patients were discontinued. ORs for relapse prevention on pregabalin were similar whether administratively discontinued patients were included or excluded. However, it is possible that early study closure may have introduced bias in some other way.
In conclusion, the results of this study show pregabalin (450 mg/day) to be a safe and efficacious treatment for the prevention of relapse in SAD. Future studies are needed to determine whether escalation to a dosage of 600 mg/day might have improved the outcome in the 27.5% of patients who relapsed on the 450 mg/day dosage. Additional comparative clinical trials are also needed to clarify whether other demographic or clinical variables can be identified that predict a more favorable outcome to long-term treatment with pregabalin versus a selective serotonin-reuptake inhibitor.
Conflicts of interest
Dr Greist has had grant/research support from AstraZeneca, Forest, Janssen, Jazz, Lilly, National Institutes of Mental Health and Aging, Novartis, Otsuka, Pfizer, Taked, and Transcept, and he has been a consultant for GlaxoSmith Kline, Jazz, Lilly, Pfizer, and Transcept. He is a principal stock shareholder of Healthcare Technology Systems. At the time the study was conducted, Dr Feltner and Ms Liu-Dumaw were full-time employees of Pfizer Inc. In addition, Dr Feltner owns stock in Pfizer Inc.
Dr Edward Schweizer owns stock in Pfizer Inc., and has received payments for consulting and/or medical writing services from Alkermes, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eli Lilly, Memory Pharmaceuticals, Neurocrine Biosciences, Orexigen Therapeutics, Sunovion Pharmaceuticals Inc., Titan Pharmaceticals, and Pfizer Inc. He is an employee of Paladin Consulting Group Inc., which was a paid consultant to Pfizer Inc., in connection with the development of this manuscript. Editorial support to prepare this manuscript for submission was provided by UBC Scientific Solutions and funded by Pfizer Inc.
This study was funded by Pfizer Inc. It was presented in part at the 163rd Annual Meeting of the American Psychiatric Association; 22–26 May 2010; New Orleans, Louisiana, USA.
Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha TS, Bryson H, et al.ESEMeD/MHEDEA 2000 Investigators, European Study of the Epidemiology of Mental Disorders (ESEMeD) Project. Disability and quality of life impact of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl. 2004;420:38–46
Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJWFSPB Task Force on Treatment Guidelines for Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders. . World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders–first revision. World J Biol Psychiatry. 2008;9:248–312
Beard C, Moitra E, Weisberg RB, Keller MB. Characteristics and predictors of social phobia course in a longitudinal study of primary-care patients. Depress Anxiety. 2010;27:839–845
Bian F, Li Z, Offord J, Davis MD, McCormick J, Taylor CP, et al. Calcium channel alpha2
-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autoradiographic study in alpha2
-delta type 1 genetically modified mice. Brain Res. 2006;1075:68–80
Bruce SE, Yonkers KA, Otto MW, Eisen JL, Weisberg RB, Pagano M, et al. Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a 12-year prospective study. Am J Psychiatry. 2005;162:1179–1187
Connor KM, Davidson JR, Potts NL, Tupler LA, Miner CM, Malik ML, et al. Discontinuation of clonazepam in the treatment of social phobia. J Clin Psychopharmacol. 1998;18:373–378
Crofford LJ, Mease PJ, Simpson SL, Young JP Jr, Martin SA, Haig GM, et al. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain. 2008;136:419–431
Elashoff JD. NQuery advisor version 3.0 users guide. 1999 Statistical Solutions, Los Angeles, CA
Feltner D, Wittchen HU, Kavoussi R, Brock J, Baldinetti F, Pande AC. Long-term efficacy of pregabalin in generalized anxiety disorder. Int Clin Psychopharmacol. 2008;23:18–28
Feltner DE, Liu-Dumaw M, Schweizer E, Bielski R. Efficacy of pregabalin in generalized social anxiety disorder: results of a double-blind, placebo-controlled, fixed-dose study. Int Clin Psychopharmacol. 2011 [Epub ahead of print].
Guy W ECDEU assessment manual for psychopharmacology. 1976 Rockville, MD Department of Health, Education and Welfare
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50–55
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62
Heimberg RG. Cognitive-behavioral therapy for social phobia: current status and future directions. Biol Psychiatry. 2002;51:101–108
Heimberg RG, Horner KJ, Juster HR, Safren SA, Brown EJ, Schneier FR, et al. Psychometric properties of the Liebowitz Social Anxiety Scale. Psychol Med. 1999;29:199–212
Ipser JC, Kariuki CM, Stein DJ. Pharmacotherapy for social anxiety disorder: a systematic review. Expert Rev Neurother. 2008;8:235–257
Kessler RC, Wang PS. The descriptive epidemiology of commonly occurring mental disorders in the United States. Annu Rev Public Health. 2008;29:115–129
Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617–627
Leon AC, Shear MK, Portera L, Klerman GL. Assessing impairment in patients with panic disorders: the Sheehan Disability Scale. Soc Psychiatry Psychiatr Epidemiol. 1992;27:78–82
Marks I, Mathews A. Brief standard self-rating for phobic patients. Behav Res Ther. 1979;17:263–267
Marubini E, Valsecchi MG Analysing survival data from clinical trials and observational studies. 1995 New York, New York John Wiley and Sons:127–141
Montgomery SA. Pregabalin for the treatment of generalised anxiety disorder. Expert Opin Pharmacother. 2006;7:2139–2154
Montgomery SA, Nil R, Dürr-Pal N, Loft H, Boulenger JP. A 24-week randomized, double-blind, placebo-controlled study of escitalopram for the prevention of generalized social anxiety disorder. J Clin Psychiatry. 2005;66:1270–1278
Pande AC, Feltner DE, Jefferson JW, Davidson JR, Pollack M, Stein MB, et al. Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol. 2004;24:141–149
Rickels K, Case WG, Schweizer E, Garcia-Espana F, Fridman R. Benzodiazepine dependence: management of discontinuation. Psychopharmacol Bull. 1990;26:63–68
Rodebaugh TL, Holaway RM, Heimberg RG. The treatment of social anxiety disorder. Clin Psychol Rev. 2004;24:883–908
Ruscio AM, Brown TA, Chiu WT, Sareen J, Stein MB, Kessler RC. Social fears and social phobia in the USA: results from the National Comorbidity Survey Replication. Psychol Med. 2008;38:15–28
Saarni SI, Suvisaari J, Sintonen H, Pirkola S, Koskinen S, Aromaa A, et al. Impact of psychiatric disorders on health-related quality of life: general population survey. Br J Psychiatry. 2007;190:326–332
SAS Institute. SAS/Stat user's guide volumes 1 and 2, version 612. 1989 Cary, NC SAS Institute
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22–33 ; quiz 34–57.
Stein MB, Kean YM. Disability and quality of life in social phobia: epidemiologic findings. Amer J Psychiatry. 2000;157:1606–1613
Stein DJ, Versiani M, Hair T, Kumar R. Efficacy of paroxetine for relapse prevention in social anxiety disorder: a 24-week study. Arch Gen Psychiatry. 2002;59:1111–1118
Stein DJ, Westenberg HG, Yang H, Li D, Barbato LM. Fluvoxamine CR in the long-term treatment of social anxiety disorder: the 12- to 24-week extension phase of a multicentre, randomized, placebo-controlled trial. Int J Neuropsychopharmacol. 2003;6:317–323
Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel α2
-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007;73:137–150
Walker JR, Van Ameringen MA, Swinson R, Bowen RC, Chokka PR, Goldner E, et al. Prevention of relapse in generalized social phobia: results of a 24-week study in responders to 20 weeks of sertraline treatment. J Clin Psychopharmacol. 2000;20:636–644
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