Matthieu Boucher

Predictors of functional improvement in employed adults with major depressive disorder treated with desvenlafaxine.

We carried out a secondary analysis of a double-blind, placebo-controlled trial of desvenlafaxine for major depressive disorder (MDD) to explore the associations between depressive symptoms and subtypes, and functional outcomes, including work functioning. Employed outpatients with MDD were assigned randomly in a 2 : 1 ratio to receive desvenlafaxine 50 mg/day or placebo for 12 weeks. Analyses were carried out post-hoc with the intent-to-treat (ITT) sample (N=427) and a prospectively defined modified ITT sample (N=310), composed of patients with baseline 17-item Hamilton Rating Scale for Depression score of at least 20. Functional outcomes at week 12 included items and factors from the Montgomery–Åsberg Depression Rating Scale, Sheehan Disability Scale, and the Work Productivity and Activity Impairment questionnaire. In the modified ITT sample, but not in the ITT sample, desvenlafaxine-treated patients showed significantly greater improvement in several functional outcomes in the responder, nonanxious, and normal-energy patient subgroups. Improvement in the 17-item Hamilton Rating Scale for Depression total score at week 2 predicted change at week 12 in several functional outcomes. Functional improvement at 12 weeks was greater in subgroups of patients and was also significantly predicted by early improvement in depressive symptoms in employed patients with MDD treated with desvenlafaxine.

Desvenlafaxine for the treatment of major depressive disorder.

Introduction: Major depressive disorder (MDD) is a chronic and debilitating condition often characterized by inadequate treatment. Notwithstanding the availability of more than a dozen first-line agents across disparate classes (e.g., selective serotonin reuptake inhibitors), the majority of individuals with MDD do not achieve and sustain a recovered state. A substantial percentage of MDD patients require a treatment change due to poor efficacy or tolerability. Areas covered: This review focuses on recent (≤ 5 years) literature describing the pharmacokinetics, efficacy, and tolerability of desvenlafaxine, one of the more recently approved antidepressant drugs. Published papers identified via PubMed search and congress presentations were included. Results from short-term, placebo-controlled, MDD trials and randomized withdrawal trials, as well as post hoc analyses in patient subgroups, are reviewed. Expert opinion: Desvenlafaxine has been shown to be an effective antidepressant with a favorable safety and tolerability profile in the general MDD population and in important patient subgroups. It has several notable differences from other serotonin-norepinephrine reuptake inhibitors, and those differences suggest populations in which it may have the most clinical benefit.

An integrated analysis of the efficacy and safety of desvenlafaxine in the treatment of major depressive disorder.

The chronic course of major depressive disorder (MDD) often impedes the ability of patients to achieve full remission. Return of full functioning is a critical goal of antidepressant pharmacotherapy as the presence of residual depressive symptoms is associated with an increased risk of relapse. Treatment guidelines recommend selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, or atypical antidepressants as first-line treatment for moderate to severe MDD. Desvenlafaxine, administered as desvenlafaxine succinate, is an serotonin–norepinephrine reuptake inhibitor approved for the treatment of adults with MDD at the recommended dose of 50 mg/day. The aim of this integrated analysis was to assess the efficacy and safety of desvenlafaxine 50 and 100 mg/day compared with placebo in adult outpatients with MDD. The analysis used data from nine fixed-dose, short-term, placebo-controlled studies in adult outpatients diagnosed with MDD who had depressive symptoms for at least 30 days. Data from 4279 and 4317 patients were pooled for the efficacy and safety analyses, respectively. Statistically significant improvements were observed with desvenlafaxine 50 and 100 mg/day versus placebo for all efficacy endpoints assessed, including improvements in depressive symptoms, response and remission rates, as well as functional and cognitive outcomes. Treatment with desvenlafaxine 50 and 100 mg/day was generally safe and well tolerated. The findings of this integrated analysis of data from a large population of patients with MDD confirmed the antidepressant efficacy of both desvenlafaxine doses and add to previous evidence supporting the efficacy of desvenlafaxine.

Efficacy of Desvenlafaxine Compared With Placebo in Major Depressive Disorder Patients by Age Group and Severity of Depression at Baseline

Purpose This post hoc meta-analysis evaluated the efficacy and safety of desvenlafaxine 50 and 100 mg versus placebo across age groups and severity of depression at baseline in patients with major depressive disorder. Methods Data from placebo and desvenlafaxine 50-mg and 100-mg dose arms were pooled from 9 short-term, placebo-controlled, major depressive disorder studies (N = 4279). Effects of age (18–40 years, >40 to <55 years, 55–<65 years, and ≥65 years) and baseline depression severity (mild, 17-item Hamilton Rating Scale for Depression total score [HAM-D17] ⩽18; moderate, HAM-D17 >18 to <25; severe, HAM-D17 ≥25) on desvenlafaxine efficacy were assessed using analysis of covariance for continuous end points and logistic regression for categorical end points. Findings Desvenlafaxine-treated (50 or 100 mg/d) patients had significantly (P < 0.05, 2-sided) greater improvement in most measures of depression and function compared with placebo for patients 18 to 40 years, older than 40 to younger than 55 years, and 55 to younger than 65 years, with no significant evidence of an effect of age. Desvenlafaxine significantly improved most measures of depression and function in moderately and severely depressed patients. There was a significant baseline severity by treatment interaction for HAM-D17 total score only (P = 0.027), with a larger treatment effect for the severely depressed group. Implications Desvenlafaxine significantly improved depressive symptoms in patients younger than 65 years and in patients with moderate or severe baseline depression. Sample sizes were not adequate to assess desvenlafaxine efficacy in patients 65 years or older or with mild baseline depression.

Effect of metabolic syndrome and thyroid hormone on efficacy of desvenlafaxine 50 and 100 mg/d in major depressive disorder

ABSTRACT Objective This pooled, post hoc analysis evaluated the efficacy of desvenlafaxine vs placebo in adults with major depressive disorder (MDD) with and without metabolic syndrome, and above or at or below median baseline thyroid-stimulating hormone (TSH) levels. Research design and methods Patients were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo in nine short-term, double-blind studies. Metabolic syndrome was defined as meeting at least three of five criteria based on body mass index, triglycerides, high-density lipoprotein, fasting glucose, blood pressure, current medication, and medical history. Clinical trial registration NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457 Main outcome measures Treatment effects on change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D17) total score at week 8 (last observation carried forward [LOCF]) were analyzed in four subgroups—metabolic syndrome and no metabolic syndrome, baseline TSH levels above median or at or below median—using analysis of covariance with treatment, study, and baseline in the model. Metabolic syndrome and TSH were examined as predictors of change in HAM-D17 total score using regression analysis. Results The pooled analysis included 4279 patients; 971 (22.7%) patients had metabolic syndrome. In all subgroups, HAM-D17 total scores improved significantly from baseline to week 8 (LOCF) with desvenlafaxine 50 or 100 mg/d compared with placebo (all p ≤ 0.006). There was no significant treatment by metabolic syndrome or by TSH interaction. Neither metabolic syndrome nor TSH above median predicted change in HAM-D17 total scores, response (≥50% reduction in HAM-D17 total score), or remission (HAM-D17 total score ≤7; all p > 0.05). Limitations Individual studies included in this analysis were not designed to examine the relationship between metabolic syndrome or TSH and response to desvenlafaxine treatment. Metabolic syndrome status was determined post hoc based on available baseline measures and not diagnosed at study entry. Exclusion criteria were selected to enroll medically healthy patients with a primary diagnosis of MDD (i.e., patients healthier than the general MDD population). Conclusions Desvenlafaxine 50 and 100 mg/d significantly improved depression compared with placebo in patients with and without metabolic syndrome, and in patients with baseline TSH above median and at or below median levels.

Effects of desvenlafaxine on blood pressure in patients treated for major depressive disorder: a pooled analysis

Abstract Objective: To evaluate the effect of the serotonin-norepinephrine re-uptake inhibitor desvenlafaxine on blood pressure and incidence of new onset hypertension in pooled short-term studies and in two longer-term, randomized withdrawal studies. Research design and methods: Data from patients randomly assigned to desvenlafaxine 10 mg to 400 mg/day or placebo in 11 short-term (8–12 weeks), fixed-dose, double-blind, placebo-controlled studies of major depressive disorder (MDD) were pooled for analysis; two desvenlafaxine randomized withdrawal studies (36 and 46 weeks) were analyzed separately. Clinical trial registration: www.clinicaltrials.gov, NCT00072774, NCT00073762, NCT00277823, NCT00300378, NCT00384033, NCT00798707, NCT00863798, NCT01121484, NCT00824291, NCT01432457, NCT00075257, NCT00887224. Main outcome measures: Outcomes included change from baseline in supine systolic blood pressure (SSBP) and supine diastolic blood pressure (SDBP), assessed using a mixed model repeated measures (MMRM) analysis, and incidence of hypertension (defined as three consecutive second SDBP measures ≥90 mm Hg AND increase of ≥10 mm Hg from baseline and/or SSBP ≥140 mm Hg AND increase of ≥10 mm Hg), analyzed using Cochran Mantel Hanzael tests. Potential predictors of change in SSBP and SDBP at LOCF were examined by including predictor variables in a regression model. Results: In the pooled, short-term studies, mean changes from baseline over time in SSBP and SDBP were statistically significant compared with placebo for the desvenlafaxine doses of 10 mg/day or greater for SSBP (p ≤ 0.0004; MMRM) and 25 mg/day or greater for SDBP (p ≤ 0.0449; MMRM). The proportion of patients with new onset hypertension differed significantly from placebo for the 50, 200, and 400 mg/day doses (1.9%, 2.4%, 4.8%, respectively, vs 0.8%; all p ≤ 0.0244). Predictors of change in BP included baseline SDBP, baseline SSBP, dose, body mass index, gender, age, race, and history of hypertension. Limitations: Data were pooled from studies which differed somewhat in study design and patient demographics. None of the studies were originally designed to examine treatment effects on BP. Study entry criteria limit generalization of these results to medically stable patients with a primary diagnosis of MDD. Conclusions: Short-term desvenlafaxine treatment was associated with small but statistically significant increases in SSBP and SDBP.

Effects of 50 and 100 mg desvenlafaxine versus placebo on sexual function in patients with major depressive disorder: a meta-analysis.

The primary objective of this post-hoc analysis was to evaluate the effect of short-term treatment with desvenlafaxine versus placebo on sexual dysfunction (SD), assessed from Arizona Sexual Experiences Scale scores, in adult outpatients with major depressive disorder. Data from three randomized, double-blind, placebo-controlled trials of 50 or 100 mg/day desvenlafaxine for major depressive disorder were pooled. SD status, determined from Arizona Sexual Experiences Scale scores, was assessed at baseline and week 8, last observation carried forward. Subgroup analyses addressed the effects of sex, baseline SD, and antidepressant response. At week 8, last observation carried forward (n=1562), SD rates were 54, 47, and 49% for 50 mg/day desvenlafaxine, 100 mg/day desvenlafaxine, and placebo, respectively [adjusted odds ratios (95% confidence interval) vs. placebo: 1.205 (0.928, 1.564) and 1.129 (0.795, 1.604), respectively]. The treatment by baseline SD interaction approached statistical significance (P=0.0663), mainly driven by poorer scores for desvenlafaxine versus placebo in the 100 mg group. Treatment by sex interactions were not statistically significant. Small but statistically significant treatment by sex interactions were observed for sex drive (P=0.0011) and ease of erection/lubrication (P=0.0151). Although there was no overall effect of desvenlafaxine on SD, a treatment by baseline SD interaction was suggested for 100 mg desvenlafaxine.

A Post Hoc Analysis of the Effect of Weight on Efficacy in Depressed Patients Treated With Desvenlafaxine 50 mg/d and 100 mg/d.

OBJECTIVE To assess the effect of baseline body mass index (BMI) on efficacy and weight change in adults with major depressive disorder (MDD) treated with desvenlafaxine or placebo in a pooled, post hoc analysis. METHOD Adults with MDD were randomly assigned to placebo or desvenlafaxine (50 mg or 100 mg) in 8 short-term, double-blind studies and 1 longer-term randomized withdrawal study (the studies were published between 2007 and 2013). Change from baseline in 17-item Hamilton Depression Rating Scale (HDRS-17) total score at week 8 was analyzed in normal (BMI ≤ 25 kg/m(2)), overweight (25 kg/m(2) < BMI ≤ 30 kg/m(2)), and obese (BMI > 30 kg/m(2)) subgroups using analysis of covariance (ANCOVA). Weight change was analyzed in BMI subgroups using ANCOVA and a mixed-effects model for repeated measures. RESULTS Desvenlafaxine 50 mg/d or 100 mg/d improved HDRS-17 scores significantly from baseline to week 8 (last observation carried forward) versus placebo in all BMI subgroups (normal: n = 1,122; overweight: n = 960; obese: n = 1,302; all P ≤ .0027); improvement was greatest in normal BMI patients. There was a statistically significant decrease in weight (< 1 kg) with short-term desvenlafaxine 50 mg/d and 100 mg/d versus placebo in all BMI subgroups (all P < .0001). In the randomized withdrawal study (n = 548), no statistically significant difference in weight was observed for desvenlafaxine versus placebo in any BMI subgroup. Baseline BMI predicted weight change in short-term and longer-term desvenlafaxine treatment. CONCLUSIONS Desvenlafaxine significantly improved symptoms of depression versus placebo regardless of baseline BMI. In all BMI subgroups, desvenlafaxine was associated with statistically significant weight loss (< 1 kg) versus placebo over 8 weeks, but no significant differences longer term. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT00072774, NCT00277823, NCT00300378, NCT00384033, NCT00798707, NCT00863798, NCT01121484, NCT00824291, NCT00887224.

Effect of desvenlafaxine 50 mg and 100 mg on energy and lassitude in patients with major depressive disorder: A pooled analysis

Nine randomized, double-blind, placebo-controlled studies of major depressive disorder were pooled to evaluate the effects of desvenlafaxine 50- and 100-mg/d on energy and lassitude in adults with major depressive disorder (n=4279). Changes from baseline to endpoint in 17-item Hamilton Rating Scale for Depression (HAM-D17) Work and Activities, Retardation, and Somatic Symptoms General items, HAM-D17 psychomotor retardation factor, and Montgomery-Åsberg Depression Rating Scale Lassitude item were analyzed with a mixed model for repeated measures analysis of variance. Associations between residual energy measures and functional impairment, based on the Sheehan Disability Scale, were modeled using stepwise multiple linear regression. Improvement from baseline was significantly greater for both desvenlafaxine doses versus placebo on all energy symptom outcomes at week 8 (all p⩽0.005). Both early improvement in HAM-D17 psychomotor retardation at week 2 and residual energy symptoms at week 8 were associated with Sheehan Disability Scale total score at week 8 (all p⩽0.001). Among Sheehan Disability Scale remitters and responders, the HAM-D17 psychomotor retardation score at week 8 was significantly lower with desvenlafaxine (both doses) than placebo. Desvenlafaxine 50 and 100 mg/d significantly improved energy and lassitude symptoms in patients with major depressive disorder. Both early improvement in energy and fewer residual energy symptoms were associated with functional improvement.

Speed of Improvement in Symptoms of Depression With Desvenlafaxine 50 mg and 100 mg Compared With Placebo in Patients With Major Depressive Disorder.

Purpose/Background This post hoc analysis examined the time point at which clinically significant improvement in major depressive disorder (MDD) symptoms occurs with desvenlafaxine versus placebo. Methods Data were pooled from 9 short-term, double-blind, placebo-controlled studies in adults with MDD randomly assigned to desvenlafaxine 50 mg/d, 100 mg/d, or placebo. A mixed-effects model for repeated-measures analysis of change from baseline score was used to determine the time point at which desvenlafaxine treatment groups separated from placebo on the 17-item Hamilton Rating Scale for Depression and psychosocial outcomes. The association between early improvement and week 8 outcomes was examined using logistic regression analyses. Time to remission for patients with early improvement versus without early improvement was assessed using Kaplan-Meier techniques. Comparisons between groups were performed with log-rank tests. Results In the intent-to-treat population (N = 4279 patients: desvenlafaxine 50 mg/d, n = 1714; desvenlafaxine 100 mg/d, n = 870; placebo, n = 1695), a statistically significant improvement on the 17-item Hamilton Rating Scale for Depression was observed with desvenlafaxine 50 mg/d at week 1 (P = 0.0129) and with desvenlafaxine 100 mg/d at week 2 (P = 0.0002) versus placebo. Early improvement was a significant predictor of later remission. Treatment assignment, baseline depression scale scores, and race were significantly associated with probability of early improvement. On several measures of depressive symptoms and function, desvenlafaxine 50 mg/d and 100 mg/d separated from placebo as early as week 1 and no later than week 4 in patients with MDD. Implications/Conclusions These findings suggest that clinicians may be able to use depression rating scale scores early in treatment as a guide to inform treatment optimization.