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Publications (8)29.39 Total impact

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    ABSTRACT: Evaluate the 8-week efficacy and safety of desvenlafaxine at the recommended dose of 50 mg/d in perimenopausal and postmenopausal women with major depressive disorder (MDD) based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. This phase 4, multicenter, parallel-group, randomized, double-blind, placebo-controlled study was conducted from June 30, 2010, to June 8, 2011. Patients received placebo or desvenlafaxine 50 mg/d (1:1 ratio; n = 217 in each group). The primary outcome measure was the change at week 8 in the 17-item Hamilton Depression Rating Scale (HDRS17) total score. Secondary outcome measures included change in the Sheehan Disability Scale (SDS), the Clinical Global Impressions-Improvement scale (CGI-I), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Visual Analog Scale-Pain Intensity (VAS-PI). At end point, compared to placebo, desvenlafaxine was associated with a significantly greater decrease in HDRS17 total scores (last-observation-carried-forward analysis; adjusted mean change from baseline -9.9 vs -8.1, respectively; P = .004) and significant improvements on the CGI-I (P < .001), MADRS (P = .002), SDS (P = .038), and VAS-PI (P < .001). Improvements on the SDS and VAS-PI reached significance by week 2. Desvenlafaxine was generally safe and well tolerated. Short-term treatment with desvenlafaxine 50 mg/d was effective for the treatment of MDD in perimenopausal and postmenopausal women, with significant benefits on pain and functional outcomes evident as early as week 2. The safety and tolerability of desvenlafaxine were consistent with data in other populations. ClinicalTrials.gov identifier: NCT01121484.
    The Journal of Clinical Psychiatry 10/2013; 74(10):1010-1017. · 5.81 Impact Factor
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    ABSTRACT: 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.
    The Journal of Clinical Psychiatry 03/2013; · 5.81 Impact Factor
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    ABSTRACT: Introduction.  The symptoms of major depressive disorder (MDD) include sexual dysfunction, but antidepressant pharmacotherapies are also associated with treatment-emergent sexual dysfunction. Aim.  These secondary and post hoc analyses evaluated sexual functioning in employed adult outpatients with MDD treated with desvenlafaxine (administered as desvenlafaxine succinate) and placebo. Method.  Patients were randomly assigned (2:1 ratio) to 12 weeks of double-blind treatment with desvenlafaxine 50 mg/day or placebo. Main Outcome Measures.  The Arizona Sexual Experiences Scale (ASEX) was administered every 4 weeks. Analysis of covariance was used to compare differences in mean change from baseline ASEX scores between desvenlafaxine and placebo for women and men. Results.  There were 422 evaluable patients with baseline ASEX scores (desvenlafaxine, N = 281; placebo, N = 141). Among women (desvenlafaxine, N = 184; placebo, N = 92), baseline scores were 20.0 (5.2) and 20.5 (5.3) for desvenlafaxine and placebo, respectively; mean changes at week 12 were -1.93 (0.37) and -1.03 (0.54), respectively (mean difference: 0.90 [-0.38, 2.18]; P = 0.169). Among men (desvenlafaxine, N = 97; placebo, N = 49), baseline scores were 16.4 (4.9) and 15.9 (4.8) for desvenlafaxine and placebo, respectively; mean changes at week 12 were -1.13 (0.47) and -1.06 (0.70), respectively (mean difference: 0.07 [-1.59, 1.74]; P = 0.932). Significantly greater orgasmic dysfunction at week 12 was observed in the subgroup of men without baseline sexual dysfunction treated with desvenlafaxine relative to placebo. Conversely, women without baseline sexual dysfunction experienced poorer overall sexual functioning and orgasm satisfaction at week 12 with placebo relative to desvenlafaxine treatment. Subgroup analyses of treatment responders and nonresponders found no difference in the proportion of men or women that developed or had resolution of sexual dysfunction in the desvenlafaxine and placebo groups. Conclusion.  With the exception of orgasmic dysfunction in men without preexisting sexual dysfunction, no significant negative effect on sexual functioning was observed over 12 weeks of treatment with desvenlafaxine. Clayton AH, Reddy S, Focht K, Musgnung J, and Fayyad R. An evaluation of sexual functioning in employed outpatients with major depressive disorder treated with desvenlafaxine 50 mg or placebo. J Sex Med **;**:**-**.
    Journal of Sexual Medicine 08/2012; · 3.51 Impact Factor
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    ABSTRACT: 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.
    Journal of clinical psychopharmacology 08/2011; 31(5):569-76. · 5.09 Impact Factor
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    ABSTRACT: 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.
    CNS Drugs 03/2011; 25(3):227-38. · 4.38 Impact Factor
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    ABSTRACT: Genetically driven variations in the level of cytochrome P450 (CYP) 2D6 metabolic activity have been shown to significantly affect the pharmacokinetic behaviour of medications that are substrates of this enzyme. To evaluate the impact of CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) phenotypes on the pharmacokinetics of single doses of venlafaxine extended release (ER) and desvenlafaxine (administered as desvenlafaxine succinate). This study used a randomized, open-label, two-period, parallel-group, crossover design. The enrolled healthy subjects participated in the study for approximately 8 weeks, which included ≤ 6 weeks of screening procedures and two separate 1-week partial inpatient confinement periods (separated by a 4-day washout period), during which venlafaxine ER or desvenlafaxine was administered and blood samples were collected. Subjects were admitted to partial inpatient confinement in a laboratory setting for the two separate study periods where each study drug was individually administered. Blood samples for pharmacokinetic analyses were collected during the 120 hours following administration of each study drug. Plasma concentrations of the study drugs were measured by a third-party analyst using liquid chromatography-tandem mass spectrometry. Healthy subjects were recruited through newspaper advertisements and genotyped to determine their CYP2D6 metabolic phenotype (i.e. EM or PM) using internally developed and commercially available assays. Subjects were reimbursed for their participation in this study. Single, sequentially administered oral doses of the dual-acting, serotonin and norepinephrine reuptake inhibiting antidepressants venlafaxine ER (75  mg) and desvenlafaxine (50  mg) were administered. The main outcome measures were differences in the geometric means for area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) and peak plasma concentration (C(max)) between EMs and PMs. Comparisons were made using a 2-tailed Wilcoxon exact test. No carryover effect was observed between treatment sequence groups. There was no statistically significant difference in either C(max) or AUC(∞) of O-desmethylvenlafaxine between PMs (n = 7) and EMs (n = 7) following administration of desvenlafaxine 50  mg. However, when subjects received venlafaxine ER 75  mg, the AUC(∞) and C(max) of O-desmethylvenlafaxine (the primary active metabolite) were 445% and 434% higher, respectively, in EMs compared with PMs (p ≤ 0.001), and the AUC(∞) and C(max) of venlafaxine were 445% and 180% higher, respectively, in PMs compared with EMs (p < 0.01). In addition, the ratios of O-desmethylvenlafaxine : venlafaxine AUC(∞) and C(max) for subjects receiving venlafaxine ER 75  mg were higher for EMs (6.2 and 3.3) than PMs (0.21 and 0.22; p ≤ 0.001 for both comparisons). In contrast to venlafaxine ER 75  mg, the pharmacokinetics of desvenlafaxine 50  mg is not significantly impacted by CYP2D6 genetic polymorphisms. PMs receiving venlafaxine ER 75  mg had significantly lower O-desmethylvenlafaxine and higher venlafaxine plasma concentrations.
    Clinical Drug Investigation 01/2011; 31(3):155-67. · 1.70 Impact Factor
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    ABSTRACT: 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. 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-D17) 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-D17 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. Reductions in HAM-D17 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. 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.
    Menopause (New York, N.Y.) 07/2010; 17(4):700-11. · 3.08 Impact Factor
  • Journal of Affective Disorders - J AFFECT DISORDERS. 01/2010; 122.