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Few studies in the literature have examined the efficacy of antidepressant drugs in perimenopausal and postmenopausal women. The objective of the current study was to assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) separately in perimenopausal and postmenopausal women with major depressive disorder (MDD).Data were pooled from two double-blind, placebo-controlled clinical trials enrolling perimenopausal and postmenopausal women (40-70 years old) diagnosed with MDD. Patients were randomly assigned to receive desvenlafaxine 100 to 200 mg/day or placebo (8 weeks) or desvenlafaxine 50 mg/day or placebo (10 weeks). The primary efficacy end point for each trial was change from baseline in Hamilton Rating Scale for Depression (HAM-D17) total score at week 8. Secondary end points included change from baseline in Sheehan Disability Scale (SDS) and Menopause Rating Scale (MRS) scores. Changes from baseline in continuous variables were analyzed using analysis of covariance with treatment, region, and baseline in the model. All treatment comparisons were carried out separately in perimenopausal or postmenopausal women, in individual studies, and in the pooled population, adjusting for menopausal status and study.A total of 798 patients were included in the full analysis set (perimenopausal, n=252; postmenopausal, n=546). Desvenlafaxine significantly reduced HAM-D17 total scores versus placebo at week 8 in both perimenopausal (-10.3 vs. -6.5; p0.001) and postmenopausal women (-10.1 vs. -7.6; p0.001). Significant improvements in SDS and MRS total scores were also observed for desvenlafaxine versus placebo in perimenopausal (p ≤ 0.024) and postmenopausal women (p ≤ 0.009). A significant treatment by menopausal status interaction was observed for SDS only (p=0.036).Desvenlafaxine demonstrated antidepressant efficacy in both perimenopausal and postmenopausal subgroups of women with MDD.In September 2011, Pfizer received a Complete Response Letter from the United States Food and Drug Administration on its application for approval to market desvenlafaxine for the treatment of moderate to severe vasomotor symptoms associated with menopause. The Complete Response Letter states that the data included in the application are not sufficient to establish an acceptable risk/benefit profile for the treatment of vasomotor symptoms in the general population of postmenopausal women, and therefore desvenlafaxine is not approved for the treatment of vasomotor symptoms in the United States at this time. This decision does not impact desvenlafaxine's approval for the treatment of MDD in adults.

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.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.www.clinicaltrials.gov , NCT00072774, NCT00073762, NCT00277823, NCT00300378, NCT00384033, NCT00798707, NCT00863798, NCT01121484, NCT00824291, NCT01432457, NCT00075257, NCT00887224.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.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.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.Short-term desvenlafaxine treatment was associated with small but statistically significant increases in SSBP and SDBP.

Background Desvenlafaxine (administered as desvenlafaxine succinate) for anxious depression was assessed in a post hoc analysis. Methods Data were pooled from patients randomly assigned to desvenlafaxine 50 mg/day or placebo in seven double-blind, fixed-dose studies in adults with major depressive disorder. Patients with “anxious depression” had baseline 17-item Hamilton Rating Scale for Depression, anxiety–somatization factor (HAM-D17 A/S) scores ≥7. Primary end point was change in HAM-D17 scores from baseline at week 8 (last observation carried forward), evaluated using analysis of covariance with treatment, study, and baseline value as covariates. Results A total of 1873/2706 (69%) patients were identified as “anxious depressed”. Desvenlafaxine significantly improved HAM-D17 total scores versus placebo in anxious (adjusted mean [95% CI] −1.72 [−2.35, −1.09]; p

Purpose The purpose of this study was to identify potential discordance between physician and patient rated measures of depression used by primary care physicians and psychiatrists. Primary practice setting This study collected data from primary care physicians and psychiatrists in the United States between October and December 2009. Methodology and sample A real-world, cross-sectional study was conducted using the Neuroses Disease-Specific Programme (Adelphi Real World, Macclesfield, United Kingdom). Treatment practice data were collected by 180 physicians (100 primary care and 80 psychiatrists) who were asked to provide information for the next 15 outpatients presenting prospectively with symptoms of anxiety and/or depression (n = 2,704 patients). The primary outcome measures were the Clinical Global Impressions-and Patient Global Impressions-Improvement scales, completed by both physicians and their matched patients, respectively. Cohen's kappa coefficient (κ) was calculated to assess the level of agreement between the Clinical Global Impressions-and Patient Global Impressions-Improvement scale responses. Results Physician- and patient-rated overall improvement in illness was 82% and 89%, respectively. Results of the kappa analysis demonstrated fair agreement between patients and physicians regarding overall improvement in illness (44% agreement; κ= 0.23). Physician ratings of patient improvement progressively decreased with increased severity of illness. Implications for case management practice These real-world data suggest that the degree of reduction in symptoms of anxiety and/or depression may be estimated differently by physicians when compared with their patients. Understanding the potential for disparities between physician- and patient-rated measures in reviewing patient care, particularly in patients with more severe depressive symptoms, can help ensure that treatment plans are aligned with patient needs.

Background Relationships between brain-derived neurotrophic factor (BDNF), interleukin (IL)-6, and salivary cortisol and both depression severity and treatment response were assessed in patients enrolled in a double-blind, placebo-controlled trial of desvenlafaxine 50 mg/d for MDD. Methods Outpatients with MDD were randomly assigned to 12 weeks of double-blind treatment with desvenlafaxine 50 mg/d or placebo (2:1). Baseline severity was assessed using the 17-item Hamilton Rating Scale for Depression (HAM-D 17 ); treatment response at week 12 was based on HAM-D 17 total score and response and remission status. Saliva (cortisol) and blood (BDNF, IL-6) samples for biomarker assay were collected at baseline and week 12. Spearman correlations were calculated between the biomarkers at baseline, and between biomarkers and HAM-D 17 total score at baseline. Logistic regression analyses were used to assess whether baseline biomarker levels predicted treatment response at week 12, with and without adjustment for baseline HAM-D 17 score, treatment, and geographic region. Similarly, an analysis of covariance was used to assess whether baseline disease severity predicted biomarker change at week 12. Results A total of 427 patients who received ≥ 1 dose of study drug and had baseline and ≥ 1 on-therapy primary efficacy evaluations were included in the analysis. At baseline, there was a statistically significant although weak correlation between levels of IL-6 and BDNF (Spearman correlation coefficient [r s ] = 0.120; P = 0.014), but no significant correlation between baseline biomarker levels and baseline HAM-D 17 total score (absolute value of all r s , ≤ 0.061). Desvenlafaxine 50 mg/d treatment significantly reduced HAM-D 17 total score from baseline at week 12 compared with placebo ( P = 0.006), but the three potential biomarkers did not predict treatment effects. No significant correlations were observed between the change from baseline in any biomarker level and change in HAM-D 17 total score at week 12, either overall, or in desvenlafaxine or placebo groups (absolute value of all r s , 0.003–0.196). Baseline levels of BDNF, IL-6, and salivary cortisol did not significantly predict response to treatment at week 12. Although median increase in BDNF was not significantly different between desvenlafaxine (13.7%) and placebo (5.7%) groups, the increase was significantly greater (33.4% vs 4.3%; P = 0.003) in patients with more severe depression at baseline (HAM-D 17 > 22) vs those with less severe depression (HAM-D 17 ≤ 22). No similar findings were observed for IL-6 or salivary cortisol. Discussion Weak or no relationships were observed at baseline between the potential biomarkers or between biomarkers and disease severity. While baseline biomarker level did not predict treatment response, improvement in BDNF was significantly greater among patients who were more severely depressed at baseline.

This study assessed the efficacy of desvenlafaxine 50 mg/day compared with placebo for treating moderate or severe major depressive disorder (MDD). Data were pooled from six double-blind, placebo-controlled, desvenlafaxine 50 mg/day fixed-dose studies in adults with MDD. The primary endpoint was improvement in 17-item Hamilton Rating Scale for Depression (HAM-D17) scores from baseline at week 8. HAM-D17 changes were evaluated in patients with moderate (18

OBJECTIVE Determine the point prevalence of phenoconversion to cytochrome P450 2D6 (CYP2D6) poor metabolizer status in clinical practice. METHOD This multicenter, open-label, single-visit naturalistic study was conducted from October 2008 to July 2009 in adult patients (≥ 18 years) who had been receiving venlafaxine extended-release (ER) (37.5-225 mg/d) treatment for up to 8 weeks. A 15-mL blood sample was drawn 4 to 12 hours after patients' last venlafaxine ER dose. Plasma O-desmethylvenlafaxine and venlafaxine concentrations were determined for each patient. CYP2D6 poor metabolizer phenotype was defined as O-desmethylvenlafaxine to venlafaxine ratio < 1 based on published data. CYP2D6 genotype was determined for each patient; patients were classified as poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultrarapid metabolizer. Agreement between poor metabolizer phenotype and genotype classifications was assessed using the McNemar test. RESULTS Phenoconversion to CYP2D6 poor metabolizer status occurred in 209 of 865 individuals (24%) with a CYP2D6 non-poor metabolizer genotype. The incidence of CYP2D6 poor metabolizer status based on phenotype was almost 7 times higher than that expected based on genotype: only 4% (35/900) of patients were genotypic CYP2D6 poor metabolizers, but 27% (243/900) were phenotypic CYP2D6 poor metabolizers (McNemar test, P < .0001). CONCLUSIONS CYP2D6 phenotype conversion is common in patients being treated for depression. These results are important because differences in CYP2D6 drug metabolic capacity, whether genetically determined or due to phenoconversion, can affect clinical outcomes in patients treated with drugs substantially metabolized by CYP2D6. These results demonstrate that personalized medicine based solely on genetics can be misleading and support the need to consider drug-induced variability as well. TRIAL REGISTRATION ClinicalTrials identifier: NCT00788944.

OBJECTIVE The purpose of this study was to assess the 1-year maintenance of the efficacy of desvenlafaxine 100 mg/day (administered as desvenlafaxine succinate) established on week 12 in a 1-year, double-blind, randomized, placebo-controlled trial in postmenopausal women seeking treatment of bothersome vasomotor symptoms. METHODS Primary efficacy endpoints were changes in hot flush (HF) frequency and severity on weeks 12, 26, and 52 in an efficacy substudy population (≥50 moderate and severe HFs per week at baseline). Secondary endpoints were Greene climacteric scale, patient global impression symptom rating, and patient global impression of change scores (weeks 12, 26, and 52) for the main study efficacy population. Safety was assessed throughout the trial. RESULTS The mean baseline HF frequency (efficacy substudy population, n = 365) was 12 moderate and severe HFs per day; the mean baseline severity score was 2.4. At 1 year, women treated with desvenlafaxine maintained the efficacy established on week 12. Desvenlafaxine reduced HF frequency by 7.47 moderate and severe HFs per day on week 12 (adjusted mean difference from placebo, -2.48; 95% CI, -3.47 to -1.50; P < 0.001) and by 7.70 moderate and severe HFs per day on month 12 (adjusted mean difference from placebo, -2.86; 95% CI, -4.14 to -1.57; P < 0.001). Desvenlafaxine reduced the mean severity score by 0.63 on week 12 (placebo, -0.30; P < 0.001) and by 0.75 on month 12 (placebo, -0.44; P = 0.003). Reductions in Greene Climacteric Scale total score (main study efficacy population, n = 1,950) were significantly greater for desvenlafaxine than for placebo on months 3, 6, and 12 (all P < 0.001). Treatment-emergent adverse event rates were 84% for desvenlafaxine and 79% for placebo (P = 0.006). Full safety results are reported separately. CONCLUSIONS The treatment efficacy of desvenlafaxine 100 mg/day achieved on week 12 in postmenopausal women with vasomotor symptoms is maintained for 1 year.

The objective of this substudy was to examine the effect of desvenlafaxine 50 mg/day compared with placebo on cognitive function in employed outpatients with major depressive disorder. A total of 11/55 (20%) study sites in a 12-week, randomized, double-blind, placebo-controlled trial administered cognitive assessments in memory, attention, and executive functioning domains using the cognitive drug research system. Changes from baseline were subjected to analysis of covariance with baseline levels as covariates, using last observation carried forward data. A significant improvement with desvenlafaxine 50 mg/day ( n=52) compared with placebo ( n=29) was observed on the quality of working memory composite measure (0.081 units (0.005, 0.156); P=0.0365) at last observation carried forward. Improvement from baseline on the speed of working memory composite was significant for desvenlafaxine (−226.6 msec (−316.7, −136.4); PClinical Trial Registry No.: Clinicaltrials.gov identifier: NCT00824291

Many currently used antidepressants are substrates of the cytochrome P450 (CYP) 2D6 enzyme. In patients who experience variations in the activity of this enzyme (e.g., CYP2D6 poor and ultrarapid metabolizers [PMs and UMs]), whether caused by genetic polymorphisms or concomitant administration of a CYP2D6 inhibitor (i.e., phenoconversion), the pharmacokinetics, and hence the effects, of CYP2D6 substrate antidepressants can be altered.This literature review describes the clinical and empirical evidence indicating that alterations in CYP2D6 activity can negatively affect treatment outcomes in patients receiving antidepressant pharmacotherapies that are CYP2D6 substrates.Based on results from a small, prospective trial, a population analysis, and a pooled analysis, CYP2D6 PMs treated with agents dependent on CYP2D6 metabolism to form an active metabolite can experience a decline in antidepressant effect. Based on a population analysis and two case studies, CYP2D6 UMs treated with antidepressants that are CYP2D6 substrates and administered in a pharmacologically active form do not experience an antidepressant effect due to the agent being too rapidly eliminated from the body. Conversely, based on prospective trials, population analyses, and case studies, phenotypic and phenoconverted CYP2D6 PMs can experience an increase in concentration-dependent adverse events due to the agent being eliminated too slowly from the body.Despite these examples, few large-scale, prospective trials exploring the effect of altered CYP2D6 metabolism on antidepressant outcomes have been conducted. Future clinical trials of CYP2D6-dependent antidepressants should be designed to allow for stratification of treatment outcomes by CYP2D6 metabolizer status.

This post hoc analysis examined efficacy and tolerability of open-label desvenlafaxine in patients with major depressive disorder switched from blinded placebo, venlafaxine extended release (ER), or desvenlafaxine.Patients who completed 8 weeks of double-blind therapy with placebo (n = 176), venlafaxine ER (n = 175), or desvenlafaxine (n = 143) enrolled in a 10-month, open-label extension study and received desvenlafaxine 200 to 400 mg/d. Efficacy (17-item Hamilton Depression Rating Scale [HDRS(17)]) was assessed separately for nonresponders and responders to double-blind treatment. Tolerability during the first month of open-label desvenlafaxine was assessed.Among nonresponders (n = 134) to double-blind placebo, venlafaxine ER, and desvenlafaxine, mean decreases in HDRS(17) scores were -10.9, -7.3, and -7.7, respectively; HDRS(17) response rates were 67%, 53%, and 48%, respectively. Although responders (n = 360) to double-blind placebo, venlafaxine ER, and desvenlafaxine had more modest decreases on the HDRS(17), response rates were higher (84%, 87%, and 83%, respectively). Rates of adverse events were highest during week 1, and decreased afterward for the remainder of the first month of treatment.Among nonresponders to 8 weeks of double-blind venlafaxine ER, desvenlafaxine, or placebo, 48% to 67% subsequently responded to open-label desvenlafaxine. Over 80% of responders to double-blind therapy maintained response on open-label desvenlafaxine. The switch from venlafaxine ER to desvenlafaxine was well tolerated.

This pooled analysis evaluated the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) for the treatment of major depressive disorder (MDD) in patients grouped by age and sex. Nine clinical trials were pooled. Outpatients 18 years or older with MDD received desvenlafaxine 50, 100, 200, or 400 mg/d (men = 709; women = 1096) or placebo (men = 399; women = 709) for 8 weeks. Data were analyzed by sex and by age groups of 40 years and younger, 41 to 54 years, 55 to 64 years, and 65 years and older. The primary outcome was change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score at the final evaluation. Secondary measures included response (> or =50% reduction in HAM-D17) and remission (HAM-D17 < or =7). No significant sex-treatment, age-treatment, or sex-age-treatment interactions were observed. Differences in the HAM-D17 change from baseline for desvenlafaxine versus placebo were -1.72 for women (P < 0.001) and -2.11 for men (P < 0.001); these changes were significant among women of the 18-to-40 (P = 0.01), 41-to-54 (P = 0.002), and 65-years-and-older subgroups (P = 0.02), and significant among men for the 18-to-40 (P = 0.03) and 41-to-54 subgroups (P = 0.002). The response rates for desvenlafaxine and placebo were 53% and 42% (P < 0.001), respectively, among women, and 53% and 41% (P < 0.001), respectively, among men; the remission rates were 31% and 21% (P < 0.001) and 34% and 26% (P = 0.007), respectively. The response rates were similar across age subgroups, with significant differences from placebo observed in the 18-to-40 (P < or = 0.05), 41-to-54 (P < or = 0.005), and 65-and-older subgroups (P = 0.02). The remission rates were significant versus placebo in the 41-to-54 (P = 0.006), 55-to-64 (P = 0.01), and 65-and-older (P = 0.02) subgroups among women but not in any age subgroup among men. Desvenlafaxine generally improved depressive symptoms across age and sex subgroups.

Introduction Venlafaxine, a serotonin-norepinephrine reuptake inhibitor antidepressant, is metabolized primarily by the cytochrome P450 2D6 enzyme into O-desmethylvenlafaxine (ODV). The ODV/venlafaxine ratio can be used to distinguish between extensive metabolizers (EMs) and poor metabolizers (PMs). Objectives To determine the relative efficacy and tolerability of venlafaxine in EM vs PM patients with major depressive disorder (MDD). Method Data from 4 double-blind, placebo-controlled studies of patients with MDD were pooled. Blood samples were analyzed for plasma concentrations of venlafaxine, ODV, total venlafaxine + ODV, and ODV/venlafaxine ratio. Patients were classified as EMs or PMs on the basis of ODV/venlafaxine ratios. Changes from baseline in depression scale scores were compared between EMs and PMs using t tests. Rates of response, remission, discontinuation, and adverse events (AEs) were compared for EMs and PMs using Fisher exact tests. Results Compared with PMs, EMs had significantly greater mean changes from baseline on 4 of 5 depression rating scales (all 4 comparisons, P ≤ .020). A significantly greater percentage of EMs achieved response or remission by most measures compared with PMs (4 of 5 comparisons, P ≤ .015). Rates of discontinuation and AEs did not differ significantly between EMs and PMs. Since there were no substantial differences between EMs and PMs in terms of venlafaxine dose or tolerability, these factors are not likely to account for the efficacy findings. Conclusions Venlafaxine treatment in EMs was associated with greater efficacy in MDD on virtually all measures compared with PMs, with no important tolerability differences.

Major depressive disorder (MDD) is a common, seriously impairing illness. Desvenlafaxine (administered as desvenlafaxine succinate) is the third serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States for the treatment of MDD. Short-term clinical studies have demonstrated the efficacy and safety of 50 to 400 mg/d doses, with no evidence that doses greater than 50 mg/d confer additional benefit.This paper summarizes published data on the efficacy, safety, and tolerability of the desvenlafaxine 50-mg/d recommended therapeutic dose for MDD and discusses clinical practice considerations.A systematic review of MEDLINE, PsycINFO, and PubMed (all years through June 2009) was performed using the terms desvenlafaxine, DVS, and ODV. The criteria for inclusion in the review were a double-blind design, a placebo control or active comparator group, the 50-mg desvenlafaxine dose group, and enrollment of patients with a diagnosis of MDD. Posters were included if they reported on a study that was subsequently published in a manuscript.Overall results of two randomized, placebo-controlled, 8-week clinical trials demonstrated the efficacy of desvenlafaxine 50 mg/d for MDD. Statistically significant improvements compared with placebo were observed on the primary efficacy measure (17-item Hamilton Rating Scale for Depression [HAM-D(17)] total score; P0.05). Significant differences were observed on several secondary measures (Montgomery Asberg Depression Rating Scale scores in both trials [P0.05]; Clinical Global Impressions-Improvement scores [Por = 0.01], Clinical Global Impressions-Severity scores [Por = 0.01], HAM-D(17) response [Por = 0.01] and remission [P0.05] in one trial each). Functional outcomes measures (Sheehan Disability Scale total and World Health Organization 5-Item Well-Being Index scores) were significant in both trials (P0.05). Safety results indicate desvenlafaxine treatment was safe and well tolerated; findings were consistent with the SNRI class. The generalizability of these findings is limited by the study protocols, which excluded patients with unstable comorbid medical conditions and also those with other Axis 1 and 2 psychiatric illnesses. Additionally, comparisons with other SNRIs are challenging given differences in study design. Desvenlafaxine can be initiated with the 50-mg/d therapeutic dose without titration and provides efficacy with rates of discontinuation due to treatment-emergent adverse events similar to placebo. In vitro data indicate desvenlafaxine has minimal inhibitory effects on cytochrome P450 (CYP) 2D6 and clinical studies show desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism. In vitro data also indicate desvenlafaxine is not a substrate or inhibitor of the p-glycoprotein transporter. Plasma protein binding of desvenlafaxine is low (30%) and independent of drug concentration. Bioavailability is high at 80% after oral administration and is not affected by food.Desvenlafaxine 50 mg/d has demonstrated efficacy, safety, and tolerability for the treatment of MDD in two placebo-controlled trials. The metabolic profile of desvenlafaxine suggests a low risk of drug-drug interactions owing to minimal inhibitory effects on CYP2D6, lack of interaction with p-glycoprotein, and low protein binding.

OBJECTIVE: To evaluate the effects of desvenlafaxine therapy on functioning and well-being in major depressive disorder (MDD). METHOD: Total and individual item Sheehan Disability Scale (SDS) and 5-item World Health Organization Well-Being Index (WHO-5) scores from 8 double-blind, placebo-controlled, 8-week desvenlafaxine clinical trials were pooled. Scores on the 17-item Hamilton Depression Rating Scale (HDRS(17)) work/activities and Montgomery-Asberg Depression Rating Scale (MADRS) lassitude items were pooled from 9 studies. Outpatients with DSM-IV MDD were randomly assigned to fixed (5 studies; 50, 100, 200, or 400 mg/d; n = 1,342) or flexible (4 studies, 100-400 mg/d; n = 463) doses of desvenlafaxine or placebo (n = 1,108). Data from each patient's final evaluation were analyzed for the total population and for individual dose groups from the fixed-dose studies and were compared between groups using analysis of covariance. RESULTS: Compared with placebo, desvenlafaxine therapy resulted in significantly greater improvements in SDS total score (-2.0) and individual items regarding work (-0.6), social life/leisure activities (-0.8), and family life/home responsibilities (-0.7; P < .001 for all comparisons), as well as WHO-5 total score (1.7) and individual items (good spirits [0.4], calm/relaxed [0.4], active/vigorous [0.3], fresh/rested [0.3], and interest [0.3]; P < .001 for all comparisons). Desvenlafaxine treatment resulted in significant improvements on the HDRS(17) work/activities (-0.2; P < .001) and MADRS lassitude (-0.3; P < .001) items compared with placebo. Significant differences were observed for the individual fixed-dose groups on all outcomes (P < .05); there was no evidence of a dose-response relationship. CONCLUSIONS: Desvenlafaxine therapy resulted in significant improvements in the functioning and well-being among MDD patients.

One of the major enzymes of the cytochrome P450 drug-metabolizing system, CYP2D6, shows a high degree of genetic polymorphism and variability in activity. Based on the degree of CYP2D6 activity, individuals can be broadly classified as poor metabolizers (PMs) or extensive metabolizers (EMs); the metabolism of CYP2D6 substrates differs among PMs and EMs. The metabolism of various drugs that are substrates of CYP2D6 has been used as a marker for metabolic phenotype, calculating the plasma or urinary metabolic ratio of the parent compound to its metabolite. The current analysis evaluates the use of the O-desmethylvenlafaxine-venlafaxine ratio (ODV/VEN) after administration of VEN, a CYP2D6 substrate, for determining CYP2D6 metabolic phenotype in healthy adults receiving VEN.The analysis included data from 2 studies in which healthy adults were classified as either EMs or PMs using established methods (1 genotypic and 1 phenotypic) and were then administered VEN at daily dosages ranging from 75 to 150 mg. Blood plasma samples were taken at various time points, and the ODV/VEN ratio was calculated.Blood samples from 28 participants in the 2 studies were available for analysis. The ODV/VEN ratio distinguished the EM and PM phenotypes; ratios were 1 or greater for EMs and less than 1 for PMs at 4 hours after dose administration.The ratio of ODV/VEN is an effective means of phenotyping individuals according to their CYP2D6 metabolizer status.

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 desvenla-faxine 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 desvenla-faxine-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.

Introduction: To assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) in outpatients with major depressive disorder.Methods: A meta-analysis of individual patient data was performed on the complete set of registration trials (nine randomized, double-blind, placebo-controlled 8-week studies) of desvenlafaxine. Patients received fixed (50, 100, 200, or 400 mg/day; n = 1,342) or flexible doses (100–400 mg/day; n = 463) of desvenlafaxine or placebo (n = 1,108). The primary efficacy variable was the 17-item Hamilton Rating Scale for Depression (HAM-D17); the primary intent to treat analyses used the last-observation-carried-forward method.Results: Significantly greater improvement with desvenlafaxine versus placebo on the HAM-D17 total score was observed for the full data set (difference in adjusted means: −1.9; PPP=.024). Overall rates of HAM-D17 response (≥50% decrease from baseline score: 53% vs 41%) and remission (HAM-D17 ≤7: 32% vs 23%) were significantly greater for desvenlafaxine versus placebo (all PConclusion: Desvenlafaxine demonstrated short-term efficacy for treating major depressive disorder across the range of doses studied. No evidence of greater efficacy was observed with doses >50 mg/day; a strong dose-response effect on tolerability was observed.

BACKGROUND The cytochrome P450 2D6 (CYP2D6) enzyme is responsible for metabolizing approximately 25% of pharmaceutical agents. Individuals with impaired CYP2D6 metabolism and those concomitantly receiving agents that inhibit CYP2D6 can have variations in concentrations of such medications and their metabolites. METHODS Five studies assessing the interaction between desvenlafaxine and CYP2D6 are reviewed. Study 1 compared desvenlafaxine area under the plasma concentration-versus-time curve (AUC) in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) after administration of 100 mg of desvenlafaxine or 75 mg of venlafaxine extended release (ER). Studies 2 to 5 assessed the effect of concomitant administration of desvenlafaxine 100 mg (studies 2, 4, and 5) or 400 mg (study 3), paroxetine (20 mg, study 4), and duloxetine (30 mg twice daily; study 5) on the CYP2D6 probe desipramine. RESULTS In study 1, there was no significant difference in mean desvenlafaxine AUC between the CYP2D6 EMs and PMs (-11%; P=0.641) who were administered desvenlafaxine. However, PMs receiving venlafaxine ER had significantly higher venlafaxine and lower desvenlafaxine AUCs compared with EMs (+350% and -74%, respectively; P

A number of antidepressants inhibit the activity of the cytochrome P450 2D6 enzyme system, which can lead to drug-drug interactions. Based on its metabolic profile, desvenlafaxine, administered as desvenlafaxine succinate, a new serotonin-norepinephrine reuptake inhibitor, is not expected to have an impact on activity of CYP2D6. This single-center, randomized, open-label, four-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/day, twice the recommended therapeutic dose for major depressive disorder in the United States) and duloxetine (30 mg b.i.d.) on the pharmacokinetics (PK) of a single dose of desipramine (50 mg). A single dose of desipramine was given first to assess its PK. Desvenlafaxine or duloxetine was then administered, in a crossover design, so that steady-state levels were achieved; a single dose of desipramine was then coadministered. The geometric least-square mean ratios (coadministration versus desipramine alone) for area under the plasma concentration versus time curve (AUC) and peak plasma concentrations (C(max)) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and C(max) of desipramine associated with duloxetine administration (122 and 63%, respectively) were significantly greater than those associated with desvenlafaxine (22 and 19%, respectively; P < 0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine C(max) that was significant compared with the small increase seen with desvenlafaxine and desipramine (-24 versus 9%; P < 0.001); the difference between changes in 2-hydroxydesipramine AUC did not reach statistical significance (P = 0.054). Overall, desvenlafaxine had a minimal impact on the PK of desipramine compared with duloxetine, suggesting a lower risk for CYP2D6-mediated drug interactions.

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) 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.

Objective: To evaluate relapse rates and predictors of relapse in 2 randomized, placebo-controlled trials of desvenlafaxine for major depressive disorder (MDD). Method: Study 1: week 8 responders to open-label desvenlafaxine 50 mg/d entered a 12-week open-label stability phase. Patients with a continuing, stable response at week 20 were randomly assigned to 6-month, double-blind treatment (desvenlafaxine 50 mg/d or placebo). Study 1 was conducted between June 2009 and March 2011 at 87 sites worldwide. Study 2: week 12 responders to open-label desvenlafaxine 200 or 400 mg/d were randomly assigned to 6-month, double-blind treatment (desvenlafaxine 200 mg/d, 400 mg/d, or placebo). Study 2 was conducted between June 2003 and August 2005 at 49 sites in Europe, the United States, and Taiwan. Relapse was assessed separately by study with log-rank test using protocol definitions of relapse and with 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 16 at any time during the double-blind phase. Kaplan-Meier estimates evaluated time to relapse, censoring data at months 1, 2, and 3 and overall; treatments were compared using hazard ratios. Cox proportional hazards models assessed relapse predictors. Results: Overall relapse rates for all definitions were significantly lower for desvenlafaxine versus placebo for both studies (all P ≤ .002). In study 1, rates were significantly lower for desvenlafaxine versus placebo at month 2 (P = .016) and month 3 (P = .007) using the protocol definition. In study 2, relapse rates were significantly lower for desvenlafaxine versus placebo at months 1, 2, and 3 for both definitions (P < .0001–.002). Hazard ratios were similar at months 1, 2, and 3 and overall for both studies (0.382–0.639). Conclusions: Desvenlafaxine 50 to 400 mg/d effectively prevented relapse at 6 months. Desvenlafaxine significantly prevented relapse early (month 1) versus placebo only in study 2. Trial Registration: ClinicalTrials.gov identifiers:NCT00887224 and NCT00075257

Objective: The purpose of this post hoc analysis was to evaluate the incidence and timing of taper/posttherapy–emergent adverse events (TPAEs) following discontinuation of long-term treatment with desvenlafaxine (administered as desvenlafaxine succinate). Method: This was a phase 4, randomized, double-blind, placebo-controlled study conducted at 38 research centers within the United States between March 2010 and February 2011. Adult outpatients with major depressive disorder (MDD; DSM-IV-TR criteria) who completed 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to 1 of 3 groups for the double-blind taper phase: desvenlafaxine 50 mg/d for 4 weeks (no discontinuation), desvenlafaxine 25 mg/d for 1 week followed by placebo for 3 weeks (taper), or placebo for 4 weeks (abrupt discontinuation). The primary endpoint, Discontinuation-Emergent Signs and Symptoms Scale (DESS) score over the first 2 weeks of the taper phase, was described previously. Secondary assessments included incidence and timing of TPAEs (any adverse event that started or increased in severity during the double-blind phase) and the percentage of patients who could not continue the taper phase due to discontinuation symptoms. The Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) assessed MDD status. Results: A total of 480 patients enrolled in the open-label phase; the full analysis set included 357 patients (taper, n = 139; abrupt discontinuation, n = 146; no discontinuation, n = 72). TPAEs occurred in all groups through week 4. The incidence of any TPAE was lower for taper versus abrupt discontinuation at week 1 (P < .001), similar at week 2, and lower for taper versus abrupt discontinuation at weeks 3 and 4 (P ≤ .034). The most common TPAEs (incidence ≥ 3%) in the taper group were nausea and headache (3% each) at week 1 and dizziness (5%) and headache (4%) at week 2. The most common TPAEs in the abrupt discontinuation group were dizziness (8%), headache (8%), nausea (4%), irritability (3%), and diarrhea (3%) at week 1 and headache (3%) at weeks 2 and 3. The most common TPAE in the no discontinuation group was nausea (6%) at week 2. Conclusion: The overall incidence of any TPAE was lower in the taper versus abrupt discontinuation groups. Trial Registration: ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01056289","term_id":"NCT01056289"}}NCT01056289

This prospective, pre- and postevaluation of a worksite cardiovascular health management program consisted of employee education, measurement of cardiovascular risk factors, and on-site individual counseling for all employees, along with follow up screening for high risk participants. Of 1,099 employees (16.4% of those eligible) who participated in the initial screening, 596 (54.2%) were classified as high risk. A total of 167 (28.0%) high risk participants completed the 6 month follow up screening. Most high risk participants in the 6 month follow up screening reported they had increased their exercise (64.7%), improved their diet (71.3%), and visited a physician (61.7%). A minority of the participants (16.8%) began new cardiovascular medications, and 2.4% were diagnosed with diabetes. In addition, there were statistically significant decreases in the percentages of participants with elevated systolic blood pressure, diastolic blood pressure, low density lipoprotein cholesterol, and total cholesterol to high density lipoprotein ratio. Almost all (99.7%) of the 909 participants (82.7% of all participants) who completed the satisfaction survey were satisfied or very satisfied with the overall program. Screening in the workplace can identify individuals at high risk for cardiovascular disease. In this study, more than half of the participants were classified as high risk. Most high risk individuals who attended the 6 month follow up screening had improved their cardiovascular health, but attrition remains a challenge for worksite programs.

BackgroundThe predictive value of early functional improvement for treatment success at week 8 was assessed in a pooled analysis in patients with major depressive disorder (MDD).MethodsData were pooled from 7 double-blind studies in adult patients with MDD randomly assigned to desvenlafaxine 50 mg/d or placebo. Four levels of treatment success were determined at week 8 for patients with baseline Sheehan Disability Scale (SDS) score > 12 (N = 2156): functional response (SDS ≤12 and ≥50% improvement in SDS), functional/depression response (SDS ≤12 and ≥50% improvement in both SDS and 17-item Hamilton Rating Scale for Depression [HAM-D17] score), functional remission (SDS < 7), and functional/depression remission (SDS < 7 and HAM-D17 ≤7). Week 2 improvement in SDS was evaluated as a predictor of later functional response/remission using receiver operating characteristic analysis. Odds ratios (ORs) of the predictability of improvement thresholds were computed from a logistic regression model.ResultsThe proportion of patients achieving each level of treatment success was significantly greater for patients treated with desvenlafaxine (40%, 32%, 23%, 15%, respectively) vs placebo (31%, 22%, 17%, 10%; all P ≤ 0.002). Early change in SDS was a highly significant predictor of functional response/remission (ORs, 0.958–0.970; all P < 0.0001).DiscussionPatients’ early functional response to desvenlafaxine 50 mg/d is predictive of treatment success.

This post hoc analysis assessed the efficacy of desvenlafaxine 50 mg/day for treating major depressive disorder in perimenopausal versus postmenopausal women enrolled in a 10-week, double-blind, placebo-controlled study.Perimenopausal and postmenopausal women (40-70 y) diagnosed with major depressive disorder were randomly assigned to receive desvenlafaxine 50 mg/day or placebo. Changes from baseline in the primary efficacy variable (17-item Hamilton Rating Scale for Depression [HAM-D17] score, week 8) and in other secondary efficacy variables (Sheehan Disability Scale and Menopause Rating Scale) were analyzed using analysis of covariance with treatment, region, and baseline in the model. Clinical Global Impressions-Improvement Scale was analyzed with the Cochran-Mantel-Haenszel test. Response and remission rates were evaluated using logistic regression with treatment, region, and baseline HAM-D17 in the model.Of 426 women (desvenlafaxine, n = 216; placebo, n = 210) included in this analysis, 135 (32%) were perimenopausal and 291 (68%) were postmenopausal at baseline. In both subgroups, improvement from baseline in HAM-D17 scores was significantly greater for desvenlafaxine 50 mg/day than for placebo. Menopause status and time since menopause did not significantly affect HAM-D17 total score. The drug-placebo difference in Sheehan Disability Scale scores was significant in perimenopausal women (-9.3 vs. -5.1, P0.001) but not in postmenopausal women (-8.8 vs. -8.1). Menopause Rating Scale and Clinical Global Impressions-Improvement Scale scores were significantly improved with desvenlafaxine in postmenopausal women.Desvenlafaxine 50 mg/day is effective in treating depression in both perimenopausal and postmenopausal women. Placebo response on measures of functional impairment is lower in perimenopausal women than in postmenopausal women, resulting in a greater apparent treatment benefit with desvenlafaxine among perimenopausal women.

OBJECTIVE This post hoc analysis assessed the predictive value of improvement in depressive scores at early time points for treatment outcomes at week 8 in patients with major depressive disorder treated with desvenlafaxine 50 mg/d or placebo. METHODS Pooled data from 6 double-blind, fixed-dose studies in adult patients with major depressive disorder. Patients were randomly assigned to desvenlafaxine or placebo. Primary end point was change in 17-item Hamilton Rating Scale for Depression (HAM-D17) scores from baseline to week 8 (or last observation carried forward). Optimal thresholds of improvement (percent change from baseline HAM-D17) at weeks 2 and 3 for predicting 4 levels of treatment success (≥ 45%, ≥ 50%, and ≥ 65% decrease from baseline HAM-D17, HAM-D17 ≤ 7) at week 8 (last observation carried forward) were determined using receiver operating characteristic analysis. Odds ratios of the predictability of improvement thresholds were computed from a logistic regression model adjusting for significant baseline predictors. RESULTS Desvenlafaxine 50 mg/d (n = 1207) had significantly greater rates of treatment success for each level of treatment success at 8 weeks compared with placebo (n = 1067). Optimal early improvement thresholds for weeks 2 (20%-30%) and 3 (28%-41%) were highly predictive of all 4 levels of treatment success after adjusting for significant baseline predictors (odds ratios, 0.951-0.960; all P < 0.0001). Negative predictive value of early improvement increased, and positive predictive value decreased, for increasingly stringent definitions of treatment success at week 8. CONCLUSIONS Clinical observations of patients' early response to desvenlafaxine 50 mg/d may have clinical value in predicting treatment success and guiding patient management.

Background Diminished quality of life (QOL) is associated with major depressive disorder (MDD). Methods QOL was assessed in a post-hoc analysis of a double-blind, placebo-controlled trial. Employed adult outpatients with MDD were randomly assigned to 12 weeks of treatment with desvenlafaxine 50 mg/d or placebo. Changes from baseline in the Short Form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) item scores at week 12 were analyzed using analysis of covariance with treatment, region, and baseline in the model. Correlations between change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D 17 ) total score and Q-LES-Q scores were computed. Results The intent-to-treat population included 427 patients. There were statistically significant improvements from baseline for desvenlafaxine vs placebo in 10 of 16 Q-LES-Q item scores ( P values ≤0.0441). The percentage of patients with severe QOL impairment (≥2 SD below community norm) at week 12 was significantly lower for desvenlafaxine (46%) vs placebo (62%; P =0.0024; baseline: 95% and 94%, respectively). Change in Q-LES-Q total score was highly correlated with change in HAM-D 17 score at week 12, LOCF ( P 17 total score at week 2 predicted change in Q-LES-Q total score at week 12 for the desvenlafaxine group ( F =24.89; P Limitations This analysis excluded patients who were unemployed, had severe comorbidities, and those taking multiple, concomitant medications. Conclusion Improvement in QOL and depressive symptoms was significantly greater for employed depressed patients treated with desvenlafaxine vs placebo.

Desvenlafaxine (administered as desvenlafaxine succinate) for anxious depression was assessed in a post hoc analysis.Data were pooled from patients randomly assigned to desvenlafaxine 50 mg/day or placebo in seven double-blind, fixed-dose studies in adults with major depressive disorder. Patients with "anxious depression" had baseline 17-item Hamilton Rating Scale for Depression, anxiety-somatization factor (HAM-D17 A/S) scores ≥7. Primary end point was change in HAM-D17 scores from baseline at week 8 (last observation carried forward), evaluated using analysis of covariance with treatment, study, and baseline value as covariates.A total of 1873/2706 (69%) patients were identified as "anxious depressed". Desvenlafaxine significantly improved HAM-D17 total scores versus placebo in anxious (adjusted mean [95% CI] -1.72 [-2.35, -1.09]; p 0.001) and nonanxious (-1.48 [-2.40, -0.57]; p = 0.002) populations, with no significant treatment-by-anxiety interaction. Response and remission rates (HAM-D17 ) were significantly higher with desvenlafaxine compared with placebo in both populations. Treatment-emergent adverse events were reported by 78% and 69% (desvenlafaxine versus placebo, respectively) of anxious depressed patients and by 77% and 68% of nonanxious patients.Desvenlafaxine 50 mg/day significantly improved depressive symptoms compared with placebo in major depressive disorder patients with clinically relevant anxiety symptoms. Improvement in the HAM-D17 total score was similar for anxious/nonanxious groups.

Objective A previous trial of the serotonin-norepinephrine reuptake inhibitor desvenlafaxine (administered as desvenlafaxine succinate) raised concerns on potential serious cardiovascular and hepatic events. The current study was designed to estimate these events in desvenlafaxine versus placebo in a larger population followed for 1 year. Methods Healthy postmenopausal women seeking treatment of vasomotor symptoms were randomized to placebo or desvenlafaxine 100 mg/day in a 1-year, multicenter, double-blind study. Safety was monitored throughout. Potential ischemic cardiovascular events (coronary heart disease-related death, new-onset myocardial infarction or unstable angina requiring hospitalization, and unscheduled revascularization procedures) and cerebrovascular events (definite stroke or probable stroke) identified by investigator reports and periodic adverse event review based on Standardized medical dictionary for regulatory activities Query were reviewed by blinded adjudication boards. Hepatic events (aspartate aminotransferase or alanine aminotransferase >5 times the upper limit of normal) were evaluated. Results A total of 2,118 participants (1,066 desvenlafaxine, 1,052 placebo) took one or more doses of study medication (mean, 280 d). There was one cardiovascular event; a placebo-treated participant was adjudicated to have had a myocardial infarction. One desvenlafaxine-treated participant was adjudicated to have had a probable stroke. Two participants in each treatment group had hepatic events. The excess risk (90% CI) of desvenlafaxine over placebo per 1,000 woman-years was -1.07 (-2.86 to 0.72) for cardiovascular events, 1.11 (-0.68 to 2.9) for cerebrovascular events, and 0.08 (-3.51 to 3.67) for hepatic events. Conclusions There is no evidence for an increased risk of cardiovascular, cerebrovascular, or hepatic events associated with desvenlafaxine 100 mg/day compared with placebo for the treatment of menopausal vasomotor symptoms.

Variability in placebo response greatly complicates the design, conduct, and interpretation of clinical trials of antidepressant medications. To identify factors that impact detection of antidepressant–placebo differences, we conducted a meta-analysis of all relevant phase II–IV clinical trials for major depressive disorder conducted by the manufacturer of venlafaxine and desvenlafaxine completed by March 2011. We examined 15 factors potentially relevant to trial outcomes, using the standardized mean difference on the Hamilton Rating Scale for Depression (HAM-D17) score as the primary outcome. Thirty trials comprising 8933 patients were included. In univariate analyses, antidepressant efficacy (ie, drug vs placebo difference) was predicted most strongly (β=3.74, p=0.0002) by the proportion of patients in the trial enrolled from academic sites. Other factors predicting larger drug–placebo differences included lower participant completion rate, fewer post-baseline study visits, earlier year of study, and study drug (venlafaxine>desvenlafaxine). In multivariate meta-regression modeling, only the proportion of patients from academic sites maintained statistical significance as a predictor of drug–placebo separation for both HAM-D17 continuous score change (β=2.24, p=0.034) and response rate (β=2.26, p=0.035). Including a higher proportion of academic sites may increase the ability to detect differences between active drug and placebo in clinical trials of major depressive disorder.

The objective of this study was to explore the relationship between assessments of functional impairment, emotional well-being, and depression symptoms. Data were pooled from 3530 outpatients with major depressive disorder enrolled in 10 desvenlafaxine clinical trials. The primary outcome measures included (a) the 17-item Hamilton Rating Scale for Depression (HAM-D17) as a measure of depressive symptom severity and (b) the Sheehan Disability Scale (SDS) and five-item World Health Organization Well-Being Index (WHO-5) as measures of functional impairment and well-being. A linear regression model was used to identify the SDS and WHO-5 values that equate to the predetermined clinically relevant three-point difference between active treatment and placebo on the HAM-D17. A receiver operating characteristic analysis was conducted to determine the SDS score that equates to a remission of depression symptoms (i.e. HAM-D17≤7). An approximate three-point difference between active treatment and placebo on the SDS (2.8) and WHO-5 (2.5) was determined to be clinically relevant in relation to improvements in depressive symptoms. An SDS of less than or equal to 7 was equivalent to a remission of depression symptoms, providing a definition of functional remission. A better understanding of the relationship between depressive symptoms and functional impairment and well-being may provide clinicians with a more comprehensive means of assessing treatment effects in major depressive disorder.

This is the first study to assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) for improving depressive symptoms and functioning exclusively in employed patients with major depressive disorder (MDD).Gainfully employed (≥20 h/wk) male and female outpatients with MDD were randomly assigned (2:1 ratio) to 12 weeks of double-blind treatment with desvenlafaxine 50 mg/d or placebo. Analysis of covariance was used to compare differences in week 12 adjusted mean changes from baseline on the 17-item Hamilton Depression Rating Scale (HAM-D₁₇) (primary outcome) and Sheehan Disability Scale (SDS) (key secondary outcome) in the intent-to-treat (ITT) population. A predefined, modified ITT population (ie, those in the ITT population with baseline HAM-D₁₇ ≥20) was also analyzed. Tolerability was assessed by recording adverse events and change on the Arizona Sexual Experience Scale.Baseline HAM-D₁₇ scores for desvenlafaxine (n = 285) and placebo (n = 142) were 22.0 and 21.8, whereas baseline SDS scores were 19.8 and 20.4. Adjusted mean differences between desvenlafaxine and placebo were 2.1 (95% confidence interval [CI], 0.78-3.46; P = 0.002) on the HAM-D₁₇ and 1.3 (95% CI, -0.09 to 2.76; P = 0.067) on the SDS. For the modified ITT sample, desvenlafaxine (n = 208) and placebo (n = 102), baseline HAM-D₁₇ scores were 23.8 and 23.9; the SDS baseline scores were 20.1 and 20.8. Mean differences were 2.6 (95% CI, 0.93-4.22; P = 0.002) on the HAM-D₁₇ and 2.1 (95% CI, 0.36-3.76; P = 0.017) on the SDS. Adverse events and Arizona Sexual Experience Scale scores were comparable between groups.Desvenlafaxine 50 mg/d was efficacious for treating MDD in gainfully employed adults. Between-group differences on the SDS narrowly missed statistical significance in the ITT population alone, but the totality of data suggests functional improvements with active treatment.

Preliminary clinical evidence indicates that menopausal status might impact on the efficacy of certain classes of antidepressants.The aim of this study was to evaluate open-label desvenlafaxine treatment (administered as desvenlafaxine succinate) in postmenopausal women who did not achieve clinical response to acute, double-blind treatment with desvenlafaxine or escitalopram.This phase IIIb, multicentre study included a 6-month open-label extension phase of patients who did not respond in the initial 8-week, randomized, double-blind acute phase.Postmenopausal women aged 40-70 years with a primary diagnosis of major depressive disorder were recruited. PRIMARY INTERVENTION: Non-responders to acute treatment with double-blind desvenlafaxine or escitalopram received flexible-dose, open-label desvenlafaxine 100-200 mg/day for the 6-month extension phase.The primary efficacy assessment was the 17-item Hamilton Rating Scale for Depression (HAM-D(17)) total score. Secondary efficacy outcome measures were the Clinical Global Impressions-Improvement (CGI-I) and -Severity scales, Hamilton Rating Scale for Anxiety, Quick Inventory of Depressive Symptomatology-Self-Report, Visual Analogue Scale-Pain Intensity and the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary health assessments were the Changes in Sexual Functioning Questionnaire, 5-Dimension EuroQoL Index, Health State Today, Menopause Rating Scale, Sheehan Disability Scale, treatment response (≥ 50% decrease in total HAM-D(17) and MADRS score from acute-phase baseline and CGI-I total score ≤ 2), HAM-D(17) remission (total score ≤ 7) and safety. Descriptive statistics were used to summarize outcomes.The efficacy analysis included 123 patients (desvenlafaxine/desvenlafaxine = 64; escitalopram/desvenlafaxine = 59). At final evaluation of the open-label extension phase, mean reductions from acute-phase baseline in HAM-D(17) total scores were -11.33 for the desvenlafaxine/desvenlafaxine group and -11.41 for the escitalopram/desvenlafaxine group. HAM-D(17) response or remission after 6 months of open-label extension phase desvenlafaxine treatment were achieved in 56-58% and 41-48% of patients, respectively. The results of the other secondary efficacy outcome measures and other definitions of treatment response were generally consistent with the primary analyses. The observed adverse events were similar to those reported during previous desvenlafaxine clinical trials.Postmenopausal women with major depressive disorder who did not respond to acute, double-blind treatment with escitalopram or desvenlafaxine achieved modest, continued improvement with long-term, open-label desvenlafaxine therapy. Further interpretation of these findings is limited by aspects of the study design (i.e. open-label, non-placebo-controlled) and the lack of randomized comparison groups in the extension phase, which prevents statistical assessment of the efficacy of longer term treatment with desvenlafaxine. Clinicaltrials.gov identifier: NCT00406640.

Approximately 6%–10% of primary care patients meet diagnostic criteria1 for major depressive disorder (MDD). However, only 50% of patients with MDD are accurately diagnosed by primary care physicians, and many patients do not receive guideline-level treatment for MDD.2 For example, among primary care patients with diabetes and comorbid MDD, 51% of patients identified with MDD were diagnosed with depression in the 12 months prior to screening, approximately 33% of treated patients received adequate pharmacotherapy (duration ≥ 90 days), and 6.7% received adequate psychotherapy (≥ 4 visits in 1 year).3 The lack of recognition and effective treatment of patients with MDD is significant due to the potential chronicity of the illness. Successful treatment of MDD should involve a chronic disease management strategy that requires patient care that is consistent with treatment guidelines, with the overall goals of remission, recovery of psychosocial functioning, and prevention of recurrent episodes.4,5 The collaborative care model is a promising approach to achieving these goals.6 Earlier studies of collaborative care models in primary care settings demonstrated success in improving clinical outcomes7,8 and patient satisfaction with treatment.7 The objectives of this review are to establish the need for a chronic disease management strategy for MDD, discuss challenges in the implementation of treatment guidelines/algorithms, and provide examples of successful collaborative care programs. This review includes clinical studies evaluating the effectiveness of collaborative care interventions for the treatment of depression in the primary care setting. A systematic literature search of MEDLINE and the US National Library of Medicine was performed using the keywords collaborative care, depression, and MDD. This review includes articles describing clinical studies published through May 2010 and excludes all non–English-language articles.

Objective: This study assessed the efficacy, safety, and tolerability of the serotonin-norepinephrine reuptake inhibitor desvenlafaxine and the selective serotonin reuptake inhibitor escitalopram for major depressive disorder (MDD) in postmenopausal women. Methods: In this randomized, double-blind study, postmenopausal outpatients (aged 40-70 y) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition MDD received flexible-dose desvenlafaxine (100-200 mg/d) or escitalopram (10-20 mg/d) for 8 weeks. Acute-phase responders, that is, women with a 50% or greater reduction from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D 17 ) total score, were eligible to continue the same double-blind treatment in the 6-month continuation phase. The primary efficacy outcomes were mean change from baseline in HAM-D 17 total score (acute phase), analyzed using a mixed-effects model for repeated measures, and the proportion of women who maintained response (continuation phase), analyzed using logistic regression. Results: Reductions in HAM-D 17 total score at acute-phase endpoint were similar for desvenlafaxine- and escitalopram-treated women (—13.6 vs —14.3, respectively; P = 0.24). No significant difference was observed between groups at continuation-phase endpoint in the proportion of women who maintained response (desvenlafaxine, 82%; escitalopram, 80%; P = 0.70). In both phases, desvenlafaxine and escitalopram were generally safe and well tolerated. Conclusions: Among postmenopausal outpatients with MDD, there were no significant differences in the efficacy of desvenlafaxine and escitalopram based on primary efficacy analyses. The results do not support the overall hypothesis that the serotonin-norepinephrine reuptake inhibitor desvenlafaxine has an efficacy advantage for the treatment of MDD in postmenopausal women because, in this particular subgroup, desvenlafaxine failed to prove superiority over escitalopram. Safety and tolerability were comparable.

According to the National Comorbidity Survey (NCS), major depressive disorder (MDD) has an estimated lifetime prevalence of 16%. NCS data also reveal that the majority of participants that met MDD criteria were currently employed and during the past year experienced some form of role impairment in work, family, or social functioning. The degree of impairment was commensurate with the severity of depressive symptomatology.1 Furthermore, the World Health Organization has estimated that, among the 10 most disabling diseases (eg, diabetes, tuberculosis, hepatitis, sexually transmitted diseases), MDD is responsible for 5% of the total global disease burden associated with these disorders2 and is ranked fourth among the leading causes of disease burden.3 Despite the overwhelming evidence demonstrating that MDD exerts a significantly negative effect on functioning and quality of life (Table 1), when depressed patients are assessed, either in a clinical or research setting, the focus primarily remains on the severity of depressive symptoms, with significantly less attention being paid to the impact that MDD has on these “real-world” outcomes. Other areas of medicine (eg, cardiovascular medicine,4,5 diabetes6) have begun to expand the assessment of treatment outcomes from simply measuring symptomatic improvement to include a broader range of outcomes, thereby providing a useful example of how assessing these outcomes can help in the decision-making process of the various health care stakeholders (ie, physicians, employers, and payors/managed care plans) involved in the treatment of depressed patients. Table 1 Summary of Key Studies Assessing the Disability Associated With Major Depressive Disorder (MDD) The objective of this systematic review was to quantify the negative impact that MDD has on quality of life, disability, and work, family, and overall psychosocial functioning. Available scales that assess these areas of impairment as they relate to patients with MDD are also described.

BACKGROUND The risk for major depressive disorder (MDD) increases during the menopausal transition. Nonetheless, no large, placebo-controlled studies have prospectively assessed the efficacy of antidepressants in perimenopausal or postmenopausal women. This randomized, double-blind, placebo-controlled trial evaluated the short-term efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) in perimenopausal and postmenopausal women with DSM-IV-defined MDD. METHOD 387 depressed perimenopausal and postmenopausal women aged 40 to 70 years were randomly assigned to placebo or desvenlafaxine (100 or 200 mg/d at the discretion of the investigator) in an 8-week, flexible-dose trial conducted from September 2006 to June 2008. The primary efficacy variable was change from baseline in 17-item Hamilton Depression Rating Scale (HDRS(17)) total score, analyzed using a mixed-effects model for repeated-measures analysis. Safety data were collected throughout the trial. RESULTS The reduction in adjusted HDRS17 total scores from baseline to week 8 (mean daily dose after titration, 162 to 176 mg/d) was significantly greater for desvenlafaxine (-12.64) compared with placebo (-8.33; P < .001). Statistical separation from placebo was observed at week 1 and was sustained through week 8. Both the perimenopausal and postmenopausal subgroups achieved significant reductions in HDRS(17) total scores with desvenlafaxine treatment (perimenopausal, P = .003; postmenopausal, P < .001). Response (58.6%) and remission (38.2%) rates were significantly higher for desvenlafaxine compared with placebo (31.6% [P < .001] and 22.4% [P = .008], respectively). In all, 19/256 (7.4%) desvenlafaxine-treated patients and 4/125 (3.2%) placebo-treated patients discontinued due to adverse events. Treatment-emergent adverse events were reported by 94/125 (75.2%) placebo-treated patients and 218/256 (85.2%) desvenlafaxine-treated patients. CONCLUSIONS Short-term treatment with desvenlafaxine was effective and generally well tolerated in perimenopausal and postmenopausal women with MDD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00369343.

The objective of this study was to assess discontinuation symptoms with desvenlafaxine (administered as desvenlafaxine succinate) treatment for major depressive disorder. Data were analyzed from nine 8-week, double-blind (DB), placebo-controlled studies of desvenlafaxine (50, 100, 200, or 400 mg/day; placebo, n = 319; desvenlafaxine, n = 578) and a relapse-prevention study [12-week, open-label (OL) 200 or 400 mg/day desvenlafaxine (n = 373); 6-month DB placebo (n = 73) or desvenlafaxine (n = 118)]. Rates of taper/poststudy-emergent adverse events were summarized. Discontinuation-Emergent Signs and Symptoms (DESS) checklist scores were analyzed in treatment completers at the end of OL and DB treatment. The most common (> or = 5%) taper/poststudy-emergent adverse events among desvenlafaxine patients were dizziness, nausea, headache, irritability, diarrhea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In the short-term studies, the highest DESS scores observed for desvenlafaxine groups occurred at first assessment after discontinuation of all active treatment (1.9-5.7). Desvenlafaxine 50- and 100-mg/day groups had significantly increased scores versus placebo (P values < or = 0.028). DESS scores increased significantly for patients discontinuing 12-week, OL desvenlafaxine 200 and 400 mg/day doses compared with those continuing desvenlafaxine (P values < or = 0.022). After the 6-month DB phase, DESS scores increased significantly compared with placebo for patients discontinuing 400 mg/day only (P = 0.029). In conclusion, cessation of desvenlafaxine use is associated with discontinuation symptoms after both short-term and long-term treatment.

Exacerbation of common medical and mental health disorders at specific phases of the menstrual cycle is a prevalent phenomenon. Although the precise cause is unclear, studies implicate complex interactions between the immune and neuroendocrine systems. The menstrual cycle also is a trigger for the onset of depressive disorders, including premenstrual dysphoric disorder, a disorder specific to the luteal phase of the menstrual cycle, and depression associated with the transition to menopause. This article discusses common mental health problems exacerbated by the menstrual cycle, with a particular focus on premenstrual dysphoric disorder and perimenopausal depression. Throughout the reproductive lifespan, routine screening and assessment for the presence of common psychiatric disorders are critical for accurate diagnosis and provision of effective treatment. Management options include referral or consultation with a primary care provider or psychiatrist; treatment options for premenstrual dysphoric disorder and perimenopausal depression include pharmacotherapy with antidepressant agents and/or psychotherapy. Hormones may be helpful.

Objective Depression is particularly prevalent among women in the reproductive years. This article reviews research on the risk of depression during the transition to menopause and discusses screening methods and management options. Design Systematic literature searches were conducted using MEDLINE (1966 to May 2007), and all relevant papers published in English were included. Results During the transition to menopause, most women do not experience depression, although this period represents a time of increased vulnerability for some women. Recent studies suggest that even in women without a history of depression, the risk of a new onset of depression is double or more during the menopausal transition. Certain patient factors, such as vasomotor symptoms and depression during the reproductive years, are commonly seen in gynecologic practice and are significant and independent risk factors for developing a new or recurrent episode of depression during the menopausal transition. Identifying depression in the context of menopausal symptoms may be challenging; however, various questionnaires may facilitate diagnosis. Effective short- and long-term management of depression is critical, and treatment options include antidepressant pharmacotherapy with or without estrogen therapy. Evidence suggests that some antidepressant classes have differential efficacy depending on menopausal status. Conclusions Obstetricians and gynecologists are in a unique position to recognize depression in potentially at-risk patients. Proactive screening and diagnosis of depression are critical for successful treatment outcomes. Additional studies are needed to evaluate the effects of menopausal status on antidepressant response and to identify new, safe, and efficacious treatment options for depression during perimenopause.

This prospective, pre- and post-evaluation of a worksite cardiovascular health management program consisted of employee education, measurement of cardiovascular risk factors, and onsite individual counseling for all employees, along with follow up screening for high risk participants. Of 1,099 employees (16.4% of those eligible) who participated in the initial screening, 596 (54.2%) were classified as high risk. A total of 167 (28.0%) high risk participants completed the 6 month follow up screening. Most high risk participants in the 6 month follow up screening reported they had increased their exercise (64.7%), improved their diet (71.3%), and visited a physician (61.7%). A minority of the participants (16.8%) began new cardiovascular medications, and 2.4% were diagnosed with diabetes. In addition, there were statistically significant decreases in the percentages of participants with elevated systolic blood pressure, diastolic blood pressure, low density lipoprotein cholesterol, and total cholesterol to high density lipoprotein ratio. Almost all (99.7%) of the 909 participants (82.7% of all participants) who completed the satisfaction survey were satisfied or very satisfied with the overall program. Screening in the workplace can identify individuals at high risk for cardiovascular disease. In this study, more than half of the participants were classified as high risk. Most high risk individuals who attended the 6 month follow up screening had improved their cardiovascular health, but attrition remains a challenge for worksite programs.