Depression and cerebrovascular disease: could vortioxetine represent a valid treatment option?
ABSTRACT: Depression and cerebrovascular atherosclerosis often occur in comorbidity showing neuropsychological impairment and poor response to antidepressant treatment. Objective is to evaluate if new antidepressant vortioxetine may be a potential treatment option. Mechanism of Action : Vortioxetine has 5-HT3, 5-HT7 and 5-HT1D antagonists, 5-HT1B partial agonist and a 5-HT1A agonist and serotonin transporter inhibitor property. Efficacy and safety in Major Depressive Disorders and in cognitive impairment : The majority of trials (one of them in older people) showed efficacy for vortioxetine against placebo and no differences against other active treatments. The Adverse Effects ranged from 15.8% more to 10.8% less than placebo. In the elderly, only nausea was found higher than placebo. Effects on arterial blood pressure and cardiac parameters including the ECG-QT segment were similar to placebo. Elderly depressive patients on vortioxetine showed improvement versus placebo and other active comparators in Auditory Verbal Learning Test and Digit Symbol Substitution Test scores. The inclusion criteria admitted cases with middle cerebrovascular disease. Conclusion : The mechanism of action, the efficacy on depression and safety profile and early data on cognitive impairment make Vortioxetine a strong candidate for use in depression associated with cerebrovascular disease. This information must be supported by future randomized controlled trials.
Project description:This 2-week randomized, double-blind, placebo-controlled fixed-dose study (NCT02919501) explored the potential of accelerating onset of antidepressant efficacy and plasma exposure with single-dose intravenous vortioxetine at oral vortioxetine treatment initiation. Outpatients (ages 18-65 years) with major depressive disorder and a current depressive episode (Montgomery Åsberg Depression Rating Scale total score ?30) were randomized to an initial single dose of either intravenous vortioxetine 17 mg (n = 27) or intravenous placebo (n = 28), both treatments followed by 2 weeks of oral vortioxetine (10 mg/day). From baseline to day 7, both groups exhibited fast and substantial improvements by approximately 14 Montgomery Åsberg Depression Rating Scale points, with no statistically significant treatment difference for this primary endpoint. Improvements were substantial already within 24 hours, with numerical treatment differences of 1.3 and 1.6 points at days 1 and 3, respectively, in favour of intravenous vortioxetine + oral vortioxetine. Pharmacokinetic data confirmed that intravenous vortioxetine facilitated reaching steady-state plasma concentration within 24 hours. Intravenous vortioxetine + oral vortioxetine was safe and well-tolerated, with nausea as the most common adverse event. This study supported intravenous vortioxetine as a means of rapidly reaching therapeutic vortioxetine blood levels.
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:This 7-day randomized, double-blind, placebo-controlled fixed-dose study (NCT03766867) explored the potential for accelerating the onset of antidepressant efficacy of single-dose intravenous (IV) vortioxetine at oral vortioxetine treatment initiation. Patients (ages 18-65?years) hospitalized per standard-of-care with major depressive disorder, who were currently treated with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor for a major depressive episode [Montgomery-Åsberg Depression Rating Scale (MADRS) total score???30], received one dose of single-blind IV placebo (1-day placebo lead-in period) before being randomly switched to either single-dose IV vortioxetine 25?mg plus daily oral vortioxetine 10?mg (n?=?39), or IV placebo plus daily oral placebo (n?=?41). In the placebo lead-in period, patients improved slightly by 0.6 MADRS-6 point; however, at day 1 after randomization, both treatment groups had improved by approximately 3 MADRS-6 points (mean difference?=?-0.8; P?=?0.263), the study thus not meeting its primary endpoint. Similar results were seen for other outcomes except a numerically larger improvement in anxiety symptoms with vortioxetine vs placebo. Pharmacokinetic data confirmed that IV vortioxetine facilitated reaching steady-state plasma concentration within 24?h. IV plus oral vortioxetine was well tolerated, with low levels of nausea as the most common adverse event.
Project description:This article reviews the pharmacological profile and available efficacy and tolerability/safety data for vortioxetine, one of the most recent antidepressant drugs to be approved in the USA for the treatment of major depressive disorder (MDD) in adults. The efficacy of vortioxetine for treating MDD in adults is supported by eight positive short-term (6- to 12-weeks) randomized, placebo-controlled trials, and one positive randomized, double-blind, 52-week relapse prevention trial. Based on pooled data from short-term randomized trials and from longer-term studies, vortioxetine appears to be well tolerated and to have a low incidence of adverse effects on sexual functioning. Vortioxetine also appears to be effective for treating symptoms of MDD in the elderly based on the results of one randomized trial for which recruitment was focused on this specific population. Nevertheless, effectiveness studies that directly compare the clinical effects of vortioxetine with other established antidepressant drugs are lacking, and there is no evidence as yet that vortioxetine is more clinically effective than other types of antidepressants. Some preliminary suggestions concerning the place of vortioxetine among the broad range of pharmacological treatments for adults with MDD are provided.
Project description:<h4>Objective</h4>This study aimed to compare the efficacy and safety of escitalopram, vortioxetine, and desvenlafaxine for acute treatment of major depressive disorder (MDD) with cognitive complaint (CC).<h4>Methods</h4>A total of 129 patients with MDD who also complained of CC were randomized evenly to either escitalopram, vortioxetine, or desvenlafaxine group and underwent a multi-center, six-week, rater-blinded, and head-to-head comparative trial. Differences in depressive symptoms following treatment were measured using the Hamilton Depression Rating Scale (HAMD) and the Montgomery-Åsberg Depression Rating Scale (MADRS). Subjective cognitive function and the presence of adverse events were assessed.<h4>Results</h4>The three antidepressant treatment groups did not show significant differences in the improvement of depressive symptoms as measured by HAMD and MADRS. Desvenlafaxine treatment was associated with a superior treatment response rate in depressive symptoms compared to vortioxetine or escitalopram treatment. However, no significant differences were found in the remission rate of depressive symptoms. The three antidepressant treatment groups did not show significant differences in the improvement of CC. Adverse profiles of each treatment group were tolerable, with no significant differences.<h4>Conclusion</h4>In acute antidepressant treatment for MDD with CC, escitalopram, vortioxetine, and desvenlafaxine presented similar efficacy in relief of depressive symptoms; however, desvenlafaxine was associated with a superior treatment. Further studies are needed to confirm these results by investigating the therapeutic efficacy and safety profile of long-term antidepressant treatment of MDD with CC (Clinical Trial Registry, http://cris.nih.go.kr/cris/en/: KCT0002173).
Project description:<h4>Background</h4>Partial response to antidepressant medication as well as relapse and treatment resistance are common in major depressive disorder (MDD). Therefore, for most patients with MDD, there will be a need to consider changing antidepressant medication at some stage during the course of the illness. The PREDDICT study investigates the efficacy of augmenting vortioxetine with celecoxib.<h4>Methods</h4>We describe the method used in the PREDDICT study to change participants, who were already taking antidepressant medication at the time of the screening visit, to vortioxetine. We used a cross-titration to change study participants to vortioxetine.<h4>Results</h4>Of a total of 122 study participants who were randomized to receive vortioxetine plus celecoxib or vortioxetine plus placebo at the study baseline visit, 82 were taking antidepressant medication (other than vortioxetine) prior to randomization. These medications were selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants, mirtazapine, or agomelatine. Eighty of these 82 participants completed the changeover to vortioxetine as well as the study baseline visit. We found side effects were generally mild during this changeover period. In addition, there was a reduction in mean total Montgomery-Åsberg Depression Rating Scale score of 2.5 (SD 6.0) from study baseline to week 2 and a further reduction in mean total Montgomery-Åsberg Depression Rating Scale of 2.5 (SD 5.9) from week 2 to week 4.<h4>Conclusion</h4>Changing other antidepressants to vortioxetine can be done safely and was generally well-tolerated. However, there are some antidepressant classes, in particular monoamine oxidase inhibitors that require a washout period, which were not represented in this study.<h4>Trial registration</h4>Australian New Zealand Clinical Trials Registry (ANZCTR); ID number 12617000527369p; http://www.anzctr.org.au/ACTRN12617000527369p.aspx.
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:In patients with major depressive disorder (MDD), antidepressant response and remission rates are low, highlighting the need for new treatment approaches. Recently, the abundant literature linking inflammatory processes and depressive symptoms have led to the hypothesis that selecting treatment for MDD based on the patient's inflammatory status could be a promising strategy to improve outcomes in patients suffering from MDD. The aim of the randomised control trial we propose is to investigate the antidepressant efficacy of the combined treatment of MDD with antidepressant medication plus anti-inflammatory medication in individuals with raised inflammation levels. For the first time, this study will prospectively test the efficacy of an antidepressant plus anti-inflammatory augmentation based on baseline inflammatory maker levels in MDD using a randomised controlled trial design.This study proposes to measure blood C-reactive protein (CRP) levels before the initiation of treatment in 200 participants with MDD. Study participants are then assigned into one of two study strata: either into the 'Depression with inflammation' stratum (CRP levels >?3 mg/L); or into the 'Depression without inflammation' stratum (CRP levels ? 3 mg/L). Within each of the two study strata, participants randomly receive either antidepressant medication alone (vortioxetine) plus anti-inflammatory medication (celecoxib) or vortioxetine plus placebo for six weeks. At the end of the treatment period, participants have the opportunity to continue vortioxetine alone for a six-month post-trial period. Clinical outcomes are measured at baseline, fortnightly during the treatment period and at the three-month and six-month post-trial visits. The primary outcome is change in MADRS score, with a primary endpoint of a score reduction by 50% from baseline to six weeks (end of augmentation treatment with celecoxib). Secondary clinical outcomes are changes in the cognitive dimensions of depression (cognitive function, emotion processing and social cognition). Biological outcome measures (levels of CRP and other inflammatory markers) are measured at baseline, after six weeks of treatment and at the six-month post-trial visit.The current study will generate novel evidence for biomarker-based personalised antidepressant treatment selection based on patient inflammatory status before treatment.Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p . Registered on 11 April 2017.
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:This study assessed the efficacy, tolerability and safety of vortioxetine versus placebo in adults with recurrent major depressive disorder. This double-blind, randomized, placebo-controlled study included 608 patients [Montgomery-Åsberg Depression Rating Scale (MADRS) total score ? 26 and Clinical Global Impression - Severity score ? 4]. Patients were randomly assigned (1 : 1 : 1 : 1) to vortioxetine 15 mg/day, vortioxetine 20 mg/day, duloxetine 60 mg/day or placebo. The primary efficacy endpoint was change from baseline in MADRS total score at week 8 (mixed model for repeated measurements). Key secondary endpoints were: MADRS responders; Clinical Global Impression - Improvement scale score; MADRS total score in patients with baseline Hamilton Anxiety Rating Scale ? 20; remission (MADRS ? 10); and Sheehan Disability Scale total score at week 8. On the primary efficacy endpoint, both vortioxetine doses were statistically significantly superior to placebo, with a mean difference to placebo (n = 158) of -5.5 (vortioxetine 15 mg, P < 0.0001, n = 149) and -7.1 MADRS points (vortioxetine 20 mg, P < 0.0001, n = 151). Duloxetine (n = 146) separated from placebo, thus validating the study. In all key secondary analyses, both vortioxetine doses were statistically significantly superior to placebo. Vortioxetine treatment was well tolerated; common adverse events (incidence ? 5%) were nausea, headache, diarrhea, dry mouth and dizziness. No clinically relevant changes were seen in clinical safety laboratory values, weight, ECG or vital signs parameters. Vortioxetine was efficacious and well tolerated in the treatment of patients with major depressive disorder.