Maju Mathews

Efficacy and safety of vilazodone 20 and 40 mg in major depressive disorder: a randomized, double-blind, placebo-controlled trial

Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for major depressive disorder (MDD) treatment in adults. This was a 10-week, multicenter, double-blind, placebo-controlled and active-controlled, fixed-dose trial (NCT01473381). Adult patients with MDD (Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision criteria) were randomized 1 : 1 : 1 : 1 to vilazodone 20 or 40 mg/day, citalopram 40 mg/day, or placebo. Primary efficacy: Montgomery–Åsberg Depression Rating Scale (MADRS); secondary efficacy: Clinical Global Impressions-Severity and sustained response (MADRS total score⩽12 for at least the last two consecutive double-blind visits). The intent-to-treat population comprised 1133 patients, (placebo=281; vilazodone 20 mg/day=288; vilazodone 40 mg/day=284; citalopram=280). MADRS and Clinical Global Impressions-Severity score change from baseline to week 10 was significantly greater for vilazodone 20 mg/day, vilazodone 40 mg/day, and citalopram versus placebo. Sustained response rates were numerically higher, but not significantly different, in all active treatment groups versus placebo. The most common adverse events (≥5% of vilazodone patients, twice the rate of placebo) were diarrhea, nausea, vomiting (vilazodone 40 mg/day only), and insomnia. Improved sexual function (Changes in Sexual Functioning Questionnaire scores) was seen in all groups; between-group differences were not significant. Vilazodone 20 and 40 mg/day demonstrated efficacy and tolerability in the treatment of MDD.

Efficacy and safety of vilazodone in major depressive disorder: a randomized, double-blind, placebo-controlled trial.

INTRODUCTION Vilazodone is a potent serotonin (5-HT) reuptake inhibitor and 5-HT₁A receptor partial agonist approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD) in adults. This study evaluated the efficacy and tolerability of vilazodone in the treatment of MDD. METHOD This 8-week, randomized (1:1), double-blind, placebo-controlled, parallel-group, fixed-dose study conducted from January 2012 to February 2013 compared vilazodone 40 mg/d with placebo in outpatients with DSM-IV-TR-diagnosed MDD. The primary efficacy measure was Montgomery-Asberg Depression Rating Scale (MADRS) total score change from baseline to week 8 analyzed by a mixed-effects model for repeated measures on the intent-to-treat population (placebo = 252, vilazodone = 253). Secondary efficacy outcomes were Clinical Global Impressions-Severity of Illness (CGI-S) Scale score change from baseline and MADRS sustained response rate (total score ≤ 12 for at least the last 2 consecutive double-blind visits). RESULTS Approximately 83% of patients completed the study. Least squares mean differences (95% CI) were statistically significant for vilazodone versus placebo on MADRS (-5.117 [-6.886 to -3.347], P < .00001) and CGI-S (-0.622 [-0.845 to -0.399], P < .00001) change from baseline; statistically significant improvements versus placebo occurred at week 2 and persisted for the study duration. The MADRS sustained response rate was 17% for placebo and 27% for vilazodone (P < .01). Patients taking vilazodone versus placebo had higher rates of diarrhea and nausea; most incidences were mild in severity. Weight increase and sexual dysfunction adverse events were low in both groups. CONCLUSIONS A large and significant treatment effect on the MADRS and statistically significant improvement on the CGI-S demonstrated meaningful depressive symptom improvements. Vilazodone was generally well tolerated. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01473394.

A double-blind, randomized, placebo-controlled, fixed-dose phase III study of vilazodone in patients with generalized anxiety disorder.

Vilazodone, a selective serotonin reuptake inhibitor and 5‐HT1A receptor partial agonist, is approved for treating major depressive disorder in adults. This study (NCT01629966 ClinicalTrials.gov) evaluated the efficacy and safety of vilazodone in adults with generalized anxiety disorder (GAD).

Sexual dysfunction during treatment of major depressive disorder with vilazodone, citalopram, or placebo: results from a phase IV clinical trial

Sexual dysfunction commonly occurs with major depressive disorder (MDD). Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist antidepressant approved for the treatment of MDD in adults, was evaluated to determine its effects on sexual function. The primary study was a double-blind, randomized, controlled trial comparing vilazodone 20 and 40 mg/day with placebo; citalopram 40 mg/day was an active control (NCT01473381; http://www.clinicaltrials.gov). Post-hoc analyses evaluated change from baseline to week 10 on the Changes in Sexual Functioning Questionnaire (CSFQ); no inferential statistics were performed. CSFQ scores increased for women [1.2 (citalopram) to 3.0 (vilazodone 40 mg)] and men [1.2 (vilazodone 40 mg) to 3.5 (placebo)] in all treatment groups. Greater changes in CSFQ scores were seen in responders [women: 2.33 (citalopram) to 5.06 (vilazodone 40 mg); men: 2.26 (vilazodone 40 mg) to 4.35 (placebo)] versus nonresponders. CSFQ change from baseline was small for patients with normal baseline sexual function; in patients with baseline sexual dysfunction, CSFQ scores improved across groups [women: 2.35 (citalopram) to 4.52 (vilazodone 40 mg); men 2.83 (vilazodone 40 mg) to 6.43 (placebo)]. Across treatment groups, baseline sexual function improved in women and men, MDD responders, and patients with baseline sexual dysfunction.

Safety and Efficacy from an 8 Week Double-Blind Trial and a 26 Week Open-Label Extension of Asenapine in Adolescents with Schizophrenia.

OBJECTIVE The purpose of this study was to evaluate the safety and efficacy of asenapine in adolescents with schizophrenia. METHODS In an 8 week, randomized, double-blind placebo-controlled trial, subjects (12-17 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria for schizophrenia were randomized 1:1:1 to placebo, asenapine 2.5 mg b.i.d., or asenapine 5 mg b.i.d. Subjects who completed the 8 week acute study could participate in a 26 week flexible-dose asenapine-only open-label extension (OLE). RESULTS A similar percentage of subjects completed treatment on day 56 (2.5 mg b.i.d. (n=98): 83%; 5 mg b.i.d. [n=106]: 79%; placebo [n=102]: 79%). In the mixed model for repeated measures analysis of the primary end-point (with Hochberg correction for multiplicity), least squares (LS) mean differences between asenapine and placebo on the Positive and Negative Syndrome Scale (PANSS) total score at day 56 were not significant (-4.8 for 2.5 mg b.i.d., p=0.070; -5.6 for 5 mg b.i.d., p=0.064). Significant improvement in the Clinical Global Impressions-Severity score was observed in the 5 mg b.i.d. group versus placebo on day 56 (LS mean -0.3, p=0.024). In the acute phase, ≥7% weight gain and the composite event of somnolence, sedation, and hypersomnia were more common in both asenapine groups than in the placebo group. Akathisia, fasting glucose elevation, and extrapyramidal syndrome were more common in the 5 mg b.i.d. group than in the placebo group. There were no unexpected adverse events in the OLE, and PANSS total scores decreased by -16.1 points in the group previously treated with placebo (n=62) and by -11.2 points in the continuous asenapine group (n=131) from OLE baseline to week 26. CONCLUSIONS Although improvements in PANSS total score at day 56 of the acute phase were numerically greater for both asenapine 2.5 and 5 mg b.i.d. than for placebo and were maintained in the OLE, the primary end-point did not achieve statistical significance in the acute phase. No new or unexpected safety concerns were detected during the acute phase or after an additional 26 weeks of asenapine treatment in the adolescent population with schizophrenia. CLINICAL TRIALS REGISTRY NCT01190254 and NCT1190267 at ClinicalTrials.gov.

Vilazodone in patients with generalized anxiety disorder: a double-blind, randomized, placebo-controlled, flexible-dose study

Vilazodone is a selective serotonin reuptake inhibitor and a 5-HT1A receptor partial agonist that is approved for treatment of major depressive disorder in adults in the USA and Mexico. The efficacy, safety, and tolerability of vilazodone for generalized anxiety disorder (GAD) were investigated in a clinical trial (NCT01766401 ClinicalTrials.gov). Participants (18–70 years, inclusive) who met Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision, criteria for GAD were randomized (1 : 1) to placebo or flexible-dose vilazodone (20–40 mg/day) for 8 weeks of double-blind treatment. Primary and secondary efficacy parameters were changes from baseline to week 8 in Hamilton Rating Scale for Anxiety and Sheehan Disability Scale total scores, respectively. Analysis was based on a mixed-effects model for repeated measures approach on the intent-to-treat population. The intent-to-treat population comprised 395 patients (placebo=197, vilazodone=198); 77% completed the study. The least squares mean difference in change from baseline to week 8 in the Hamilton Rating Scale for Anxiety total score was statistically significant for vilazodone versus placebo [−1.50 (−2.96, −0.04), P=0.0438]. The mean change from baseline to week 8 in the Sheehan Disability Scale total score for vilazodone versus placebo was not statistically significant. Adverse events were reported in 60% of placebo-treated and 83% of vilazodone-treated patients. This was a positive clinical trial of 20–40 mg/day vilazodone versus placebo in the treatment of GAD.

Early and sustained improvement with vilazodone in adult patients with major depressive disorder: post hoc analyses of two phase III trials

Abstract Objective: To retrospectively examine the timing of depressive symptom improvement in patients treated with vilazodone, a selective serotonin reuptake inhibitor (SSRI) and 5-HT1A partial agonist. Research design and methods: Post hoc analyses were conducted on pooled data from two phase III, multicenter, 8 week, double-blind, randomized, controlled trials (RCTs) of vilazodone 40 mg/day or placebo in adult patients with major depressive disorder (MDD). Clinical trial registration: ClinicalTrials.gov identifier: NCT00285376. ClinicalTrials.gov identifier: NCT00683592. Main outcome measures: Montgomery–Åsberg Depression Rating Scale (MADRS) total score least squares (LS) mean change from baseline to Week 8; MADRS single items LS mean change from baseline; MADRS responder analyses: response = ≥50% reduction in baseline score; cumulative response = proportion of patients at each assessment who achieved response that was sustained at all subsequent weeks; sustained response = ≥50% reduction in baseline MADRS total score at last two visits; and sustained response plus MADRS score ≤12 at the last two visits of the study. Results: LS mean difference (LSMD) and 95% confidence interval (95% CI) for change from baseline to Week 8 was significantly greater in favor of vilazodone versus placebo (−2.8 [−4.1 to −1.4]; p < 0.0001); differences between vilazodone and placebo were statistically significant beginning at Week 1. Early improvement in depressive symptoms was suggested by statistically significant separation from placebo on seven of ten MADRS single items as early as Week 1 or Week 2. A significantly greater proportion of vilazodone patients achieved response using all responder criteria, with early and sustained improvement consistently observed. Conclusions: Early and sustained improvement of depressive symptoms was retrospectively observed in patients treated with vilazodone; early findings may be related to overall treatment outcomes.

Asenapine: Efficacy and safety of 5 and 10 mg bid in a 3-week, randomized, double-blind, placebo-controlled trial in adults with a manic or mixed episode associated with bipolar I disorder

BACKGROUND Asenapine is an atypical antipsychotic for acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. The recommended asenapine starting dose is 10mg bid with the option to reduce the dose to 5mg bid if needed due to adverse effects/tolerability. METHODS Phase IIIb, international, double-blind, fixed-dose, parallel-group, 3-week placebo-controlled trial of asenapine 5 and 10mg bid in adults with an acute bipolar I disorder manic or mixed episode. Primary outcome was difference in asenapine versus placebo in mean change from baseline to day 21 in the Young-Mania Rating Scale (YMRS) total score. Others included difference in asenapine versus placebo in the Clinical Global Impression Scale for Bipolar Severity (CGI-BP-S) and rate of YMRS responders. RESULTS Both asenapine doses were statistically superior to placebo in mean change from baseline to day 21 in YMRS total score (-10.9, -14.4, and -14.9 for placebo, asenapine 5mg bid, 10mg bid, respectively). Both asenapine doses had statistically superior improvement in mean change in CGI-BP-S score at day 21. Neither asenapine dose had significantly more YMRS responders at day 21 than placebo. LIMITATIONS Results may not be generalizable to the entire population with bipolar I disorder owing to strict inclusion criteria. CONCLUSIONS This study evaluated, by a fixed-dose design, the efficacy and safety of asenapine versus placebo in patients with bipolar I disorder. Both asenapine 5 and 10mg bid were efficacious in treating mania associated with bipolar I disorder and were generally well tolerated.

Efficacy and safety of vilazodone in patients with generalized anxiety disorder: a randomized, double-blind, placebo-controlled, flexible-dose trial.

OBJECTIVE To evaluate the efficacy, safety, and tolerability of vilazodone as an acute treatment for generalized anxiety disorder (GAD). Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder in adults. METHODS This was a randomized, placebo-controlled, parallel-group, multicenter, flexible-dose study conducted from May 2013-March 2014. Adult patients (18-70 years, inclusive) who met DSM-IV-TR criteria for GAD were randomized (1:1) to placebo or vilazodone 20-40 mg/d for 8 weeks of double-blind treatment. Primary and secondary efficacy parameters were change from baseline to week 8 in the Hamilton Anxiety Rating Scale (HARS) total score and in the Sheehan Disability Scale (SDS) total score, respectively, analyzed using a mixed-effects model for repeated measures approach on a modified intent-to-treat population. Safety outcomes were summarized descriptively. RESULTS Efficacy analyses were based on 400 patients (placebo = 200, vilazodone = 200); 76% completed the study (placebo = 81%, vilazodone = 71%). The least squares mean difference (95% CI) in total score change from baseline to week 8 was statistically significant for vilazodone versus placebo on the HARS (-2.20 [-3.72 to -0.68]; P = .0048) and on the SDS (-1.89 [-3.52 to -0.26]; P = .0236). Treatment-emergent adverse events reported in ≥ 5% of vilazodone patients and at least twice the rate of placebo were nausea, diarrhea, dizziness, fatigue, delayed ejaculation, and erectile dysfunction. CONCLUSION Statistically significant differences in favor of vilazodone 20-40 mg/d versus placebo were seen on all measures of anxiety and functional impairment in patients with GAD. Vilazodone was generally well tolerated, and no new safety concerns were noted. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01844115.

Randomized, Double-Blind, Placebo-Controlled Trial of Asenapine Maintenance Therapy in Adults With an Acute Manic or Mixed Episode Associated With Bipolar I Disorder

OBJECTIVE The authors determined the efficacy and safety of asenapine in preventing recurrence of any mood episode in adults with bipolar I disorder. METHOD Adults with an acute manic or mixed episode per DSM-IV-TR criteria were enrolled in this randomized, placebo-controlled trial consisting of an initial 12- to 16-week open-label period and a 26-week double-blind randomized withdrawal period. The target asenapine dosage was 10 mg b.i.d. in the open-label period but could be titrated down to 5 mg b.i.d. After completing the open-label period, subjects meeting stabilization/stable-responder criteria were randomized to asenapine or placebo treatment in the double-blind period. The primary efficacy endpoint was time to recurrence of any mood event during the double-blind period. Kaplan-Meier estimation was performed, and 95% confidence intervals were determined. Safety was assessed throughout. RESULTS A total of 549 subjects entered the open-label period, of whom 253 enrolled in the double-blind randomized withdrawal period (127 in the placebo group; 126 in the asenapine group). Time to recurrence of any mood episode was statistically significantly longer for asenapine- than placebo-treated subjects. In post hoc analyses, significant differences in favor of asenapine over placebo were seen in time to recurrence of manic and depressive episodes. The most common treatment-emergent adverse events were somnolence (10.0%), akathisia (7.7%), and sedation (7.7%) in the open-label period and mania (11.9% of the placebo group compared with 4.0% of the asenapine group) and bipolar I disorder (6.3% compared with 1.6%) in the double-blind period. CONCLUSIONS Long-term treatment with asenapine was more effective than placebo in preventing recurrence of mood events in adults with bipolar I disorder and was generally well-tolerated.