desvenlafaxine-succinate and Depressive-Disorder--Major

A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to treat adults with major depressive disorder (MDD) in the maintenance phase. This study searched the PubMed, Cochrane Library, and Embase databases and included only double-blind, randomized, placebo-controlled trials with an enrichment design: patients were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or placebo. The outcomes were the 6-month relapse rate (primary outcome, efficacy), all-cause discontinuation (acceptability), discontinuation due to adverse events (tolerability), and the incidence of individual adverse events. The risk ratio with a 95% credible interval was calculated. The meta-analysis comprised 34 studies (n = 9384, mean age = 43.80 years, and %females = 68.10%) on 20 antidepressants (agomelatine, amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, vilazodone, and vortioxetine) and a placebo. In terms of the 6-month relapse rate, amitriptyline, citalopram, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, and vortioxetine outperformed placebo. Compared to placebo, desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had lower all-cause discontinuation; however, sertraline had a higher discontinuation rate due to adverse events. Compared to placebo, venlafaxine was associated with a lower incidence of dizziness, while desvenlafaxine, sertraline, and vortioxetine were associated with a higher incidence of nausea/vomiting. In conclusion, desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had reasonable efficacy, acceptability, and tolerability in the treatment of adults with stable MDD.

Topics: Adult; Amitriptyline; Antidepressive Agents; Citalopram; Depressive Disorder, Major; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Female; Fluoxetine; Fluvoxamine; Humans; Mirtazapine; Network Meta-Analysis; Paroxetine; Randomized Controlled Trials as Topic; Reboxetine; Sertraline; Venlafaxine Hydrochloride; Vortioxetine

Topics: Adolescent; Adult; Antidepressive Agents; Child; Cyclohexanols; Depression; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Drug Interactions; Female; Humans

Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and physical and mental health and well-being. There is an association between major depressive disorder and suicidal ideation, suicide attempts, and suicide. Antidepressant medication is used in moderate to severe depression; there is now a range of newer generations of these medications.. To investigate, via network meta-analysis (NMA), the comparative effectiveness and safety of different newer generation antidepressants in children and adolescents with a diagnosed major depressive disorder (MDD) in terms of depression, functioning, suicide-related outcomes and other adverse outcomes. The impact of age, treatment duration, baseline severity, and pharmaceutical industry funding was investigated on clinician-rated depression (CDRS-R) and suicide-related outcomes.. We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (CDSR)), together with Ovid Embase, MEDLINE and PsycINFO till March 2020.. Randomised trials of six to 18 year olds of either sex and any ethnicity with clinically diagnosed major depressive disorder were included. Trials that compared the effectiveness of newer generation antidepressants with each other or with a placebo were included. Newer generation antidepressants included: selective serotonin reuptake inhibitors; selective norepinephrine reuptake inhibitors (SNRIs); norepinephrine reuptake inhibitors; norepinephrine dopamine reuptake inhibitors; norepinephrine dopamine disinhibitors (NDDIs); and tetracyclic antidepressants (TeCAs).. Two reviewers independently screened titles/abstracts and full texts, extracted data, and assessed risk of bias. We analysed dichotomous data as Odds Ratios (ORs), and continuous data as Mean Difference (MD) for the following outcomes: depression symptom severity (clinician rated), response or remission of depression symptoms, depression symptom severity (self-rated), functioning, suicide related outcomes and overall adverse outcomes. Random-effects network meta-analyses were conducted in a frequentist framework using multivariate meta-analysis. Certainty of evidence was assessed using Confidence in Network Meta-analysis (CINeMA). We used "informative statements" to standardise the interpretation and description of the results.. Twenty-six studies were included. There were no data for the two primary outcomes (depressive disorder established via clinical diagnostic interview and suicide), therefore, the results comprise only secondary outcomes. Most antidepressants may be associated with a "small and unimportant" reduction in depression symptoms on the CDRS-R scale (range 17 to 113) compared with placebo (high certainty evidence: paroxetine: MD -1.43, 95% CI -3.90, 1.04; vilazodone: MD -0.84, 95% CI -3.03, 1.35; desvenlafaxine MD -0.07, 95% CI -3.51, 3.36; moderate certainty evidence: sertraline: MD -3.51, 95% CI -6.99, -0.04; fluoxetine: MD -2.84, 95% CI -4.12, -1.56; escitalopram: MD -2.62, 95% CI -5.29, 0.04; low certainty evidence: duloxetine: MD -2.70, 95% CI -5.03, -0.37; vortioxetine: MD 0.60, 95% CI -2.52, 3.72; very low certainty evidence for comparisons between other antidepressants and placebo). There were "small and unimportant" differences between most antidepressants in reduction of depression symptoms (high- or moderate-certainty evidence). Results were similar across other outcomes of benefit. In most studies risk of self-harm or suicide was an exclusion criterion for the study. Proportions of suicide-related outcomes were low for most included studies and 95% confidence intervals were wide for all comparisons. The evidence is very uncertain about the effects of mirtazapine (OR 0.50, 95% CI 0.03, 8.04), duloxetine (OR 1.15, 95% CI 0.72, 1.82), vilazodone (OR 1.01, 95% CI 0.68, 1.48), desvenlafaxine (OR 0.94, 95% CI 0.59, 1.52), citalopram (OR 1.72, 95% CI 0.76, 3.87) or vortioxetine (OR 1.58, 95% CI 0.29, 8.60) on suicide-related outcomes compared with placebo. There is low certainty evidence that escitalopram may "at least slightly" reduce odds of suicide-related outcomes compared with placebo (OR 0.89, 95% CI 0.43, 1.84). There is low certainty evidence that fluoxetine (OR 1.27, 95% CI 0.87, 1.86), paroxetine (OR 1.81, 95% CI 0.85, 3.86), sertraline (OR 3.03, 95% CI 0.60, 15.22), and venlafaxine (OR 13.84, 95% CI 1.79, 106.90) may "at least slightly" increase odds of suicide-related outcomes compared with placebo. There is moderate certainty evidence that venlafaxine probably results in an "at least slightly" increased odds of suicide-related outcomes compared with desvenlafaxine (OR 0.07, 95% CI 0.01, 0.56) and escitalopram (OR 0.06, 95% CI 0.01, 0.56). There was very low certainty evidence regarding other comparisons between antidepressants.. Overall, methodological shortcomings of the randomised trials make it difficult to interpret the findings with regard to the efficacy and safety of newer antidepressant medications. Findings suggest that most newer antidepressants may reduce depression symptoms in a small and unimportant way compared with placebo. Furthermore, there are likely to be small and unimportant differences in the reduction of depression symptoms between the majority of antidepressants. However, our findings reflect the average effects of the antidepressants, and given depression is a heterogeneous condition, some individuals may experience a greater response. Guideline developers and others making recommendations might therefore consider whether a recommendation for the use of newer generation antidepressants is warranted for some individuals in some circumstances. Our findings suggest sertraline, escitalopram, duloxetine, as well as fluoxetine (which is currently the only treatment recommended for first-line prescribing) could be considered as a first option. Children and adolescents considered at risk of suicide were frequently excluded from trials, so that we cannot be confident about the effects of these medications for these individuals. If an antidepressant is being considered for an individual, this should be done in consultation with the child/adolescent and their family/caregivers and it remains critical to ensure close monitoring of treatment effects and suicide-related outcomes (combined suicidal ideation and suicide attempt) in those treated with newer generation antidepressants, given findings that some of these medications may be associated with greater odds of these events. Consideration of psychotherapy, particularly cognitive behavioural therapy, as per guideline recommendations, remains important.

Topics: Adolescent; Antidepressive Agents; Bias; Child; Citalopram; Depressive Disorder, Major; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Female; Fluoxetine; Humans; Male; Mirtazapine; Network Meta-Analysis; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Suicidal Ideation; Venlafaxine Hydrochloride; Vilazodone Hydrochloride; Vortioxetine

Major depressive disorder is characterized by the presence of at least five of nine specific symptoms that contribute to clinically significant functional impairment. This analysis examined the effect of desvenlafaxine (50 or 100 mg) versus placebo on symptom cluster scores and the association between early improvement in symptom clusters and symptomatic or functional remission at week 8.. Using data from nine double-blind, placebo-controlled studies of desvenlafaxine for the treatment of major depressive disorder (. Desvenlafaxine 50 or 100 mg was associated with significant improvement from baseline compared to placebo for all symptom clusters (. Early improvement in symptom clusters significantly predicts symptomatic or functional remission at week 8 in patients with depression receiving desvenlafaxine (50 or 100 mg) or placebo. Importantly, patients without early improvement were less likely to remit.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Remission Induction; Young Adult

This post hoc analysis examined the time point at which clinically significant improvement in major depressive disorder (MDD) symptoms occurs with desvenlafaxine versus placebo.. Data were pooled from 9 short-term, double-blind, placebo-controlled studies in adults with MDD randomly assigned to desvenlafaxine 50 mg/d, 100 mg/d, or placebo. A mixed-effects model for repeated-measures analysis of change from baseline score was used to determine the time point at which desvenlafaxine treatment groups separated from placebo on the 17-item Hamilton Rating Scale for Depression and psychosocial outcomes. The association between early improvement and week 8 outcomes was examined using logistic regression analyses. Time to remission for patients with early improvement versus without early improvement was assessed using Kaplan-Meier techniques. Comparisons between groups were performed with log-rank tests.. In the intent-to-treat population (N = 4279 patients: desvenlafaxine 50 mg/d, n = 1714; desvenlafaxine 100 mg/d, n = 870; placebo, n = 1695), a statistically significant improvement on the 17-item Hamilton Rating Scale for Depression was observed with desvenlafaxine 50 mg/d at week 1 (P = 0.0129) and with desvenlafaxine 100 mg/d at week 2 (P = 0.0002) versus placebo. Early improvement was a significant predictor of later remission. Treatment assignment, baseline depression scale scores, and race were significantly associated with probability of early improvement. On several measures of depressive symptoms and function, desvenlafaxine 50 mg/d and 100 mg/d separated from placebo as early as week 1 and no later than week 4 in patients with MDD.. These findings suggest that clinicians may be able to use depression rating scale scores early in treatment as a guide to inform treatment optimization.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Young Adult

This post hoc meta-analysis evaluated the efficacy and safety of desvenlafaxine 50 and 100 mg versus placebo across age groups and severity of depression at baseline in patients with major depressive disorder.. Data from placebo and desvenlafaxine 50-mg and 100-mg dose arms were pooled from 9 short-term, placebo-controlled, major depressive disorder studies (N = 4279). Effects of age (18-40 years, >40 to <55 years, 55-<65 years, and ≥65 years) and baseline depression severity (mild, 17-item Hamilton Rating Scale for Depression total score [HAM-D17] ≤18; moderate, HAM-D17 >18 to <25; severe, HAM-D17 ≥25) on desvenlafaxine efficacy were assessed using analysis of covariance for continuous end points and logistic regression for categorical end points.. Desvenlafaxine-treated (50 or 100 mg/d) patients had significantly (P < 0.05, 2-sided) greater improvement in most measures of depression and function compared with placebo for patients 18 to 40 years, older than 40 to younger than 55 years, and 55 to younger than 65 years, with no significant evidence of an effect of age. Desvenlafaxine significantly improved most measures of depression and function in moderately and severely depressed patients. There was a significant baseline severity by treatment interaction for HAM-D17 total score only (P = 0.027), with a larger treatment effect for the severely depressed group.. Desvenlafaxine significantly improved depressive symptoms in patients younger than 65 years and in patients with moderate or severe baseline depression. Sample sizes were not adequate to assess desvenlafaxine efficacy in patients 65 years or older or with mild baseline depression.

Topics: Adolescent; Adult; Age Factors; Aged; Controlled Clinical Trials as Topic; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Serotonin and Noradrenaline Reuptake Inhibitors; Severity of Illness Index; Young Adult

The chronic course of major depressive disorder (MDD) often impedes the ability of patients to achieve full remission. Return of full functioning is a critical goal of antidepressant pharmacotherapy as the presence of residual depressive symptoms is associated with an increased risk of relapse. Treatment guidelines recommend selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or atypical antidepressants as first-line treatment for moderate to severe MDD. Desvenlafaxine, administered as desvenlafaxine succinate, is an serotonin-norepinephrine reuptake inhibitor approved for the treatment of adults with MDD at the recommended dose of 50 mg/day. The aim of this integrated analysis was to assess the efficacy and safety of desvenlafaxine 50 and 100 mg/day compared with placebo in adult outpatients with MDD. The analysis used data from nine fixed-dose, short-term, placebo-controlled studies in adult outpatients diagnosed with MDD who had depressive symptoms for at least 30 days. Data from 4279 and 4317 patients were pooled for the efficacy and safety analyses, respectively. Statistically significant improvements were observed with desvenlafaxine 50 and 100 mg/day versus placebo for all efficacy endpoints assessed, including improvements in depressive symptoms, response and remission rates, as well as functional and cognitive outcomes. Treatment with desvenlafaxine 50 and 100 mg/day was generally safe and well tolerated. The findings of this integrated analysis of data from a large population of patients with MDD confirmed the antidepressant efficacy of both desvenlafaxine doses and add to previous evidence supporting the efficacy of desvenlafaxine.

Topics: Adolescent; Adult; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Treatment Outcome; Young Adult

New generation antidepressant therapies, including serotonin-norepinephrine reuptake inhibitor (SNRIs), were introduced in the late 1980s; however, few comprehensive studies have compared the benefits and risks of various contemporary treatments for major depressive disorder (MDD) in young patients. A comprehensive literature search of PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to January 2015. Only clinical trials that randomly assigned one SNRI or placebo to patients aged 7 to 18 years who met the diagnostic criteria for major depressive disorder were included. Treatment success, dropout rate, and suicidal ideation/attempt outcomes were measured. Primary efficacy was determined by pooling the risk ratios (RRs) of treatment response and remission. Acceptability was determined by pooling the RRs of dropouts for all reasons and for adverse effects as well as suicide-risk outcomes. Five trials with a total of 973 patients were included. SNRIs were not significantly more effective than placebo for treatment response but were for remission. The comparison of patients taking SNRIs that dropped out for all reasons and those taking placebo did not reach statistical significance. Significantly more patients taking SNRIs dropped out for adverse effects than those taking placebo. No significant difference was found in suicide-related risk outcomes. SNRI therapy does not display a superior efficacy and is not better tolerated compared to placebo in these young patients. However, duloxetine has a potential beneficial effect for depression in young populations, showing a need for further research.

Topics: Adolescent; Antidepressive Agents; Child; Cyclopropanes; Depressive Disorder, Major; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Female; Humans; Male; Milnacipran; Placebos; Randomized Controlled Trials as Topic; Serotonin and Noradrenaline Reuptake Inhibitors; Treatment Outcome; Venlafaxine Hydrochloride

To evaluate the effect of the serotonin-norepinephrine re-uptake inhibitor desvenlafaxine on blood pressure and incidence of new onset hypertension in pooled short-term studies and in two longer-term, randomized withdrawal studies.. Data from patients randomly assigned to desvenlafaxine 10 mg to 400 mg/day or placebo in 11 short-term (8-12 weeks), fixed-dose, double-blind, placebo-controlled studies of major depressive disorder (MDD) were pooled for analysis; two desvenlafaxine randomized withdrawal studies (36 and 46 weeks) were analyzed separately.. www.clinicaltrials.gov , NCT00072774, NCT00073762, NCT00277823, NCT00300378, NCT00384033, NCT00798707, NCT00863798, NCT01121484, NCT00824291, NCT01432457, NCT00075257, NCT00887224.. Outcomes included change from baseline in supine systolic blood pressure (SSBP) and supine diastolic blood pressure (SDBP), assessed using a mixed model repeated measures (MMRM) analysis, and incidence of hypertension (defined as three consecutive second SDBP measures ≥90 mm Hg AND increase of ≥10 mm Hg from baseline and/or SSBP ≥140 mm Hg AND increase of ≥10 mm Hg), analyzed using Cochran Mantel Hanzael tests. Potential predictors of change in SSBP and SDBP at LOCF were examined by including predictor variables in a regression model.. In the pooled, short-term studies, mean changes from baseline over time in SSBP and SDBP were statistically significant compared with placebo for the desvenlafaxine doses of 10 mg/day or greater for SSBP (p ≤ 0.0004; MMRM) and 25 mg/day or greater for SDBP (p ≤ 0.0449; MMRM). The proportion of patients with new onset hypertension differed significantly from placebo for the 50, 200, and 400 mg/day doses (1.9%, 2.4%, 4.8%, respectively, vs 0.8%; all p ≤ 0.0244). Predictors of change in BP included baseline SDBP, baseline SSBP, dose, body mass index, gender, age, race, and history of hypertension.. Data were pooled from studies which differed somewhat in study design and patient demographics. None of the studies were originally designed to examine treatment effects on BP. Study entry criteria limit generalization of these results to medically stable patients with a primary diagnosis of MDD.. Short-term desvenlafaxine treatment was associated with small but statistically significant increases in SSBP and SDBP.

Topics: Adult; Antidepressive Agents; Blood Pressure; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome

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

Topics: Adolescent; Adrenergic Uptake Inhibitors; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Drug Administration Schedule; Female; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Remission Induction; Selective Serotonin Reuptake Inhibitors; Time Factors; Treatment Outcome; Young Adult

Major depressive disorder (MDD) is a chronic and debilitating condition often characterized by inadequate treatment. Notwithstanding the availability of more than a dozen first-line agents across disparate classes (e.g., selective serotonin reuptake inhibitors), the majority of individuals with MDD do not achieve and sustain a recovered state. A substantial percentage of MDD patients require a treatment change due to poor efficacy or tolerability.. This review focuses on recent (≤ 5 years) literature describing the pharmacokinetics, efficacy, and tolerability of desvenlafaxine , one of the more recently approved antidepressant drugs. Published papers identified via PubMed search and congress presentations were included. Results from short-term, placebo-controlled, MDD trials and randomized withdrawal trials, as well as post hoc analyses in patient subgroups, are reviewed.. Desvenlafaxine has been shown to be an effective antidepressant with a favorable safety and tolerability profile in the general MDD population and in important patient subgroups. It has several notable differences from other serotonin-norepinephrine reuptake inhibitors, and those differences suggest populations in which it may have the most clinical benefit.

Topics: Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Drug Interactions; Humans; Secondary Prevention; Selective Serotonin Reuptake Inhibitors

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

Topics: Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Randomized Controlled Trials as Topic

Vortioxetine is an antidepressant with multimodal activity which has shown efficacy in major depressive disorder (MDD) patients in six of ten short-term, randomized, placebo-controlled trials (completed end 2012).. We performed meta-regression analyses to indirectly compare vortioxetine to seven marketed antidepressants with different mechanisms of action. To ensure study comparability, only experimental drug and placebo arms from placebo-controlled registration studies were included in primary analyses. The main outcomes were efficacy (standardized mean difference in change from baseline to 2 months on primary endpoint [MADRS/HAM-D]), and tolerability (withdrawal rate due to adverse events).. For efficacy, estimates of treatment effect (negative estimates favor vortioxetine) for vortioxetine versus comparators were: agomelatine, -0.16 (p = 0.11); desvenlafaxine, 0.03 (p = 0.80); duloxetine, 0.09 (p = 0.42); escitalopram, -0.05 (p = 0.70); sertraline, -0.04 (p = 0.83); venlafaxine IR/XR, 0.12 (p = 0.33); and vilazodone, -0.25 (p = 0.11). For tolerability, all but one combination was numerically in favor of vortioxetine (odds ratio < 1), although not all differences were statistically significant: agomelatine, 1.77 (p = 0.03); desvenlafaxine, 0.58 (p = 0.04); duloxetine, 0.75 (p = 0.26); escitalopram, 0.67 (p = 0.28); sertraline, 0.30 (p = 0.01); venlafaxine, 0.47 (p = 0.01); and vilazodone, 0.64 (p = 0.18). Sensitivity analyses did not significantly alter antidepressant effect estimates or relative ranking.. These meta-regression data show that vortioxetine offers a comparable or favorable combination of efficacy (measured by MADRS/HAM-D) and tolerability (measured by withdrawal rate due to adverse events) versus other antidepressants in registration studies in MDD. Alternative methods like mixed-treatment comparison and inclusion of all randomized studies and active reference arms may provide complementary information to this analysis (more evidence but also more heterogeneity). Key messages: Indirect comparisons based on registration studies allow a useful comparison between a recently approved antidepressant and an approved drug. Vortioxetine offers a comparable or favorable combination of efficacy (measured by MADRS/HAM-D assessments) and tolerability (measured by withdrawal rate due to adverse events) versus other antidepressants in registration studies in MDD.

Topics: Acetamides; Adult; Aged; Antidepressive Agents; Benzofurans; Citalopram; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Female; Humans; Hypnotics and Sedatives; Indoles; Male; Middle Aged; Piperazines; Selective Serotonin Reuptake Inhibitors; Sertraline; Sulfides; Thiophenes; Venlafaxine Hydrochloride; Vilazodone Hydrochloride; Vortioxetine

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

Topics: Adult; Antidepressive Agents; Clinical Trials as Topic; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Disability Evaluation; Emotions; Evidence-Based Medicine; Female; Humans; Linear Models; Logistic Models; Male; Middle Aged; Predictive Value of Tests; Psychiatric Status Rating Scales; Recovery of Function; Remission Induction; Severity of Illness Index; Time Factors; Treatment Outcome

Desvenlafaxine (DESV) is a newer antidepressant, which inhibits serotonin-norepinephrine reuptake neurotransmission, similarly to venlafaxine, milnacipran and duloxetine. It was approved in February 2008 by the FDA for the treatment of major depressive disorder (MDD), based on well-controlled and adequately powered, large clinical trials demonstrating efficacy and safety for patients with MDD. Currently available data show that DESV has proven efficacy, acceptable safety and tolerability profiles, convenient once-daily dosing and minimal impact on the cytochrome P450 enzyme system in patients with MDD. This mini-review summarizes the clinical data and practical use of DESV under this approved indication.

Topics: Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

Major depressive disorder (MDD) is a common, seriously impairing illness. Desvenlafaxine (administered as desvenlafaxine succinate) is the third serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States for the treatment of MDD. Short-term clinical studies have demonstrated the efficacy and safety of 50 to 400 mg/d doses, with no evidence that doses greater than 50 mg/d confer additional benefit.. This paper summarizes published data on the efficacy, safety, and tolerability of the desvenlafaxine 50-mg/d recommended therapeutic dose for MDD and discusses clinical practice considerations.. A systematic review of MEDLINE, PsycINFO, and PubMed (all years through June 2009) was performed using the terms desvenlafaxine, DVS, and ODV. The criteria for inclusion in the review were a double-blind design, a placebo control or active comparator group, the 50-mg desvenlafaxine dose group, and enrollment of patients with a diagnosis of MDD. Posters were included if they reported on a study that was subsequently published in a manuscript.. Overall results of two randomized, placebo-controlled, 8-week clinical trials demonstrated the efficacy of desvenlafaxine 50 mg/d for MDD. Statistically significant improvements compared with placebo were observed on the primary efficacy measure (17-item Hamilton Rating Scale for Depression [HAM-D(17)] total score; P < 0.05). Significant differences were observed on several secondary measures (Montgomery Asberg Depression Rating Scale scores in both trials [P < 0.05]; Clinical Global Impressions-Improvement scores [P < or = 0.01], Clinical Global Impressions-Severity scores [P < or = 0.01], HAM-D(17) response [P < or = 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.. 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.

Topics: Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Humans; Neurotransmitter Uptake Inhibitors; Placebos; Randomized Controlled Trials as Topic; Treatment Outcome

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.

Topics: Adult; Antidepressive Agents; Anxiety; Clinical Trials, Phase III as Topic; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Middle Aged; Outpatients; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Treatment Outcome

The pharmacological treatment of older adults with major depressive disorder presents a variety of challenges, including a relative lack of high quality studies designed to measure the efficacy and safety of antidepressants specific to this patient population. Gaining a clear understanding of how to use antidepressants in elderly patients with depression, especially new and widely used agents, would provide valuable insight to clinicians. The purpose of the current article is to review the pharmacology, efficacy and safety of newer antidepressants (i.e. escitalopram, duloxetine and desvenlafaxine) in the treatment of late-life depression. To accomplish this goal, a MEDLINE and PubMed search (1966 - February 2010) was conducted for relevant articles. Animal and human studies have clearly demonstrated the effects of desvenlafaxine, duloxetine and escitalopram on monoamine reuptake transporters. The serotonergic and noradrenergic actions of desvenlafaxine and duloxetine may provide for a faster onset of antidepressant activity in the elderly, but more definitive data are needed and the clinical effects of the possible faster onset of action need to be elucidated. Duloxetine and escitalopram are extensively metabolized via cytochrome P450 (CYP) enzymes and the decreased hepatic metabolism present in many older adults should be taken into account when prescribing these medications. Duloxetine possesses the greatest likelihood of producing clinically relevant drug-drug interactions because of its inhibition of CYP2D6. All three agents must also be used cautiously in older adults with poor renal function. In terms of clinical efficacy, 14 prospective published trials involving escitalopram (n = 8) and duloxetine (n = 6) in the treatment of older adults with major depressive disorder were identified. No such studies involving desvenlafaxine were found. Of the five randomized, double-blind, controlled trials, 46% and 37% of antidepressant-treated patients were considered responders and remitters, respectively. In contrast to escitalopram, duloxetine-treated patients experienced improvements in depressive symptoms that more consistently differentiated themselves from the symptoms of placebo-treated patients. Escitalopram and duloxetine were generally well tolerated, but 5-20% and 10-27% of patients, respectively, dropped out because of medication-related adverse effects. Adverse effects experienced by older adults were generally similar to those experienced by youn

Topics: Aged; Antidepressive Agents; Citalopram; Clinical Trials as Topic; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Drug Interactions; Duloxetine Hydrochloride; Humans; Thiophenes

genetic and pharmacologically-driven variations in common mechanisms involved in the disposition of antidepressant medications may contribute to variable interpatient response. This review describes the pharmacological properties underlying the safety and efficacy of desvenlafaxine, a second-generation serotonin-norepinephrine reuptake inhibitor (SNRI).. literature published between January 2006 and September 2010 evaluating desvenlafaxine was reviewed.. Desvenlafaxine therapy is initiated at the therapeutic dose (50 mg/day) without a need for dose titration. Desvenlafaxine metabolism and distribution are not appreciably affected by altered function of cytochrome P450 (CYP) enzymes or permeability glycoprotein (P-gp). Desvenlafaxine has clinically insignificant effects on the activity of CYP and P-gp. The efficacy of desvenlafaxine in treating major depressive disorder has been established. Adverse events are characteristic of the SNRI class. Notably, the rate of discontinuation due to adverse events with the 50 mg/day recommended therapeutic dose is comparable to that seen with placebo.. incremental benefits with desvenlafaxine, derived from straight-forward dosing, a simple metabolic profile and lack of interaction with active transporter P-gp and CYP enzymes may contribute to more consistent response, good tolerability and lower incidence of drug-drug interactions with concomitant medications.

Topics: Adrenergic Uptake Inhibitors; Animals; Antidepressive Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclohexanols; Cytochrome P-450 Enzyme System; Depressive Disorder, Major; Desvenlafaxine Succinate; Drug Interactions; Humans; Selective Serotonin Reuptake Inhibitors

Desvenlafaxine (DVS) is a serotonin-norepinephrine reuptake inhibitor (SNRI) with a different pharmacokinetic and pharmacodynamic profile to venlafaxine. It was approved in February 2008 by the United States Food and Drug Administration for the treatment of major depressive disorder (MDD) based on a number of randomized, placebo-controlled clinical trials demonstrating efficacy and safety for patients with MDD. Current evidence indicates that DVS has proven efficacy, acceptable safety and tolerability profiles, convenient once-daily dosing and minimal impact on cytochrome P450 enzyme system and adverse event-prone neuroreceptors. As with all monoamine-based antidepressants, DVS has mixed efficacy results from individual studies, unestablished dosing strategies and limited long-term data, and comparative efficacy/safety with other existing antidepressants should be further investigated. Preliminary evidence also suggests the clinical usefulness of DVS in the treatment of vasomotor symptoms of menopause, anxiety symptoms and painful physical symptoms, although only MDD is the approved indication.

Topics: Animals; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Nausea; Randomized Controlled Trials as Topic

Desvenlafaxine succinate, a serotonin-norepinephrine reuptake inhibitor (SNRI), was approved by the US Food and Drug Administration (FDA) in February 2008 for the treatment of adult patients with major depressive disorder (MDD). Desvenlafaxine is the third SNRI approved by the FDA for this indication.. This article reviews the available information for desvenlafaxine, focusing on its pharmacodynamics, pharmacokinetics, clinical efficacy, and safety profile.. A comprehensive search of MEDLINE (1950-March 2009), International Pharmaceutical Abstracts (1970-March 2009), ISI Web of Knowledge (1996-March 2009), and EMBASE (1974-March 2009) was conducted using the terms desvenlafaxine, O-desmethylvenlafaxine, and Pristiq. Reference lists of articles were reviewed for other relevant publications. Abstracts of unpublished clinical studies presented at the American Psychiatric Association annual meetings (2004-2008) were included in the review; also included were data from the FDA and the European Medicines Agency Web sites.. After oral administration, desvenlafaxine reaches T(max) in 7 to 8 hours and is slowly eliminated, with t((1/2)) values of 9 to 15 hours. With once-daily dosing, steady-state plasma concentrations are achieved within 4 to 5 days. Alternate-day dosing should be implemented in patients with severe renal impairment (creatinine clearance, < or =30 mL/min) and those with end-stage renal disease. In patients with moderate to severe hepatic impairment, daily doses should not exceed 100 mg. Nine short-term studies of desvenlafaxine have been conducted but only 8 were published. These 8 clinical studies evaluated oral desvenlafaxine 50 to 400 mg/d using randomized controlled trials for the treatment of MDD in adult outpatients. Significantly greater efficacy in the reduction of depressive symptoms was found in patients taking desvenlafaxine 50 mg/d (P < 0.05) compared with placebo. No additional therapeutic benefits were found at doses >50 mg/d. Preliminary data support desvenlafaxine's efficacy and tolerability in the treatment of menopause-associated vasomotor symptoms. Desvenlafaxine was generally well tolerated in clinical trials; the most common adverse events were nausea, suicidal ideation, and changes in blood pressure and weight.. Desvenlafaxine 50 mg/d has been found to be efficacious and generally well tolerated in short-term trials for the treatment of adults with MDD. Further studies are needed to determine des-venlafaxine's role in the management of MDD and its efficacy compared with other antidepressants.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Area Under Curve; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Half-Life; Humans; Male; Middle Aged; Neurotransmitter Uptake Inhibitors; Pregnancy

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.

Topics: Adult; Antidepressive Agents; Cyclohexanols; Delayed-Action Preparations; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Health Status; Humans; Male; Placebos; Psychometrics; Randomized Controlled Trials as Topic; Surveys and Questionnaires; Treatment Outcome

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.

Topics: Adrenergic Uptake Inhibitors; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors

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.

Topics: Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Selective Serotonin Reuptake Inhibitors

To compare desvenlafaxine with its parent drug, venlafaxine, to determine the usefulness of this new medication.. Information was obtained through a MEDLINE search (1966-June 2008) and from published abstracts. Search terms included desvenlafaxine, O-desmethylvenlafaxine, Pristiq, major depressive disorder, and venlafaxine.. All English-language studies and abstracts pertaining to desvenlafaxine and venlafaxine were considered for inclusion. Preference was given to human data.. Desvenlafaxine is a serotonin-norepinephrine reuptake inhibitor and is the active metabolite of the antidepressant venlafaxine. The recommended dose is 50 mg daily, based on the efficacy and safety data of 50, 100, 150, 200, and 400 mg of desvenlafaxine. The response and remission rates of depression at 8 weeks for the 50-mg dose are 51-63% and 31-45%, respectively. These rates are comparable with those seen with venlafaxine (58% and 45%, respectively). Adverse effects are also similar to those of venlafaxine, with the most common being insomnia, somnolence, dizziness, and nausea. The decreased potential of CYP2D6 activity with desvenlafaxine compared with the parent drug may be a potential advantage in patients on other medications metabolized via this enzymatic pathway. Also, desvenlafaxine tablets are less expensive than extended-release (XR) venlafaxine, which may decrease healthcare costs in the short term. However, venlafaxine XR is expected to go off patent in 2010.. With the overall similarity between these 2 drugs and the potential lack of cost savings, the need for desvenlafaxine and its ultimate utility in treating major depressive disorder appears to be insignificant.

Topics: Antidepressive Agents; Clinical Trials as Topic; Cyclohexanols; Cytochrome P-450 CYP2D6; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Drug Costs; Drug Interactions; Humans; Remission Induction; Venlafaxine Hydrochloride

Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of venlafaxine. Desvenlafaxine succinate is now undergoing active evaluation for its therapeutic efficacy in a variety of disorders, including major depressive disorder, vasomotor symptoms associated with menopause, fibromyalgia and diabetic neuropathy. Desvenlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) with similar activity to its parent compound venlafaxine, and little affinity for other brain targets, including muscarinic, cholinergic, histamine H(1) and alpha-adrenergic receptors. Desvenlafaxine has linear pharmacokinetics, low protein binding, a half-life of approximately 10 hours and is metabolized primarily via glucuronidation, and to a minor extent through CYP3A4. The desvenlafaxine succinate formulation appears to have good oral bioavailability. Clearance rates are reduced in the elderly, those with severe renal dysfunction and those with moderate to severe hepatic dysfunction, which may require dosage adjustments. Three published clinical trials have shown supportive but mixed results for the efficacy of desvenlafaxine in the treatment of major depressive disorder with daily doses ranging from 100 mg to 400 mg. One published clinical trial has shown mixed results for the efficacy of desvenlafaxine in the treatment of vasomotor symptoms associated with menopause with daily doses ranging from 50 mg to 200 mg. In these four clinical trials, desvenlafaxine was associated with several mild adverse effects, with the most common effect being nausea. Less common, but more serious, adverse effects reported in these trials included hypertension, QTc interval prolongation, exacerbation of ischemic cardiac disease, elevated lipids and elevated liver enzymes. The exact nature of these serious adverse effects, including the prevalence, clinical significance and potential risk factors, still needs to be fully elucidated. Desvenlafaxine has a low propensity for pharmacokinetic-based drug interactions, although it has the same potential for pharmacodynamic interactions as other serotonin-norepinephrine reuptake inhibitors. Desvenlafaxine is currently another treatment option for major depressive disorder. The only identified potential advantage of desvenlafaxine over venlafaxine or other antidepressant agents at this time is the apparently reduced risk for pharmacokinetic drug interactions.

Topics: Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Selective Serotonin Reuptake Inhibitors

Topics: Adult; Antidepressive Agents; Cyclohexanols; Delayed-Action Preparations; Depressive Disorder, Major; Desvenlafaxine Succinate; Drug Administration Schedule; Humans; Neurotransmitter Uptake Inhibitors

The cytochrome P450 2D6 (CYP2D6) enzyme is responsible for metabolizing approximately 25% of pharmaceutical agents. Individuals with impaired CYP2D6 metabolism and those concomitantly receiving agents that inhibit CYP2D6 can have variations in concentrations of such medications and their metabolites.. Five studies assessing the interaction between desvenlafaxine and CYP2D6 are reviewed. Study 1 compared desvenlafaxine area under the plasma concentration-versus-time curve (AUC) in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) after administration of 100 mg of desvenlafaxine or 75 mg of venlafaxine extended release (ER). Studies 2 to 5 assessed the effect of concomitant administration of desvenlafaxine 100 mg (studies 2, 4, and 5) or 400 mg (study 3), paroxetine (20 mg, study 4), and duloxetine (30 mg twice daily; study 5) on the CYP2D6 probe desipramine.. In study 1, there was no significant difference in mean desvenlafaxine AUC between the CYP2D6 EMs and PMs (-11%; P=0.641) who were administered desvenlafaxine. However, PMs receiving venlafaxine ER had significantly higher venlafaxine and lower desvenlafaxine AUCs compared with EMs (+350% and -74%, respectively; P<0.001 for each). In studies 2, 4, and 5, the mean increases in desipramine AUC with concomitant administration of desvenlafaxine 100 mg ranged from 17% to 36%; the increase with concomitant administration of desvenlafaxine 400 mg (study 3) was 90%. Paroxetine and duloxetine produced increases in mean desipramine AUC of 419% and 122%, respectively, which were significantly greater than the increases seen with desvenlafaxine 100 mg (P<0.001 for each comparison).. Based on the findings presented here, desvenlafaxine is expected to have a low risk for variability in efficacy and safety/tolerability resulting from CYP2D6 polymorphisms or drug-drug interactions when coadministered with CYP2D6 substrates or inhibitors.

Topics: Antidepressive Agents; Antidepressive Agents, Tricyclic; Cyclohexanols; Cytochrome P-450 CYP2D6; Depressive Disorder, Major; Desipramine; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Duloxetine Hydrochloride; Health Status; Humans; Paroxetine; Thiophenes

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.

Topics: Antidepressive Agents; Clinical Trials as Topic; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans

Desvenlafaxine and duloxetine are selective serotonin and norepinephrine reuptake inhibitors. Their efficacy has not been directly compared using statistical hypotheses. This study evaluated the non-inferiority of desvenlafaxine extended-release (XL) to duloxetine in patients with major depressive disorder (MDD).. In this study, 420 adult patients with moderate-to-severe MDD were enrolled and randomly assigned (1:1) to receive 50 mg (once daily [QD]) of desvenlafaxine XL (n = 212) or 60 mg QD of duloxetine (n = 208). The primary endpoint was evaluated using a non-inferiority comparison based on the change from baseline to 8 weeks in the 17-item Hamilton Depression Rating Scale (HAMD. Least-squares mean change in HAM-D. A short-term non-inferiority study without a placebo arm.. This study demonstrated that desvenlafaxine XL 50 mg QD was non-inferior to duloxetine 60 mg QD in efficacy in patients with MDD. Desvenlafaxine had a lower incidence of TEAEs than duloxetine did.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Duloxetine Hydrochloride; Humans; Treatment Outcome

The anatomical changes that antidepressant medications induce in the brain and through which they exert their therapeutic effects remain largely unknown. We randomized 61 patients with Persistent Depressive Disorder (PDD) to receive either desvenlafaxine or placebo in a 12-week trial and acquired anatomical MRI scans in 42 of those patients at baseline before randomization and immediately at the end of the trial. We also acquired MRIs once in 39 age- and sex-matched healthy controls. We assessed whether the serotonin-norepinephrine reuptake inhibitor, desvenlafaxine, differentially changed cortical thickness during the trial compared with placebo. Patients relative to controls at baseline had thinner cortices across the brain. Although baseline thickness was not associated with symptom severity, thicker baseline cortices predicted greater reduction in symptom severity in those treated with desvenlafaxine but not placebo. We did not detect significant treatment-by-time effects on cortical thickness. These findings suggest that baseline thickness may serve as predictive biomarkers for treatment response to desvenlafaxine. The absence of treatment-by-time effects may be attributable either to use of insufficient desvenlafaxine dosing, a lack of desvenlafaxine efficacy in treating PDD, or the short trial duration.

Topics: Brain; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Humans

Desvenlafaxine succinate is a selective serotonin-norepinephrine reuptake inhibitor for the treatment of major depressive disorder. The pharmacokinetic profile of desvenlafaxine succinate at the clinically recommended dose of 50 mg in Chinese healthy subjects has been reported rarely. The objective of this study was to evaluate the pharmacokinetics and bioequivalence of desvenlafaxine succinate in Chinese healthy subjects. A single-dose, open-label, randomized, two-way crossover study with a 7-day washout period was conducted. A total of 88 individuals were incorporated to show bioequivalence of a generic and a reference drug, with 48 individuals in the fasting state and 40 receiving a high-fat diet. Finally, 46 and 38 individuals completed the fasting and the fed study, respectively. The 90% confidence intervals of the adjusted geometric mean ratios for maximum plasma concentration, area under the concentration-time curve from time zero to the last measurable concentration, and area under the concentration-time curve from time zero to infinity all fell in the bioequivalent interval of 80%-125% in both the fasting and fed states. A total of 33 adverse events were reported, and all were mild or moderate in severity. In summary, the generic and reference formulations were bioequivalent, with no observable safety differences in the fasting/fed state.

Topics: Area Under Curve; Cross-Over Studies; Depressive Disorder, Major; Desvenlafaxine Succinate; East Asian People; Fasting; Feeding Behavior; Healthy Volunteers; Humans; Selective Serotonin Reuptake Inhibitors; Therapeutic Equivalency

Network analysis (NA) conceptualizes psychiatric disorders as complex dynamic systems of mutually interacting symptoms. Major depressive disorder (MDD) is a heterogeneous clinical condition, and very few studies to date have assessed putative changes in its psychopathological network structure in response to antidepressant (AD) treatment.. In this randomized trial with adult depressed outpatients (n = 151), we estimated Gaussian graphical models among nine core MDD symptom-domains before and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Networks were examined with the measures of cross-sectional and longitudinal structure and connectivity, centrality and predictability as well as stability and accuracy.. At baseline, the most connected MDD symptom-domains were fatigue-cognitive disturbance, whereas at week 8 they were depressed mood-suicidality. Overall, the most central MDD symptom-domains at baseline and week 8 were, respectively, fatigue and depressed mood; in contrast, the most peripheral symptom-domain across both timepoints was appetite/weight disturbance. Furthermore, the psychopathological network at week 8 was significantly more interconnected than at baseline, and they were also structurally dissimilar.. Our findings highlight the utility of focusing on the dynamic interaction between depressive symptoms to better understand how the treatment with ADs unfolds over time. In addition, depressed mood, fatigue, and cognitive/psychomotor disturbance seem to be central MDD symptoms that may be viable targets for novel, focused therapeutic interventions.

Topics: Adult; Affect; Antidepressive Agents; Cognitive Dysfunction; Cross-Sectional Studies; Depressive Disorder, Major; Desvenlafaxine Succinate; Escitalopram; Fatigue; Female; Humans; Longitudinal Studies; Male; Normal Distribution; Psychopathology; Suicide

The value of early functional improvement at week 2 for predicting subsequent functional outcomes at week 8 was assessed in a pooled analysis of patients with major depressive disorder (MDD) treated with desvenlafaxine (50 or 100 mg/d) or placebo.. Data were pooled from eight double-blind, placebo-controlled studies of desvenlafaxine 50 mg/d or 100 mg/d for the treatment of MDD. Optimal week-2 improvement thresholds in Sheehan Disability Scale (SDS) score, which best predicted week-8 treatment success, were determined using receiver operating characteristic (ROC) analysis. Four definitions of treatment success were established: (1) functional response, (2) functional/depression response, (3) functional remission, and (4) functional/depression remission. Odds ratios (ORs) of early improvement for prediction (based on thresholds determined in the ROC analysis) of week-8 treatment success were computed using logistic regression models.. Functional early improvement thresholds of 17%-32% were predictive of week-8 treatment success across treatment groups and definitions of treatment success. Optimal thresholds were higher for more stringent definitions. Negative predictive value exceeded positive predictive value, indicating that failure to achieve early functional improvement was more informative about later treatment success than was the achievement of early functional improvement. Early change in SDS was a highly significant predictor of functional response/remission (ORs, 4.981-8.737; all p < 0.0001); the interaction between treatment and early functional improvement was not significant.. Early improvement in SDS total score was predictive of functional outcomes for patients treated with desvenlafaxine 50 mg, desvenlafaxine 100 mg, or placebo.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Remission Induction; Treatment Outcome

Two similarly designed extension studies evaluated the long-term safety and tolerability of desvenlafaxine for the treatment of children and adolescents with major depressive disorder (MDD). Efficacy was evaluated as a secondary objective.. Both 6-month, open-label, flexible-dose extension studies enrolled children and adolescents who had completed one of two double-blind, placebo-controlled, lead-in studies. One lead-in study included a 1-week transition period prior to the extension study. Patients received 26-week treatment with flexible-dose desvenlafaxine (20-50 mg/d). Safety assessments included comprehensive psychiatric evaluations, vital sign assessments, laboratory evaluations, 12-lead electrocardiogram, physical examination with Tanner assessment, and Columbia-Suicide Severity Rating Scale. Adverse events (AEs) were collected throughout the studies. Efficacy was assessed using the Children's Depression Rating Scale-Revised (CDRS-R).. A total of 552 patients enrolled (completion rates: 66.4 and 69.1%). AEs were reported by 79.4 and 79.1% of patients in the two studies; 8.9 and 5.2% discontinued due to AEs. Treatment-emergent suicidal ideation or behavior was reported for 16.6 and 14.1% of patients in the two studies. Mean (SD) CDRS-R total score decreased from 33.83 (11.93) and 30.92 (10.20) at the extension study baseline to 24.31 (7.48) and 24.92 (8.45), respectively, at week 26.. Desvenlafaxine 20 to 50 mg/d was generally safe and well tolerated with no new safety signals identified in children and adolescents with MDD who received up to 6 months of treatment in these studies. Patients maintained the reduction in severity of depressive symptoms observed in all treatment groups at the end of the lead-in study.

Topics: Adolescent; Antidepressive Agents; Child; Depressive Disorder, Major; Desvenlafaxine Succinate; Drug Tolerance; Female; Humans; Long Term Adverse Effects; Male; Treatment Outcome

Pharmacotherapy of non-major persistent depressive disorder (PDD) is little studied. We report a study of the serotonin-norepinephrine reuptake inhibitor (SNRI) desvenlafaxine (DVLX) for PDD.. Non-psychotic, non-bipolar outpatients aged 20-65 having PDD without concurrent major depression (MDD) were randomized double-blind to desvenlafaxine or placebo for 12 weeks. All had Hamilton Depression Rating Scale (HDRS-24) score ≥ 12. Open-label DVLX was offered for 12 weeks following the acute trial.. Seventy-one subjects having mean baseline HDRS-24 20.27 ± 4.77 were eligible, of whom post-RZ data was available for all 59 randomized. The primary 12 week analysis did not differentiate DVLX-treated subjects' mean HDRS scores from those on placebo (6.53 ± 3.98 vs. 8.24 ± 4.96, F = 3.33, df = 1, p = .07). Several secondary analyses yielded statistically significant results, including Responder, CGI and QIDS.. As the primary analysis did not reach statistical significance, this is a negative study which does not support the use of DVLX for non-major PDD. Nevertheless, statistically significant secondary analyses suggest the overall negative result could be due to sample size or sampling, suggesting further studies of this medication might be appropriate in this population.

Topics: Adult; Aged; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Middle Aged; Outpatients; Psychiatric Status Rating Scales; Serotonin and Noradrenaline Reuptake Inhibitors; Treatment Outcome; Young Adult

Thickness of the cerebral cortex has been previously investigated for its potential as a biomarker in major depressive disorder (MDD). This is the first study to examine the longitudinal effects of a serotonin-norepinephrine reuptake inhibitor, desvenlafaxine succinate (DVS), on whole-brain cortical thickness (CT) in patients treated for MDD. We also aimed to replicate a previous finding of an association between improvement in clinical severity and CT in one of five predefined regions-of-interest (ROI). Twenty-five individuals with MDD received treatment with DVS (50 mg/day) for 8 weeks, with 19 completing the study. We used FreeSurfer 6.0 to compare group differences between MDD and controls (n=23) and between treatment responders, treatment nonresponders and controls. We tested correlations between 8-week change in depression severity and regional CT in five ROIs: the rostral and caudal anterior cingulate cortex, lateral and medial orbitofrontal cortex and inferior temporal gyrus. There were no differences in CT between MDD and controls or DVS responders and controls. There was greater CT in DVS nonresponders in the left pars orbitalis when compared to controls [MNI (X, Y, Z=-38.4, 37.6, -11.1); P=0.027]. There were no significant correlations between change in depression severity and CT in any of the five ROIs. Brain CT does not seem to be a sensitive marker of short-term antidepressant response in MDD, except increased CT in nonresponders. Duration of the intervention and interindividual heterogeneity may impede identification of discriminating features of treatment response as associated to CT.

Topics: Adult; Antidepressive Agents; Cerebral Cortex; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged

To evaluate the short-term efficacy and safety of desvenlafaxine versus placebo in the treatment of children and adolescents with major depressive disorder (MDD).. Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8 weeks of treatment with placebo, low exposure desvenlafaxine (20, 30, or 35 mg/day based on baseline weight), or higher exposure desvenlafaxine (25, 35, or 50 mg/day based on baseline weight). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy assessments included Clinical Global Impressions-Severity and Clinical Global Impressions-Improvement scales. Safety assessments included adverse events and the Columbia-Suicide Severity Rating Scale.. The safety population included 363 patients (children, n = 109; adolescents, n = 254). No statistical separation from placebo was observed for either desvenlafaxine group for CDRS-R total score or for any secondary efficacy endpoint. At week 8, adjusted mean (standard error) changes from baseline in CDRS-R total score for the desvenlafaxine low exposure, desvenlafaxine high exposure, and placebo groups were -23.7 (1.1), -24.4 (1.1), and -22.9 (1.1), respectively. The incidence of adverse events was similar among groups.. Low and high exposure desvenlafaxine groups did not demonstrate efficacy for the treatment of MDD in children and adolescents in this double-blind, placebo-controlled trial. Desvenlafaxine (20-50 mg/day) was generally safe and well tolerated with no new safety signals identified in pediatric patients with MDD in this study.

Topics: Adolescent; Antidepressive Agents; Child; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Psychiatric Status Rating Scales; Treatment Outcome

To evaluate the short-term efficacy and safety of desvenlafaxine (25-50 mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD).. Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50 mg/d based on baseline weight), or fluoxetine (20 mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement (CGI-I), and response (CGI-I ≤ 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale.. The safety population included 339 patients (children, n = 130; adolescents, n = 209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, -22.6 [1.17]) or fluoxetine (-24.8 [1.17]; placebo, -23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p = 0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%).. Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25-50 mg/d was generally safe and well tolerated in children and adolescents in this study.

Topics: Adolescent; Antidepressive Agents; Child; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluoxetine; Humans; Male; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome

Desvenlafaxine exposure in Korean and US populations was compared using population pharmacokinetic (PK) analysis. Data from a single- and multiple-dose study of desvenlafaxine (50, 100, and 200 mg) in 30 healthy Korean subjects were added to a population PK model previously developed using sparse PK samples from patients with major depressive disorder, including 140 Korean patients, combined with rich PK data from healthy volunteers. The structural PK model was an open 1-compartment linear disposition model with parallel first-order and 0-order inputs. The effects of Korean status on apparent oral clearance (CL/F) and apparent volume of distribution (V/F) were tested against the base model separately. External validation results indicated good agreement between the model predictions and observed desvenlafaxine concentrations for Korean subjects. The geometric mean CL/F and V/F of Korean subjects were 9.1% and 16.7% lower, respectively, than those of US subjects, who had a 20% higher mean body weight. Results for patients with major depressive disorder were similar. There were no meaningful differences for weight-normalized CL/F and V/F values between Korean and US subjects or patients. The minor differences in CL/F and V/F observed between Korean and US populations appear to be solely due to lower body weights in the Korean population.

Topics: Adult; Body Weight; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Republic of Korea; United States; Young Adult

Depression is one of the most prevalent psychiatric disorders among opioid-dependent individuals. Clinical trials testing selective serotonin reuptake inhibitors among depressed patients on methadone maintenance therapy (MMT) failed to show efficacy, whereas those on tricyclic antidepressants produced mixed results with potential for cardiotoxicity. Desvenlafaxine (DESV) is a SNRI with minimal cardiotoxicity and drug interactions. This study sought to assess feasibility and tolerability of using DESV in depressed patients on MMT. A total of 18 depressed individuals on MMT received DESV (50-100 mg/day) for 8 weeks. Participants were assessed for the following: (a) Safety of DESV using Systematic Assessment for Treatment Emergent Events-GI, ECG [corrected Q-T (QTc) interval measurement] and methadone serum levels; (b) depressive symptoms using Montgomery-Äsberg Depression Rating Scale (MADRS); and (c) other outcomes including anxiety, suicidality, craving, substance use, quality of life, and other depression scales. Registration number on ClinicalTrials.gov is NCT02200406. Among participants who completed the study, MADRS scores significantly decreased at week 8 compared with baseline. Responders and remitters on MADRS at week 8 were 61 and 50%, respectively. There was no significant change in [corrected Q-T (QTc) interval measurement] between baseline and week 4. DESV was well tolerated and associated with improvement of depressive symptoms. DESV may be a promising contender to treat depression in individuals on MMT and deserves further exploration in a randomized double-blinded clinical trial.

Topics: Adult; Antidepressive Agents; Anxiety; Craving; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pilot Projects; Psychiatric Status Rating Scales; Quality of Life; Selective Serotonin Reuptake Inhibitors; Suicidal Ideation

Major depressive disorder is a debilitating illness, which is most commonly treated with antidepressant drugs. As the majority of patients do not respond on their first trial, there is great interest in identifying biological factors that indicate the most appropriate treatment for each patient. Studies suggest that microRNA represent excellent biomarkers to predict antidepressant response.. We investigated the expression of miR-1202, miR-135a, and miR-16 in peripheral blood from 2 cohorts of depressed patients who received 8 weeks of antidepressant therapy. Expression was quantified at baseline and after treatment, and its relationship to treatment response and depressive symptoms was assessed.. In both cohorts, responders displayed lower baseline miR-1202 levels compared with nonresponders, which increased following treatment.. Ultimately, our results support the involvement of microRNA in antidepressant response and suggest that quantification of their levels in peripheral samples represents a valid approach to informing treatment decisions.

Topics: Antidepressive Agents; Biomarkers; Citalopram; Clinical Decision-Making; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Humans; MicroRNAs; Psychiatric Status Rating Scales; ROC Curve; Treatment Outcome

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Fatigue; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Young Adult

To determine if patients with childhood onsets (CO) of both major depression and insomnia disorder show blunted depression and insomnia treatment responses to concurrent interventions for both disorders compared to those with adult onsets (AO) of both conditions.. This study was a secondary analysis of data obtained from a multisite randomized clinical trial designed to test the efficacy of combining a psychological/behavior insomnia therapy with antidepressant medication to enhance depression treatment outcomes in patients with comorbid major depression and insomnia. This study included 27 adults with CO of depression and insomnia and 77 adults with AO of both conditions. They underwent a 16-week treatment including: (1) a standardized two-step pharmacotherapy for depression algorithm, consisting of escitalopram, sertraline, and desvenlafaxine in a prescribed sequence; and (2) either cognitive behavioral insomnia therapy (CBT-I) or a quasi-desensitization control (CTRL) therapy. Main outcome measures were the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Insomnia Severity Index (ISI) completed pre-treatment and every 2 weeks thereafter.. The AO and CO groups did not differ significantly in regard to their pre-treatment HRSD-17 and ISI scores. Mixed model analyses that adjusted for the number of insomnia treatment sessions attended showed that the AO group achieved significantly lower, subclinical scores on the HRSD-17 and ISI than did the CO group by the time of study exit. Moreover, a significant group by treatment arm interaction suggested that HRSD-17 scores at study exit remained significantly higher in the CO group receiving the CTRL therapy than was the case for the participants in the CO group receiving CBT-I. Greater proportions of the AO group achieved a priori criteria for remission of insomnia (49.3% vs. 29.2%, p = 0.04) and depression (45.5% vs. 29.6%, p = 0.07) than did those in the CO group.. Patients with comorbid depression and insomnia who experienced the first onset of both disorders in childhood are less responsive to the treatments offered herein than are those with adult onsets of these comorbid disorders. Further research is needed to identify therapies that enhance the depression and insomnia treatment responses of those with childhood onsets of these two conditions.

Topics: Adult; Age of Onset; Antidepressive Agents; Citalopram; Cognitive Behavioral Therapy; Combined Modality Therapy; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Middle Aged; Sertraline; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Treatment Outcome; United States

This pooled, post hoc analysis evaluated the efficacy of desvenlafaxine vs placebo in adults with major depressive disorder (MDD) with and without metabolic syndrome, and above or at or below median baseline thyroid-stimulating hormone (TSH) levels.. Patients were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo in nine short-term, double-blind studies. Metabolic syndrome was defined as meeting at least three of five criteria based on body mass index, triglycerides, high-density lipoprotein, fasting glucose, blood pressure, current medication, and medical history.. NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457.. Treatment effects on change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D17) total score at week 8 (last observation carried forward [LOCF]) were analyzed in four subgroups-metabolic syndrome and no metabolic syndrome, baseline TSH levels above median or at or below median-using analysis of covariance with treatment, study, and baseline in the model. Metabolic syndrome and TSH were examined as predictors of change in HAM-D17 total score using regression analysis.. The pooled analysis included 4279 patients; 971 (22.7%) patients had metabolic syndrome. In all subgroups, HAM-D17 total scores improved significantly from baseline to week 8 (LOCF) with desvenlafaxine 50 or 100 mg/d compared with placebo (all p ≤ 0.006). There was no significant treatment by metabolic syndrome or by TSH interaction. Neither metabolic syndrome nor TSH above median predicted change in HAM-D17 total scores, response (≥50% reduction in HAM-D17 total score), or remission (HAM-D17 total score ≤7; all p > 0.05).. Individual studies included in this analysis were not designed to examine the relationship between metabolic syndrome or TSH and response to desvenlafaxine treatment. Metabolic syndrome status was determined post hoc based on available baseline measures and not diagnosed at study entry. Exclusion criteria were selected to enroll medically healthy patients with a primary diagnosis of MDD (i.e., patients healthier than the general MDD population).. Desvenlafaxine 50 and 100 mg/d significantly improved depression compared with placebo in patients with and without metabolic syndrome, and in patients with baseline TSH above median and at or below median levels.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Blood Pressure; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Lipoproteins, HDL; Male; Metabolic Syndrome; Middle Aged; Thyroid Hormones; Thyrotropin; Young Adult

The objective of this substudy was to examine the effect of desvenlafaxine 50 mg/day compared with placebo on cognitive function in employed outpatients with major depressive disorder. A total of 11/55 (20%) study sites in a 12-week, randomized, double-blind, placebo-controlled trial administered cognitive assessments in memory, attention, and executive functioning domains using the cognitive drug research system. Changes from baseline were subjected to analysis of covariance with baseline levels as covariates, using last observation carried forward data. A significant improvement with desvenlafaxine 50 mg/day (n=52) compared with placebo (n=29) was observed on the quality of working memory composite measure (0.081 units (0.005, 0.156); P=0.0365) at last observation carried forward. Improvement from baseline on the speed of working memory composite was significant for desvenlafaxine (-226.6 msec (-316.7, -136.4); P<0.0001) and for placebo (-133.3 msec (-257.2, -9.4); P=0.0354); however, the treatment effect was not significant. No significant differences between groups were observed on composite measures for attention. Treatment of depression with desvenlafaxine 50 mg/day may improve aspects of cognitive functioning, including working memory.Clinical Trial Registry No.: Clinicaltrials.gov identifier: NCT00824291.

Topics: Adult; Antidepressive Agents; Cognition; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Middle Aged; Outpatients

Major depressive disorder (MDD) is associated with staggering personal and economic costs, a major proportion of which stem from impaired psychosocial and occupational functioning. Few studies have examined the impact of depression-related cognitive dysfunction on work functioning. We examined the association between neurocognitive and work functioning in employed patients with MDD.. Employed adult outpatients (n=36) with MDD of at least moderate severity (≥23 on the Montgomery Asberg Depression Rating Scale, MADRS) and subjective cognitive complaints completed neurocognitive tests (CNS Vital Signs computerized battery) and validated self-reports of their work functioning (LEAPS, HPQ) before and after 8 weeks of open-label treatment with flexibly-dosed desvenlafaxine 50-100mg/day. Relationships between neurocognitive tests and functional measures were examined using bivariate correlational and multiple regression analyses, as appropriate. An ANCOVA model examined whether significant change in neurocognitive performance, defined as improvement of ≥1SD in the Neurocognition Index (NCI) from baseline to post-treatment, was associated with improved outcomes.. Patients showed significant improvements in depressive symptom, neurocognitive, and work functioning measures following treatment with desvenlafaxine (e.g., MADRS response=77% and MADRS remission=49%). There were no significant correlations between changes in NCI or cognitive domain subscales and changes in MADRS, LEAPS, or HPQ scores. However, patients demonstrating significant improvement in NCI scores (n=11, 29%) had significantly greater improvement in clinical and work functioning outcomes compared to those without NCI improvement.. The limitations of this study include small sample size, lack of a placebo control group, and lack of a healthy comparison group. Our sample also had more years of education and higher premorbid intelligence than the general population.. There were no significant correlations between changes in neurocognitive and work functioning measures in this study. However, meaningful improvement in neurocognitive functioning with desvenlafaxine was associated with greater improvement in both mood and occupational outcomes. This suggests that addressing cognitive dysfunction may improve clinical and occupational outcomes in employed patients with MDD. However, the relationship between neurocognitive and work functioning in MDD is complex and requires further study.

Topics: Adult; Antidepressive Agents; Cognition; Depressive Disorder, Major; Desvenlafaxine Succinate; Drug Administration Schedule; Employment; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Occupational Health; Psychiatric Status Rating Scales; Self Report; Treatment Outcome

To investigate the safety and pharmacokinetic profile of ascending doses of desvenlafaxine in children and adolescents with major depressive disorder. Assessment of the effect of desvenlafaxine on depression symptoms was exploratory.. The 8-week, open-label study included an initial 3.5-day inpatient period followed by a 7.5-week outpatient period. Children (7-11 years) received a single desvenlafaxine dose of 10, 25, 50, or 100 mg on day 1; adolescents (12-17 years) received desvenlafaxine 25, 50, 100, or 200 mg/day. Plasma and urine samples were collected over the initial 72-hour inpatient period. Evaluations included treatment-emergent adverse events (TEAEs), physical examinations (including Tanner Staging), vital signs, laboratory assessments, 12-lead electrocardiogram, Columbia-Suicide Severity Rating Scale, and the Children's Depression Rating Scale-Revised (CDRS-R).. In all, 29 children and 30 adolescents took at least one dose of desvenlafaxine and were included in the safety population (children: 10 mg, n = 6; 25 mg, n = 7; 50 mg, n = 9; 100 mg, n = 7; adolescents: 25 mg, n = 7; 50 mg, n = 7; 100 mg, n = 8; 200 mg, n = 8). Total area under the drug concentration-time curve from 0 to infinity (AUC) appeared to increase linearly with increasing dose. Mean (standard deviation [SD]) AUC ranged from 628 (346) ng/mL (desvenlafaxine 10 mg) to 6732 (3031) ng/mL (100 mg) in children and from 1123 (361) ng/mL (25 mg) to 11,730 (3113) ng/mL (200 mg) in adolescents. During the combined inpatient and outpatient period, 16/29 (55%) children and 21/30 (70%) adolescents reported at least one TEAE. One serious adverse event (suicidal behavior) was reported. Mean (SD) change from baseline in CDRS-R total scores at week 8 was -19.00 (9.87) for children and -21.57 (11.50) for adolescents.. Desvenlafaxine AUC values increased linearly with dose; body weight alone provided an adequate prediction for dose-normalized AUC. Desvenlafaxine was generally safe and well tolerated in children and adolescents for treatment up to 8 weeks.

Topics: Adolescent; Antidepressive Agents; Area Under Curve; Body Weight; Child; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Male; Psychiatric Status Rating Scales; Severity of Illness Index; Suicide

To assess short-term efficacy and safety of desvenlafaxine 50 and 100 mg/d versus placebo for treating major depressive disorder (MDD). Assessment of sexual function was a secondary objective.. Outpatients (≥ 18 years) who met criteria for MDD from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision and had screening and baseline 17-item Hamilton Depression Rating Scale (HDRS17) total scores ≥ 20 were randomly assigned to placebo or desvenlafaxine 50 or 100 mg/d in an 8-week study conducted from October 2011 to August 2012. The primary efficacy end point was change from baseline in HDRS17 total score at week 8, analyzed using a mixed-effects model for repeated measures. Sexual function was assessed using the Arizona Sexual Experiences Scale (ASEX).. The safety population included 909 patients (intent-to-treat population, n = 886). Significantly greater improvement in adjusted mean HDRS17 total score from baseline to week 8 was observed for desvenlafaxine 50 mg (-11.28; P = .006) and desvenlafaxine 100 mg (-11.67; P < .001) compared with placebo (-9.71), with adjustment for multiplicity. In the ASEX total score analysis (n = 422), the treatment by gender interaction was not significant; thus, genders were combined for subsequent analyses. Comparisons for desvenlafaxine versus placebo for change from baseline in ASEX total and all item scores found P > .05, with no adjustment for multiplicity. Rates of sexual dysfunction based on ASEX were comparable among treatment groups.. These results support previous findings demonstrating antidepressant efficacy, safety, and tolerability of desvenlafaxine 50 and 100 mg/d versus placebo. Sexual function was comparable between desvenlafaxine and placebo.. ClinicalTrials.gov identifier: NCT01432457.

Topics: Adult; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurotransmitter Uptake Inhibitors; Sexual Dysfunction, Physiological; Treatment Outcome

This randomized, open label, prospective, observational study compared clinical efficacy, safety alongwith plasma BDNF levels in outpatients of depression treated with fluoxetine and desvenlafaxine. Patients (aged 18-60 years) with moderate to severe major depressive disorder (MDD) diagnosed by DSM-IV criteria, and Hamilton Rating Scale for Depression (HAM-D) score ≥14, who were prescribed fluoxetine or desvenlafaxine were included (n=30 in each group). Patients were followed up for 12 weeks for evaluation of clinical efficacy, safety along with BDNF levels. In the fluoxetine group, HAM-D scores at the start of treatment was 19±4.09 which significantly (p<0.05) reduced to 9.24±3.98 at 12 weeks. In the desvenlafaxine group, HAM-D scores at the start of treatment was 18±3.75 which significantly (p<0.05) reduced to 10±3.75 at 12 weeks. The BDNF levels in the fluoxetine group were 775.32±30.38pg/ml at the start of treatment which significantly (p<0.05) increased to 850.3±24.92pg/ml at 12 weeks. The BDNF levels in the desvenlafaxine group were 760.5±28.53pg/ml at the start of treatment which significantly (p<0.05) increased to 845.8±32.82pg/ml at 12 weeks. Both the antidepressants were found to be safe and well tolerated. The efficacy and the safety profile of desvenlafaxine is comparable to fluoxetine in patients of MDD. BDNF levels were significantly increased post-treatment with both the antidepressive agents. Whether BDNF may have a prognostic value in predicting treatment response to antidepressant drugs needs to be investigated in a larger patient population.

Topics: Adult; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Depressive Disorder, Major; Desvenlafaxine Succinate; Diagnostic and Statistical Manual of Mental Disorders; Drug Monitoring; Female; Fluoxetine; Humans; Male; Middle Aged; Prognosis; Psychiatric Status Rating Scales; Treatment Outcome

This post hoc analysis assessed the efficacy of desvenlafaxine 50 mg/day for treating major depressive disorder in perimenopausal versus postmenopausal women enrolled in a 10-week, double-blind, placebo-controlled study.. Perimenopausal and postmenopausal women (40-70 y) diagnosed with major depressive disorder were randomly assigned to receive desvenlafaxine 50 mg/day or placebo. Changes from baseline in the primary efficacy variable (17-item Hamilton Rating Scale for Depression [HAM-D17] score, week 8) and in other secondary efficacy variables (Sheehan Disability Scale and Menopause Rating Scale) were analyzed using analysis of covariance with treatment, region, and baseline in the model. Clinical Global Impressions-Improvement Scale was analyzed with the Cochran-Mantel-Haenszel test. Response and remission rates were evaluated using logistic regression with treatment, region, and baseline HAM-D17 in the model.. Of 426 women (desvenlafaxine, n = 216; placebo, n = 210) included in this analysis, 135 (32%) were perimenopausal and 291 (68%) were postmenopausal at baseline. In both subgroups, improvement from baseline in HAM-D17 scores was significantly greater for desvenlafaxine 50 mg/day than for placebo. Menopause status and time since menopause did not significantly affect HAM-D17 total score. The drug-placebo difference in Sheehan Disability Scale scores was significant in perimenopausal women (-9.3 vs. -5.1, P < 0.001) but not in postmenopausal women (-8.8 vs. -8.1). Menopause Rating Scale and Clinical Global Impressions-Improvement Scale scores were significantly improved with desvenlafaxine in postmenopausal women.. Desvenlafaxine 50 mg/day is effective in treating depression in both perimenopausal and postmenopausal women. Placebo response on measures of functional impairment is lower in perimenopausal women than in postmenopausal women, resulting in a greater apparent treatment benefit with desvenlafaxine among perimenopausal women.

Topics: Administration, Oral; Adult; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Menopause; Middle Aged; Psychiatric Status Rating Scales; Treatment Outcome

We carried out a secondary analysis of a double-blind, placebo-controlled trial of desvenlafaxine for major depressive disorder (MDD) to explore the associations between depressive symptoms and subtypes, and functional outcomes, including work functioning. Employed outpatients with MDD were assigned randomly in a 2 : 1 ratio to receive desvenlafaxine 50 mg/day or placebo for 12 weeks. Analyses were carried out post-hoc with the intent-to-treat (ITT) sample (N=427) and a prospectively defined modified ITT sample (N=310), composed of patients with baseline 17-item Hamilton Rating Scale for Depression score of at least 20. Functional outcomes at week 12 included items and factors from the Montgomery-Åsberg Depression Rating Scale, Sheehan Disability Scale, and the Work Productivity and Activity Impairment questionnaire. In the modified ITT sample, but not in the ITT sample, desvenlafaxine-treated patients showed significantly greater improvement in several functional outcomes in the responder, nonanxious, and normal-energy patient subgroups. Improvement in the 17-item Hamilton Rating Scale for Depression total score at week 2 predicted change at week 12 in several functional outcomes. Functional improvement at 12 weeks was greater in subgroups of patients and was also significantly predicted by early improvement in depressive symptoms in employed patients with MDD treated with desvenlafaxine.

Topics: Adult; Aged; Antidepressive Agents; Canada; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Efficiency; Employment; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Neurotransmitter Uptake Inhibitors; Psychiatric Status Rating Scales; Self Report; Severity of Illness Index; Time Factors; United States; Young Adult

The purpose of this study was to assess long-term safety and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) in children and adolescents with major depressive disorder (MDD).. An 8 week, multicenter, open-label, fixed-dose study of children (ages 7-11 years) and adolescents (ages 12-17 years) with MDD was followed by a 6 month, flexible-dose extension study. Patients were administered desvenlafaxine 10-100 mg/day (children) or 25-200 mg/day (adolescents) for a total of 8 months. Treatment-emergent adverse events (AEs), withdrawals because of AEs, laboratory tests, vital signs, and the Columbia Suicide-Severity Rating Scale (C-SSRS) were collected. Eight month safety results from the lead-in plus extension studies are reported for extension study participants, using lead-in study day -1 as baseline.. Forty patients were enrolled in both studies (20 children; 20 adolescents). Of those, four children and three adolescents withdrew because of AEs. Treatment-emergent AEs reported by three or more patients were upper abdominal pain (15%) and headache (15%) in children, and somnolence (30%), nausea (20%), upper abdominal pain (15%), and headache (15%) in adolescents. Negativism (oppositional behavior) in a child was the single serious AE reported. No deaths occurred during the lead-in or extension studies. Mean pulse rates demonstrated statistically significant increases from lead-in study baseline to final evaluation (children, +5.2 bpm; adolescents, +5.9 bpm; p≤0.05). No statistically significant change in blood pressure was observed at final evaluation. Two adolescents (0 children) reported suicidal ideation on the C-SSRS at screening assessment and during the lead-in and/or extension trials; one adolescent reported suicidal ideation after screening only.. Long-term (8 month) treatment with desvenlafaxine was generally safe and well tolerated in depressed children and adolescents.

Topics: Adolescent; Antidepressive Agents; Child; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Female; Humans; Male; Severity of Illness Index; Suicidal Ideation; Time Factors

The objective of this study was to determine whether the occurrence of discontinuation symptoms was equivalent for abrupt discontinuation versus 1-week taper to desvenlafaxine 25 mg/d after a 24-week treatment with desvenlafaxine 50 mg/d (administered as desvenlafaxine succinate) for major depressive disorder. Adult outpatients with major depressive disorder who completed the 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to no discontinuation (desvenlafaxine 50 mg/d), taper (desvenlafaxine 25 mg/d), or abrupt discontinuation (placebo) groups for the double-blind (DB) taper phase. The primary end point was Discontinuation-Emergent Signs and Symptoms (DESS) scale total score during the first 2 weeks of the DB phase. The null hypothesis that the absolute difference of greater than 2.5 in DESS scores between taper and abrupt discontinuation groups was tested by calculating the 95% 2-sided confidence interval on the mean difference between the 2 groups. Of the 480 patients enrolled in the open-label phase, 357 (≥1 postrandomization DESS record) were included in the primary analysis. Adjusted mean ± SE DESS scores were 4.1 ± 0.72 for no discontinuation (n = 72), 4.8 ± 0.54 for taper (n = 139), and 5.3 ± 0.52 for abrupt discontinuation (n = 146) groups. The difference in adjusted mean DESS total scores between the abrupt discontinuation and taper groups was 0.50 (95% confidence interval, -0.88 to 1.89) within the prespecified margin (±2.5) for equivalence. The number of patients who discontinued because of adverse events or discontinuation symptoms during the DB period was similar between the taper (2.8%) and abrupt discontinuation (2.1%) groups. These findings indicate that an abrupt discontinuation of desvenlafaxine 50 mg/d produces statistically equivalent DESS scores compared with the 1-week taper using 25 mg/d.

Topics: Adult; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Drug Administration Schedule; Humans; Outpatients; Substance Withdrawal Syndrome

Diminished quality of life (QOL) is associated with major depressive disorder (MDD).. QOL was assessed in a post-hoc analysis of a double-blind, placebo-controlled trial. Employed adult outpatients with MDD were randomly assigned to 12 weeks of treatment with desvenlafaxine 50mg/d or placebo. Changes from baseline in the Short Form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) item scores at week 12 were analyzed using analysis of covariance with treatment, region, and baseline in the model. Correlations between change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score and Q-LES-Q scores were computed.. The intent-to-treat population included 427 patients. There were statistically significant improvements from baseline for desvenlafaxine vs placebo in 10 of 16 Q-LES-Q item scores (P values ≤0.0441). The percentage of patients with severe QOL impairment (≥2 SD below community norm) at week 12 was significantly lower for desvenlafaxine (46%) vs placebo (62%; P=0.0024; baseline: 95% and 94%, respectively). Change in Q-LES-Q total score was highly correlated with change in HAM-D17 score at week 12, LOCF (P<0.0001), and improvement in HAM-D17 total score at week 2 predicted change in Q-LES-Q total score at week 12 for the desvenlafaxine group (F=24.89; P<0.0001) but not placebo.. This analysis excluded patients who were unemployed, had severe comorbidities, and those taking multiple, concomitant medications.. Improvement in QOL and depressive symptoms was significantly greater for employed depressed patients treated with desvenlafaxine vs placebo.

Topics: Adult; Aged; Antidepressive Agents; Cyclohexanols; Depression; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Employment; Female; Humans; Male; Middle Aged; Placebos; Quality of Life; Surveys and Questionnaires; Young Adult

The effects of genetic variants in genes encoding the target structures of antidepressants on the therapeutic efficacy of antidepressant drugs have been investigated with unconclusive results. One possible confounding factor in most studies was the fact that drug serum concentrations had not been determined.. Within a clinical setting, 56 inpatients suffering from depressive episodes in the context of either major depressive disorder or bipolar affective disorder were studied. Response to venlafaxine was assessed after 4 weeks of treatment and correlated to serum concentration and functional variants in genes encoding the norepinephrine (SLC6A2; rs28386840) and the serotonin transporter (SLC6A4; [5-HTTLPR], rs25531). Symptom change was evaluated using the Clinical Global Impression-Improvement (CGI-I) scale.. No association between therapeutic response, venlafaxine serum concentration (active moiety) and rs28386840 was found. In carriers of the high expressing SLC6A4 genotype (lAlA-), a poor response to venlafaxine was found significantly more often. In subsamples stratified for serum concentration this held true for patients with serum concentrations between 201 and 400 ng/mL (n=21), while in patients with sub- (≤ 200 ng/mL; n=12) and supra-recommended (> 400 ng/mL; n=23) concentrations, no significant differences were observed.. The observed association is consistent with findings of some previous studies, whereas others showed differing results highlighting the need for further investigations.

Topics: Adolescent; Adult; Aged; Alleles; Antidepressive Agents; Bipolar Disorder; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Genotype; Humans; Male; Middle Aged; Norepinephrine Plasma Membrane Transport Proteins; Polymorphism, Genetic; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Venlafaxine Hydrochloride; Young Adult

To evaluate the long-term (11-month) efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) at the recommended 50-mg/d dose in preventing relapse in patients with major depressive disorder (MDD).. Adult outpatients (age ≥ 18 years) with MDD (DSM-IV criteria) and a 17-item Hamilton Depression Rating Scale (HDRS17) total score ≥ 20 at screening and baseline were enrolled in a multicenter, double-blind, placebo-controlled, randomized withdrawal trial conducted between June 2009 and March 2011. Patients who responded to 8-week open-label treatment with desvenlafaxine 50 mg/d with continuing stable response through week 20 were randomly assigned to receive placebo or desvenlafaxine 50 mg/d in a 6-month, double-blind, randomized withdrawal period. The primary efficacy endpoint was time to relapse following randomization to double-blind treatment, which was compared between groups using the log-rank test. Relapse was defined as HDRS17 total score ≥ 16, discontinuation for unsatisfactory response, hospitalization for depression, suicide attempt, or suicide. Safety and tolerability data were collected throughout the trial.. A total of 874 patients were enrolled; 548 patients were randomly assigned to receive placebo (n = 276) or desvenlafaxine 50 mg/d (n = 272) in the double-blind withdrawal period. Time to relapse was significantly shorter for placebo versus desvenlafaxine (P < .001). At the end of the 6-month double-blind treatment, the estimated probability of relapse was 30.2% for placebo versus 14.3% for desvenlafaxine 50 mg/d. Safety and tolerability results were generally consistent with those in short-term studies of desvenlafaxine 50 mg/d.. Desvenlafaxine at the recommended dose of 50 mg/d was effective in relapse prevention of depression during a 6-month period in patients who demonstrated stable response after 20 weeks of open-label desvenlafaxine treatment.. ClinicalTrials.gov identifier: NCT00887224.

Topics: Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Secondary Prevention; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

In an effort to establish the lowest effective dose of desvenlafaxine (administered as desvenlafaxine succinate), we assessed the efficacy, safety, and tolerability of 10- and 50-mg/day desvenlafaxine vs placebo for the treatment of major depressive disorder.. Adult outpatients with DSM-IV-defined major depressive disorder and a 17-item Hamilton Rating Scale for Depression (HAM-D(17)) total score ≥20 were randomly assigned to receive placebo or desvenlafaxine (10 or 50 mg/day) after a 6- to 14-day single-blind placebo lead-in period in an 8-week, phase 3, fixed-dose trial. The primary efficacy measure was change from baseline in the HAM-D(17) score analyzed using analysis of covariance. Efficacy analyses were conducted with the intent-to-treat population, using the last observation carried forward.. The intent-to-treat population included 673 patients. Change from baseline to final evaluation in adjusted HAM-D(17) total scores was not significantly different comparing desvenlafaxine 10 mg/day (-9.28) and desvenlafaxine 50 mg/day (-8.92) with placebo (-8.42). There were no differences among treatment groups in the rates of treatment response or remission. Discontinuations due to adverse events occurred in 1.8%, 0.9%, and 1.8% of patients in the placebo and desvenlafaxine 10- and 50-mg/day groups, respectively. Overall rates of treatment-emergent adverse events with both doses were similar to placebo.. Both doses of desvenlafaxine failed to separate from placebo. However, in a companion study reported separately, desvenlafaxine 50 mg, but not 25 mg, separated from placebo. Taken together, these studies suggest that 50 mg is the minimum effective dose of desvenlafaxine for the treatment of major depressive disorder. CLINICALTRIALS.GOV IDENTIFIER: NCT00863798 http://clinicaltrials.gov/ct2/show/NCT00863798?term=00863798&rank=1.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Treatment Outcome

The objective of this study was to evaluate the long-term safety of desvenlafaxine for continuation treatment of major depressive disorder (MDD) in Japanese patients. This was a phase 3, multicenter, 10-month, open-label study with flexible dosing of desvenlafaxine (25, 50, 100 mg/day). Japanese patients with MDD who had completed an 8-week, double-blind, placebo-controlled study in which patients received 25 or 50 mg/day desvenlafaxine or placebo were enrolled. In this study, patients received desvenlafaxine 25 mg/day from days 1 to 14, with subsequent upward titration, to a maximum of 100 mg/day, determined by clinical response. Of 304 patients, 75 (24.7%) discontinued during the on-therapy period; patient request was the most common reason (11.5%). Treatment-emergent adverse events were reported by 240 patients (78.9%) during the on-therapy period; the most common adverse events were nasopharyngitis (37.2%), somnolence (11.5%), headache (10.5%), and nausea (10.2%). For the ITT-LOCF population, the mean change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D₁₇) total score was -4.76 (95% confidence interval: -5.47 to -4.05); continued numerical improvements in the HAM-D₁₇ total scores and other depression outcome measures were observed irrespective of treatment in the previous study. Long-term use of desvenlafaxine was safe and well tolerated, with a clinical benefit/risk profile similar to that in other populations.

Topics: Adult; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Diagnostic and Statistical Manual of Mental Disorders; Disorders of Excessive Somnolence; Drug Monitoring; Female; Headache; Humans; Incidence; Intention to Treat Analysis; Japan; Male; Middle Aged; Nasopharyngitis; Nausea; Neurotransmitter Uptake Inhibitors; Psychiatric Status Rating Scales

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

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Middle Aged; Placebo Effect; Severity of Illness Index; Young Adult

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.

Topics: Adult; Aged; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Female; Humans; Menopause; Middle Aged; Psychiatric Status Rating Scales; Treatment Outcome

The symptoms of major depressive disorder (MDD) include sexual dysfunction, but antidepressant pharmacotherapies are also associated with treatment-emergent sexual dysfunction.. These secondary and post hoc analyses evaluated sexual functioning in employed adult outpatients with MDD treated with desvenlafaxine (administered as desvenlafaxine succinate) and placebo.. Patients were randomly assigned (2:1 ratio) to 12 weeks of double-blind treatment with desvenlafaxine 50 mg/day or placebo.. 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.. 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.. 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.

Topics: Adult; Analysis of Variance; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Prospective Studies; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Surveys and Questionnaires

This study evaluated the efficacy and safety of low-dose desvenlafaxine (administered as desvenlafaxine succinate) in treating major depressive disorder (MDD).. Adult outpatients (aged 18 years) in the United States and (aged 20 years) in Japan, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for MDD and had a 17-item Hamilton Depression Rating Scale (HAM-D17) score 20, were ran-domly assigned to placebo, low-dose desvenlafaxine (25▒mg/day), or the recommended dose (50▒mg/day) after a 6to 14-day placebo lead-in, in an 8-week, fixed-dose trial. The primary efficacy variable was change from baseline in HAMD17 total score at final on-therapy evaluation. Efficacy analyses were based on the intent-totreat (ITT) population, using the last observation carried forward.. The ITT population included 699 patients. Reduction in HAM-D17 scores from baseline to final evaluation was not significantly greater for desvenlafaxine 25▒mg/day (-8.98) but was significantly greater for desvenlafaxine 50▒mg/day (-10.02; P = 0.016) versus placebo (-8.52) after adjusting for multiplicity. P-values were < 0.05 versus placebo for percentage of patients responding to treatment ( 50% decrease in HAM-D17 score) with desven-lafaxine 50▒mg/day (46%; P = 0.015), but not with desvenlafaxine 25▒mg/day (42% versus 35% with placebo). P-values for remission rates (HAM-D17 score ≤ 7) were not < 0.05 versus placebo for either desvenlafaxine treatment group. Discontinuations due to adverse events were observed in 2.6%, 3.4%, and 3.4% of patients treated with placebo, desvenlafaxine 25▒mg/day, and desvenlafaxine 50▒mg/day, respectively.. Consistent with other clinical studies, desvenlafaxine 50▒mg/day demonstrated antidepressant efficacy and appears to be the minimally effective dosage for MDD. ClinicalTrials study identifier NCT00798707.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Treatment Outcome; Young Adult

Pindolol has been widely investigated as an augmenter of antidepressant drug response. Results have been inconsistent. In this study, we used pindolol together with venlafaxine because of its ability to achieve a rapid onset of serotonin transporter blockade.. The object of this study was thus to investigate if pindolol augments the antidepressant response to venlafaxine.. Patients with major depression were randomized to either active or placebo pindolol 20 mg retard daily dosage and concomitantly treated with venlafaxine for 19 days. Depression severity was evaluated at four visits. Plasma concentrations of venlafaxine and its major metabolites O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) and pindolol were analysed. The ratio of ODV/venlafaxine was calculated. A low ratio corresponds to patients being poor metabolizers and a high ratio corresponds to patients being extensive metabolizers.. No statistically significant difference in depression outcome was found between treatment groups. A statistically significant effect was, however, found of the ratio of ODV/venlafaxine on depression outcome, showing an augmenting effect of pindolol in patients with a low ratio, and the reverse in patients with a high ratio.. The differential effect of pindolol, on depression outcome, in patients with varying degrees of venlafaxine metabolism into ODV, corresponds to patients being poor or extensive metabolizers of venlafaxine. From this finding, we conclude that only patients who are poor metabolizers of venlafaxine might benefit from pindolol augmentation. This mechanism might explain some of the variability of outcome in pindolol augmentation studies.

Topics: Adult; Aged; Cyclohexanols; Depressive Disorder; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Pindolol; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Severity of Illness Index; Treatment Outcome; Venlafaxine Hydrochloride

This study investigated the safety and efficacy of long-term treatment with high-dose desvenlafaxine (administered as desvenlafaxine succinate) in major depressive disorder (MDD).. In this multicenter, open-label study, adult outpatients with MDD aged 18-75 were treated with flexible doses of desvenlafaxine (200-400 mg/d) for ≤ 1 year. Safety assessments included monitoring of treatment-emergent adverse events (TEAEs), patient discontinuations due to adverse events, electrocardiograms, vital signs, and laboratory determinations. The primary efficacy measure was mean change from baseline in the 17-item Hamilton Rating Scale for Depression [HAM-D(17)] total score.. The mean daily desvenlafaxine dose range over the duration of the trial was 267-356 mg (after titration). The most frequent TEAEs in the safety population (n = 104) were nausea (52%) and headache (41%), dizziness (31%), insomnia (29%), and dry mouth (27%). All TEAEs were mild or moderate in severity. Thirty-four (33%) patients discontinued from the study because of TEAEs; nausea (12%) and dizziness (9%) were the most frequently cited reasons. The mean change in HAM-D(17) total score for the intent-to-treat population (n = 99) was -9.9 at the last on-therapy visit in the last-observation-carried-forward analysis and -14.0 at month 12 in the observed cases analysis. Conclusion High-dose desvenlafaxine (200-400 mg/d) was generally safe and effective in the long-term treatment of MDD.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Longitudinal Studies; Male; Middle Aged; Outpatients; Psychiatric Status Rating Scales; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult

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.

Topics: Adult; Antidepressive Agents; Citalopram; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Drug Resistance; Female; Humans; Middle Aged; Postmenopause; Psychiatric Status Rating Scales; Treatment Outcome

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

Topics: Adolescent; Adult; Aged; Algorithms; Cyclohexanols; Delayed-Action Preparations; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Drug Resistance; Drug Substitution; Female; Humans; Male; Middle Aged; Placebos; Treatment Outcome; Venlafaxine Hydrochloride; Young Adult

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.

Topics: Adult; Analysis of Variance; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Employment; Female; Follow-Up Studies; Humans; Male; Middle Aged; Outpatients; Prospective Studies; Psychiatric Status Rating Scales; Treatment Outcome

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= 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.

Topics: Adult; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Psychiatric Status Rating Scales; Secondary Prevention; Treatment Outcome

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.

Topics: Adult; Aged; Blood Pressure; Citalopram; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Liver Function Tests; Middle Aged; Neurotransmitter Uptake Inhibitors; Postmenopause; Selective Serotonin Reuptake Inhibitors; Sleep; Weight Gain

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.

Topics: Adult; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Menopause; Middle Aged; Postmenopause; Psychiatric Status Rating Scales; Treatment Outcome

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.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Nausea; Outpatients; Placebos; Treatment Outcome; Young Adult

Major depressive disorder (MDD) is a common, chronic illness associated with substantial disability and economic burden. Although a number of effective antidepressants are available, the need for new medications that are effective and well tolerated remains.. The aim of this study was to compare the efficacy and tolerability of fixed-dose desvenlafaxine 50 and 100 mg/d with placebo for MDD. A post hoc pooled analysis was conducted to evaluate this study in the context of all similarly designed, completed studies with the 2 doses.. This was an 8-week, Phase III, randomized, double-blind, duloxetine-referenced, placebo-controlled, parallel-group trial conducted in 21 centers across the United States. Duloxetine was included for assay sensitivity as a positive control; the study was not designed or powered to compare desvenlafaxine with duloxetine. Participants were outpatients aged > or =18 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined MDD and a 17-item Hamilton Rating Scale for Depression (HAM-D(17)) score > or =20. Patients were randomly assigned at baseline to fixed-dose desvenlafaxine (50 or 100 mg/d), fixed-dose duloxetine (60 mg/d), or placebo. The primary outcome measure was HAM-D(17) total score at the final evaluation. Additional measures included the Clinical Global Impressions-Improvement (CGI-I) score, Montgomery Asberg Depression Rating Scale (MADRS) score, Clinical Global Impressions-Severity (CGI-S) score, and 6-item Hamilton Rating Scale for Depression, Bech version (HAM-D(6)). Tolerability assessments included discontinuation rates, adverse events (AEs), vital signs, and laboratory tests. The post hoc pooled analysis was performed using data from the current study and 2 previously published, positive studies that compared the efficacy and tolerability of desvenlafaxine 50 and 100 mg/d with placebo for MDD. The design and methodologies of the 2 studies were similar to the methodology of the current trial, other than not including a reference compound.. Of the 925 patients who were screened, 287 did not meet entry criteria, and 638 patients enrolled in the study; the intent-to-treat (ITT) population included 615 patients who were evaluated for efficacy (mean [SD] age range, 38.8-40.7 [12.1-13.2] years; mean weight range, 83.3-87.0 [22.8-23.9] kg; female sex, 398 [64.7%]; white race, 458 [74.5%]). The primary end point did not reach significance based on the global F test for controlling multiplicity of the desvenlafaxine doses. Based on pairwise comparison, significantly greater improvements on the HAM-D(17) were observed in the desven-lafaxine 100 mg/d (-10.5; P = 0.028, unadjusted for multiple comparisons) and duloxetine 60 mg/d groups (-10.3; P = 0.047) compared with placebo (-8.7). Desvenlafaxine 100 mg/d and duloxetine 60 mg/d were associated with significantly better scores compared with placebo on the CGI-I, MADRS, CGI-S, and HAM-D(6). No significant differences were observed in any scale between the desvenlafaxine 50 mg/d and placebo groups. Discontinuation rates due to AEs were 5%, 7%, 13%, and 6% for the desvenlafaxine 50-mg/d, desvenlafaxine 100-mg/d, duloxetine 60-mg/d, and placebo groups, respectively. The ITT population from all 3 studies in the pooled analysis consisted of 1388 patients (mean [SD] age range, 38.8-45.7 [12.1-12.6] years; mean weight range, 73.1-87.0 [17.6-23.9] kg; female sex, 896 [64.6%]; white race, 1136 [81.8%]). Significantly greater improvements on the HAM-D(17) were observed for desvenlafaxine 50 mg/d (-11.5; P < 0.001) and 100 mg/d (-11.8; P < 0.001) versus placebo (-9.6). Both doses were significantly better than placebo on the CGI-I, MADRS, and HAM-D(6).. The current study failed to meet its primary efficacy end point based on the a priori analysis plan. Desvenlafaxine was generally well tolerated. A post hoc pooled analysis of this trial and 2 previously published trials with both desvenlafaxine 50 and 100 mg/d found both doses to be effective for MDD compared with placebo. ClinicalTrials.gov Identifier: 00384033.

Topics: Adult; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Neurotransmitter Uptake Inhibitors; Placebos

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).. Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) MDD and 17-item Hamilton Rating Scale for Depression (HAM-D(17)) scores > or =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-D(17). Changes from baseline in HAM-D(17) 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-D(17) (-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 > or =10% in either desvenlafaxine group and twice the rate of placebo) were dry mouth, constipation, insomnia, decreased appetite, hyperhidrosis, and dizziness.. 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.

Topics: Adolescent; Adult; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Outpatients; Placebos; Treatment Outcome

This study evaluated the efficacy and safety of desvenlafaxine succinate extended-release in major depressive disorder (MDD).. Adult outpatients with DSM-IV-defined MDD were randomly assigned to desvenlafaxine 100 mg/day (N = 114), 200 mg/day (N = 116), or 400 mg/day (N = 113) or placebo (N = 118) for 8 weeks. Efficacy variables included change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D(17), the primary efficacy measure), Clinical Global Impressions-Improvement scale (CGI-I), Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions-Severity of Illness scale (CGI-S), rates of response (> or = 50% decrease from baseline HAM-D(17) score) and remission (HAM-D(17) score < or =7), and Visual Analog Scale-Pain Intensity overall score. The study was conducted from November 2003 to November 2004.. At the final on-therapy evaluation, the mean HAM-D(17) scores for desvenlafaxine 100 mg/day (12.75) and 400 mg/day (12.50) were significantly lower than for placebo (15.31; p = .0038 and p = .0023, respectively); for desvenlafaxine 200 mg/day, the mean score was 13.31 (p = .0764). CGI-I and Montgomery-Asberg Depression Rating Scale results were significant for all groups; CGI-S results were significant with 100 mg/day and 400 mg/day. Response rates were significantly greater for desven-lafaxine 100 mg/day (51%) and 400 mg/day (48%) versus placebo (35%; p = .017 and p = .046, respectively); the response rate for desvenlafaxine 200 mg/day was 45% (p = .142). Remission rates were significantly greater for desvenlafaxine 400 mg/day (32%) versus placebo (19%; p = .035); remission rates were 30% for desvenlafaxine 100 mg/day (p = .093) and 28% for desvenlafaxine 200 mg/day (p = .126). Visual Analog Scale-Pain Intensity results were significant for desvenlafaxine 100 mg/day versus placebo (p = .002), but not for the higher doses. The most commonly reported adverse events were nausea, insomnia, somnolence, dry mouth, dizziness, sweating, nervousness, anorexia, constipation, asthenia, and abnormal ejaculation/orgasm.. Desvenlafaxine is effective and well tolerated in the short-term treatment of MDD.

Topics: Adult; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Remission Induction; Treatment Outcome

The antidepressant efficacy and safety of desvenlafaxine succinate (desvenlafaxine) were evaluated in a phase III, double-blind, placebo-controlled study. Outpatients with a primary diagnosis of major depressive disorder were treated with fixed once-daily doses of desvenlafaxine 200 or 400 mg for 8 weeks. The primary efficacy measure was change from baseline on the 17-item Hamilton Rating Scale for Depression. At the final on-therapy evaluation, adjusted mean change from baseline in 17-item Hamilton Rating Scale for Depression total score was greater for desvenlafaxine 200 and 400 mg/day vs. placebo. Both desvenlafaxine doses showed greater efficacy than placebo on the secondary efficacy measures, including the Clinical Global Impressions-Improvement scale scores, Montgomery-Asberg Depression Rating Scale scores, CGI-Severity, and 17-item Hamilton Rating Scale for Depression response rate. Desvenlafaxine 200 mg/day was also significantly better than placebo on remission, Visual Analog Scale-Pain Intensity overall scores, and some Visual Analog Scale-Pain Intensity subscale scores. Desvenlafaxine 400 mg/day was significantly better than placebo on selected Visual Analog Scale-Pain Intensity subscale scores. Most adverse events were mild or moderate in severity, and safety assessments revealed few clinically significant changes in vital signs, laboratory tests, and electrocardiogram results. These data provide support for the efficacy and safety of desvenlafaxine in the treatment of major depressive disorder.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Nausea; Patient Dropouts; Psychiatric Status Rating Scales; Sex Factors; Sweating; Treatment Outcome

This study evaluated the efficacy and tolerability of desvenlafaxine succinate (desvenlafaxine) in the treatment of major depressive disorder (MDD).. In this 8-week, multicenter, randomized, double-blind, placebo-controlled trial, adult outpatients (aged 18-75 years) with a primary diagnosis of MDD (DSM-IV criteria) were randomly assigned to treatment with desvenlafaxine (100-200 mg/day) or placebo. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression (HAM-D(17)) score at final on-therapy evaluation. The Clinical Global Impressions-Improvement scale (CGI-I) was the key secondary measure. Other secondary measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Severity of Illness scale, Visual Analog Scale-Pain Intensity (VAS-PI) overall and subcomponent scores, and HAM-D(17) response and remission rates. The study was conducted from June 2003 to May 2004.. Of the 247 patients randomly assigned to treatment, 234 comprised the intent-to-treat population. Following titration, mean daily desvenlafaxine doses ranged from 179 to 195 mg/day. At endpoint, there were no significant differences in scores between the desvenlafaxine (N = 120) and placebo (N = 114) groups on the HAM-D(17) or CGI-I. However, the desvenlafaxine group had significantly greater improvement in MADRS scores (p = .047) and in VAS-PI overall pain (p = .008), back pain (p = .006), and arm, leg, or joint pain (p < .001) scores than the placebo group. The most common treatment-emergent adverse events (at least 10% and twice the rate of placebo) were nausea, dry mouth, constipation, anorexia, somnolence, and nervousness.. Desvenlafaxine was generally safe and well tolerated. In this study, it did not show significantly greater efficacy than placebo on the primary or key secondary efficacy endpoints, but it did demonstrate efficacy on an alternate depression scale and pain measure associated with MDD.. ClinicalTrials.gov identifier NCT00063206.

Topics: Adult; Ambulatory Care; Antidepressive Agents; Cholesterol, HDL; Cholesterol, LDL; Cyclohexanols; Demography; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Drug Administration Schedule; Electrocardiography; Female; Humans; Male; Remission Induction; Severity of Illness Index

The objectives of the study were to compare efficacy and tolerability of venlafaxine ER 75-150 mg/day with that of citalopram 10-20 mg/day in elderly patients with major depression according to DSM-IV criteria.. A randomised, double-blind, parallel group 6-month study. Efficacy was assessed by MADRS, CGI Global Improvement, CGI Severity of Illness and GDS-20 scores and safety by physical examinations, vital signs, adverse events and UKU side effect rating. Plasma levels of venlafaxine, its major metabolite O-desmethylvenlafaxine and citalopram were followed.. One hundred and fifty-one male and female patients (64-89 years) were enrolled and 118 patients completed the study. Comparable improvements in MADRS, CGI Severity of Illness, CGI Global Improvement and GDS-20 were observed during venlafaxine and citalopram treatment. The MADRS remission rate was 19% for venlafaxine and 23% for citalopram. Side effects were common during both treatments but differed in tremor being more common during citalopram and nausea/vomiting during venlafaxine treatment. There were no clinically significant changes in blood pressure or body weight.. The observed benefits of venlafaxine treatment in elderly patients with major depression were similar to those observed in younger adults as were reported adverse events and side effects. Treatment with venlafaxine ER was well tolerated and induced beneficial effects of similar magnitude as those of citalopram.

Topics: Aged; Aged, 80 and over; Antidepressive Agents; Antidepressive Agents, Second-Generation; Body Weight; Citalopram; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Severity of Illness Index; Venlafaxine Hydrochloride

Major depressive disorder (MDD) is a common and burdensome condition that has low rates of treatment success for each individual treatment. This means that many patients require several medication switches to achieve remission; selecting an effective antidepressant is typically a sequential trial-and-error process. Machine learning techniques may be able to learn models that can predict whether a specific patient will respond to a given treatment, before it is administered. This study uses baseline clinical data to create a machine-learned model that accurately predicts remission status for a patient after desvenlafaxine (DVS) treatment.. Our resulting classifier, a trained linear support vector machine, had a holdout set accuracy of 69.0%, significantly greater than the probability of classifying a patient correctly by chance. We demonstrate that this learning process is stable by repeatedly sampling part of the training dataset and running the learner on this sample, then evaluating the learned model on the held-out instances of the training set; these runs had an average accuracy of 67.0% ± 1.8%.. Our model, based on 26 clinical features, proved sufficient to predict DVS remission significantly better than chance. This may allow more accurate use of DVS without waiting 8 weeks to determine treatment outcome, and may serve as a first step toward changing psychiatric care by incorporating clinical assistive technologies using machine-learned models.

Topics: Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Machine Learning; Treatment Outcome

Desvenlafaxine succinate (DVS) inhibits serotonin reuptake selectively and is approved for major depressive disorders. This research investigated influence of DVS on modulating brain monoamine and oxidative stress in mice. The antiepileptic potential of DVS (10, 20, or 30 mg/kg/i.p.) in pentylenetetrazole (PTZ; 85 mg/kg) with i.p. route of administration, strychnine (STR; 75 mg/kg) with i.p. route, pilocarpine (400 mg/kg) with s.c. route and maximal electroshock MES-induced convulsion in mouse models. The activities of oxidative stress, i.e. superoxide dismutase (SOD), glutathione (GSH) and lipid peroxidation (LPO) as well as gamma-aminobutyric acid (GABA) in the brains of PTZ-induced convulsive mice. Treatment with DVS increased the latency to develop siezures and declined mortalities in rodents against PTZ, STR and pilocarpine-induced convulsions. Results of MES-leaded siezures revealed that DVS reduced tonic hind limb extension duration and mortalities significantly. Brain, SOD, GSH and GABA level were significantly (P<0.01) increased and LPO reduced significantly (P<0.01) after DVS treatment. Furthermore, the DVS did not show any motor coordination signs in the rotarod test. We demonstrated that the role of DVS in convulsion genesis in mice under control condition and attenuate the PTZ-induced oxidative damage.

Topics: Animals; Anticonvulsants; Brain; Depressive Disorder, Major; Desvenlafaxine Succinate; Mice; Oxidative Stress

Low adherence to treatment is associated with poorer clinical outcome and greater healthcare resources utilization (HRU). Limited data are available on the extent of adherence to each individual antidepressant. The goal of this study was to compare the adherence rate to desvenlafaxine versus usual care with selective serotonin reuptake inhibitors (SSRI) and/or other serotonin-norepinephrine reuptake inhibitors (SNRI), in subjects with major depressive disorder (MDD).. Retrospective, multi-centric, observational study including 574 outpatients with MDD. Data were collected from mental and primary care centers. Adherence, persistence, effectiveness, and HRU was evaluated through multivariate regression models.. At 12-months, adjusted adherence rate was higher with desvenlafaxine versus SNRI/SSRI, 67.9% versus 59.9% (OR 1.66, 95% CI 1.07-2.59, p = 0.024). Remission rate was numerically higher with desvenlafaxine versus SNRI/SSRI, 55.9% versus 50.1% (OR 1.35, 95% CI 0.93-1.98, p = 0.118), as well as treatment response, 76.5% in desvenlafaxine group versus 70.8% in SNRI/SSRI group (OR 1.25, 95% CI 0.82-1.90, p = 0.300). Medical visits use was higher in SNRI/SSRI than in desvenlafaxine group [9.8 (4.8) versus 9.1 (6.0), p = 0.019].. Desvenlafaxine is significantly associated with a higher adherence rate at 12 months compared to usual care based on SSRI or other SNRI. This suggests that desvenlafaxine could improve disease management having a positive impact on disease-associated costs.

Topics: Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Retrospective Studies; Selective Serotonin Reuptake Inhibitors

Topics: Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Humans; Infant, Newborn; Serotonin Syndrome

The response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease severity and inflammation. Increasing evidence indicates that the kynurenine metabolic pathway is activated by inflammation in MDD patients and plays a role in the pathophysiology of depression. Antidepressant treatments have been reported to affect kynurenine pathway metabolite levels as well. This study investigates differential associations between the antidepressant treatment outcome to escitalopram versus desvenlafaxine with the pre-treatment and post-treatment-changes in serotonin and kynurenine pathway metabolite levels.. The levels of serotonin and of kynurenine pathway metabolites were measured in plasma using liquid chromatography-mass spectrometry (LC-MS) in 161 currently depressed patients with MDD at baseline and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Treatment response was defined conventionally by a reduction of at least 50% in the Hamilton Depression Rating Scale 21 item (HAMD-21) total score from baseline; remission was defined by reaching a post-treatment HAMD-21 score ≤7.. Response to escitalopram treatment was associated with higher baseline serotonin levels (p = 0.022), lower baseline kynurenine (Kyn)/tryptophan (Trp) ratio (p = 0.008) and lower baseline quinolinic acid (QuinA)/tryptophan (Trp) ratio (p = 0.047), suggesting a lower inflammation state. Greater improvement in depression symptoms as measured by percent change of HAMD-21 score from baseline was also associated with higher baseline serotonin levels (p = 0.033) in escitalopram treatment arm. Furthermore, remitters to escitalopram treatment showed significant increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio after treatment (p = 0.015). In contrast, response to desvenlafaxine treatment was not associated with any metabolite analyzed. We also confirmed a previous report that plasma serotonin levels are lower in MDD patients compared to healthy controls (p = 0.004) and that the kynurenine plasma level is negatively associated with depression symptom severity (p = 0.047).. In MDD patients the antidepressant response to escitalopram was positively associated with baseline serotonin levels and inversely associated with activation of the kynurenine pathway. These results appear consistent with previous literature showing that biomarker evidence of inflammation is associated with lower response to antidepressants from the selective serotonin reuptake inhibitor class. Moreover, increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio, which previously has been characterized as a neuroprotective index, were associated with full remission under escitalopram treatment.

Topics: Citalopram; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Kynurenic Acid; Kynurenine; Plasma; Serotonin

Psychological pain increases the risk of suicidal ideas and acts, and represents a potential therapeutic target. However, the mechanisms of mental pain remain unclear. Here, we assessed the peripheral transcriptomic and central neural correlates of mental pain during a depressive episode.. 172 adult un-medicated depressed patients were recruited. Leucocytes were extracted for RNA quantification at baseline (T0) and after 8 weeks (T8) of an antidepressant treatment. Ninety-nine genes of the cortisol, immune, opioid, serotonergic, and kynurenine systems were a priori selected, and 41 were sufficiently expressed to be analyzed. At both T0 and T8, mean level of mental pain over the last 15 days was measured with a visual analog scale. A subset of 38 patients was additionally scanned with Magnetic Resonance Imaging at T0. Resting-state sequences of 4 networks (default-mode, basal ganglia, central executive, salience) were examined.. Mean psychological pain scores significantly decreased between T0 and T8. At conservative p-corrected levels, T0 mental pain was significantly correlated with 11 brain clusters encompassing the prefrontal, parietal, and temporal cortices, the striatum, and the cerebellum. There was no direct association between peripheral gene expression and mean mental pain at any time points or in terms of temporal changes. However, expressions of 5HTR2B at p-corrected levels, and 5HTR3A, TPH1, and OPRL1 were correlated with the activity of several identified brain clusters at T0. Finally, while suicidal ideas and mental pain were correlated, the neural and molecular correlates of suicidal ideas were not the same.. Our study suggests that the serotonergic and nociceptin systems are associated with the activity of a cortico-subcortical brain network underlying the perception of mental pain during depression. Mental pain may be a necessary but insufficient condition for the emergence of suicidal ideation during depression.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pain; Pain Measurement; Serotonin and Noradrenaline Reuptake Inhibitors; Suicidal Ideation; Suicide, Attempted

Topics: Adult; Adult Survivors of Child Abuse; Antidepressive Agents; Antipsychotic Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Eye Movement Desensitization Reprocessing; Female; Humans; Olanzapine; Paranoid Disorders; Psychotic Disorders; Stress Disorders, Post-Traumatic

Patients with major depressive disorder (MDD) often report that cognitive difficulties, such as memory problems or poor concentration, interfere with their work functioning. We examined the association between self-reported cognitive complaints and work functioning in employed patients with MDD treated with desvenlafaxine. A sample of 36 adult outpatients with MDD completed subjective cognition (British Columbia Cognitive Complaints Inventory [BC-CCI]) and functioning scales (Sheehan Disability Scale [SDS]; Lam Employment Absence and Productivity Scale [LEAPS]; and Health and Work Performance Questionnaire [HPQ]) before and after 8 weeks of open-label treatment with flexibly-dosed desvenlafaxine (50-100 mg/day). Multiple regression analyses were used to assess the relationship between subjective cognitive measures and work functioning scales. Patients showed significant improvements in clinical, cognitive, and work functioning measures following treatment with desvenlafaxine. A predictive association was found between the BC-CCI and both the SDS and LEAPS, but not with the HPQ, when adjusted for depression severity. Self-report cognitive questionnaires can provide useful information to monitor changes in cognitive functioning over time and to predict improvement in work functioning outcomes.

Topics: Adult; Antidepressive Agents; Cognition; Cognitive Dysfunction; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Outpatients; Regression Analysis; Self Report; Work

Topics: Adolescent; Antidepressive Agents; Child; Depressive Disorder, Major; Desvenlafaxine Succinate; Fluoxetine; Humans; Psychopharmacology

Topics: Adolescent; Antidepressive Agents; Child; Depressive Disorder, Major; Desvenlafaxine Succinate; Fluoxetine; Humans; Psychopharmacology; Research Design; Serotonin and Noradrenaline Reuptake Inhibitors

Fatigue and low energy are cardinal symptoms of major depressive disorder (MDD) that have an impact on work functioning. Antidepressants with noradrenergic activity have been hypothesized to improve symptoms of fatigue and low energy. We examined the impact of these symptoms on work functioning in patients with MDD treated with the serotonin and noradrenaline reuptake inhibitor, desvenlafaxine. A secondary analysis was carried out from a study of employed adult outpatients (n=35) with MDD and subjective cognitive complaints treated with desvenlafaxine 50-100 mg/day for 8 weeks. Multiple regression analyses modeled improvement in work functioning measures (Lam Employment Absence and Productivity Scale, Health and Work Performance Questionnaire, Sheehan Disability Scale) with measures of fatigue (Patient-Reported Outcomes Measurement Information System Fatigue scale and 20-item Hopkins Symptom Check List Energy scale). Patients showed a significant improvement in Montgomery-Åsberg Depression Rating Scale scores as well as in fatigue and work functioning measures following treatment. Fatigue measures were significantly associated with improvement in some (Lam Employment Absence and Productivity Scale, Sheehan Disability Scale), but not all (Health and Work Performance Questionnaire) work functioning measures, independent of improvement in overall depressive symptoms. The limitations of this study include the small sample size and the lack of a placebo or a comparison group. Fatigue and low energy are important symptoms that are associated with occupational impairment in MDD. Treatments that improve these symptoms are likely to improve work functioning.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Efficiency; Employment; Fatigue; Female; Follow-Up Studies; Humans; Male; Middle Aged; Treatment Outcome

Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants.. To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission.. A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission.. Among remitters (n=95), there was a strong concordance (Kendall's τ-b=0.84, P=0.0001; Cohen's κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool.. Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing.

Topics: Adult; Antidepressive Agents; ATP Binding Cassette Transporter, Subfamily B; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucuronosyltransferase; Humans; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Pharmacogenomic Variants; Prospective Studies; Psychiatric Status Rating Scales; Treatment Outcome; White People

MicroRNAs are short non-coding molecules that play a major role in regulating gene expression. Peripheral levels of miR-1202 have been shown to predict and mediate antidepressant response. However, it is not clear to what extent these peripheral measures reflect central neural changes in vivo. We approached this problem with the combined use of peripheral miR-1202 measures and neuroimaging. At baseline and after 8 weeks of desvenlafaxine (50-100 mg die), 20 patients were scanned with 3T magnetic resonance imaging, first at rest then during the Go/NoGo task, a classical test of response inhibition. Blood samples were collected at both time points. During resting state, lower baseline miR-1202 levels were predictive of increased connectivity from T0 to T8 between the posterior cingulate and the prefrontal, parietal, and occipital cortices. Changes in miR-1202 levels following desvenlafaxine treatment were negatively correlated with changes in activity in right precuneus within the default-mode network, and in connectivity between the posterior cingulate and the temporal and prefrontal cortices, and the precuneus. During the Go/NoGo task, baseline miR-1202 levels and changes in these levels were correlated with activity changes in different regions, including bilateral prefrontal, insular, cingulate, and temporal cortices, and left putamen and claustrum. Finally, secondary analyses in a subset of patients showed a trend for a significant correlation between miR-1202 levels and glutamate levels measured by spectroscopy. Changes in peripheral miR-1202 levels were therefore associated with changes in brain activity and connectivity in a network of brain regions associated with depression and antidepressant response. These effects may be mediated by the glutamatergic system.

Topics: Adult; Antidepressive Agents; Brain; Brain Mapping; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Inhibition, Psychological; Magnetic Resonance Imaging; Male; MicroRNAs; Motor Activity; Neural Pathways; Neuropsychological Tests; Rest; Serotonin and Noradrenaline Reuptake Inhibitors; Treatment Outcome

No studies to date have evaluated

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Norepinephrine Plasma Membrane Transport Proteins; Pharmacogenetics; Pilot Projects; Polymorphism, Single Nucleotide; Prospective Studies; Serotonin Plasma Membrane Transport Proteins

To investigate whether drug concentrations of venlafaxine and its metabolite O-desmethylvenlafaxine in plasma can be considered as a surrogate marker of concentrations in brain/cerebrospinal fluid (CSF).. For therapeutic drug monitoring purposes, plasma and CSF concentrations of venlafaxine and O-desmethylvenlafaxine were measured between November 2011 and August 2013 in 16 depressive inpatients (ICD-10 diagnoses) who were treated with daily doses of venlafaxine extended release (dose range, 75-225 mg). Daily doses were correlated with plasma and CSF levels. The correlation between venlafaxine, O-desmethylvenlafaxine, and the active moiety (AM) in plasma and CSF was calculated.. Venlafaxine in plasma (P = .005) and CSF (P = .023) correlated significantly with the daily dose, while O-desmethylvenlafaxine and the active moiety (AM = venlafaxine + O-desmethylvenlafaxine) did not. The correlation between venlafaxine, O-desmethylvenlafaxine, and the AM in plasma and CSF was highly significant (P < .001). The calculated CSF/plasma ratio was 0.74 for venlafaxine, 0.88 for O-desmethylvenlafaxine, and 0.84 for the AM.. Venlafaxine and O-desmethylvenlafaxine were found to penetrate well into CSF in patients, which indicated good availability of the drug in the brain, although the findings on CSF concentrations do not allow calculation of concentrations at the target structure within the brain. CSF/plasma ratios for venlafaxine and its metabolite were high probably due to low plasma protein binding. The poor correlation of dose to concentrations in body fluids and the highly significant correlation of plasma to CSF concentrations indicate that plasma concentration is a much better marker of drug concentration in brain than the dose.

Topics: Adult; Aged; Aged, 80 and over; Antidepressive Agents; Cyclohexanols; Delayed-Action Preparations; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Venlafaxine Hydrochloride

Few studies in the literature have examined the efficacy of antidepressant drugs in perimenopausal and postmenopausal women. The objective of the current study was to assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) separately in perimenopausal and postmenopausal women with major depressive disorder (MDD).. Data were pooled from two double-blind, placebo-controlled clinical trials enrolling perimenopausal and postmenopausal women (40-70 years old) diagnosed with MDD. Patients were randomly assigned to receive desvenlafaxine 100 to 200 mg/day or placebo (8 weeks) or desvenlafaxine 50 mg/day or placebo (10 weeks). The primary efficacy end point for each trial was change from baseline in Hamilton Rating Scale for Depression (HAM-D17) total score at week 8. Secondary end points included change from baseline in Sheehan Disability Scale (SDS) and Menopause Rating Scale (MRS) scores. Changes from baseline in continuous variables were analyzed using analysis of covariance with treatment, region, and baseline in the model. All treatment comparisons were carried out separately in perimenopausal or postmenopausal women, in individual studies, and in the pooled population, adjusting for menopausal status and study.. A total of 798 patients were included in the full analysis set (perimenopausal, n=252; postmenopausal, n=546). Desvenlafaxine significantly reduced HAM-D17 total scores versus placebo at week 8 in both perimenopausal (-10.3 vs. -6.5; p<0.001) and postmenopausal women (-10.1 vs. -7.6; p<0.001). Significant improvements in SDS and MRS total scores were also observed for desvenlafaxine versus placebo in perimenopausal (p ≤ 0.024) and postmenopausal women (p ≤ 0.009). A significant treatment by menopausal status interaction was observed for SDS only (p=0.036).. Desvenlafaxine demonstrated antidepressant efficacy in both perimenopausal and postmenopausal subgroups of women with MDD.. In September 2011, Pfizer received a Complete Response Letter from the United States Food and Drug Administration on its application for approval to market desvenlafaxine for the treatment of moderate to severe vasomotor symptoms associated with menopause. The Complete Response Letter states that the data included in the application are not sufficient to establish an acceptable risk/benefit profile for the treatment of vasomotor symptoms in the general population of postmenopausal women, and therefore desvenlafaxine is not approved for the treatment of vasomotor symptoms in the United States at this time. This decision does not impact desvenlafaxine's approval for the treatment of MDD in adults.

Topics: Administration, Oral; Adult; Aged; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Menopause; Middle Aged; Postmenopause; Psychiatric Status Rating Scales; Treatment Outcome

The primary objective of this post-hoc analysis was to evaluate the effect of short-term treatment with desvenlafaxine versus placebo on sexual dysfunction (SD), assessed from Arizona Sexual Experiences Scale scores, in adult outpatients with major depressive disorder. Data from three randomized, double-blind, placebo-controlled trials of 50 or 100 mg/day desvenlafaxine for major depressive disorder were pooled. SD status, determined from Arizona Sexual Experiences Scale scores, was assessed at baseline and week 8, last observation carried forward. Subgroup analyses addressed the effects of sex, baseline SD, and antidepressant response. At week 8, last observation carried forward (n=1562), SD rates were 54, 47, and 49% for 50 mg/day desvenlafaxine, 100 mg/day desvenlafaxine, and placebo, respectively [adjusted odds ratios (95% confidence interval) vs. placebo: 1.205 (0.928, 1.564) and 1.129 (0.795, 1.604), respectively]. The treatment by baseline SD interaction approached statistical significance (P=0.0663), mainly driven by poorer scores for desvenlafaxine versus placebo in the 100 mg group. Treatment by sex interactions were not statistically significant. Small but statistically significant treatment by sex interactions were observed for sex drive (P=0.0011) and ease of erection/lubrication (P=0.0151). Although there was no overall effect of desvenlafaxine on SD, a treatment by baseline SD interaction was suggested for 100 mg desvenlafaxine.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Erectile Dysfunction; Female; Humans; Libido; Male; Middle Aged; Psychiatric Status Rating Scales; Sex Factors; Sexual Dysfunctions, Psychological

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

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Disability Evaluation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Predictive Value of Tests; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult

Topics: Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Menopause

Topics: Antidepressive Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclohexanols; Cytochrome P-450 CYP2D6; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Meta-Analysis as Topic

This meta-analysis compared the efficacy and safety of desvenlafaxine and venlafaxine at the Australian approved doses.. A systematic literature search was conducted to identify all placebo-controlled studies of desvenlafaxine and venlafaxine in the treatment of major depression. The pivotal outcome measure used to assess comparative efficacy was the mean change in Hamilton Rating Scale for Depression-17 score from baseline. Tolerability and safety were compared by an evaluation of reported adverse events. Standard and Bayesian methods were used to conduct the indirect comparisons. Findings Using a mixed model repeated measures analysis, the pooled weighted mean difference for the mean change in Hamilton Rating Scale for Depression-17 score from baseline was -2.81 (-3.72, -1.91; p < 0.001) for desvenlafaxine and -2.61 (-3.17, -2.05; p < 0.001) for venlafaxine. An indirect Bayesian analysis adjusted for baseline Hamilton Rating Scale for Depression-17 score showed no significant difference between the two treatments (weighted mean difference -0.27; -1.17, 0.65). A standard indirect comparison of any adverse events showed no significant difference between desvenlafaxine and venlafaxine (relative risk 1.01; 0.96, 1.06; p = 0.70 and risk difference -0.01; -0.05, 0.03; p = 0.59). Standard indirect comparisons of both nausea and drop-outs identified potential differences between treatments, with the risk difference analyses suggesting a trend in favor of desvenlafaxine (nausea: relative risk 0.97; 0.77, 1.22; p = 0.80/RD -0.07; -0.12, -0.01; p = 0.02; and drop-outs due to adverse events: RR 0.86; 0.58, 1.29; p = 0.48/RD -0.04; -0.08, 0.00; p = 0.06).. Based on the results of this meta-analysis, desvenlafaxine was shown to be non-inferior to venlafaxine in terms of efficacy, and has an advantage in terms of less nausea.

Topics: Adult; Aged; Antidepressive Agents; Australia; Bayes Theorem; Cyclohexanols; Databases, Factual; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Meta-Analysis as Topic; Middle Aged; Nausea; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Treatment Outcome; Venlafaxine Hydrochloride; Young Adult

The terms 'tolerance' and 'poop out' are commonly applied to describe the progressive loss of effectiveness of a previously effective antidepressant and where the individual may be a rapid metabolizer of those drugs as a consequence of possessing certain polymorphisms of P450 (CYP) liver enzymes, especially CYP2D6 and CYP2C19. As the antidepressant desvenlafaxine is not metabolized by those enzymes, it might be hypothesized that it would be less likely to be associated with tolerance or poop out, even for patients whose genotyping pattern is indicative of rapid metabolizing. In this study, we report on five patients who had a historical pattern suggestive of tolerance to other antidepressant drugs, whose genotyping test indicated that they were CYP2C19 rapid metabolizers, and who experienced 'poop out' again when commenced on desvenlafaxine. Although desvenlafaxine is theoretically an option in patients with a history of tolerance to antidepressants, these case reports indicate that this drug may not necessarily overcome the problem of tolerance in rapid metabolizing patients.

Topics: Adult; Aged; Antidepressive Agents, Second-Generation; Cyclohexanols; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Depressive Disorder, Major; Desvenlafaxine Succinate; Drug Tolerance; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic

A case is presented of the occurrence of an episode of mania apparently induced by desvenlafaxine, in a patient with a history of major depressive disorder and no apparent history of previous mania or hypo-mania. To our knowledge, this is the first such documented case with this new antidepressant. The discussion focuses on the concept of the bipolar spectrum, and how to view patients who have only become manic while taking antidepressants.

Topics: Antidepressive Agents; Bipolar Disorder; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Male; Middle Aged

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

Topics: Adolescent; Adult; Age Factors; Aged; Ambulatory Care; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Sex Factors; Statistics as Topic; Treatment Outcome; Young Adult

Topics: Citalopram; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Middle Aged; Neurotransmitter Uptake Inhibitors; Randomized Controlled Trials as Topic; Research Design; Selective Serotonin Reuptake Inhibitors

The objective of this analysis was to assess the risk of increased suicidal thoughts and behavior (suicidality) with desvenlafaxine (administered as desvenlafaxine succinate) in patients with major depressive disorder (MDD). Data from 9 double-blind, 8-week studies in outpatients with MDD were analyzed retrospectively. Patients were randomly assigned to desvenlafaxine (n = 1834) or placebo (n = 1116). Adverse events (AEs) related to suicidality were identified by searching the AE database for text strings possibly related to suicidality; false positives were excluded. Narratives for each case were prepared and blinded for review. Events were classified according to the Columbia Classification Algorithm of Suicide Assessment. Odds ratios were calculated; chi tests were used to compare treatment groups. Occurrence of emerging or worsening suicidality, based on the 17-item Hamilton Rating Scale for Depression suicide item, was compared for desvenlafaxine and placebo using chi tests. In all, 17 (0.93%) of 1834 patients receiving desvenlafaxine and 8 (0.72%) of 1116 receiving placebo reported possible suicidality-related AEs. Events were relatively evenly distributed across treatment groups. One patient randomly assigned to desvenlafaxine treatment died of completed suicide during the on-therapy period. There were no significant differences between groups in the risk for any class of suicide-related events, including completed suicide or suicide attempt. Odds of emergence or worsening of suicidality 17-item (Hamilton Rating Scale for Depression suicide item) did not differ significantly between treatment groups. No evidence of a signal for increased suicidality was detected in adult patients treated with desvenlafaxine in short-term MDD trials. As suicidal events were extremely rare, a true increased risk cannot be ruled out.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Humans; Middle Aged; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Retrospective Studies; Risk; Suicide; Suicide, Attempted; Young Adult

This retrospective analysis compared sensitivity to change on the 17-item and 6-item Hamilton Rating Scales For Depression (HAM-D (17) and HAM-D (6), respectively) in relation to antidepressant dose and baseline depression severity.. Data were derived from 6 randomized, double-blind, placebo-controlled, 8-week trials of fixed-dose desvenlafaxine (50, 100, 200 or 400 mg/d) for major depressive disorder. HAM-D (17) and HAM-D (6) effect sizes were assessed.. HAM-D (17) effect sizes were negative (favoured placebo) for higher desvenlafaxine doses (200-400 mg/d) at week 1, but were positive for all doses after week 2, with no clear dose-response pattern. However, HAM-D (6) effect sizes were positive for all doses at all weeks. Effect sizes were consistently greater for HAM-D (6) vs. HAM-D (17), regardless of time spent under therapy. Effect sizes were greater for HAM-D (6) vs. HAM-D (17) for all desvenlafaxine doses among patients with baseline HAM-D (17) <25, but not among patients with baseline HAM-D (17) ≥ 25.. The HAM-D (6) demonstrated greater sensitivity to change and robustness than the HAM-D (17), supporting the greater homogeneity of the HAM-D (6).

Topics: Adult; Aged; Aged, 80 and over; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome; Young Adult

Desvenlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI) developed by Wyeth, is a novel salt form of the isolated major active metabolite of the antidepressant venlafaxine. Desvenlafaxine was developed as a slow-release tablet formulation and rapidly penetrates the brain upon administration supporting its direct effects on neuronal systems of the brain. Unlike various other antidepressants including venlafaxine, desvenlafaxine is not metabolized by cytochrome p450 (CYP) enzyme pathways and is associated with minimal inhibition of CYP enzymes. This feature results in a comparatively low risk of drug-drug interaction and consistent intra-individual and inter-individual pharmacokinetic profiles. Desvenlafaxine has been recently approved by the US FDA for the treatment of major depressive disorder (MDD) based on a series of randomized, double-blind, placebo-controlled clinical trials indicating efficacy and safety for patients with MDD. Studies have also supported the potential utility of desvenlafaxine in the treatment of vasomotor symptoms of menopause, anxiety symptoms and painful physical symptoms. However, concerns including mixed efficacy and adverse events need to be further explored in future studies.

Topics: Animals; Clinical Trials as Topic; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Menopause; Molecular Structure; Neuralgia; Norepinephrine; Selective Serotonin Reuptake Inhibitors; Structure-Activity Relationship; Vasomotor System

Topics: Antidepressive Agents; Aryl Hydrocarbon Hydroxylases; Cyclohexanols; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Depressive Disorder, Major; Desvenlafaxine Succinate; Gene Expression Profiling; Humans; Oligonucleotide Array Sequence Analysis

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 0.05). 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.

Topics: Adult; Analysis of Variance; Antidepressive Agents; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Treatment Outcome

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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Clinical Trials as Topic; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Substance Withdrawal Syndrome; Time Factors; Treatment Outcome

Topics: Attitude of Health Personnel; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluoxetine; Humans; Neurotransmitter Uptake Inhibitors; Paroxetine; Physicians; Randomized Controlled Trials as Topic; Sertraline; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Antidepressive Agents; Cyclohexanols; Depression; Depressive Disorder, Major; Desvenlafaxine Succinate; Drug Interactions; Humans; Neurotransmitter Uptake Inhibitors

The elderly are at increased risk for medication-related adverse events. Recent reports indicate that venlafaxine may put the elderly at increased risk of cardio- and cerebrovascular adverse events. We investigated the relationship between the CYP2D6 polymorphism and steady-state plasma concentration of venlafaxine (VEN) and its primary metabolite o-desmethylvenlafaxine (ODV) in elderly participants receiving venlafaxine-XR for major depression in order to explore the contribution of pharmacogenetics to medication tolerability.. Forty-six elderly participants received venlafaxine-XR for the treatment of major depression. CYP2D6 genotype and steady-state plasma levels of VEN and ODV were determined.. Sixty-five percent of participants were homozygous of the wild type (WT) allele, whereas 35% carried one or more variant alleles associated with intermediate and poor 2D6 metabolizer status. VEN concentration per unit dose was significantly higher and ODV concentration per unit dose was significantly lower in participants who carried one or more variant alleles compared to participants who were homozygous for the WT allele. The VEN and ODV concentrations per unit dose were also correlated with creatinine clearance. CYP2D6 genotype was not associated with medication associated side-effects.. Plasma dose-corrected concentrations of VEN and ODV correlated with genetically determined CYP2D6 enzymatic activity in depressed elders treated with venlafaxine-XR. This relationship was not masked by the effects of age-related illness or polypharmacy. Future clinical application of pharmacogenetics to examine 2D6-dependent medications may help reduce the incidence of medication adverse events particularly in those elders at higher risk for medication adverse events due to impaired renal or cardiac function.

Topics: Aged; Aged, 80 and over; Antidepressive Agents, Second-Generation; Creatinine; Cyclohexanols; Cytochrome P-450 CYP2D6; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Genotype; Humans; Male; Venlafaxine Hydrochloride