A double-blind, randomized, placebo-controlled study assessing the efficacy and tolerability of desvenlafaxine 10 and 50 mg/day in adult outpatients with major depressive disorder.

BACKGROUND: In an effort to establish the lowest effective dose of desvenlafaxine (administered as desvenlafaxine succinate), we assessed the efficacy, safety, and tolerability of 10- and 50-mg/day desvenlafaxine vs placebo for the treatment of major depressive disorder. METHODS: Adult outpatients with DSM-IV-defined major depressive disorder and a 17-item Hamilton Rating Scale for Depression (HAM-D(17)) total score ≥20 were randomly assigned to receive placebo or desvenlafaxine (10 or 50 mg/day) after a 6- to 14-day single-blind placebo lead-in period in an 8-week, phase 3, fixed-dose trial. The primary efficacy measure was change from baseline in the HAM-D(17) score analyzed using analysis of covariance. Efficacy analyses were conducted with the intent-to-treat population, using the last observation carried forward. RESULTS: The intent-to-treat population included 673 patients. Change from baseline to final evaluation in adjusted HAM-D(17) total scores was not significantly different comparing desvenlafaxine 10 mg/day (-9.28) and desvenlafaxine 50 mg/day (-8.92) with placebo (-8.42). There were no differences among treatment groups in the rates of treatment response or remission. Discontinuations due to adverse events occurred in 1.8%, 0.9%, and 1.8% of patients in the placebo and desvenlafaxine 10- and 50-mg/day groups, respectively. Overall rates of treatment-emergent adverse events with both doses were similar to placebo. CONCLUSIONS: Both doses of desvenlafaxine failed to separate from placebo. However, in a companion study reported separately, desvenlafaxine 50 mg, but not 25 mg, separated from placebo. Taken together, these studies suggest that 50 mg is the minimum effective dose of desvenlafaxine for the treatment of major depressive disorder. CLINICALTRIALS.GOV IDENTIFIER: NCT00863798 http://clinicaltrials.gov/ct2/show/NCT00863798?term=00863798&rank=1.

High-dose desvenlafaxine in outpatients with major depressive disorder.

OBJECTIVE: This study investigated the safety and efficacy of long-term treatment with high-dose desvenlafaxine (administered as desvenlafaxine succinate) in major depressive disorder (MDD). METHODS: In this multicenter, open-label study, adult outpatients with MDD aged 18-75 were treated with flexible doses of desvenlafaxine (200-400 mg/d) for ≤ 1 year. Safety assessments included monitoring of treatment-emergent adverse events (TEAEs), patient discontinuations due to adverse events, electrocardiograms, vital signs, and laboratory determinations. The primary efficacy measure was mean change from baseline in the 17-item Hamilton Rating Scale for Depression [HAM-D(17)] total score. RESULTS: The mean daily desvenlafaxine dose range over the duration of the trial was 267-356 mg (after titration). The most frequent TEAEs in the safety population (n = 104) were nausea (52%) and headache (41%), dizziness (31%), insomnia (29%), and dry mouth (27%). All TEAEs were mild or moderate in severity. Thirty-four (33%) patients discontinued from the study because of TEAEs; nausea (12%) and dizziness (9%) were the most frequently cited reasons. The mean change in HAM-D(17) total score for the intent-to-treat population (n = 99) was -9.9 at the last on-therapy visit in the last-observation-carried-forward analysis and -14.0 at month 12 in the observed cases analysis. Conclusion High-dose desvenlafaxine (200-400 mg/d) was generally safe and effective in the long-term treatment of MDD.

Retrospective analysis of suicidality in patients treated with the antidepressant desvenlafaxine.

The objective of this analysis was to assess the risk of increased suicidal thoughts and behavior (suicidality) with desvenlafaxine (administered as desvenlafaxine succinate) in patients with major depressive disorder (MDD). Data from 9 double-blind, 8-week studies in outpatients with MDD were analyzed retrospectively. Patients were randomly assigned to desvenlafaxine (n = 1834) or placebo (n = 1116). Adverse events (AEs) related to suicidality were identified by searching the AE database for text strings possibly related to suicidality; false positives were excluded. Narratives for each case were prepared and blinded for review. Events were classified according to the Columbia Classification Algorithm of Suicide Assessment. Odds ratios were calculated; chi tests were used to compare treatment groups. Occurrence of emerging or worsening suicidality, based on the 17-item Hamilton Rating Scale for Depression suicide item, was compared for desvenlafaxine and placebo using chi tests. In all, 17 (0.93%) of 1834 patients receiving desvenlafaxine and 8 (0.72%) of 1116 receiving placebo reported possible suicidality-related AEs. Events were relatively evenly distributed across treatment groups. One patient randomly assigned to desvenlafaxine treatment died of completed suicide during the on-therapy period. There were no significant differences between groups in the risk for any class of suicide-related events, including completed suicide or suicide attempt. Odds of emergence or worsening of suicidality 17-item (Hamilton Rating Scale for Depression suicide item) did not differ significantly between treatment groups. No evidence of a signal for increased suicidality was detected in adult patients treated with desvenlafaxine in short-term MDD trials. As suicidal events were extremely rare, a true increased risk cannot be ruled out.

Desvenlafaxine for the prevention of relapse in major depressive disorder: results of a randomized trial.

OBJECTIVES: To compare the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) with placebo in reducing relapse rate in patients with major depressive disorder (MDD). METHODS: This phase 3, multicenter, randomized trial included a 12-week, open-label (OL) treatment phase (intent-to-treat population, n = 575) followed by a 6-month, double-blind (DB) relapse prevention phase. Patients who responded to the OL treatment (17-item Hamilton Rating Scale for Depression total score or= 16 at any visit, Clinical Global Impression-Improvement score >or= 6 at any visit, or discontinuation due to unsatisfactory response). RESULTS: Patients receiving desvenlafaxine (n = 189) experienced significantly longer times to relapse of MDD versus patients receiving placebo (n = 185) during the DB period (log-rank test, P < 0.0001). The percentages of patients relapsing were 42% (78/185) and 24% (45/189) for placebo and desvenlafaxine, respectively (P < 0.001). The most common primary reason cited for discontinuation in the OL period was adverse events (19%), which consisted of nausea, dizziness, and insomnia. A total of 159 patients (42%) discontinued treatment during the DB period, including 101 placebo- (55%) and 58 desvenlafaxine-treated patients (31%). The most frequent adverse event reported as reason for treatment discontinuation in the DB period was depression, reported by 14 placebo- (8%) and 7 desvenlafaxine-treated patients (4%). CONCLUSIONS: Desvenlafaxine effectively prevented relapse of MDD during 6 months of DB treatment in patients who had responded to 12 weeks of OL desvenlafaxine therapy.

Analysis of the effect of desvenlafaxine on anxiety symptoms associated with major depressive disorder: pooled data from 9 short-term, double-blind, placebo-controlled trials.

BACKGROUND: This analysis evaluated the effects of the serotonin-norepinephrine reuptake inhibitor, desvenlafaxine (administered as desvenlafaxine succinate), on anxiety symptoms associated with depression. METHODS: Data were pooled from 9 randomized, placebo-controlled, double-blind, 8 week studies of desvenlafaxine (50-400 mg/day, fixed or flexible dose) in patients with major depressive disorder (MDD), without a primary anxiety diagnosis. Changes from baseline in scores on the anxiety/somatization factor of the 17-item Hamilton Rating Scale for Depression (HAM-D17) and on the Covi Anxiety Scale at the final evaluation (last observation carried forward) were compared between desvenlafaxine and placebo groups using analysis of covariance. RESULTS: In the overall data set (intent to treat n=2,913 [desvenlafaxine, n=1,805; placebo, n=1,108]), desvenlafaxine was associated with significantly greater reductions compared with placebo in scores on the HAM-D17 anxiety/somatization factor (-3.41 vs -2.92, P<.001) and Covi Anxiety Scale (-1.35 vs -1.04, P<.001). In the subset of fixed-dose studies, significant differences were observed for all dose groups on the HAM-D17 anxiety/somatization factor (P= or <.011), and for the 50, 100, and 200 mg/day dose groups on the Covi Anxiety Scale (all P= or <.015 vs placebo). CONCLUSIONS: Desvenlafaxine was associated with significantly greater improvement in anxiety symptoms compared with placebo in patients with MDD.

An integrated analysis of the safety and tolerability of desvenlafaxine compared with placebo in the treatment of major depressive disorder.

INTRODUCTION: The safety and tolerability profiles of antidepressants can often influence the treatment choices of clinicians treating major depressive disorder. The purpose of this investigation was to characterize the safety and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) in treating depression. METHODS: An integrated analysis of all short-term, randomized, double-blind, placebo-controlled registration studies for major depressive disorder (four flexible-dose and five fixed-dose studies) was performed. Adult outpatients with major depressive disorder received desvenlafaxine doses ranging from 50-400 mg/day or placebo for 8 weeks. Treatment-emergent adverse events, laboratory values, vital signs, and discontinuation symptoms were evaluated. In the subset of fixed-dose studies, dose-related effects were analyzed. RESULTS: In the overall population (placebo: n=1,116; desvenlafaxine: n=1,834), adverse events resulted in discontinuations in 3% of placebo-treated patients and 12% of desvenlafaxine-treated patients; in the subset of fixed-dose studies, the rates were 4% with placebo and increased with desvenlafaxine dose (50 mg/day: 4%; 400 mg/day: 18%). The most common treatment-emergent adverse event was transient nausea that was generally mild to moderate. The most common sexual dysfunction associated with desvenlafaxine treatment was erectile dysfunction in men (7% vs 1% with placebo) and anorgasmia in women (1% and 0%). One desvenlafaxine-treated patient died of a completed suicide; there were four suicide attempts (three desvenlafaxine, one placebo) and eight cases of suicidal ideation (five desvenlafaxine, three placebo) during the on-therapy period. Small but statistically significant changes in mean blood pressure occurred at all desvenlafaxine doses; clinically meaningful changes were observed in 1% of placebo-treated patients and 2% of desvenlafaxine-treated patients. Desvenlafaxine was associated with small but statistically significant mean changes in laboratory assessments, particularly lipid and liver enzyme elevations, and electrocardiograms; few cases of these changes were clinically relevant. CONCLUSION: Desvenlafaxine in the treatment of major depressive disorder exhibited a safety and tolerability profile generally consistent with the serotonin-norepinephrine reuptake inhibitor class. The most common adverse event was transient nausea. At the recommended therapeutic dose of 50 mg/day, discontinuation due to adverse events was similar to placebo.

A placebo-controlled study evaluating the efficacy and safety of flexible-dose desvenlafaxine treatment in outpatients with major depressive disorder.

INTRODUCTION: This research compares the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) versus placebo in treating major depressive disorder. METHODS: In this randomized, double-blind study, outpatients with major depressive disorder > or =18 years of age received desvenlafaxine 200-400 mg/day or placebo for 8 weeks. Efficacy endpoints included (primary) change in 17-item Hamilton Rating Scale for Depression score at the final evaluation (last observation carried forward, analysis of covariance) and (secondary) Clinical Global Impressions-Improvement and -Severity of Illness scales. RESULTS: The difference between desvenlafaxine (n==) and placebo (n==) on the primary endpoint was not significant (-9.1 vs -7.5, P=.078). Week 8 observed cases (desvenlafaxine, n=80; placebo, n=94) results were significant (-10.7 vs -7.9, P=.008). Differences at the final evaluation (last observation carried forward) were significant for Clinical Global Impressions-Improvement (2.9 vs 2.5, P=.037) and Clinical Global Impressions-Severity of Illness (-1.9 vs -1.2, P=.041). Discontinuation rates due to adverse events (AEs) were 12% and 3% for desvenlafaxine and placebo, respectively (P=.008). The most frequently reported AE associated with desvenlafaxine was nausea (36% vs 9% [placebo]). CONCLUSION: In this study, the primary analysis did not show significant differences between desvenlafaxine and placebo; discontinuations due to AEs associated with the desvenlafaxine dose range may have contributed to the lack of statistical separation.

Efficacy, safety, and tolerability of fixed-dose desvenlafaxine 50 and 100 mg/day for major depressive disorder in a placebo-controlled trial.

The objective of this study was to assess the efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) 50 and 100 mg/day for major depressive disorder (MDD). A multicenter, randomized, double-blind, placebo-controlled trial was conducted in Europe and South Africa. Outpatients with MDD received fixed-dose desvenlafaxine (50 or 100 mg/day) or placebo for 8 weeks. The primary efficacy variable was the 17-item Hamilton Rating Scale for Depression total score; secondary measures included Clinical Global Impressions-Improvement scores. The intent-to-treat population included 483 patients: desvenlafaxine 50 mg (n=164), desvenlafaxine 100 mg (n=158), and placebo (n=161). At the last-observation-carried-forward analysis (final evaluation) using analysis of covariance, adjusted mean changes from baseline on the Hamilton Rating Scale for Depression were significantly greater for both desvenlafaxine 50 mg (-13.2; P=0.002) and 100 mg (-13.7; P<0.001) versus placebo (-10.7). Significant differences on the Clinical Global Impressions-Improvement scores were observed for desvenlafaxine 50 mg (P=0.002) and 100 mg (P<0.001) versus placebo. Both doses of desvenlafaxine were generally well tolerated. The most common treatment-emergent adverse events were nausea, dizziness, insomnia, constipation, fatigue, anxiety, and decreased appetite. Fixed doses of desvenlafaxine 50 and 100 mg/day are safe, generally well tolerated, and effective at a clinically relevant level for the treatment of MDD.

A pooled analysis of two placebo-controlled trials of desvenlafaxine in major depressive disorder.

The efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) were evaluated in two similarly designed, phase 3, randomized, double-blind, placebo-controlled, venlafaxine-extended-release-referenced, flexible-dose studies of outpatients with a primary diagnosis of major depressive disorder. Owing to a high placebo response, the individual studies were underpowered. Therefore, a post-hoc pooled analysis was performed (desvenlafaxine and placebo data were pooled; venlafaxine extended release data were not, owing to different flexible-dose regimens in the two studies). The primary outcome measure was the change from baseline on the 17-item Hamilton Rating Scale for Depression; the Clinical Global Impressions-Improvement item score was a secondary outcome. Analysis of the pooled data (using a mixed-effect model for repeated measures) revealed that after 8 weeks of treatment, desvenlafaxine was significantly better than placebo on 17-item Hamilton Rating Scale for Depression [-14.21 vs. -11.87 for desvenlafaxine and placebo, respectively; magnitude of effect=-2.34 (P<0.001)] and Clinical Global Impressions-Improvement item scores [1.95 vs. 2.32 for desvenlafaxine and placebo, respectively; magnitude of effect=-0.37 (P<0.001)]. Adverse events were comparable to those found with other drugs sharing a similar mechanism of action. These data support the efficacy, safety, and tolerability of desvenlafaxine in the treatment of major depressive disorder.

A Randomized controlled trial of venlafaxine ER versus placebo in pediatric social anxiety disorder.

BACKGROUND: Social anxiety disorder, which occurs in 2% to 5% of children and adolescents, is associated with significant distress and functional impairment. METHODS: The objective of the randomized, masked controlled trial conducted in 48 academic and community centers in the United States was to evaluate the efficacy of venlafaxine ER in children and adolescents with generalized social anxiety disorder. A volunteer sample of 293 outpatients, age 8 to 17, who met diagnostic criteria for social anxiety disorder and were enrolled between February 2000 and March 2003 participated. Venlafaxine ER or placebo was titrated from a starting dose of 37.5 mg to a maximum dose of 225 mg over 16 weeks. The primary dependent measures were the Social Anxiety Scale, child or adolescent version (SAS-CA) and for responder analysis, a (dichotomized) Clinical Global Impressions-Improvement (CGI-I) score. RESULTS: Compared with placebo, intent-to-treat random regression analyses indicated a statistically significant advantage for venlafaxine ER (p = .001) on the SAS-CA. On the CGI-I responder analysis, 56% (95% confidence interval [CI], 47%-64%) of venlafaxine ER treated subjects responded, which was statistically superior to placebo (37% [95% CI, 29%-45%]). Three venlafaxine ER and no placebo patients developed treatment-emergent suicidality; there were no completed suicides. CONCLUSIONS: Venlafaxine ER is an effective and reasonably well-tolerated treatment for generalized social anxiety disorder in children and adolescents. As with other antidepressants, careful clinical monitoring for adverse events, including treatment-emergent suicidality, is essential.