The efficacy and safety of 10 mg/day vortioxetine compared to placebo for adult major depressive disorder: a meta-analysis.
ABSTRACT: 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:Vortioxetine was approved by the U.S. Food and Drug Administration (FDA) in September 2013 for treating major depressive disorder (MDD). Thus far, a number of randomized, double-blind, placebo-controlled clinical trials (RCTs) of vortioxetine have been conducted in patients with MDD. We performed a meta-analysis to increase the statistical power of these studies and enhance our current understanding of the role of vortioxetine in the treatment of MDD.We performed an extensive search of databases and the clinical trial registry. The mean change in total scores on the 24-item Hamilton Rating Scale for Depression (HAM-D) and the Montgomery- Åsberg Depression Rating Scale (MADRS) from the baseline were the primary outcome measures. The secondary efficacy measures were the response and remission rates, as defined by a 50% or greater reduction in HAM-D/MADRS total scores and as a score of 10 or less in the MADRS and 7 or less in the HAM-D total scores at the end of treatment.We included 7 published and 5 unpublished short-term (6-12 wk) RCTs in our meta-analysis. Vortioxetine was significantly more effective than placebo, with an effect size (standardized mean difference [SMD]) of -0.217 (95% confidence interval [CI] -0.313 to -0.122) and with odds ratios (ORs) for response and remission of 1.652 (95% CI 1.321 to 2.067) and 1.399 (95% CI 1.104 to 1.773), respectively. Those treated with vortioxetine did not differ significantly from those treated with selective norepinephrine reuptake inhibitors/agomelatine with regard to the SMD of the primary outcome measure (0.081, -0.062 to 0.223) or for response (OR 0.815, 95% CI 0.585 to 1.135) and remission (OR 0.843, 95% CI 0.575 to 1.238) rates. Discontinuation owing to lack of efficacy (OR 0.541, 95% CI 0.308 to 0.950) was significantly less common among those treated with vortioxetine than among those who received placebo, whereas discontinuation owing to adverse events (AEs; OR 1.530, 95% CI 1.144 to 2.047) was significantly more common among those treated with vortioxetine than among those receiving placebo. There was no significant difference in discontinuation rates between vortioxetine and comparators owing to inefficacy (OR 0.983, 95% CI 0.585 to 1.650), whereas discontinuation owing to AEs was significantly less common in the vortioxetine than in the comparator group (OR 0.728, 95% CI 0.554 to 0.957).Studies examining the role of vortioxetine in the treatment of MDD are limited.Although our results suggest that vortioxetine may be an effective treatment option for MDD, they should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of heterogeneous RCTs.
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:Vortioxetine is the first mixed serotonin agonist and antagonist antidepressant approved in the US. We sought to evaluate all published and unpublished data available to determine the efficacy and harms of vortioxetine in adults with major depressive disorder.We used a predefined search strategy of MEDLINE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Drugs@FDA to identify studies evaluating vortioxetine in the acute treatment of major depressive disorder. Only randomized controlled trials (RCTs) that provided results on relevant clinical efficacy and safety outcomes were included. Study quality was assessed and results were pooled using mixed effect meta-analyses where applicable.We identified 11 RCTs with 6,145 participants meeting inclusion criteria (eight were published and three were unpublished). The trials did not exceed 8 weeks in duration. The response rate with vortioxetine was significantly higher for 1-mg (relative risk (RR)?=?1.91; 95% confidence interval (CI) 1.36 to 2.69), 5-mg (RR?=?1.33; 95% CI 1.10 to 1.61), 10-mg (RR?=?1.42; 95% CI 1.21 to 1.67), and 20-mg doses (RR?=?1.58; 95% CI 1.19 to 2.08) compared to placebo. Remission rates were significantly higher for the 10-mg group (RR?=?1.45; 95% CI 1.18 to 1.77) and the 20-mg group (RR?=?1.68; 95% CI 1.19 to 2.37) compared to placebo. Meta-regression of dose on the log odds ratio of response was not statistically significant (??=?0.01; P?=?0.46). Vortioxetine response rates were lower than active serotonin and norepinephrine reuptake inhibitor (SNRI) comparators for the 5-mg (RR?=?0.88; 95% CI 0.80 to 0.98), 15-mg (RR?=?0.78; 95% CI 0.68 to 0.90), and 20-mg (RR?=?0.82; 95% CI 0.72 to 0.94) doses. The most common adverse events were nausea and vomiting which increased in frequency with higher doses.Vortioxetine was significantly more effective than placebo for acute treatment of major depressive disorder (MDD). Although treatment effect estimates varied substantially between studies, a dose effect was not observed. Vortioxetine does not appear to be more effective, and is potentially less effective, than an SNRI.PROSPERO CRD42013006198 .
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:Objective:The purpose of this study was to assess the effectiveness and safety of acupuncture for functional constipation (FC). Methods:A rigorous literature search was performed in English (PubMed, Web of Science, the Cochrane Library, and EMBASE) and Chinese (China National Knowledge Infrastructure (CNKI), Chinese Biological Medical (CBM), Wanfang database, and China Science and Technology Journal (VIP)) electronic databases from their inception to October 2019. Included randomized controlled trials (RCTs) compared acupuncture therapy with sham acupuncture or pharmacological therapies. The outcome measures were evaluated, including the primary outcome of complete spontaneous bowel movement (CSBM) and secondary outcomes of Bristol Stool Form Scale (BSFS), constipation symptoms scores (CSS), responder rate, the Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire, and safety evaluation. Meta-analysis was performed by using RevMan5.3. Results:The merged data of 28 RCTs with 3525 participants indicated that acupuncture may be efficient for FC by increasing CSBMs (p < 0.00001; MD?=?0.84 [95% CI, 0.65 to 1.03]; I 2?=?0%) and improving constipation symptoms (p=0.03; SMD?=?-0.4 [95% CI, -0.78 to -0.03]; I 2?=?74%), stool formation (p < 0.00001; MD?=?0.24 [95% CI, 0.15 to 0.34]; I 2?=?0%), quality of life (p < 0.00001; N?=?1, MD?=?-0.33 [95% CI, -0.45 to -0.21]), and responder rates (p=0.02; RR?=?2.16; [95% CI, 1.1 to 4.24]; I 2?=?69%) compared with the effects of sham treatment. No increased risk of adverse events was observed (p=0.44; RR?=?1.18; [95% CI, 0.77 to 1.81]; I 2?=?0%). With regard to medication comparisons, the pooled data indicated that acupuncture was more effective in increasing CSBMs (p=0.004; MD?=?0.53 [95% CI, 0.17 to 0.88]; I 2?=?88%) and improving patients' quality of life (p < 0.00001; SMD?=?-0.73 [95% CI, -1.02 to -0.44]; I 2?=?64%), with high heterogeneity. However, there were no significant differences in responder rate (p=0.12; RR?=?1.31; [95% CI, 0.94 to 1.82]; I 2?=?53%), BSFS (p=0.5; MD?=?0.17 [95% CI, -0.33 to 0.68]; I 2?=?93%), or CSS (p=0.05; SMD?=?-0.62 [95% CI, -1.23 to -0.01]; I 2?=?89%). Regarding safety evaluation, acupuncture was safer than medications (p < 0.0001; RR?=?0.3; [95% CI, 0.18 to 0.52]; I 2?=?30%). Conclusions:Current evidence suggests that acupuncture is an efficient and safe treatment for FC. Acupuncture increased stool frequency, improved stool formation, alleviated constipation symptoms, and improved quality of life. However, the evidence quality was relatively low and the relationship between acupuncture and drugs is not clear. More high-quality trials are recommended in the future. PROSPERO registration number: CRD42019143347.
Project description:Extensive burns result in a local wound response and distant-organ injury (DOI) caused by oxidative-stress and inflammation. Melatonin (MT) shows promise in alleviating oxidative-stress and inflammation, but its role in thermal injury is largely unexplored. The present systematic review and meta-analysis were designed to assess the effects of MT on oxidative-stress and inflammatory markers against severe burn-induced DOI. Mean difference (MD)/standard mean difference (SMD) with 95% confidence interval (CI) were estimated using fixed-effect/random-effects models. Eighteen experimental studies met the inclusion criteria. Compared with the control group, MT significantly decreased the levels of malondialdehyde (SMD, -1.03; 95% CI, -1.30, -0.76, <i>p</i> < 0.00001) and 4-hydroxynonenal (MD, -1.06; 95% CI, -1.57, -0.56, <i>p</i> < 0.0001). Additionally, MT increased the levels of glutathione (SMD, 1.94; 95% CI, 1.27, 2.61, <i>p</i> < 0.00001) and superoxide-dismutase (SMD, 0.76; 95% CI, 0.08, 1.45, <i>p</i> = 0.03). Finally, MT significantly decreased the levels of tumor necrosis factor-? (SMD, -1.34; 95% CI, -1.92 to -0.77; <i>p</i> < 0.00001) and C-reactive protein (MD, -12.67; 95% CI, -16.72 to -8.62; <i>p</i> < 0.00001). Meta-analysis indicates that severe burn followed by immediate MT (10 mg/kg) intervention shows significant beneficial effects after 24-h against DOI by regulating oxidative-stress and the inflammatory response.
Project description: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?<?0.01 for each dose), respectively. MADRS response and remission rates were also significantly greater with vortioxetine than with placebo (P?<?0.05 for both doses). Vortioxetine 10 and 20?mg significantly improved HAM-D17 score, CGI-I score, and SDS total score after 8?weeks. PDQ-5 score was significantly improved in subjects administered vortioxetine, while DSST scores showed no significant difference. Vortioxetine was generally well tolerated. CONCLUSION:Vortioxetine at both the 10- and 20-mg/day doses demonstrated robust antidepressant efficacy in Japanese patients with MDD, and was well tolerated over the 8-week treatment period.
Project description:Cognitive dysfunction is often present in major depressive disorder (MDD). Several clinical trials have noted a pro-cognitive effect of antidepressants in MDD. The objective of the current systematic review and meta-analysis was to assess the pooled efficacy of antidepressants on various domains of cognition in MDD.Trials published prior to April 15, 2015, were identified through searching the Cochrane Central Register of Controlled Trials, PubMed, Embase, PsychINFO, Clinicaltrials.gov, and relevant review articles. Data from randomized clinical trials assessing the cognitive effects of antidepressants were pooled to determine standard mean differences (SMD) using a random-effects model.Nine placebo-controlled randomized trials (2 550 participants) evaluating the cognitive effects of vortioxetine (n = 728), duloxetine (n = 714), paroxetine (n = 23), citalopram (n = 84), phenelzine (n = 28), nortryptiline (n = 32), and sertraline (n = 49) were identified. Antidepressants had a positive effect on psychomotor speed (SMD 0.16; 95% confidence interval [CI] 0.05-0.27; I(2) = 46%) and delayed recall (SMD 0.24; 95% CI 0.15-0.34; I(2) = 0%). The effect on cognitive control and executive function did not reach statistical significance. Of note, after removal of vortioxetine from the analysis, statistical significance was lost for psychomotor speed. Eight head-to-head randomized trials comparing the effects of selective serotonin reuptake inhibitors (SSRIs; n = 371), selective serotonin and norepinephrine reuptake inhibitors (SNRIs; n = 25), tricyclic antidepressants (TCAs; n = 138), and norepinephrine and dopamine reuptake inhibitors (NDRIs; n = 46) were identified. No statistically significant difference in cognitive effects was found when pooling results from head-to-head trials of SSRIs, SNRIs, TCAs, and NDRIs. Significant limitations were the heterogeneity of results, limited number of studies, and small sample sizes.Available evidence suggests that antidepressants have a significant positive effect on psychomotor speed and delayed recall.
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>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.