General anxiety disorder (GAD) is a common and prominent chronic anxiety disorder characterized by persistent worry which, if not controlled, leads to impaired social and occupational functioning.1 The prevalence rates of GAD have been reported as a lifetime prevalence of 5% and an annual prevalence of 2% to 3% in Western countries2,3 and similar prevalence rates (5.6%) have also been reported in Chinese patients.4
Patients with GAD often present to their primary care physicians;5 in Chinese patients presenting at internal medicine departments, the prevalence of GAD was 2.4%.6 Mental disorders including GAD may be undertreated due to the low rate of recognition of these disorders by internists and because of low rates of care-seeking among the general population in China.6,7 Patients with GAD who visit primary care physicians for treatment have somatic symptoms (48%) and pain (35%) as their presenting complaints.8 Although similar studies examining GAD treatment in primary care have not been conducted with Chinese patients, anxiety symptoms that are similar to those associated with GAD have been shown to occur frequently in Chinese patients who have somatic diseases such as stroke, Parkinson's disease, epilepsy, irritable bowel syndrome, functional dyspepsia, and menopausal syndrome.9 Therefore, adequate recognition and treatment of patients with GAD with appropriate therapy would reduce anxiety symptoms and improve functioning as well as quality of life regardless of the cultural differences.
Based on the efficacy and safety data available, both selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are now recommended as first-line treatment for GAD10,11 although many other therapeutic options are available. SSRIs and SNRIs drugs are recommended for the treatment of GAD mainly due to their underlying mechanism(s) of action on selective neurotransmitter systems including serotonin (5-HT) and norepinephrine (NE).12 Although a majority of drugs have shown promise in the reduction of anxiety symptoms, benzodiazepines and tricyclic antidepressants are not preferred over SSRIs and SNRIs due to their safety and tolerability concerns.10,13,14 SSRIs have shown efficacy in the treatment of GAD but their use is restricted to some extent, due in part to sexual dysfunction14 and in part to poor remission rates.13 SNRIs including extended-release venlafaxine 15 and duloxetine16 have been successful in demonstrating efficacy in the treatment of GAD due to their dual acting properties both on 5-HT and on NE neurotransmission.
However, literature on pharmacotherapy in Chinese patients with GAD is very limited. Patients with depression and anxiety symptoms who were treated with paroxetine, an SSRI, showed significant improvement in emotional problems associated with somatic diseases.17 In an open-label study, patients with GAD treated with tandospirone showed a 67.4% improvement in 6 weeks.18 In another study, patients with GAD were treated with needling therapy alone, with pharmacotherapy alone, or with combined needling therapy and SSRI; SSRIs showed equipotency in efficacy.19
Duloxetine, an SNRI, has been evaluated for the treatment of GAD in several placebo-controlled trials with different dose regimens20-24 and it has been approved for the treatment of GAD in the USA, Europe, and elsewhere. The purpose of the current study was to evaluate the efficacy and safety of duloxetine 60 to 120 mg once daily versus placebo in the treatment of Chinese patients with GAD. Given that a period of 9-10 weeks was employed in all previous pivotal studies1 and that the only other long-term study of GAD with duloxetine was a relapse-prevention study,24 the duration of the current study was lengthened to examine the efficacy of duloxetine over a longer acute period of 15 weeks.
This was a phase 3, multicenter, parallel, double-blind, randomized, placebo-controlled study with 3 periods (Figure 1). The study was conducted at 9 sites in China between December 2008 and January 2010. Study period I was approximately 3 to 30 days, during which patients were screened for study eligibility and underwent psychiatric and medical screenings. During study period II, patients were randomly assigned in a 1:1 ratio to duloxetine 60-120 mg once daily or placebo for 15 weeks of treatment. Patients who were randomly assigned to duloxetine received 60 mg orally for 7 weeks; at that point, patients who had no response had their daily duluxetine dose increased to 120 mg for the remaining 8 weeks. Nonresponse was defined as a Clinical Global Impressions Improvement (CGI-I) rating of ≥3 (minimal improvement, no change or worsening). Patients who did not tolerate the increase to the 120-mg dose were discontinued from the study. During study period III, patients taking duloxetine were tapered off over a 2-week period. For patients receiving 120 mg of duloxetine, the daily dose was reduced to 60 mg for 1 week followed by 30 mg for 1 week. Patients who entered the taper phase on 60 mg of duloxetine received 30 mg for 2 weeks. Patients in the placebo arm continued on placebo during the TAPER phase.
This study was conducted in accordance with the ethical principles of Good Clinical Practice and the Declaration of Helsinki and its guidelines. The ethical review boards at each investigative site provided written approval of the study protocol and the informed consent document (ICD). No protocol-related procedures were performed before patients signed the ICD.
Male or female outpatients ≥18 years of age who met the disease diagnostic criteria for GAD as defined by the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) were included in this trial. Diagnostic assessment was based on the Mini-International Neuropsychiatric Interview for the DSM-IV25 and was confirmed by a physician. In addition, the Covi Anxiety Scale (CAS)26 was used to assess the severity of anxiety, the Raskin Depression Scale (RDS)27 was used to assess the severity of depression, and the Clinical Global Impressions of Severity (CGI-S)28 was used to rate the overall severity of the illness. To ensure that patients warranted psychiatric intervention, they were required to have an illness of at least moderate severity (rating ≥4) as assessed by the CGI-S. To ensure that anxiety symptoms were predominant over depressive symptoms, the patient's CAS score had to be greater than his or her RDS score and no item on the RDS could be greater than a rating of 3 (moderate). Patients were also required to have at least moderate functional impairment associated with their anxiety illness, which was defined by a Sheehan Disability Scale (SDS) global functioning score ≥12 at study entry. Inclusion of this measure at study entry is an additional feature of this study, which was not used in the previous pivotal trials that examined duloxetine for GAD.
The primary exclusion criteria consisted of the following: any current DSM-IV Axis I diagnosis other than GAD; major depressive disorder in the past 6 months; panic, post-traumatic stress or an eating disorder within the past year; obsessive-compulsive disorder, bipolar affective disorder, psychosis, factitious disorder, or somatoform disorder during their lifetime; or the presence of an Axis II disorder or history of antisocial behavior which, in the judgment of the investigator, would interfere with compliance with the study protocol. Patients were also excluded for additional reasons: previous treatment with duloxetine; history of use of drugs of abuse (as defined by the DSM-IV) within the prior 6 months; benzodiazepine use in the 14 days prior to visit 2; clinical judgment of serious suicidal risk for the patient; serious medical illness; initiation of psychotherapy or change in intensity of psychotherapy or other nondrug therapies within 6 weeks prior to study entry or during the study period; treatment with a monoamine oxidase inhibitor or fluoxetine within the 30 days prior to visit 2; uncontrolled narrow-angle glaucoma; lack of response to 2 or more adequate trials of antidepressants and/or benzodiazepines at a clinically appropriate dose for a minimum of 4 weeks; and women who were breast feeding or pregnant.
The Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale total score was the primary measure. The HADS29 is a patient-rated instrument that consists of 14 items rated on a 4-point scale (ranging from 0 to 3). The HADS-A subscale is the sum of the 7 odd-numbered items with scores ranging from 0 to 2; higher scores indicate greater symptom severity. The primary objective was to test the hypothesis that duloxetine 60-120 mg once daily is superior to placebo in the treatment of Chinese patients with GAD, determined by the change from baseline to endpoint in the HADS-A subscale total score during the treatment period of 15 weeks.
As a secondary efficacy measure, clinicians also assessed anxiety using the Structured Interview Guide for the Hamilton Anxiety Rating scale (SIGH-A).30 The Hamilton Anxiety Rating Scale (HAMA)31 consists of 14 items that include psychic, somatic, and behavioral symptoms associated with anxiety. Each item is rated on a 5-point scale of 0 (not present) to 4 (very severe) so that scores may range from 0 to 56, with higher scores indicating greater illness severity. The HAMA also has 2 types of factor scores: the psychic factor score consists of the sum of items 1-6 and item 14 (including items such as anxious mood, tension, fear, insomnia, and behavioral symptoms) whereas the somatic factor score is the sum of items 7-13 (including items such as cardiovascular, respiratory, and gastrointestinal symptoms). Although the HAMA is often used as a primary outcome in clinical trials, the selection of the HADS-A subscale for use as the primary measure for this study was based on its greater reliance on psychic symptoms of anxiety instead of the broader somatic symptoms assessed by the HAMA. However, both measures are considered to be valid and reliable for assessing the improvement in symptoms and severity of GAD.32
Other secondary efficacy measures included were: HADS depression subscale (HADS-D) score, which is the total sum of the ratings from the 7 even-numbered items of the scale; the CGI-I scale, which is a clinician-rated instrument that assesses the patient's improvement since taking the study drug using a 7-point scale (1: very much improved since the initiation of treatment; 2: much improved; 3: minimally improved; 4: no change from baseline (the initiation of treatment); 5: minimally worse; 6: much worse; 7: very much worse since the initiation of treatment); and the Brief Pain Inventory (BPI; Modified Short Form),33 which is a self-rated scale consisting of severity and interference items that are rated using a 0-10 scale (0, no pain and 10, pain as bad as you can imagine). The BPI average score is the average severity of pain experienced in the last week and the BPI interference score is the sum of the 7 individual interference items. An additional pain measure was the Visual Analog Scale for Pain (VAS),34 which consists of 6 questions including overall pain, headache, back pain, shoulder pain, pain interference with daily activities, and proportion of the day with pain. For each VAS question, patients were asked to mark on a 100 mm line their degree of pain where 0, not at all and 100, extremely. Patient's role functioning was assessed by the Sheehan Disability Scale,35 which is a patient-rated scale that assesses the amount of interference in different life domains due to the anxiety illness. The scale consists of 3 items evaluating impairment in work/school, social life/leisure activities, and family life/home responsibilities. Each item is scored on a scale of 0 (unimpaired) to 10 (highly impaired). The SDS global functioning score is the sum of the 3 individual items. If a work/school item is missing because it is not applicable, then the global functioning score is computed by using the average of the other 2 items for the missing work/school item.
Safety and tolerability measures
Safety and tolerability were assessed in patients treated with duloxetine 60-120 mg once daily for 15 weeks and compared with placebo treatment using discontinuation rates due to adverse events (AEs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), vital signs, and laboratory analytes.
Suicide-related events (behavior and/or ideations) were assessed at every visit using Colombia Suicide Severity Rating Scale (C-SSRS). The Self-harm Follow-up Form was completed at any visit when suicidal or nonsuicidal self-injurious behavior was identified. If a suicide-related event was identified at any time during the study, a thorough evaluation was performed by a study physician and appropriate medical care was provided.
All analyses were conducted on an intent-to-treat basis. For efficacy analyses, all patients with a baseline and at least 1 postbaseline measurement were included. For safety analyses, all patients randomly assigned to a treatment were included. With 100 patients planned per treatment arm, the study had 80% power to detect a difference of -2.1 points (effect size=0.42) on the HADS-A total score. The sample size was determined using a two-sided test with α=0.05, assuming a common standard deviation of 5 and that 10% of patients would be missing postbaseline values on the HADS-A subscale total score.
Treatment effects were evaluated based on a two-sided significance level of 0.05 and interaction effects at 0.05 without adjustment for multiple comparisons. An analysis of variance (ANOVA) model was used for analysis of continuous efficacy variables with treatment and investigator in the model. An analysis of covariance (ANCOVA) model was used with baseline values added to the ANOVA model for continuous variables. Type III sum-of-squares for the least squares mean (LS mean) were used for the statistical comparisons using ANOVA and ANCOVA. Additional considerations were applied in the calculation of efficacy variables with missing items: if ≤20% of the items were missing, the mean score for all items was imputed and if >20% of the items were missing, then the total or subscale score was considered missing. In all analyses for the double-blind acute therapy phase, baseline refers to the last nonmissing observation at or before the randomization visit (visit 2, week 0) and endpoint refers to the last nonmissing observation at or before visit 7 (week 15).
Mean change from baseline to endpoint on the HADS-A subscale was the primary outcome, calculated using the last-observation-carried-forward (LOCF) method. In addition, all other secondary measures including HADS depression subscale, HAMA total score, BPI-severity and -interference items, VAS items, and SDS global functioning score and item scores were calculated using the LOCF method. All of these efficacy measures were also analyzed with the mixed-effects-model-repeated-measures (MMRM) method to assess change over time.
Categorical variables including response rate, remission rate, and improvement at endpoint were analyzed using a Cochran-Mantel-Haenzel test controlling for investigator. Response was defined as a ≥50% reduction from baseline to endpoint in the HADS-A subscale total score and the HAMA-A subscale total score. Remission was defined as a HAMA total score ≤7 at endpoint and also by a score ≤10, as both definitions have been discussed in the literature.36
Categorical safety measures were analyzed using Fisher's exact test. Continuous baseline and safety measures were evaluated using the ANOVA model with treatment and investigator in the model.
All analyses were performed using SAS® (version 9.1, SAS Institute Inc., UAS).
Of the total patients randomly assigned to receive either placebo (N=102) or duloxetine 60-120 mg once daily (N=108), 74 (72.5%) in the placebo group and 82 (75.9%) in the duloxetine group completed the 15-week double-blind acute-therapy phase. The most common reasons for discontinuation were AEs, lack of efficacy, loss to follow-up, patient decision, and protocol violation (Table 1). More patients in the duloxetine treatment group (12.0%) discontinued due to AEs compared with the placebo group (2.9%, P=0.017). None of the rates of individual AEs leading to discontinuation were statistically significant between the 2 treatment groups. Significantly (P=0.022) more patients in the placebo-treated group discontinued from the study due to lack of efficacy. Of the patients receiving duloxetine (N=108) from randomization, 41 (38.0%) required dose escalation to 120 mg once daily at week 7 based on the dose-escalation criteria, and 67 (62.0%) patients remained on the 60 mg once daily dose for the remainder of treatment period.
Patient baseline characteristics
No statistically significant differences between the 2 treatment groups were observed in the patients' demographics, disease characteristics, or use of benzodiazepines at baseline (Table 2). Male and female patients were equally distributed in both treatment groups with a mean age of 37.6 years.
Duloxetine-treated patients demonstrated statistically significant (P=0.006) improvement compared with placebo-treated patients on the primary measure, the HADS-A subscale total score (Figure 2). There was a 51.4% improvement from baseline to endpoint (LOCF) with duloxetine treatment compared to 36.4% with placebo treatment. Significant differences were evident between the 2 treatment groups when analyzed by the MMRM method at week 7 (P=0.006) and remained significant at all other subsequent visits up to endpoint at week 15 (P=0.013, Figure 3).
Response rates were significantly greater in the duloxetine treatment group (69.2%) compared to placebo (53.0%) on HAMA total score (P=0.020). When remission was defined as ≤10 on the HAMA total score, 63.6% of patients in the duloxetine group achieved remission compared with 46.0% in the placebo group and the difference was statistically significant (P=0.014). However, when remission was defined as ≤7 on the HAMA total score, the difference between the 2 treatment groups was not significant (duloxetine 43.0%, placebo 32.0%, P=0.118).
Several secondary efficacy measures also showed significant improvement in patients treated with duloxetine compared with placebo-treated patients, and the results are summarized in Table 3. Statistically significant differences between treatment groups (LS mean changes) from baseline to endpoint were observed on the following measures: HAMA total score (P=0.024); HAMA psychic anxiety factor score (P=0.026); HAMA somatic anxiety factor score (P=0.040); BPI-severity items including average pain (P=0.012), least pain (P=0.014), and pain right now (P=0.002); VAS back pain (P=0.025), VAS awake with pains (P=0.011); and CGI-improvement at endpoint (P=0.004). For the BPI-interference items, several of the VAS pain items, and the SDS global functioning impairment and items scores, there were no statistically significant differences in the amount of improvement for the duloxetine-treated patients compared with the placebo-treated patients, although there were numerical improvements favoring duloxetine on most of these measures.
Safety and tolerability
Of the total patients (N=210), 45 (44.1%) in the placebo group and 65 (60.2%) in the duloxetine group (P=0.027) reported at least 1 TEAE (Figure 4). Only nausea (P ≤0.001), dizziness (P=0.015), and somnolence (P=0.003) were more frequently reported in duloxetine-treated patients compared with placebo-treated patients. No deaths occurred during this study. The single serious adverse event (SAE) that occurred was hospitalization secondary to suicide attempt for a patient who was taking placebo. Suicidal behaviors were observed in 2 other patients (1 with placebo, 1 with duloxetine) but were not classified as SAEs by the investigators and the difference was not significant (P=0.714). No significant differences occurred between the 2 treatment groups with regard to treatment-emergent suicidal ideation or behavior as measured by the CSSR-S. Five (5.0%) patients in the placebo group and 3 (2.8%) patients in the duloxetine group reported treatment-emergent suicidal ideation (P=0.487).
Changes from baseline to endpoint (LOCF) for most of the laboratory values were not significant between placebo- and duloxetine-treated patients, except for alkaline phosphatase (LS (mean change ± standard error (SE)): placebo, (-1.97±1.47) U/L, duloxetine, (1.50±1.37) U/L, P=0.015) and chloride (LS (mean change ± SE): placebo, (0.39±0.34) mmol/L, duloxetine, (-0.33±0.32) mmol/L, P=0.042). These changes were not interpreted as being clinically meaningful.
No statistically significant differences of LS (mean change ± SE) from baseline to endpoint (LOCF) were reported with regard to blood pressure (systolic: placebo, (-0.58±0.99) mmHg, duloxetine, (-3.09±0.96) mmHg, P=0.065; diastolic: placebo, (-0.60±0.79) mmHg, duloxetine, (-0.65±0.76) mmHg, P=0.963), pulse rate: placebo (-0.56±0.83) beats per minute, duloxetine, (0.06±0.80) beats per minute, P=0.583), or weight (placebo, (0.02±0.20) kg, duloxetine, (-0.16±0.19) kg, P=0.503) during the study either in placebo-treated or in duloxetine-treated patients.
Results from this double-blind, placebo-controlled study demonstrate that duloxetine at a dose of 60-120 mg once daily is an effective and well-tolerated treatment for Chinese patients with GAD. Compared with placebo, duloxetine treatment showed significantly greater improvements in GAD illness symptoms and severity as measured both by the HADS anxiety subscale score and by the HAMA total score. Duloxetine was shown to be efficacious in the reduction of HADS-A scores starting at 7 weeks after treatment initiation compared with placebo and maintained its significant efficacy at all subsequent time points through the end of the study at 15 weeks. Within the HAMA scores, duloxetine treatment significantly improved both the psychic symptoms associated with anxiety as well as the somatic symptoms measured by its psychic and somatic factor scores, respectively. Although this study employed a different scale as a primary measure, the data are in agreement with previous studies in which the HAMA scale was used.20-24
Treatment response and remission are integral parts of the therapeutic intervention of patients with GAD.13 Duloxetine has been shown to be effective and persistent with regard to clinical response and remission in other GAD studies conducted with Western patient population.20-22 Likewise, in this study duloxetine showed a significantly greater response rate (69.2% of patients with ≥50% response rate) and remission rate (63.6% of patients achieved remission when defined as ≤10 on the HAMA total score) compared with placebo treatment. Lack of significant difference in remission rates between the 2 treatment groups using the more conservative definition (≤7 on the HAMA total score) may be due to the fact that GAD has a fluctuating course with symptoms that wax and wane. The evaluation of the difference between duloxetine and placebo for Chinese patients compared with patients from the western countries is of interest. The differences in response and remission rates between placebo and duloxetine treatments in both patient populations are very much similar. For example, the difference of response rate between placebo and duloxetine in a meta-analysis of trials conducted in Western countries1 was 18.0% as compared with 16.2% in Chinese patients in this study. Similarly, difference in the remission rate between placebo and duloxetine treatment was 13% in western patients1 as compared with 11% in Chinese patients in this study. These comparisons clearly demonstrate that Chinese patients respond similarly to western patients in regard to duloxetine treatment.
Duloxetine, an SNRI, has shown clinical efficacy in the treatment of painful physical symptoms associated with GAD.37,38 These post hoc analysis showed that duloxetine was superior to placebo in reducing the severity of VAS overall pain and other pain items. The findings of the current study were consistent with these previous results as there were significant improvements in duloxetine-treated patients as compared to placebo-treated patients in pain severity items including average pain, pain right now, and least pain. However, none of the BPI-I items were significantly improved with duloxetine treatment. On the VAS scale, back pain and awake with pain were significantly improved with duloxetine treatment compared with placebo. These findings deviate somewhat from earlier studies in which patients with GAD had significant improvements in interference due to pain as measured by the VAS.37-39 This difference may be due to the previous analyses being pooled across trials, whereas the current study was not powered to detect differences specifically for pain at the individual study level. Furthermore, the baseline VAS values for overall pain and interference due to pain were within the mild severity level.
Duloxetine did not show a significant improvement compared with placebo on overall functioning as assessed by the SDS global functioning impairment scale and other SDS items, although there was a numerical improvement favoring duloxetine compared with placebo. This outcome differs substantially from the findings in each of the prior duloxetine trials for GAD. In these previous studies, significant improvement in global functioning as measured by the SDS occurred for duloxetine-treated patients compared with placebo-treated patients. Similarly, the previous trials have also showed significant improvement on the individual SDS domain items for the duloxetine group compared to the placebo group.40 The main difference between the current study and the previous study with regard to these measures is that the current study used the SDS as part of the inclusion criteria, which potentially could have resulted in elevations at baseline that may have obscured drug/placebo differences. Evidence supporting this interpretation is that the mean SDS global functioning score at baseline in the previous studies40 was approximately 15.5 compared with the mean SDS global functioning score of 17.2 at baseline in this study.
The overall safety and tolerability findings of the current study were consistent with previously reported results from GAD studies (Kornstein et al1). In fact, compared to previous studies, duloxetine-treated patients experienced less adverse events, including no significant changes in SAEs, vital signs or weight changes. As in other studies, significantly more patients discontinued due to AEs in the duloxetine group compared with the placebo group, with no significant differences with any single AE leading to discontinuation. Nausea, dizziness, and somnolence were the three TEAEs reported significantly more often in duloxetine-treated patients compared to placebo-treated patients and are consistent with overall AE profile associated with duloxetine across indications.
Strengths of this study include a study design that employed a 15-week treatment duration, which is longer than the usual 9-10 weeks of treatment used in previous studies.20-24 Such design improvement is logical in view of the fact that GAD is a progressive and chronic disorder and the patients may benefit from longer duration of treatment with duloxetine. Another feature of this study is the use of a patient-rated scale as the primary outcome measure, which demonstrated consistency between outcomes reported by patients and those assessed by clinicians. One limitation of this study is that similarly to previous trials, patients had to have a primary diagnosis of GAD, whereas other significant comorbid psychiatric illnesses were excluded. Thus, these results may not be generalizable to the clinical patient who has comorbid disorders such as comorbid anxiety and depression. Additionally, because this study did not use an active comparator, direct inferences cannot be made between duloxetine and other medications for GAD, although previous studies did support noninferiority of duloxetine compared with venlafaxine XR treatment for GAD.41
Duloxetine at a dose of 60-120 mg QD was effective in reducing the severity of anxiety in Chinese patients with GAD on both patient-reported and clinician-rated anxiety measures. The safety profile for duloxetine treatment within this study was consistent with the profile observed in the GAD registration trials.
This study was sponsored by Eli Lilly and Company, Indianapolis, IN, USA and Boehringer Ingelheim, Ingelheim am Rheim, Germany. Additional information on this trial can be found at www.clinicaltrials.gov; ID: NCT00803361. The authors wish to thank the patients for their participation in this trial. The authors extend their thanks to all the participating investigators for their efforts in conduct of this study (XIE Shi-ping, Nanjing Brain Hospital, Nanjing, Jiangsu, China; XU Yi, Zhejiang Medical University Affiliated No. 1 Hospital, Hangzhou, Zhejiang, China; LI Hui-chun, Second Affiliated Hospital of Zhejiang Medical University, Hangzhou, Zhejiang, China; DENG He-huang, Guangzhou Fangcun Mental Hospital, Guangzhou, Guangdong, China; TAN Rong, First Affiliated Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; GAO Cheng-ge, First Affiliated Hospital of Medical College, Xi'an Jiaotong university, Xi'an, Shaanxi, China; XU Xiu-feng, No. 1 Affiliated Hospital of Kunming Medical College, Kunming, Yunnan, China).
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Keywords:© 2011 Chinese Medical Association
generalized anxiety disorder; Chinese; patients; duloxetine; acute, therapy