Vortioxetine (Lu AA21004) 5 mg in generalized anxiety disorder: Results of an 8-week randomized,double-blind,placebo-controlled clinical trial in the United States

The goal of the current clinical study, conducted in the United States (US), was to evaluate the efficacy and tolerability of vortioxetine 5 mg vs placebo in adults with a primary diagnosis of generalized anxiety disorder (GAD; HAM-A total score ≥20 and MADRS score ≤16). Subjects were randomized (1:1) to receive vortioxetine 5 mg (n=152) or placebo (n=152) for 8 weeks. Efficacy was assessed using change from baseline in HAM-A total scores after 8 weeks of treatment compared with placebo, using mixed-model repeated measures (MMRM) analyses. Adverse events (AEs) were assessed throughout the study. A total of 304 subjects were randomized (mean age, 41.2 years). After 8 weeks of treatment, there was no statistically significant difference in the reduction in HAM-A total score from baseline between the Vortioxetine (n=145) and placebo (n=145) groups. There were no statistically significant differences in any key secondary efficacy outcome between vortioxetine and placebo. Factors potentially contributing to the differences between the results of this study and those of one of identical design conducted outside the US are discussed. The most common treatment-emergent AEs were nausea, headache, dizziness, and dry mouth. Nausea was more frequently reported in the vortioxetine group (25% vs 4.6% for the placebo group). Most AEs were mild to moderate in severity. In conclusion, in this trial, vortioxetine did not improve symptoms of GAD (compared with placebo) over 8 weeks of treatment. Vortioxetine was well tolerated in this study.     

Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder

Abstract

Objective:

The primary objective of this study was to evaluate the safety and tolerability of the investigational drug vortioxetine (Lu AA21004) in the long-term treatment of patients with major depressive disorder.     

Efficacy of pregabalin and venlafaxine-XR in generalized anxiety disorder: results of a double-blind, placebo-controlled 8-week trial

The objective of this study was to evaluate the anxiolytic efficacy, and speed of onset of efficacy, of pregabalin (PGB) and venlafaxine-XR (VXR) in patients with generalized anxiety disorder (GAD). In this double-blind trial, outpatients, ages 18-65 years, who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for GAD were randomized to 8 weeks of flexible-dose treatment with PGB (300-600 mg/day), VXR (75-225 mg/day), or placebo (PBO). The intent-to-treat sample consisted of 121 patients on PGB [least square (LS) mean ± SE baseline Hamilton Anxiety Rating Scale (HAM-A), 27.6 ± 0.4], 125 patients on VXR (baseline HAM-A, 27.4 ± 0.4), and 128 patients on PBO (baseline HAM-A, 26.8 ± 0.4). Treatment with PGB was associated with a significantly greater LS mean change in the HAM-A total score at last observation carried forward endpoint versus PBO (-14.5 ± 0.9 vs. -11.7 ± 0.9; P = 0.028). Treatment with VXR was not significant versus PBO at endpoint (-12.0 ± 0.9; -11.7 ± 0.9; P =0.968). Treatment with PGB showed an early onset of improvement, with significantly greater LS mean change in the HAM-A by day 4 versus both PBO (-5.3 ± 0.5 vs. -3.4± 0.5; P = 0.008) and VXR (-2.9 ± 0.5; P = 0.0012). The proportion of patients reporting a severe adverse event was similar for PGB (9.1%) and PBO (7.8%), but higher for VXR (20.0%; P < 0.05). In conclusion, PGB was a safe and effective treatment of GAD, with a significantly earlier onset of anxiolytic activity than VXR.     

Adjunctive risperidone in the treatment of generalized anxiety disorder: a double-blind, prospective, placebo-controlled, randomized trial

Background:Residual symptoms despite treatment are common in generalized anxiety disorders (GAD). The Patient-Rated Troubling Symptoms for Anxiety (PaRTS-A) is a newly created and validated instrument that measures the symptoms most troublesome to each individual patient and was used to test the hypothesis that adjunctive risperidone improves residual GAD symptoms. Methods: Primary care and psychiatry clinicians enrolled adults (n = 417) with GAD and a Clinical Global Impressions of Severity rating >/=4 despite >/=8 weeks of anxiolytic treatment. Subjects were randomized to adjunctive risperidone or placebo. The primary endpoint was change from baseline to week 4 endpoint in PaRTS-A. Results: Improvement from baseline to week 4 endpoint in PaRTS-A total score (mean +/-SE) was similar between treatment groups (-8.54 [0.63] and -7.61 [0.64] for adjunctive risperidone and placebo, respectively; P = .265). Patients in each treatment group exhibited significant improvements from baseline in nearly all patient- and clinician-rated measures. A post-hoc analysis of PaRTS-A symptoms of moderate to severe severity at baseline suggested greater improvement with risperidone than placebo (P = .04). Headache, weight increase, and increased appetite were the most frequently reported adverse events in both groups. Conclusions: Residual GAD symptoms assessed by the PaRTS-A improved with either adjunctive risperidone or placebo. Alternative analyses or scoring approaches may improve the ability of the PaRTS-A to provide clinically meaningful information on patient-rated symptoms. Further exploration of the benefits of risperidone in patients with more severe GAD may be indicated.     

A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder

The efficacy and tolerability of Lu AA21004 at 5 mg/day, a novel multimodal antidepressant, were assessed in elderly patients with recurrent major depressive disorder. Patients were randomly assigned (1:1:1) to Lu AA21004 5 mg/day, duloxetine 60 mg/day (reference) or to placebo in an 8-week double-blind study. The primary efficacy measure was the 24-item Hamilton Depression Scale (HAM-D(24)) total score (analysis of covariance, last observation carried forward). Patients (mean age 70.6 years) had a mean baseline HAM-D(24) score of 29.0. Lu AA21004 showed significantly (P = 0.0011) greater improvement on the primary efficacy endpoint compared with placebo at week 8 (3.3 points). Duloxetine also showed superiority to placebo at week 8, thereby validating the study. HAM-D(24) response (53.2 vs. 35.2%) and HAM-D(17) remission (29.2 vs. 19.3%) rates at endpoint were higher for Lu AA21004 than for placebo. Lu AA21004 showed superiority to placebo in cognition tests of speed of processing, verbal learning and memory. The withdrawal rate due to adverse events was 5.8% (Lu AA21004), 9.9% (duloxetine) and 2.8% (placebo). Whereas nausea was the only adverse event with a significantly higher incidence on treatment with Lu AA21004 (21.8%) compared with placebo (8.3%), the incidence of nausea, constipation, dry mouth, hyperhidrosis and somnolence was higher for duloxetine. In conclusion, Lu AA21004 was efficacious and well tolerated in the treatment of elderly patients with recurrent major depressive disorder.     

Lu AA21004, a multimodal psychotropic agent, in the prevention of relapse in adult patients with generalized anxiety disorder

The purpose of this study was to investigate the long-term maintenance of the efficacy of Lu AA21004 5 or 10 mg/day in the prevention of relapse in patients with generalized anxiety disorder (GAD). Patients (n = 687) with a primary diagnosis of GAD (DSM-IV criteria) and a baseline Hamilton Anxiety (HAM-A) total score of at least 20 underwent a 20-week, open-label Lu AA21004 treatment. In all, 459 patients responded and were randomized to 24-56 weeks of a double-blind treatment with Lu AA21004 (n = 229) or placebo (n = 230). The predefined primary efficacy endpoint was time to relapse (HAM-A total score ≥ 15) using a Cox model; the key secondary efficacy endpoint under multiplicity control was time to relapse for patients responding to treatment for at least 12 weeks. The primary analysis showed a statistically significant effect of Lu AA21004 relative to the placebo on the time to relapse of GAD, with a hazard ratio of 2.71 (P < 0.001). There was a statistically significant effect of Lu AA21004 in the stable responders (hazard ratio = 3.06, P < 0.001). Lu AA21004 was well tolerated, with withdrawal rates due to adverse events of 9% (open-label) and 3% (placebo) and 4% (Lu AA21004) in the double-blind period. In this study, Lu AA21004 5 or 10 mg/day was efficacious in preventing relapse and was well tolerated in the maintenance treatment of GAD.     

Fluvoxamine treatment of generalized social anxiety disorder in Japan: a randomized double-blind, placebo-controlled study

The efficacy of selective serotonin reuptake inhibitors (SSRIs) for the treatment of social anxiety disorder (SAD) has been reported in the USA and Europe. However, no clinical investigation has been done with SSRIs in Japanese patients with SAD. This study was performed to determine the effectiveness and safety of fluvoxamine for generalized SAD (GSAD) in Japanese patients. In this double-blind study, patients meeting DSM-IV criteria for GSAD were randomized to receive treatment with fluvoxamine or placebo for 10 wk. Fluvoxamine treatment was initiated at 50 mg/d, and increased by 50 mg weekly to a maximum of 150 or 300 mg/d. The primary efficacy outcome was mean change from baseline on the Liebowitz Social Anxiety Scale - Japanese Version (LSAS-J) total score. The secondary outcomes were response according to the Clinical Global Impressions - Global Improvement (CGI-I) score and three domains of the Sheehan Disability Scale (SDS; used to assess psychosocial impairment). A total of 176 fluvoxamine-treated patients and 89 placebo-treated patients were eligible for the efficacy analysis. At week 10, the fluvoxamine-treated patients had a significantly greater reduction in the LSAS-J total score compared with placebo-treated patients (p=0.0197), with significantly more fluvoxamine recipients being at least much improved on the CGI-I scale compared with placebo-treated patients (p=0.024). Fluvoxamine-treated patients also had better responses on the SDS compared with placebo-treated patients (p=0.0208). Fluvoxamine was safe and well tolerated. These results suggest that fluvoxamine is effective for the treatment of Japanese patients with GSAD.     

Adjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind,randomized, controlled trial,

There has been increasing interest in nutraceutical augmentation strategies to boost the efficacy of antidepressants. This study assessed whether S-adenosylmethionine (SAMe), a methyl donor that occurs naturally in the body, may be of such benefit. We conducted an 8-week, double-blind RCT in which 107 treatment non-remittent outpatients with DSM-5 diagnosed Major Depressive Disorder (MDD) were randomized to either SAMe or placebo adjunctively to antidepressants. One-carbon cycle nutrients, pertinent single nucleotide polymorphisms (SNPs), and BDNF were also analysed as potential moderators of response. A linear mixed-effects model revealed a significant overall reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score across time, however there was no significant between-group difference observed (p?=?0.51). Response rates at Week 8 were 54.3% in the SAMe group and 50.0% in the placebo group, with remission rates 43.5% for SAMe and 38.3% for placebo (all results NS). No effect of SAMe was found on any secondary outcome. Differential response to SAMe was not modified by a range of key genotypes (e.g. COMT), nor reflected in a change of homocysteine, red cell folate, or BDNF. Use of SAMe elicited no significant adverse effects beyond placebo, however it was implicated in one case of serotonin syndrome-like symptoms. This study concludes that 800?mg/day of SAMe is not an effective adjunctive treatment in MDD, and no obvious biomarker reflected any differential response to treatment. Due to such a distinctly high placebo-response (despite rigorous screening), future studies should employ a placebo run-in period and other strategies to minimize placebo response.     

A randomized,double-blind,placebo-controlled,fixed-dose,multicenter study of pregabalin in patients with generalized anxiety disorder

Pregabalin is a novel compound under development for the treatment of several types of anxiety disorders. To obtain an initial evaluation of the efficacy and safety of pregabalin in the treatment of generalized anxiety disorder (GAD), we conducted a double-blind, fixed-dose, parallel-group, placebo and active-controlled multicenter 4-week study that compared 271 patients randomized to receive pregabalin 50 mg tid (N = 70), pregabalin 200 mg tid (N = 66), placebo (N = 67), or lorazepam 2 mg tid (N = 68), followed by a 1-week double-blind taper. The primary efficacy parameter was change from baseline to endpoint (last observation carried forward) in the Hamilton Anxiety Scale (HAM-A) total score; adjusted mean change scores on the HAM-A were significantly improved for pregabalin 200 mg tid (difference of 3.90 between drug and placebo; p = 0.0013 [ANCOVA], df = 252) and for lorazepam (difference of 2.35; p = 0.0483 [ANCOVA], df = 252), with the significant difference between the pregabalin 200 mg tid and placebo groups seen at week 1 of treatment (p = 0.0001 [ANCOVA], df = 238). Safety analysis, which included assessment of spontaneously reported adverse events, laboratory monitoring, and withdrawal symptoms, showed pregabalin to be generally well-tolerated. The most common adverse events seen with pregabalin 200 mg tid were somnolence and dizziness. They were usually mild or moderate in intensity and were often transient. Pregabalin-treated patients had a higher completion rate than lorazepam-treated patients. This study supports the hypothesis that pregabalin is effective and safe in short-term therapy for GAD. More studies are needed to determine the best dosing regimen to optimize efficacy and tolerability.     

Tiagabine in adult patients with generalized anxiety disorder: results from 3 randomized, double-blind, placebo-controlled, parallel-group studies

The objective of these studies was to evaluate the efficacy and tolerability of tiagabine, a selective gamma-aminobutyric acid reuptake inhibitor, in adult patients with generalized anxiety disorder (GAD). Patients with a diagnosis of GAD were enrolled in 1 of 3 randomized, placebo-controlled, 10-week studies. In each study, tiagabine was taken twice daily in divided doses--4, 8, or 12 mg/d in a fixed-dose study and 4-16 mg/d in two flexible-dose trials. The primary efficacy measure was the change from baseline in the 14-item Hamilton Rating Scale for Anxiety (HAM-A) total score at the final visit (last observation carried forward). Additional measures included change from baseline in the anxiety subscale of the Hospital Anxiety and Depression Scale, the Sheehan Disability Scale, and Clinical Global Impressions-Improvement scale. Tolerability was assessed via spontaneous reports as well as rating scales throughout the study period. In all 3 studies, there was no significant differentiation from placebo on the primary measure (change in HAM-A) for any tiagabine dose (P > 0.05). In the 2 flexible-dose studies, the tiagabine group showed improvements over time in the HAM-A that reached significance only in those patients who completed 10 weeks of treatment (study 2, P = 0.018; study 3, P = 0.036). The most common adverse events were dizziness, headache, nausea, fatigue, and somnolence. In conclusion, the results of these studies do not support the efficacy of tiagabine in adult patients with GAD.     

A randomized double-blind placebo-controlled study of tropisetron in the treatment of outpatients with generalized anxiety disorder

The selective 5HT₃ antagonist tropisetron was studied in 91 outpatients meeting DSM-III criteria for Generalized Anxiety Disorder. Following a placebo washout period of up to 1 week, one of three active treatments (tropisetron 0.5 mg, 5 mg, or 25 mg daily) or placebo was given for a further 3 weeks. After 7 days treatment termination rates due to inefficacy showed a statistically significant dose-related therapeutic effect of tropisetron. Similar effects were seen on the Hopkins Symptom Check List total score and the Global Impression Scale. The Hamilton Anxiety Scale showed a similar trend which, however, failed to reach statistical significance. At day 21 tropisetron showed significant dose-dependent effects on all anxiety-related outcome measures. The incidence of adverse events was low and the severity generally mild. Most frequent complaints were headache, nausea, constipation and nervousness. Laboratory tests and physical examination performed at baseline and study end showed no significant treatment effects.(Drs Braconnier, Combes Lepastier, Danic, Deyrieux, Fabiani, Lazartigues, Peyrouzet, Raikovic and Supino-Viterbo)     

Duloxetine treatment for relapse prevention in adults with generalized anxiety disorder: A double-blind placebo-controlled trial.

The objective was to examine duloxetine 60-120 mg/day treatment for relapse prevention in adults with generalized anxiety disorder (GAD). Adult patients (N=887; mean age=43.3 years; 61.0% female) with DSM-IV-TR-defined GAD diagnosis were treated with duloxetine for 26 weeks. Patients who completed open-label phase and were treatment responders (>/=50% reduction in Hamilton Anxiety Rating Scale total score to /=2-point increase in illness severity ratings or by discontinuation due to lack of efficacy. During the double-blind phase, placebo-treated patients (N=201) relapsed more frequently (41.8%) than duloxetine-treated patients (13.7%, N=204, P相似文献   

Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial

To evaluate the efficacy of pregabalin in facilitating taper off chronic benzodiazepines, outpatients (N = 106) with a lifetime diagnosis of generalized anxiety disorder (current diagnosis could be subthreshold) who had been treated with a benzodiazepine for 8-52 weeks were stabilized for 2-4 weeks on alprazolam in the range of 1-4 mg/day. Patients were then randomized to 12 weeks of double-blind treatment with either pregabalin 300-600 mg/day or placebo while undergoing a gradual benzodiazepine taper at a rate of 25% per week, followed by a 6-week benzodiazepine-free phase during which they continued double-blind study treatment. Outcome measures included ability to remain benzodiazepine-free (primary) as well as changes in Hamilton Anxiety Rating Scale (HAM)-A and Physician Withdrawal Checklist (PWC). At endpoint, a non-significant higher proportion of patients remained benzodiazepine-free receiving pregabalin compared with placebo (51.4% vs 37.0%). Treatment with pregabalin was associated with significantly greater endpoint reduction in the HAM-A total score versus placebo (-2.5 vs +1.3; p < 0.001), and lower endpoint mean PWC scores (6.5 vs 10.3; p = 0.012). Thirty patients (53%) in the pregabalin group and 19 patients (37%) in the placebo group completed the study, reducing the power to detect a significant difference on the primary outcome. The results on the anxiety and withdrawal severity measures suggest that switching to pregabalin may be a safe and effective method for discontinuing long-term benzodiazepine therapy.     

A double-blind, placebo-controlled trial of abecarnil and diazepam in the treatment of patients with generalized anxiety disorder

In a multicenter, double-blind trial, 310 patients who had received a diagnosis of generalized anxiety disorder were treated for 6 weeks with either abecarnil, diazepam, or placebo at mean daily doses of 12 mg of abecarnil or 22 mg of diazepam administered three times daily. Patients who were improved at 6 weeks could volunteer to continue double-blind treatment for a total of 24 weeks. The maintenance treatment phase allowed the comparison of taper results for the three treatments at several study periods (0-6 weeks, 7-12 weeks, and more than 12 weeks). Slightly more diazepam (77%) and placebo (75%) patients completed the 6-week study than abecarnil patients (66%). At intake and baseline, after a 1-week placebo washout, the patient was required to have a Hamilton Rating Scale for Anxiety score of > or =20. Major adverse events for both abecarnil and diazepam were drowsiness, dizziness, fatigue, and coordination difficulties. Clinical improvement data showed that both abecarnil and diazepam produced statistically significantly more symptom relief than did placebo after 1 week of treatment. At 6 weeks treatment (using last observation carried forward analysis), however, only diazepam still differed significantly (p < 0.01) from placebo. High placebo response (56% moderate to marked global improvement) at 6 weeks, as well as a slightly lower nonsignificant improvement rate observed with abecarnil, a partial y-aminobutyric acid (GABA) agonist, when compared with diazepam, a full GABA agonist, most likely contributed to our findings. Finally, taper results showed that only diazepam and not abecarnil caused the presence of temporary discontinuation symptoms, but only in patients who had been treated for at least 12 weeks.     

Efficacy of pregabalin in preventing relapse in patients with generalized social anxiety disorder: results of a double-blind, placebo-controlled 26-week study

The objective of this study was to evaluate the efficacy and safety of pregabalin in preventing relapse in generalized social anxiety disorder (SAD). Patients with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) generalized SAD, who met responder criteria after 10 weeks of open-label treatment with fixed-dose pregabalin (450 mg/day; n=153), were randomly assigned to 26 weeks of double-blind treatment with pregabalin (450 mg/day) or placebo. The primary a-priori outcome of time to relapse was analyzed using the Kaplan-Meier method and the log-rank test. Double-blind treatment with pregabalin was associated with significant delay in time to relapse versus placebo (P=0.035), and with significantly greater maintenance of symptomatic improvement over 26 weeks on the Liebowitz Social Anxiety Scale total (P=0.012) and subscale scores and on the Marks Fear Questionnaire total phobia (P=0.010) and social phobia (P=0.014) subscales. Pregabalin was generally well tolerated. During the double-blind phase, the adverse events that occurred more frequently with pregabalin compared with placebo were dizziness (11.3 vs. 4.1%) and infection (21.3 vs. 16.4%). The results of this study suggest that pregabalin (450 mg/day) is safe, well tolerated, and has significant relapse-prevention efficacy over 26 weeks in patients with SAD who responded to an initial course of the pregabalin treatment.     

Deramciclane in the treatment of generalized anxiety disorder: A placebo-controlled, double-blind, dose-finding study

Deramciclane, a camphor derivative, is a novel anxiolytic agent with a unique mechanism of action. It acts as a potent and specific antagonist at serotonin 5-HT_2A/2C receptors, and exhibits anxiolytic efficacy in animal models. The aim of this double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of a range of doses of deramciclane in patients with generalized anxiety disorder (GAD). Adult patients with a diagnosis of GAD (DSM-IV) and a Hamilton Anxiety Rating Scale (HAM-A) total score ≥ 18; a score ≥ 2 for the HAM-A items ‘Anxious Mood’ and ‘Tension’; a score ≥ 4 on the Clinical Global Impression of Severity of Illness (CGI-S) Scale; and a score ≤ 20 on the Montgomery–Åsberg Depression Rating Scale (MADRS) were enrolled in the study. Following a 1–2 week placebo run-in period, patients were randomized to receive deramciclane (10, 30, or 60 mg/day in two divided doses) or placebo for 8 weeks, followed by a 2-week placebo wash-out period. The primary efficacy measure was change in HAM-A score from baseline to week 8. Adverse events were monitored throughout the study. Withdrawal reactions were assessed at the end of the study (week 8) and during the placebo wash-out period using the Physician's Withdrawal Checklist (34 items). In the intent-to-treat population (n = 208), both the deramciclane 30 mg/day and 60 mg/day doses provided clinically relevant improvements in HAM-A total score after 8 weeks of treatment, reaching statistical significance compared with placebo in the 60 mg/day dose group (p = 0.024) and a clear trend in the 30 mg/day group (p = 0.059). On the HAM-A psychic anxiety factor, significant improvements were seen in patients in the deramciclane 30 mg/day and 60 mg/day treatment groups compared with those in the placebo group (p < 0.05). Adverse events were reported at a similar frequency across all four treatment groups; the most commonly reported adverse event was headache. No withdrawal reactions were observed on abrupt discontinuation of deramciclane. In conclusion, deramciclane 60 mg/day showed significant evidence of efficacy for the treatment of GAD in adult patients. The efficacy for the 30 mg/day dose was close to the larger dose although not significant in the primary analysis, and there was no significant evidence of efficacy for the 10 mg/day dose. Deramciclane was safe and well-tolerated up to the 60 mg/day dose over an 8-week period.     

Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial

The objective of this study was to evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) as maintenance monotherapy for patients with generalized anxiety disorder (GAD). Time-to-event (anxiety symptom recurrence; maximum 52 weeks) multicenter, randomized-withdrawal, parallel-group, double-blind, placebo-controlled study of quetiapine XR (50-300 mg/day) following open-label run-in (4-8 weeks) and open-label stabilization (≥ 12 weeks). Primary variable: time from randomization to anxiety event. Secondary variables included: Hamilton Anxiety Rating Scale (HAM-A) total, HAM-A psychic/somatic anxiety factors, Clinical Global Impression-Severity of Illness (CGI-S), and Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q) scores; adverse events (AE) reporting. Four hundred and thirty-two patients, stabilized on quetiapine XR, were randomized to continue quetiapine XR (N=216) or switch to placebo (N=216). Risk of anxiety symptom recurrence was significantly reduced by 81% for quetiapine XR versus placebo: hazard ratio=0.19 (95% confidence interval 0.12-0.31; P<0.001). Fewer patients receiving quetiapine XR (N=22, 10.2%) than placebo (N=84, 38.9%) experienced anxiety symptom recurrence. Significant differences were observed between quetiapine XR and placebo in: HAM-A total, psychic/somatic, CGI-S (all P<0.001) and Q-LES-Q (P<0.05) scores. AEs (>10%) during open-label treatment were dry mouth, sedation, somnolence, dizziness, fatigue, and constipation. During randomized treatment, the most common AEs for quetiapine XR were headache and nasopharyngitis. Quetiapine XR monotherapy reduced the risk of anxiety symptom recurrence in patients with GAD stabilized on quetiapine XR, with tolerability results consistent with the known profile of quetiapine.     

A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD)

The efficacy, safety, and tolerability of Lu AA21004 versus placebo, using duloxetine as active reference, in patients with DSM-IV-TR diagnosed major depressive disorder (MDD) were evaluated in this 8-week, multi-site study. Patients (n = 766) had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥ 26 and were randomly assigned (1:1:1:1:1) to 2.5, 5 or 10 mg Lu AA21004, placebo, or 60 mg duloxetine. The 5 mg and 10 mg doses of Lu AA21004 were tested separately versus placebo at p ≤ 0.025 in a pre-specified order. In the pre-defined primary efficacy analysis [mean change from baseline in MADRS total score at Week 8, full analysis set, ANCOVA, last observation carried forward (LOCF)], the differences to placebo (n = 145) of ? 1.7 (Lu AA21004 5 mg, n = 155) and ? 1.5 points (Lu AA21004 10 mg, n = 151) were not statistically significant; nor were those for Lu AA21004 2.5 mg (? 1.4 points, n = 155) or duloxetine (? 2.0 points, n = 149). Using mixed model, repeated measures (MMRM) analyses of the primary endpoint and most secondary endpoints were supportive of likely efficacy for Lu AA21004 5 mg and 10 mg and duloxetine. Treatment-emergent adverse events led to the withdrawal of 72 patients: 8% (placebo), 12% (duloxetine), and 6%, 11% and 9% in the Lu AA21004 groups (2.5 mg, 5 mg and 10 mg, respectively). The most common adverse events were nausea, headache, dizziness, and dry mouth. No clinically relevant changes were seen in vital signs, weight, ECG, or laboratory results. In summary, none of the active treatment groups, including duloxetine, separated from placebo in the primary analysis in this 'failed' study. Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5 mg and 10 mg and duloxetine. Lu AA21004 (2.5, 5 and 10 mg) was well tolerated.     

Efficacy of pregabalin in generalized social anxiety disorder: results of a double-blind, placebo-controlled, fixed-dose study

The objective of this study was to evaluate the efficacy and tolerability of pregabalin for the treatment of generalized social anxiety disorder (SAD). Patients with generalized SAD, who met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) criteria (total N=329), were randomly assigned to 11 weeks of double-blind treatment with fixed daily doses of either pregabalin (300, 450, and 600(mg) or placebo. The treatment with pregabalin (600(mg) was associated with a significantly greater mean reduction in the Liebowitz Social Anxiety Scale total score, from baseline to endpoint, compared with placebo (-29.8 vs. -19.7; P= 0.0099), whereas reduction on pregabalin (300(mg, -20.2) and pregabalin (450(mg, -25.5) was not significant Treatment with pregabalin (600(mg) was also associated with a significantly greater improvement than placebo on the fear and avoidance subscales of the Liebowitz Social Anxiety Scale, as well as the majority of other secondary measures. Onset of improvement occurred by week 1 in the pregabalin 600-mg dose group. The most common adverse events on all three doses of pregabalin were somnolence and dizziness. Consistent with a previous study, the results of this study suggest that the 600-mg dose of pregabalin per day may be efficacious in the treatment of SAD.