Desvenlafaxine Succinate Research Articles

Desvenlafaxine for the Prevention of Relapse in Major Depressive Disorder

To compare the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) with placebo in reducing relapse rate in patients with major depressive disorder (MDD). This phase 3, multicenter, randomized trial included a 12-week, open-label (OL) treatment phase (intent-to-treat population, n = 575) followed by a 6-month, double-blind (DB) relapse prevention phase. Patients who responded to the OL treatment (17-item Hamilton Rating Scale for Depression total score <or= 11) with desvenlafaxine (200-400 mg/d) were eligible to enter the DB phase. The primary efficacy end point was time until relapse (17-item Hamilton Rating Scale for Depression total score >or= 16 at any visit, Clinical Global Impression-Improvement score >or= 6 at any visit, or discontinuation due to unsatisfactory response). Patients receiving desvenlafaxine (n = 189) experienced significantly longer times to relapse of MDD versus patients receiving placebo (n = 185) during the DB period (log-rank test, P < 0.0001). The percentages of patients relapsing were 42% (78/185) and 24% (45/189) for placebo and desvenlafaxine, respectively (P < 0.001). The most common primary reason cited for discontinuation in the OL period was adverse events (19%), which consisted of nausea, dizziness, and insomnia. A total of 159 patients (42%) discontinued treatment during the DB period, including 101 placebo- (55%) and 58 desvenlafaxine-treated patients (31%). The most frequent adverse event reported as reason for treatment discontinuation in the DB period was depression, reported by 14 placebo- (8%) and 7 desvenlafaxine-treated patients (4%). Desvenlafaxine effectively prevented relapse of MDD during 6 months of DB treatment in patients who had responded to 12 weeks of OL desvenlafaxine therapy.

Desvenlafaxine Succinate: A Newer Antidepressant for the Treatment of Depression and Somatic Symptoms

Desvenlafaxine succinate (DVS) is one of several serotonin-norepinephrine reuptake inhibitors (SNRIs). Others are venlafaxine hydrochloride, milnacipran, and duloxetine. Desvenlafaxine has been approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) based on a number of randomized, placebo-controlled clinical trials. Clinical studies have investigated the efficacy of DVS in doses ranging from 50 to 400 mg/day for the treatment of MDD in adult outpatients. The effects of DVS 50 mg/day have been clearly distinguished from placebo in the reduction of MDD symptoms in such clinical trials. No additional therapeutic benefits were found at doses > 50 mg/day. The recommended dose of DVS ranges from 50 to 100 mg. Desvenlafaxine is currently the third SNRI approved by the FDA for this indication. Preliminary evidence also suggests the clinical usefulness of DVS in the treatment of vasomotor symptoms of menopause, anxiety symptoms, and painful physical symptoms. The modified pharmacokinetic and pharmacodynamic profiles of DVS differentiate this drug from the original product, venlafaxine. Significant points of difference, compared with venlafaxine, are once-daily dosing and the achievement of steady-state plasma concentrations within 4 to 5 days. To summarize, current evidence indicates that DVS has proven efficacy, acceptable safety and tolerability profiles, convenient dosing, and minimal impact on the cytochrome P450 enzyme system. A reduced risk for pharmacokinetic drug interactions is a potential advantage over other selective serotonin noradrenaline reuptake inhibitors. Desvenlafaxine succinate has demonstrated its efficacy for treating MDD but its variable efficacy, as shown in individual studies, limited long-term data, and its different risk-to-benefit ratio compared with earlier antidepressants, means that further investigation of this drug is necessary.

Correction of Venlafaxine- and Duloxetine-Induced Transaminase Elevations with Desvenlafaxine in a Patient with Gilbert's Syndrome

Recent reviews have questioned whether the serotonin-norepinephrine reuptake inhibitor (SNRI) desvenlafaxine succinate offers any practical clinical advantages over existing SNRIs. The following case is one instance where it appears that this SNRI offers unique safety and benefit. Presented is a case report of a patient with Gilbert's syndrome, longstanding social phobia, and more recent depressive disorder not otherwise specified, who was found to have elevated liver transaminases when prescribed both duloxetine and venlafaxine. The patient subsequently responded to desvenlafaxine but without liver abnormalities. In this patient with Gilbert's Syndrome, desvenlafaxine's lack of metabolism through the cytochrome P450 (CYP) 2D6 pathway may explain the avoidance of these abnormalities and thus suggests a possible therapeutic role for this SNRI in similarly susceptible patients.

Discontinuation symptoms and taper/poststudy-emergent adverse events with desvenlafaxine treatment for major depressive disorder

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.

An Integrated Analysis of the Safety and Tolerability of Desvenlafaxine Compared with Placebo in the Treatment of Major Depressive Disorder

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. 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 desvenlafaxine 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. 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 desvenlafaxine-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. 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.

An Integrated Analysis of the Efficacy of Desvenlafaxine Compared with Placebo in Patients with Major Depressive Disorder

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.

Desvenlafaxine in the treatment of major depressive disorder

Major depressive disorder (MDD) is among the most incapacitating conditions in the world. The emergence of the selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) antidepressants has improved the treatment of MDD. Desvenlafaxine succinate (DVS) is the succinate salt of the isolated major active metabolite of venlafaxine, O-desmethylvenlafaxine: it is the third SNRI to become available in the United States, and was approved in 2008 by the US Food and Drug Administration (FDA) for the treatment of MDD. Early investigations showed therapeutic efficacy for doses between 50 and 400 mg/day; however in doses above 100 mg/day there were incremental increases in side effects. Nausea was the most frequent adverse effect. Hence the recommended dosing for DVS is in the 50 to 100 mg range. Desvenlafaxine is excreted in urine, it is minimally metabolized via the CYP450 pathway, and is a weak inhibitor of CYP2D6. A reduced risk for pharmacokinetic drug interactions is a potential advantage over other SNRI. Further head-to-head trials involving comparisons of DVS in the 50 to 100 mg dose range with currently available SSRI and SNRI antidepressants are required. Evidence for relapse prevention is available in the 200 to 400 mg dose range, but this needs to be demonstrated in the 50 to 100 mg dose range, as well as health economic measures and quality of life evaluations.

The Effects of Desvenlafaxine and Paroxetine on the Pharmacokinetics of the Cytochrome P450 2D6 Substrate Desipramine in Healthy Adults

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.

Comparison of the Pharmacokinetics of Venlafaxine Extended Release and Desvenlafaxine in Extensive and Poor Cytochrome P450 2D6 Metabolizers

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.

Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-controlled trial of efficacy and safety

The objective of the study was to assess the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) for the treatment of vasomotor symptoms. This was a 26 week, double-blind, placebo-controlled trial of 567 postmenopausal women (mean age, 53.7 years; time since natural menopause, 4.8 years) experiencing 50 or more hot flushes (HFs) per week, randomly assigned to desvenlafaxine (100 or 150 mg) or placebo. Change from baseline in average daily number of moderate to severe HFs and average daily HF severity were compared with placebo at weeks 4, 12, and 26. A significantly greater decrease from baseline in number of HFs occurred at weeks 4 and 12 with 100 and 150 mg desvenlafaxine compared with placebo (week 12 reductions: 60%, 66%, and 47%, respectively; all P < or = .002). Only the 150 mg dose showed significant improvement from baseline at 26 weeks compared with placebo (week 26 reductions: 61%, 69%, and 51%, respectively), although the study was not powered to demonstrate efficacy beyond the initial 12 weeks of therapy. The average daily severity decreased significantly more at weeks 4 and 12 with desvenlafaxine compared with placebo (all P < or = .002). Significantly more desvenlafaxine-treated subjects than placebo-treated subjects discontinued because of adverse events during week 1 only. Desvenlafaxine is an effective treatment for menopausal HFs.

A Placebo-Controlled Study Evaluating the Efficacy and Safety of Flexible-Dose Desvenlafaxine Treatment in Outpatients with Major Depressive Disorder

This research compares the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) versus placebo in treating major depressive disorder. In this randomized, double-blind study, outpatients with major depressive disorder > or =18 years of age received desvenlafaxine 200-400 mg/day or placebo for 8 weeks. Efficacy endpoints included (primary) change in 17-item Hamilton Rating Scale for Depression score at the final evaluation (last observation carried forward, analysis of covariance) and (secondary) Clinical Global Impressions-Improvement and -Severity of Illness scales. The difference between desvenlafaxine (n==) and placebo (n==) on the primary endpoint was not significant (-9.1 vs -7.5, P=.078). Week 8 observed cases (desvenlafaxine, n=80; placebo, n=94) results were significant (-10.7 vs -7.9, P=.008). Differences at the final evaluation (last observation carried forward) were significant for Clinical Global Impressions-Improvement (2.9 vs 2.5, P=.037) and Clinical Global Impressions-Severity of Illness (-1.9 vs -1.2, P=.041). Discontinuation rates due to adverse events (AEs) were 12% and 3% for desvenlafaxine and placebo, respectively (P=.008). The most frequently reported AE associated with desvenlafaxine was nausea (36% vs 9% [placebo]). In this study, the primary analysis did not show significant differences between desvenlafaxine and placebo; discontinuations due to AEs associated with the desvenlafaxine dose range may have contributed to the lack of statistical separation.

Polytypism in desvenlafaxine succinate monohydrate

Two polytypes of desvenlafaxine succinate monohydrate, an antidepressant drug, contain essentially identical 2-D layers, but with different stacking arrangements, which is quite rare in organic compounds.

A double-blind, randomly assigned, placebo-controlled study of desvenlafaxine efficacy and safety for the treatment of vasomotor symptoms associated with menopause

The objective of the study was to assess the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) for menopausal vasomotor symptoms. Postmenopausal women (n = 458) experiencing 50 or more moderate to severe hot flushes per week received desvenlafaxine 100 or 150 mg/d, with titration at therapy initiation, or placebo. Hot flush number and severity were assessed at weeks 4 and 12. Safety data were collected throughout the trial. Desvenlafaxine 100 and 150 mg/d significantly reduced the number of hot flushes compared with placebo at weeks 4 and 12 (all P < or = .012), achieving 65.4% and 66.6% reductions from baseline at week 12, respectively (placebo, 50.8%). Hot flush severity and number of nighttime awakenings were significantly reduced at both time points (all P < or = .048). Desvenlafaxine groups reported significantly more adverse events compared with placebo during week 1 only. No difference in discontinuations because of adverse events was observed. Desvenlafaxine is an effective nonhormonal treatment for menopausal hot flushes. Dose titration improves initial tolerability.

Desvenlafaxine succinate for major depressive disorder: a critical review of the evidence

Desvenlafaxine succinate (DVS) is the succinate salt monohydrate of O-desmethylvenlafaxine, an active metabolite of venlafaxine. DVS is a serotonin–norepinephrine reuptake inhibitor (SNRI) like venlafaxine, but exhibits a differential serotonergic and noradrenergic activity profile. A sustained-release form of DVS is approved by the US FDA for the treatment of adult major depressive disorder (MDD). DVS has shown efficacy for the treatment of MDD in clinical trials with doses ranging from 50 to 400 mg/day. The 50–100 mg/day dose range is therapeutic, with lack of additional benefit shown at higher dosages and a significantly higher risk of side effects, especially at the 400 mg/day dosing. Advantages of DVS over other sSNRIs include its simple metabolism, lower risk of drug–drug interactions and lack of need for extensive titration to achieve therapeutic efficacy. Limitations with the use of DVS include its moderate efficacy in the treatment of MDD, a safety–tolerability profile similar to that of other SNRIs and the possibility of transient discontinuation symptoms with cessation of DVS treatment. DVS is a useful addition to the options available for the treatment of MDD in light of the limited efficacy of currently available antidepressants.

An Assessment of Drug-Drug Interactions: The Effect of Desvenlafaxine and Duloxetine on the Pharmacokinetics of the CYP2D6 Probe Desipramine in Healthy Subjects

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.

Efficacy, safety, and tolerability of fixed-dose desvenlafaxine 50 and 100 mg/day for major depressive disorder in a placebo-controlled trial

The objective of this study was to assess the efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) 50 and 100 mg/day for major depressive disorder (MDD). A multicenter, randomized, double-blind, placebo-controlled trial was conducted in Europe and South Africa. Outpatients with MDD received fixed-dose desvenlafaxine (50 or 100 mg/day) or placebo for 8 weeks. The primary efficacy variable was the 17-item Hamilton Rating Scale for Depression total score; secondary measures included Clinical Global Impressions-Improvement scores. The intent-to-treat population included 483 patients: desvenlafaxine 50 mg (n=164), desvenlafaxine 100 mg (n=158), and placebo (n=161). At the last-observation-carried-forward analysis (final evaluation) using analysis of covariance, adjusted mean changes from baseline on the Hamilton Rating Scale for Depression were significantly greater for both desvenlafaxine 50 mg (-13.2; P=0.002) and 100 mg (-13.7; P<0.001) versus placebo (-10.7). Significant differences on the Clinical Global Impressions-Improvement scores were observed for desvenlafaxine 50 mg (P=0.002) and 100 mg (P<0.001) versus placebo. Both doses of desvenlafaxine were generally well tolerated. The most common treatment-emergent adverse events were nausea, dizziness, insomnia, constipation, fatigue, anxiety, and decreased appetite. Fixed doses of desvenlafaxine 50 and 100 mg/day are safe, generally well tolerated, and effective at a clinically relevant level for the treatment of MDD.

Desvenlafaxine succinate for the treatment of major depressive disorder

Major depressive disorder (MDD) remains one of the most common psychiatric disorders with high morbidity and mortality. Effective treatment is limited and response/remission to antidepressant pharmacotherapy remains poor and unpredictable. The development of new antidepressants is thus of great importance to the field. Desvenlafaxine succinate (DVS) is the active metabolite of the serotonin and noradrenaline re-uptake inhibitor venlafaxine and was recently FDA approved for the treatment of MDD. DVS showed efficacy in clinical trials in MDD with doses ranging from 50 – 400 mg. Advantages compared to other antidepressants include once daily dosing at effective doses, no CYP450 metabolism and low drug–drug interactions. Concerns include side effect profile and moderate efficacy. DVS might be a useful addition to the arsenal of antidepressants available to the clinician. Additional studies, in particular head-to-head comparison to other antidepressants and long-term treatment studies, will be necessary to comprehensively evaluate DVS safety and efficacy for clinical practice.

A pooled analysis of two placebo-controlled trials of desvenlafaxine in major depressive disorder

The efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) were evaluated in two similarly designed, phase 3, randomized, double-blind, placebo-controlled, venlafaxine-extended-release-referenced, flexible-dose studies of outpatients with a primary diagnosis of major depressive disorder. Owing to a high placebo response, the individual studies were underpowered. Therefore, a post-hoc pooled analysis was performed (desvenlafaxine and placebo data were pooled; venlafaxine extended release data were not, owing to different flexible-dose regimens in the two studies). The primary outcome measure was the change from baseline on the 17-item Hamilton Rating Scale for Depression; the Clinical Global Impressions-Improvement item score was a secondary outcome. Analysis of the pooled data (using a mixed-effect model for repeated measures) revealed that after 8 weeks of treatment, desvenlafaxine was significantly better than placebo on 17-item Hamilton Rating Scale for Depression [-14.21 vs. -11.87 for desvenlafaxine and placebo, respectively; magnitude of effect=-2.34 (P<0.001)] and Clinical Global Impressions-Improvement item scores [1.95 vs. 2.32 for desvenlafaxine and placebo, respectively; magnitude of effect=-0.37 (P<0.001)]. Adverse events were comparable to those found with other drugs sharing a similar mechanism of action. These data support the efficacy, safety, and tolerability of desvenlafaxine in the treatment of major depressive disorder.

Identifying meaningful differences in vasomotor symptoms among menopausal women

First, to identify treatment satisfaction thresholds for interpreting treatment-related changes in vasomotor symptoms, and, second, to determine the doses of desvenlafaxine (DVS) (administered as desvenlafaxine succinate) that effectively provide relief of vasomotor symptoms considered important by menopausal women. Efficacy and treatment satisfaction were assessed in 620 postmenopausal women with moderate to severe vasomotor symptoms participating in a double-blind, placebo-controlled trial and randomly assigned to placebo or 50, 100, 150, or 200 mg DVS. Number and severity of hot flushes and number of nighttime awakenings were recorded in daily diaries for 12 weeks of treatment. At week 12, responses to the Menopause Symptoms Treatment Satisfaction Questionnaire were compared with efficacy results. Greater percentages of participants in the DVS groups reported being "satisfied" or "extremely satisfied" with daytime and nighttime control of hot flushes compared with placebo. The treatment satisfaction threshold, defined as the difference between the average reduction in vasomotor symptoms for women who were "neutral" versus "satisfied," was 1.64 for moderate to severe hot flushes and 0.42 for nighttime awakenings. Statistically significant reductions with 100, 150, and 200 mg DVS exceeded treatment satisfaction threshold results for at least one of these thresholds, and results with 100 mg DVS compared with placebo exceeded both treatment satisfaction thresholds. Among menopausal women with moderate to severe vasomotor symptoms, the treatment satisfaction thresholds that were meaningful to participants were 1.64 fewer moderate to severe hot flushes per day and 0.42 fewer nighttime awakenings per night. A dose of 100 mg DVS met both of these important vasomotor symptom change thresholds.

Efficacy, safety, and tolerability of desvenlafaxine 50 mg/day and 100 mg/day in outpatients with major depressive disorder

ABSTRACTObjective: To assess the efficacy, safety, and tolerability of 50- and 100-mg/day doses of desvenlafaxine (administered as desvenlafaxine succinate), a serotonin-norepinephrine reuptake inhibitor, for the treatment of major depressive disorder (MDD).Research design and methods: Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) MDD and 17-item Hamilton Rating Scale for Depression (HAM-D17) scores ≥20 were randomly assigned to double-blind placebo or desvenlafaxine treatment (fixed dose of 50 mg/day or 100 mg/day) for 8 weeks. The primary efficacy measure was the HAM-D17. Changes from baseline in HAM-D17 scores were analyzed using analysis of covariance. The final on-therapy evaluation was the primary endpoint for efficacy analyses, using last-observation-carried-forward data.Main outcomes measures and results: The intent-to-treat population included 447 patients. Desvenlafaxine 50 mg was associated with a significantly greater adjusted mean change from baseline on the HAM-D17 (−11.5) compared with placebo (−9.5, p = 0.018); the 100-mg dose group (−11.0) did not achieve statistical significance (p = 0.065). The 100-mg dose group experienced significant improvements compared with placebo on several secondary efficacy measures, including the 6-item Hamilton Depression Rating Scale (p = 0.038) and the Visual Analog Scale–Pain Intensity total score (p = 0.041). Both desvenlafaxine doses were generally well-tolerated. The most common adverse events (incidence ≥10% in either desvenlafaxine group and twice the rate of placebo) were dry mouth, constipation, insomnia, decreased appetite, hyperhidrosis, and dizziness.Conclusions: These results demonstrate efficacy, safety, and tolerability of desvenlafaxine 50 mg/day for treating MDD. The significant findings on secondary measures support the efficacy of desvenlafaxine 100 mg, as seen in other trials. Conclusions may be limited by the exclusion of MDD patients with comorbid conditions and the short-term desvenlafaxine treatment duration.