Randomized, double-blind, placebo-controlled study to assess the efficacy and safety of vortioxetine in Japanese patients with major depressive disorder.
ABSTRACT: AIM:The burden of major depressive disorder (MDD) in Japan is high. This study aimed to evaluate the efficacy and safety of the multimodal antidepressant vortioxetine in Japanese patients with MDD. METHODS:Japanese patients aged 20-75?years with recurrent MDD and a Montgomery-Åsberg Depression Rating Scale (MADRS) score???26 were randomized to vortioxetine 10 or 20?mg or placebo in a phase-3, double-blind, 8-week study. The primary end-point was change in MADRS total score from baseline. Secondary end-points included MADRS response and remission rates, change in Hamilton Rating Scale for Depression-17 item (HAM-D17) score, and other measures of depressive symptoms, including Clinical Global Impression of Severity (CGI-S), Clinical Global Impression of Improvement (CGI-I), and Sheehan Disability Scale (SDS). Cognitive function was assessed using Digit Symbol Substitution Test (DSST) score and Perceived Deficits Questionnaire-5 item (PDQ-5) score. RESULTS:Vortioxetine 10?mg (n = 165) and 20?mg (n = 163) reduced MADRS total score by 2.66 and 3.07 points versus placebo (n = 161) after 8?weeks (P?
Project description:This multicenter, randomized, double-blind, placebo-controlled, active-referenced (duloxetine 60 mg), parallel-group study evaluated the short-term efficacy and safety of vortioxetine (10-20 mg) on cognitive function in adults (aged 18-65 years) diagnosed with major depressive disorder (MDD) who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test (DSST)-number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire (PDQ) and physician-assessed clinical global impression (CGI) were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment (UPSA) (ANCOVA) to measure functionality, MADRS (MMRM) to assess efficacy in depression, and a prespecified multiple regression analysis (path analysis) to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST (P < 0.05), PDQ (P < 0.01), CGI-I (P < 0.001), MADRS (P < 0.05), and UPSA (P < 0.001). Path analysis indicated that vortioxetine's cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events (incidence ? 5%) for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated.
Project description:BACKGROUND:Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of vortioxetine on cognition in patients with MDD. METHODS:Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of vortioxetine (5-20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen's d ) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only). RESULTS:Before adjustment for MADRS, vortioxetine separated from placebo on DSST score (SES 0.25-0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, vortioxetine maintained DSST improvement in one individual trial ( p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04). CONCLUSIONS:Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction.
Project description:The efficacy of vortioxetine 10 and 20 mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder (MDD) was evaluated. Patients (18-65 yr, N = 602) were randomized (1:1:1) to vortioxetine 10 or 20 mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). In the pre-defined primary efficacy analysis, both doses of vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 (vortioxetine 10 mg, p < 0.0001) and 0.33 (vortioxetine 20 mg, p < 0.0001) on the composite cognition score. Significant improvement vs. placebo was observed for vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were -4.7 (10 mg: p < 0.0001) and -6.7 (20 mg: p < 0.0001). Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms.
Project description:<h4>Aim</h4> Antidepressants, including selective serotonin reuptake inhibitors, often elicit a poor response in patients with major depressive disorder (MDD) with significant anxiety symptoms. This study investigated the effects of the multimodal antidepressant vortioxetine in patients with MDD and associated anxiety. <h4>Methods</h4> This was a post hoc analysis of data from an 8-week, randomized, double-blind, placebo-controlled, Phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20–75 years with recurrent MDD and a Montgomery–Åsberg Depression Rating Scale (MADRS) score of at least 26. Changes from baseline to week 8 in MADRS total score and Hamilton Depression Rating Scale (HAM-D) anxiety/somatization factor score were assessed in patients with anxious depression (HAM-D anxiety/somatization factor score ≥7) and without anxious depression. <h4>Results</h4> Data were available for 489 patients. In patients with anxious depression, the least-squares (LS) mean difference (95% confidence interval [CI]) versus placebo in change in MADRS total score was −3.44 (−6.10, −0.77) for vortioxetine 10 mg and −4.51 (−7.15, −1.87) for vortioxetine 20 mg. In patients with non-anxious depression, the LS mean difference (95% CI) versus placebo was −1.81 (−4.71, 1.09) and −1.05 (−4.00, 1.90) for vortioxetine 10 mg and 20 mg, respectively. Changes from baseline in HAM-D anxiety/somatization factor score were greater in patients treated with vortioxetine 10 mg or 20 mg than in those treated with placebo. <h4>Conclusion</h4> Vortioxetine may be effective for patients with anxiety symptoms in MDD. Further research is warranted to investigate these effects in a real-world clinical setting. <h4>Clinical Trials Registration</h4> ClinicalTrials.gov identifier for primary study: NCT02389816.
Project description:BACKGROUND:IGF-1 is an essential neurotrophin produced peripherally and in the brain. Impairments in the brain IGF-1 concentrations might be responsible for some aspects of major depressive disorder (MDD) pathogenesis, whereas peripheral IGF-1 could have the marker value. We aimed: 1) to compare serum IGF-1 levels in MDD patients and healthy controls (HC); 2) to elucidate possible associations between changes in IGF-1 expression and crucial characteristics of the current depressive episode, MDD course; 3) to evaluate IGF-1 dynamics after 8 weeks` vortioxetine treatment. METHODS:Seventy-eight MDD patients (according to DSM-5) and 47 HC were enrolled. Serum IGF-1, psychopathological (MADRS, CGI) and neuropsychological parameters (PDQ-5, RAVLT, TMT-B, DSST) were analyzed in all subjects at admission and 48 patients after 8 weeks` vortioxetine treatment. AUC-ROCs were calculated to determine if the value of serum IGF-1 could separate MDD patients from HC. Multiple regression models were performed to explore relationships between IGF-1 and depressive episode's symptoms. RESULTS:MDD patients had significantly higher serum IGF-1 levels than HC (228 (183-312) ng/ml vs 153 (129-186) ng/ml, p?<?0.0001). IGF-1 had a good diagnostic value for predicting MDD in the whole sample with AUC of 0.820 (p?<?0.0001). For a cutoff of 178.00?ng/ml, the sensitivity and specificity were 83 and 71%, respectively, and the number needed to misdiagnose was 5, indicating that only 1 of 5 tests give an invalid result. Among MADRS items, only reported sadness, inner tension, and concentration difficulties were significantly positively associated with serum IGF-1 concentrations. Vortioxetine treatment significantly attenuated IGF-1 levels and improved all psychopathological, neuropsychological parameters. CONCLUSIONS:Significant associations between IGF-1 levels and hypothymia, anxiety, and cognitive disturbances may indicate a pathogenic role of IGF-1 for the mentioned symptoms. We assume that the activity of the cerebral-hepatic axis increases in response to insufficient IGF-1 brain expression in MDD patients, whereas, vortioxetine treatment restores cerebral IGF-1 concentrations and, consequently, decreases its compensatory production by the liver. TRIAL REGISTRATION:registered at ClinicalTrials.gov (NCT03187093). First posted on 14th June 2017.
Project description:Background:Last decades of psychiatric investigations have been marked by a search for biological markers that can clarify etiology and pathogenesis, confirm the diagnosis, screen individuals at risk, define the severity, and predict the course of mental disorders. In our study, we aimed to evaluate if BDNF and IGF-1 serum concentrations separately and in combination might be used as biomarkers for major depressive disorder (MDD) diagnosis and treatment efficacy and to evaluate the relationships among those proteins and clinical parameters of MDD. Methods:Forty-one MDD patients (according to DSM-5) and 32 healthy controls (HC) were included in this study. BDNF and IGF-1 serum concentrations, psychopathological (MADRS, CGI) and neuropsychological parameters (PDQ-5, RAVLT, TMT-B, DSST), functioning according to Sheehan Disability Scale were analyzed in all subjects at admission and 30 MDD patients after 8 weeks of vortioxetine treatment. Correlational analyses were performed to explore relationships between BDNF and IGF-1 and clinical characteristics. AUC-ROCs were calculated to determine if the value of serum BDNF and IGF-1 levels could serve for MDD diagnosis. Results:MDD patients had significantly lower serum BDNF (727.6 ± 87.9 pg/ml vs. 853.0 ± 93.9 pg/ml) and higher serum IGF-1 levels (289.15 ± 125.3 ng/ml vs. 170.2 ± 58.2 ng/ml) compared to HC. Significant correlations were obtained between BDNF levels and MDD status, depressive episode (DE) severity, precipitating factors, executive functions disruption (TMT-B, RAVLT immediate recall scores) and all subdomains of functioning. As for IGF-1, correlations were found between IGF-1 level and MDD status, DE severity, number and duration of DE, parameters of subjective and objective cognitive functioning (PDQ-5, RAVLT, TMT-B, DSST scores), and all subdomains of functioning. The associations between IGF-1 concentrations and cognitive tests' performance were stronger than those of BDNF. Separately both BDNF and IGF-1 demonstrated good discriminating ability for MDD diagnosis with AUC of 0.840 and 0.824, respectively. However, the combination of those neurotrophins had excellent diagnostic power to discriminate MDD patients from HC, providing an AUC of 0.916. Vortioxetine treatment significantly increased BDNF and attenuated IGF-1 serum concentrations, improved all psychopathological and neuropsychological parameters and functioning. Conclusions:The combination of IGF-1 and BDNF might be considered as a diagnostic combination for MDD.
Project description:Background:There is a growing interest in vortioxetine in major depressive disorder (MDD). Objectives:This meta-analysis aimed to assess the efficacy and safety of 10 mg/day (mg/d) vortioxetine compared to placebo for MDD in adult. Methods:Eight randomly controlled trials (RCTs) about the treatment of 10 mg/d vortioxetine in adult patients with MDD were identified and 2354 patients were included in meta-analysis. Results:According to the results, 10 mg/d vortioxetine showed significant differences in response rates (OR=1.88, 95% CI=1.40-2.53, P<0.0001), remission rates (OR=1.54, 95% CI=1.27-1.86, P<0.00001), change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score (SMD=-3.50, 95%CI=-4.83 to -2.17, P<0.00001), clinical global Impression-Global Improvement (CGI-I) total score (SMD=-3.40, 95% CI=-4.69 to -2.11, P<0.00001), and change from baseline in Sheehan Disability Scale (SDS) total score (SMD=-2.09, 95% CI=-2.64 to -1.55, P<0.00001). But 10 mg/d vortioxetine was easier induced nausea (OR=4.18, 95% CI=3.21-5.44, P<0.00001) and constipation (OR=1.88, 95% CI=1.14 to 3.09, P=0.01). Conclusion:10 mg/d vortioxetine was more effective, but easily induced nausea and constipation when compared to placebo for MDD in adult.
Project description:<h4>Rationale</h4>Vortioxetine has reduced depressive symptoms in adults with major depressive disorder (MDD) in multiple clinical trials.<h4>Objectives</h4>The aim of this study is to evaluate the efficacy, safety, and tolerability of vortioxetine 15 and 20 mg vs placebo in adults with MDD.<h4>Methods</h4>Patients were randomized 1:1:1:1 to vortioxetine 15 mg, vortioxetine 20 mg, duloxetine 60 mg (active reference), or placebo. The primary efficacy endpoint was mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 8 (MMRM). Safety/tolerability assessments included physical examinations, vital signs, laboratory evaluations, electrocardiograms, adverse events (AEs), Columbia-Suicide Severity Rating Scale, Arizona Sexual Experiences Scale, and Discontinuation-Emergent Signs and Symptoms checklist.<h4>Results</h4>Six hundred and fourteen patients were randomized. Mean changes in MADRS scores were -12.83 (±0.834), -14.30 (±0.890), -15.57 (±0.880), and -16.90 (±0.884) for placebo, vortioxetine 15 mg (P = .224), vortioxetine 20 mg (P = .023), and duloxetine 60 mg (P < .001) (P vs placebo), respectively. AEs reported by ≥5 % of vortioxetine patients included nausea, headache, diarrhea, dizziness, dry mouth, constipation, vomiting, insomnia, fatigue, and upper respiratory infection. Treatment-emergent sexual dysfunction, suicidal ideation or behavior, and discontinuation symptoms were not significantly different between vortioxetine and placebo.<h4>Conclusions</h4>Vortioxetine 20 mg significantly reduced MADRS total scores after 8 weeks of treatment. Both vortioxetine doses were well tolerated.<h4>Clinical trial registration</h4>ClinicalTrials.gov identifier NCT01153009; www.clinicaltrials.gov/ .
Project description:Background:Herein, we sought to determine the sensitivity to change in cognitive function, as measured by the THINC-it tool, in a sample of adults with major depressive disorder (MDD) receiving standardized antidepressant therapy. Methods:Adults meeting the DSM-5 criteria for MDD with at least moderate depressive symptom severity [i.e., Montgomery Åsberg Depression Rating Scale (MADRS) total score ? 20] were treated with open-label vortioxetine (10-20 mg/day, flexibly-dosed) for 8 weeks. The previously validated THINC-it tool was the primary dependent measure. The THINC-it tool was validated against the paper and pencil version of the Digit Symbol Substitution Test (DSST) and the Trails Making Test B (TMTB). Results:After 8 weeks of treatment, adults with MDD exhibited improvement in cognitive function relative to healthy controls (e.g., processing speed) (p = 0.031). A subdomain measure of working memory (i.e., symbol check; SC) exhibited significant improvement at Weeks 2 and 8 in latency (p = 0.032), SC accuracy (p = 0.046), and objective z-score (p = 0.001) independent of depressive symptoms. A linear regression analysis determined that the THINC-it tool measures of processing speed, as well as executive function were significantly associated with changes observed on the pencil and paper version the Digit Symbol Substitution Test (DSST) (p = 0.002) and in Trails Making Test B (TMTB) (p = 0.003), respectively. Conclusion:The THINC-it tool demonstrates sensitivity to change in adults with MDD and is highly correlated with improvements on pencil and paper versions of DSST and TMTB. Clinical Trial Registration:ClinicalTrials.gov, identifier NCT03053362.
Project description:<h4>Purpose</h4>Anhedonia is a core symptom of major depressive disorder (MDD), which has important functional consequences for the patient. This post hoc analysis investigated the relationship between anhedonia and functioning in patients with MDD treated with vortioxetine.<h4>Patients and methods</h4>We conducted a pooled analysis of all 11 short-term, double-blind, randomized, placebo-controlled studies of vortioxetine (fixed dose, 5-20 mg/day) in patients with MDD which included Montgomery-Åsberg Depression Rating Scale (MADRS) and Sheehan Disability Scale (SDS) assessments. A short-term, randomized, active-controlled trial of flexible-dose treatment with vortioxetine (10-20?mg/day) versus agomelatine (25-50 mg/day) was also analyzed. Mean changes from baseline to study endpoint in MADRS total, MADRS anhedonia subscale, SDS total, and SDS social-functioning scores were analyzed by a mixed model for repeated measures. The relationship between treatment effects on anhedonia and functioning was investigated using path analysis.<h4>Results</h4>A total of 4988 patients with MDD were included in the placebo-controlled studies and 495 in the active-comparator study. Significant dose-dependent improvements in overall depressive symptoms, anhedonia, and measures of functioning were seen in vortioxetine-treated patients compared with those who received placebo or agomelatine. Results of the path analysis for the placebo-controlled studies suggested that the effect on functioning was mostly driven by the effect of treatment on MADRS anhedonia factors.<h4>Conclusion</h4>Vortioxetine showed significant short-term efficacy against anhedonia in this large population of patients with MDD. In the placebo-controlled studies, improvements in functioning associated with vortioxetine appeared to be mostly driven by the effect of treatment on MADRS anhedonia factors.