-
[show abstract]
[hide abstract]
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. · 4.80 Impact Factor
-
[show abstract]
[hide abstract]
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. · 1.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
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.
Short-term treatment with desvenlafaxine was effective and generally well tolerated in perimenopausal and postmenopausal women with MDD.
clinicaltrials.gov Identifier: NCT00369343.
The Journal of Clinical Psychiatry 08/2010; 71(8):1088-96. · 5.80 Impact Factor
-
[show abstract]
[hide abstract]
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
-
[show abstract]
[hide abstract]
ABSTRACT: 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).
To determine the relative efficacy and tolerability of venlafaxine in EM vs PM patients with major depressive disorder (MDD).
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.
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.
Venlafaxine treatment in EMs was associated with greater efficacy in MDD on virtually all measures compared with PMs, with no important tolerability differences.
The Journal of Clinical Psychiatry 04/2010; 71(11):1482-7. · 5.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This analysis evaluated the effects of the serotonin-norepinephrine reuptake inhibitor, desvenlafaxine (administered as desvenlafaxine succinate), on anxiety symptoms associated with depression.
Data were pooled from 9 randomized, placebo-controlled, double-blind, 8 week studies of desvenlafaxine (50-400 mg/day, fixed or flexible dose) in patients with major depressive disorder (MDD), without a primary anxiety diagnosis. Changes from baseline in scores on the anxiety/somatization factor of the 17-item Hamilton Rating Scale for Depression (HAM-D17) and on the Covi Anxiety Scale at the final evaluation (last observation carried forward) were compared between desvenlafaxine and placebo groups using analysis of covariance.
In the overall data set (intent to treat n=2,913 [desvenlafaxine, n=1,805; placebo, n=1,108]), desvenlafaxine was associated with significantly greater reductions compared with placebo in scores on the HAM-D17 anxiety/somatization factor (-3.41 vs -2.92, P<.001) and Covi Anxiety Scale (-1.35 vs -1.04, P<.001). In the subset of fixed-dose studies, significant differences were observed for all dose groups on the HAM-D17 anxiety/somatization factor (P= or <.011), and for the 50, 100, and 200 mg/day dose groups on the Covi Anxiety Scale (all P= or <.015 vs placebo).
Desvenlafaxine was associated with significantly greater improvement in anxiety symptoms compared with placebo in patients with MDD.
CNS spectrums 03/2010; 15(3):187-93. · 2.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To evaluate the effects of desvenlafaxine therapy on functioning and well-being in major depressive disorder (MDD).
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.
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.
Desvenlafaxine therapy resulted in significant improvements in the functioning and well-being among MDD patients.
The Journal of Clinical Psychiatry 10/2009; 70(10):1365-71. · 5.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) in outpatients with major depressive disorder.
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-D(17)); the primary intent to treat analyses used the last-observation-carried-forward method.
Significantly greater improvement with desvenlafaxine versus placebo on the HAM-D(17) total score was observed for the full data set (difference in adjusted means: -1.9; P<.001), each fixed-dose group (all P<.001), and the flexible-dose group (P=.024). Overall rates of HAM-D1(17) response (> or =150% decrease from baseline score: 53% vs 41%) and remission (HAM-D(17) < or =7: 32% vs 23%) were significantly greater for desvenlafaxine versus placebo (all P<.001). Discontinuation rates due to adverse events increased with dose (4% to 18%; placebo: 3%).
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.
CNS spectrums 03/2009; 14(3):144-54. · 2.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The goal of this study was to evaluate the impact of cytochrome P450 2D6 extensive metabolizer (EM) or poor metabolizer (PM) status on the pharmacokinetics of single doses of venlafaxine extended release (ER) and desvenlafaxine (administered as desvenlafaxine succinate) in healthy adults.
In an open-label, crossover study, 14 healthy volunteers (aged 18-55 years; 7 EMs and 7 PMs) received, in randomized sequence, single doses of venlafaxine ER 75 mg/d or desvenlafaxine 100 mg/d. Cytochrome P450 2D6 genotyping was performed, and plasma drug levels were measured. The arithmetic means and standard deviation (SD) for area under the plasma concentration-versus-time curve (AUC) and peak plasma concentration (Cmax) were calculated. Comparisons of AUC and Cmax between cytochrome P450 2D6 EMs and PMs were calculated using a Wilcoxon exact test.
After administration of venlafaxine ER, mean Cmax and AUC of venlafaxine were significantly greater in PMs compared with EMs, whereas mean Cmax and AUC of its metabolite, desvenlafaxine, were significantly lower for PMs than for EMs (P = 0.001, all comparisons). In contrast, mean Cmax and AUC of desvenlafaxine after administration of desvenlafaxine were comparable between EMs and PMs.
Cytochrome P450 2D6 genetic polymorphisms had no discernible impact on exposure to desvenlafaxine after desvenlafaxine administration; in contrast, compared with an EM phenotype, a PM phenotype had a significant effect on venlafaxine and desvenlafaxine plasma concentrations after venlafaxine ER administration. This reduced pharmacokinetic variability of desvenlafaxine may translate into better uniformity of response for patients receiving desvenlafaxine versus venlafaxine, but additional studies are required to test this hypothesis.
Journal of clinical psychopharmacology 03/2009; 29(1):39-43. · 5.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The 17-item Hamilton Depression Rating Scale (HAM-D 17) remains the 'gold standard' for measuring treatment outcomes in clinical trials of depressed patients. The Montgomery Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Severity (CGI-S) and -Improvement (CGI-I) scales are also widely used.
This analysis of data from 22 double-blind, placebo-controlled clinical studies of venlafaxine in adult patients with major depressive disorder was aimed at assessing correlations among these 4 scales.
Changes from baseline for MADRS, HAM-D 17 and CGI-S, and end point CGI-I scores and response (>or=50% decrease from baseline HAM-D 17 or MADRS, or CGI-S or CGI-I score <or=2) were analysed. Pearson correlation coefficients were calculated for all pairs of the four scales (HAM-D 17/MADRS, HAM-D 17/CGI-S, HAM-D 17/CGI-I, MADRS/CGI-S, MADRS/CGI-I, CGI-S/CGI-I) at different time points. Effect sizes were calculated using the Cohen d.
Correlations were significant at all time points (p < 0.0001), increased over the course of treatment, and were similar across treatment groups. Effect sizes ranged from 0.31 to 0.42; MADRS and CGI-I effect sizes were slightly greater compared with HAM-D 17 or CGI-S for continuous measures and response.
Although MADRS and CGI-I were more sensitive to treatment effects, HAM-D 17, MADRS, CGI-S and CGI-I scores present a consistent picture of response to venlafaxine treatment.
Annals of General Psychiatry 01/2009; 8:4. · 1.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of this study was to evaluate the impact of desvenlafaxine on a broad range of major depressive disorder (MDD) symptoms.
Data were pooled from 9 double-blind, randomized, placebo-controlled, 8-week studies of desvenlafaxine in adult outpatients with MDD. Intent-to-treat participants received fixed- (50, 100, 200, or 400 mg/d; n = 1342) or flexible-dose (100 to 400 mg/d, n = 463) desvenlafaxine or placebo (n = 1108). Final on-therapy scores for individual items of the 17-item Hamilton Rating Scale for Depression (HAMD17) and the Montgomery Asberg Depression Rating Scale (MADRS) were compared between groups using analysis of covariance. Efficacy at different doses was examined using the subset of fixed-dose studies.
Based on differences in adjusted mean changes from baseline (desvenlafaxine vs placebo), statistically significant advantages with desvenlafaxine (50 to 400 mg/d, all doses pooled) vs placebo were seen for 10 of the 17 HAM-D17 items: depressed mood (-0.4; P < 0.001), feelings of guilt (-0.2; P < 0.001), suicide (-0.1; P < 0.001), late insomnia (-0.1; P = 0.001), work and activities (-0.2; P < 0.001), psychomotor retardation (-0.1; P < 0.001), agitation (-0.1; P < 0.001), psychic anxiety (-0.3; P < 0.001), general somatic symptoms (-0.2; P < 0.001), and genital symptoms (-0.1; P = 0.003). Desvenlafaxine (50 to 400 mg/d, pooled) was significantly better than placebo on all MADRS items (range: -0.1 to -0.5; all P </= 0.019), except "reduced appetite" (-0.01, P > 0.05). Symptom relief was similar with all desvenlafaxine doses examined, including 50 mg/d.
Shortterm desvenlafaxine therapy (50 to 400 mg/d) improved a broad range of emotional and physical symptoms in outpatients with MDD.
Psychopharmacology bulletin 01/2009; 42(3):21-35. · 1.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The potential for cytochrome P450 (CYP) 2D6 substrates to interact with desvenlafaxine (administered as desvenlafaxine succinate) and paroxetine was evaluated. In an open-label, crossover study, 20 healthy volunteers (aged 21-50) were randomized to 2 series of 9 days each of desvenlafaxine (100 mg/d) or paroxetine (20 mg/d), separated by a 5-day washout. The CYP2D6 substrate desipramine (50 mg) was administered alone on day 1 and coadministered on day 6 of dosing with either desvenlafaxine or paroxetine. CYP2D6 genotype was determined at baseline. Based on least squares geometric mean ratios between reference (desipramine alone) and test treatments, desvenlafaxine produced minor increases in desipramine area under the plasma concentration versus time curve (AUC; 36%) and peak plasma concentration (C(max); 30%) (vs paroxetine: 419%, 90%, respectively; both P < .001). Desvenlafaxine produced little change in 2-hydroxydesipramine AUC (16% increase) and C(max) (0%) versus paroxetine (18% and 82% decreases, respectively; P = .008, P < .001, respectively), indicating that desvenlafaxine, especially at the recommended therapeutic dose of 50 mg/d for major depressive disorder in the United States, has little potential to interact with CYP2D6 substrates.
The Journal of Clinical Pharmacology 11/2008; 49(2):219-28. · 2.91 Impact Factor
