Jeff Musgnung

Venlafaxine extended release in posttraumatic stress disorder: a sertraline- and placebo-controlled study.

Abstract: This 12-week, double-blind, multicenter trial evaluated the efficacy of venlafaxine extended release (ER), sertraline, and placebo in adult outpatients (N = 538) with a primary diagnosis of posttraumatic stress disorder (PTSD), as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, symptoms for 6 months or more and 17-item Clinician-administered PTSD Scale (CAPS-SX17) score of 60 or more. Patients were randomly assigned to receive placebo or flexible doses of venlafaxine ER (37.5-300 mg/d) or sertraline (25-200 mg/d) for 12 weeks or less. The primary outcome was the baseline-to-end point change in total CAPS-SX17 score (last observation carried forward). Secondary measures included CAPS-SX17 symptom cluster scores for reexperiencing/intrusion, avoidance/numbing, and hyperarousal; frequency of remission (CAPS-SX17 ≤20); and changes in Davidson Trauma Scale total score and symptom cluster scores for avoidance/numbing, hyperarousal, and reexperiencing/intrusion. Mean changes in CAPS-SX17 scores were −41.8, −39.4, and −33.9 for venlafaxine ER (P < 0.05 vs. placebo), sertraline, and placebo, respectively. Mean changes for venlafaxine ER, sertraline, and placebo in CAPS-SX17 cluster scores were −13.0, −11.7, and −11.0 for reexperiencing; −17.1, −16.8, and −13.7 (P < 0.05 both active treatments vs. placebo) for avoidance/numbing; and −11.8, −10.9, and −9.2 (P < 0.05 venlafaxine vs. placebo) for hyperarousal. Week 12 remission rates were venlafaxine ER 30.2% (P < 0.05 vs. placebo), sertraline 24.3%, and placebo 19.6%. The venlafaxine ER group had significantly better Davidson Trauma Scale total and cluster scores than placebo. Mean maximum daily doses were 225-mg venlafaxine ER and 151-mg sertraline. Both treatments were generally well tolerated. Study results suggest that venlafaxine ER is effective and well tolerated in the short-term treatment of PTSD.

Effects of venlafaxine extended release on resilience in posttraumatic stress disorder: an item analysis of the Connor-Davidson Resilience Scale

The aim was to evaluate the efficacy of venlafaxine extended release (ER) on characteristics of resilience, measured by the Connor–Davidson Resilience Scale, in patients with posttraumatic stress disorder (PTSD). Data were evaluated from a randomized, 6-month, international, multicenter study of adult outpatients with a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition PTSD for ≥6 months, and 17-item Clinician-Administered PTSD Scale score ≥60. Patients were assigned randomly to treatment with flexible-dose venlafaxine ER (37.5–300 mg/day) or placebo. Changes from baseline scores and effect sizes of response to treatment with venlafaxine ER compared with placebo were computed for each item, as well as for the newly developed 2-item and 10-item subscales. Effect sizes across items ranged from 0.41 (moderate) to 0.08 (very weak). The effect size for the Resilience Scale-2 (2-item subscale) was 0.32, which was comparable to the effect sizes of 0.35 for the 25-item full scale and 0.34 for the 10-item subscale. Venlafaxine ER improved resilience on individual Connor–Davidson Resilience Scale items that reflect four factors (hardiness, persistence/tenacity, social support, and faith in a benevolent or meaningful world), to varying degrees in patients with PTSD. The findings suggest that assessment of treatment response might be enhanced by routine evaluation of resilience.

A Meta-analysis of Factors Impacting Detection of Antidepressant Efficacy in Clinical Trials: The Importance of Academic Sites

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.

Efficacy and safety of desvenlafaxine 50 mg/d in a randomized, placebo-controlled study of perimenopausal and postmenopausal women with major depressive disorder.

OBJECTIVE 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. METHOD 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). RESULTS 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. CONCLUSIONS 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. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01121484.

Onset of activity and time to response on individual CAPS-SX17 items in patients treated for post-traumatic stress disorder with venlafaxine ER: a pooled analysis

This pooled analysis of data from two randomized, placebo-controlled trials of venlafaxine extended release (ER) assessed onset of activity and time to response on the 17 symptoms of post-traumatic stress disorder (PTSD) listed in DSM-IV and measured by the 17-item Clinician-Administered PTSD Scale (CAPS-SX17). The intent-to-treat (ITT) population comprised 687 patients (placebo, n=347; venlafaxine ER, n=340). Significant (p<0.05) separation between venlafaxine ER and placebo was observed on most CAPS-SX17 items, with earliest onset of activity and response (week 2) on items 5 (physiological reactivity on exposure to cues) and 14 (irritability or anger outbursts), and (week 4) items 1 (intrusive recollections) and 4 (psychological distress at exposure to cues). Onset of activity and response occurred later (generally, weeks 6-8) on items 9 (diminished interest/participation in activities), 10 (detachment or estrangement), 11 (restricted range of affect), 12 (sense of foreshortened future), all associated with numbing, 15 (difficulty concentrating), 16 (hypervigilance), 17 (exaggerated startle response), associated with hyperarousal, and 6 (avoidance of thoughts/feelings or conversations). Significant differences between venlafaxine ER and placebo were largely absent throughout the treatment period and at the primary week-12 end-point for items 2 (distressing dreams), 7 (avoidance of activities, places or people), 8 (inability to recall important aspect of trauma) and 13 (difficulty falling/staying asleep). These results indicate that symptoms of physiological reactivity and psychological distress in response to cues, and irritability/anger outbursts show early and robust improvement with venlafaxine ER treatment, while symptoms of numbing and hyperarousal take longer. The early and persistent effect of venlafaxine ER over placebo on anger/irritability is noteworthy in view of the clinical significance of these symptoms in PTSD.

Short-Term Efficacy and Safety of Desvenlafaxine in a Randomized, Placebo-Controlled Study of Perimenopausal and Postmenopausal Women With Major Depressive Disorder

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.

An Evaluation of Sexual Functioning in Employed Outpatients with Major Depressive Disorder Treated with Desvenlafaxine 50 mg or Placebo

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.

Efficacy of desvenlafaxine 50 mg compared with placebo in patients with moderate or severe major depressive disorder: a pooled analysis of six randomized, double-blind, placebo-controlled studies

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<HAM-D17<25) or severe (HAM-D17≥25) MDD at baseline using analysis of covariance with treatment, study, and baseline in the model. The pooled analysis included 2189 patients (desvenlafaxine 50 mg, n=1150; placebo, n=1039). Of those, 694 (32%) patients had severe depression at baseline. Desvenlafaxine improved HAM-D17 scores versus placebo in patients with either moderate [desvenlafaxine, adjusted mean (±SE), −10.26±0.24; placebo, −8.87±0.26; P<0.001] or severe MDD (desvenlafaxine, −11.91±0.40; placebo, −9.85±0.42; P<0.001). Both moderately and severely depressed patients had significantly higher rates of response and remission with desvenlafaxine treatment compared with placebo (all P’s⩽0.029). Results were similar when baseline severity was defined by Montgomery–Åsberg Depression Rating Scale or Sheehan Disability Scale scores. Desvenlafaxine 50 mg/day significantly improved depressive symptoms regardless of severity at baseline and was effective in treating both moderate and severe MDD.

Remission With Venlafaxine Extended Release or Selective Serotonin Reuptake Inhibitors in Depressed Patients: A Randomized, Open-Label Study

BACKGROUND This randomized, open-label, rater-blinded, multicenter study compared treatment outcomes with the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine extended release (ER) with selective serotonin reuptake inhibitors (SSRIs) in primary care patients with major depressive disorder. METHOD Study data were collected from November 29, 2000, to March 4, 2003. Outpatients who met diagnostic criteria for major depressive disorder according to the Mental Health Screener, a computer-administered telephone interview program that screens for the most common mental disorders, and had a total score on the 17-item Hamilton Depression Rating Scale (HDRS(17)) ≥ 20 were randomly assigned to receive up to 6 months of open-label venlafaxine ER 75-225 mg/d (n = 688) or an SSRI (n = 697): fluoxetine 20-80 mg/d, paroxetine 20-50 mg/d, citalopram 20-40 mg/d, and sertraline 50-200 mg/d. The primary outcome was remission (HDRS(17) score ≤ 7) at study end point using the last-observation-carried-forward method to account for early termination. A mixed-effects model for repeated measures (MMRM) analysis evaluated secondary outcome measures. RESULTS Fifty-one percent of patients completed the study. Month 6 remission rates did not differ significantly for venlafaxine ER and the SSRIs (35.5% vs 32.0%, respectively; P = .195). The MMRM analysis of HDRS(17) scores also did not differ significantly (P = .0538). Significant treatment effects favoring the venlafaxine ER group were observed for remission rates at days 30, 60, 90, and 135 and a survival analysis of time to remission (P = .006), as well as Clinical Global Impressions-severity of illness scale (P = .0002); Hospital Anxiety and Depression Scale-Anxiety subscale (P = .03); 6-item Hamilton Depression Rating Scale, Bech version (P = .009); and Quick Inventory of Depressive Symptomatology-Self-Report (P = .0003). CONCLUSIONS Remission rates for patients treated with venlafaxine ER or an SSRI did not differ significantly after 6 months of treatment. Results of most secondary analyses suggested that SNRI treatment had a greater antidepressant effect versus the SSRIs studied.

Clinical utility of desvenlafaxine 50 mg/d for treating MDD: a review of two randomized placebo-controlled trials for the practicing physician

Abstract Background: 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. Objective: 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. Methods: 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. Results: 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-D17] total score; P < 0.05). Significant differences were observed on several secondary measures (Montgomery Åsberg Depression Rating Scale scores in both trials [P < 0.05]; Clinical Global Impressions-Improvement scores [P ≤ 0.01], Clinical Global Impressions-Severity scores [P ≤ 0.01], HAM-D17 response [P ≤ 0.01] and remission [P < 0.05] 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 (P < 0.05). 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. Conclusions: 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.