Clinical benefits of vortioxetine 20 mg/day in patients with major depressive disorder.

BACKGROUND: Vortioxetine has demonstrated dose-dependent efficacy in patients with major depressive disorder (MDD), with the greatest effect observed with vortioxetine 20 mg/day. This analysis further explored the clinical relevance of the more rapid and greater improvement in depressive symptoms observed with vortioxetine 20 mg/day vs 10 mg/day. METHODS: Analysis of pooled data from six short-term (8-week), randomized, placebo-controlled, fixed-dose studies of vortioxetine 20 mg/day in patients with MDD (N = 2620). Symptomatic response (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] total score), sustained symptomatic response, and remission (MADRS total score ≤10) were assessed by vortioxetine dosage (20 or 10 mg/day). RESULTS: After 8 weeks, 51.4% of patients receiving vortioxetine 20 mg/day had achieved symptomatic response vs 46.0% of those receiving vortioxetine 10 mg/day (P < .05). Significantly more patients achieved symptomatic response vs placebo from week 2 onwards for vortioxetine 20 mg/day and from week 6 onwards for vortioxetine 10 mg/day (both P ≤ .05). Sustained response was achieved from week 4 for 26.0% of patients receiving vortioxetine 20 mg/day vs 19.1% of those receiving vortioxetine 10 mg/day (P < .01), increasing to 36.0% and 29.8%, respectively, over the 8-week treatment period (P < .05). At week 8, 32.0% of patients receiving vortioxetine 20 mg/day were in remission vs 28.2% of those receiving vortioxetine 10 mg/day (P = .09). Rates of adverse events and treatment withdrawal were not increased during the week following vortioxetine dose up-titration to 20 mg/day. CONCLUSION: Vortioxetine 20 mg/day provides more rapid and more sustained symptomatic response than vortioxetine 10 mg/day in patients with MDD, without compromising tolerability.

Vortioxetine in patients with major depressive disorder and high levels of anxiety symptoms: An updated analysis of efficacy and tolerability.

BACKGROUND: Patients with major depressive disorder (MDD) often experience comorbid anxiety symptoms. Vortioxetine has demonstrated efficacy in treating anxiety symptoms in patients with MDD; however, efficacy and tolerability have not been assessed across the entire approved dosage range. METHODS: The efficacy and tolerability of vortioxetine 5-20 mg/day were assessed in patients with MDD and high levels of anxiety symptoms (Hamilton Anxiety Rating Scale [HAM-A] total score ≥ 20) using pooled data from four randomized, fixed-dose, placebo-controlled studies (n = 842). Data from a randomized, double-blind study of vortioxetine 10-20 mg/day versus agomelatine 25-50 mg/day in patients with an inadequate response to prior therapy (n = 299) were analyzed separately. Mean changes from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-A, and Sheehan Disability Scale (SDS) total scores were analyzed by vortioxetine dosage. RESULTS: The pooled analysis of fixed-dose studies demonstrated a clear dose-response relationship for vortioxetine 5-20 mg/day for improvements in MADRS, HAM-A, and SDS total scores. Vortioxetine 20 mg/day demonstrated significant effects versus placebo from week 4 onwards. In the post-hoc analysis of the active-controlled study in patients with an inadequate response to prior therapy, vortioxetine 10-20 mg/day was superior to agomelatine across all outcome measures from week 4 onwards. Up-titration of vortioxetine to 20 mg/day was not associated with an increase in adverse events. LIMITATIONS: Short-term trials. CONCLUSIONS: Vortioxetine is efficacious and well tolerated in patients with MDD and high levels of anxiety symptoms, including those with an inadequate response to prior therapy. The greatest therapeutic benefits were observed with vortioxetine 20 mg/day. TRIAL REGISTRATION: NCT01140906, NCT01153009, NCT01163266, NCT01255787, NCT01488071.

Vortioxetine 20 mg/day in patients with major depressive disorder: updated analysis of efficacy, safety, and optimal timing of dose adjustment.

BACKGROUND: Analysis of efficacy and tolerability of vortioxetine 20 mg/day, and optimal timing of dose adjustment, in patients with major depressive disorder (MDD). METHODS: Pooled analysis of six randomized, fixed-dose studies of vortioxetine 5 to 20 mg/day. Mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was analyzed by vortioxetine dose using a mixed model for repeated measures. Tolerability was assessed over the 8-week treatment period and from day 8 (ie, following dose increase to 20 mg/day). Data from three randomized, flexible-dose studies were examined for frequency and timing of dose adjustment. RESULTS: A clear dose-response relationship for vortioxetine was confirmed in terms of improvement in MADRS total score. Significant differences vs placebo were seen for vortioxetine 20 mg/day from week 2 onwards; vortioxetine 10 mg did not separate from placebo until week 4. At week 8, mean change in MADRS total score from baseline was significantly greater for vortioxetine 20 mg/day vs 10 mg/day (difference, -1.03 points; P < .05). Incidence of adverse events was not increased in patients who received vortioxetine 20 mg/day vs 10 mg/day. In flexible-dose studies, dosage was increased to 20 mg/day after 1 week in 48.0% of patients; final dosage was 20 mg/day in 64.3% of patients. CONCLUSIONS: Vortioxetine 20 mg is significantly more effective than vortioxetine 10 mg in patients with MDD, with a similar tolerability profile. In flexible-dose studies, almost half of all patients received 20 mg/day after 1 week and two-thirds received 20 mg/day as their final dosage.

The Motivation and Energy Inventory (MEI): Analysis of the clinically relevant response threshold in patients with major depressive disorder and emotional blunting using data from the COMPLETE study.

BACKGROUND: The Motivation and Energy Inventory (MEI) is a patient-reported scale for assessment of the impact of mental/cognitive energy, social motivation, and physical energy on daily functioning in patients with major depressive disorder (MDD). This analysis was undertaken to establish the clinically relevant response threshold for the MEI in patients with MDD receiving antidepressant treatment. METHODS: Patients with MDD experiencing inadequate response and emotional blunting on selective serotonin reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor monotherapy (adequate dose for ≥6 weeks) were switched to vortioxetine 10-20 mg/day for 8 weeks. Anchor- and distribution-based methods were used to determine the minimal clinically important difference (MCID) in MEI total score. RESULTS: After 8 weeks of vortioxetine treatment, mean (standard deviation) change in MEI total score from baseline was 33.0 (27.3) points. At week 8, mean change in MEI total score from baseline was 37.5 (27.8) points in patients no longer reporting emotional blunting and 28.3 (26.2) points in those still experiencing emotional blunting. In patients considered minimally improved (i.e. Clinical Global Impression-Improvement [CGI-I] score of 3 after 8 weeks of vortioxetine), mean change in MEI total score from baseline was 14.7 (19.1) points. In patients defined as responders (CGI-I score of 2 at 8 weeks), mean change in MEI total score was 33.0 (24.7) points. LIMITATIONS: Short study duration. CONCLUSIONS: These results provide further validation of the clinical utility of the MEI for assessing treatment response in patients with MDD. The suggested MCID for MEI total score is 15 points. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03835715.

Endocannabinoid Modulation Using Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A Phase 1 Randomized, Placebo-Controlled Study.

INTRODUCTION: Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by chronic motor and vocal tics. While consistently effective treatment is lacking, evidence indicates that the modulation of endocannabinoid system is potentially beneficial. Lu AG06466 (previously ABX-1431) is a highly selective inhibitor of monoacylglycerol lipase, the primary enzyme responsible for the degradation of the endocannabinoid ligand 2-arachidonoylglycerol. This exploratory study aimed to determine the effect of Lu AG06466 versus placebo on tics and other symptoms in patients with TS. METHODS: In this phase 1b cross-over study, 20 adult patients with TS on standard-of-care medications were randomized to a single fasted dose of Lu AG06466 (40 mg) or placebo in period 1, followed by the other treatment in period 2. The effects on tics, premonitory urges, and psychiatric comorbidities were evaluated using a variety of scaled approaches at different time points before and after treatment. RESULTS: All scales showed an overall trend of tic reduction, with two out of three tic scales (including the Total Tic Score of the Yale Global Tic Severity Score) showing a significant effect of a single dose of Lu AG06466 versus placebo at various timepoints. Treatment with Lu AG06466 resulted in a significant reduction in premonitory urges versus placebo. Single doses of Lu AG06466 were generally well-tolerated, and the most common adverse events were headache, somnolence, and fatigue. CONCLUSION: In this exploratory trial, a single dose of Lu AG06466 showed statistically significant positive effects on key measures of TS symptoms.

Validation of the Oxford Depression Questionnaire: Sensitivity to change, minimal clinically important difference, and response threshold for the assessment of emotional blunting.

BACKGROUND: The Oxford Depression Questionnaire (ODQ) is a patient-reported scale for assessing emotional blunting in patients with major depressive disorder (MDD). This analysis was undertaken to further validate the scale in patients experiencing emotional blunting while receiving antidepressant treatment. METHODS: Patients with MDD who experienced inadequate depressive-symptom resolution and emotional blunting on selective serotonin reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor monotherapy (adequate dose for ≥6 weeks) were switched to vortioxetine 10-20 mg/day. ODQ total scores were assessed excluding and including the "antidepressant-as-cause" domain (ODQ-20 and ODQ-26, respectively). Anchor- and distribution-based methods were used to determine the minimal clinically important difference in ODQ scores in terms of change from baseline to week 8 of antidepressant treatment. RESULTS: After 8 weeks of vortioxetine treatment, the mean change in ODQ-20 and ODQ-26 scores from baseline was -24.8 and -30.1 points, respectively. Greater mean changes from baseline in ODQ-20 and ODQ-26 scores were seen in patients reporting no emotional blunting vs those still experiencing emotional blunting after 8 weeks of vortioxetine treatment (ODQ-20: -27.0 vs -22.6 points; ODQ-26: -32.8 vs -27.5 points, respectively). In patients considered clinically minimally improved (Clinical Global Impression-Improvement score, 3) after 8 weeks of vortioxetine treatment, respective mean (standard deviation) change in ODQ-20 and ODQ-26 score from baseline was -15.5 (18.1) and -20.0 (20.5) points. LIMITATIONS: Short study duration. CONCLUSIONS: These results provide further validation of the clinical utility of the ODQ for assessing emotional blunting in patients with MDD. The suggested minimal clinically important difference for change in ODQ-20 and ODQ-26 scores is 16 and 20 points, respectively, after 8 weeks of antidepressant treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03835715.

Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A 12-Week, Randomized, Controlled Study.

BACKGROUND: Modulation of the endocannabinoid system via monoacylglycerol lipase inhibition with Lu AG06466 (formerly known as ABX-1431) has previously been shown to reduce tics in patients with Tourette syndrome. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of Lu AG06466 in reducing tics, premonitory urges, and comorbidities in patients with Tourette syndrome. METHODS: This was a 12-week, multicenter, randomized, placebo-controlled, double-blind clinical trial of Lu AG06466 given at two dose levels in 49 adults with Tourette syndrome. RESULTS: Both treatment groups showed improvement on the Total Tic Score of the Yale Global Tic Severity Scale; the mean (95% CI) treatment difference at week 8 of 3.0 (0.1, 5.9) (P = 0.043) favored placebo. No significant differences were seen for other endpoints assessing changes in tic severity, premonitory urges, quality of life, and common psychiatric comorbidities. Treatment with Lu-AG06466 was generally safe. CONCLUSIONS: There was no evidence that Lu AG06466 has efficacy in suppressing tics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Efficacy of Vortioxetine on Anhedonia: Results from a Pooled Analysis of Short-Term Studies in Patients with Major Depressive Disorder.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Effectiveness of Vortioxetine on Emotional Blunting in Patients with Major Depressive Disorder with inadequate response to SSRI/SNRI treatment.

INTRODUCTION: Inadequate treatment response and emotional blunting are common challenges with selective serotonin reuptake inhibitors/serotonin-noradrenaline reuptake inhibitors (SSRIs/SNRIs) for major depressive disorder (MDD). We investigated the effectiveness of vortioxetine on emotional blunting in patients with partial response to treatment with SSRIs/SNRIs. METHODS: Patients with MDD who experienced a partial response to SSRI/SNRI monotherapy at adequate dose for ≥6 weeks were switched to 8 weeks of vortioxetine treatment 10-20 mg/day (Study NCT03835715). Key inclusion criteria were Montgomery-Åsberg Depression Rating Scale (MADRS) total score >21 and <29, current major depressive episode <12 months, Oxford Depression Questionnaire (ODQ) total score ≥50, and confirmation of emotional blunting by standardized screening question. Emotional blunting was assessed by ODQ and depressive symptoms by MADRS. Other outcomes assessed included motivation and energy (Motivation and Energy Inventory [MEI]), cognitive performance (Digit Symbol Substitution Test [DSST]), and overall functioning (Sheehan Disability Scale [SDS]). RESULTS: At week 8, patients (N=143) had improved by -29.8 points (p<0.0001) in ODQ total score; 50% reported no emotional blunting in response to standardized screening question. Significant improvements were observed on the DSST, MEI, and SDS at all time points assessed, and 47% of patients were in remission (MADRS total score ≤10) at week 8. The most common treatment-emergent adverse events included nausea, headache, dizziness, vomiting, and diarrhea. LIMITATIONS: No prospective phase before medication switch. CONCLUSION: Vortioxetine 10-20 mg effectively improved emotional blunting, overall functioning, motivation and energy, cognitive performance, and depressive symptoms in patients with MDD with partial response to SSRI/SNRI therapy and emotional blunting.

Successfully treated patients with vortioxetine versus venlafaxine: a simplified cost-effectiveness analysis based on a head-to-head study in Asian patients with major depressive disorder.

Objective: To compare the rates of successfully treated patients (STPs) with vortioxetine versus venlafaxine in major depressive disorder (MDD), using dual endpoints that combine improvement of mood symptoms with optimal tolerability or functional remission, and conduct a simplified cost-effectiveness analysis.Methods: The 8-week SOLUTION study (NCT01571453) assessed the efficacy and safety of vortioxetine (10 mg/day) versus venlafaxine XR (150 mg/day) in adult Asian patients with MDD. Rates were calculated post-hoc of STP Mood and Tolerability (≥50% reduction from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score and no treatment-emergent adverse events) and STP Mood and Functioning (≥50% reduction from baseline in MADRS total score and Sheehan Disability Scale total score ≤6). The incremental costs per STP were assessed using the 2018 pharmacy purchase prices for branded vortioxetine/branded venlafaxine in China as the base case.Results: STP Mood and Tolerability rates were 28.9% for vortioxetine and 19.9% for venlafaxine (p = .028); the corresponding STP Mood and Functioning rates were 28.0% and 23.5% (p = .281). Drug costs for the 8-week treatment period were CN¥1954 for vortioxetine and CN¥700 for venlafaxine. The incremental cost per STP for vortioxetine versus venlafaxine was CN¥13,938 for Mood and Tolerability and CN¥27,876 for Mood and Functioning.Conclusions: Higher rates of dual treatment success were seen with vortioxetine versus venlafaxine. Although vortioxetine was not dominant in the base case, the incremental cost per STP for vortioxetine versus venlafaxine were overall within acceptable ranges. These results support the benefits previously reported with vortioxetine versus other antidepressants in broad efficacy, tolerability profile and cost-effectiveness.

Efficacy of vortioxetine in patients with major depressive disorder reporting childhood or recent trauma.

BACKGROUND: This analysis investigates the efficacy of vortioxetine in adults with major depressive disorder (MDD) who report childhood or recent trauma. METHODS: Patient-level data were analyzed from 4 double-blind, randomized, placebo-controlled short-term studies investigating the efficacy of vortioxetine (5-20 mg/day) versus placebo in patients (18-75 years old) with DSM-IV-TR-defined MDD. Changes from baseline to week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression - Improvement (CGI-I), and Sheehan Disability Scale (SDS) were examined at the individual study level and as in meta-analysis. A long-term relapse prevention study of 5 and 10 mg of vortioxetine was also analyzed. Traumatic events history was recorded at baseline. RESULTS: Sixty-one percent of subjects (1113/1811) reported trauma history in the short-term studies. A significant effect vs. placebo was observed for vortioxetine on MADRS (10 mg, -2.2, P = .025; 20 mg, -4.4, P < .001), HAM-A (20 mg, -1.60, P = .012), CGI-I (5 mg, -0.3, P = .028; 10 mg, -0.3, P = .013; 20 mg, -0.50, P = .009), and SDS (20 mg, -2.3, P = .007) in patients with any trauma (childhood and/or recent). In the relapse prevention study, 51% (198/392) of subjects reported a history of trauma. Subjects with any trauma (childhood and/or recent) randomized to placebo were significantly more likely to relapse than subjects treated with vortioxetine (hazard ratio 2.8, P = .0019). LIMITATIONS: An exploratory analysis. DISCUSSION: Vortioxetine showed significant short- and long-term efficacy on depressive and anxiety symptoms and overall functioning in this large subpopulation of MDD patients with a history of trauma. A significantly lower risk of relapse was also observed with vortioxetine.

Efficacy of vortioxetine in working patients with generalized anxiety disorder.

BACKGROUND: Vortioxetine is an approved antidepressant that has also demonstrated positive effects on anxiety symptoms in subjects with generalized anxiety disorder (GAD). This post-hoc analysis evaluates the efficacy of vortioxetine in GAD subjects who are working and/or pursuing an education. METHODS: In study NCT00744627, 301 GAD subjects were randomized to vortioxetine 5 mg or placebo for 8 weeks. Efficacy measures included the Hamilton Anxiety Rating Scale (HAM-A) total score, response/remission, global functioning (Sheehan Disability Scale [SDS]), and quality of life (Short Form-36 Health Survey). In study NCT00788034, 687 GAD subjects were treated open-label with vortioxetine 5 or 10 mg for 20 weeks, after which subjects in remission were randomized to fixed-dose of vortioxetine (5 or 10 mg) or placebo for at least 24 weeks. The primary endpoint was time to relapse. Analyses were completed in subjects working and/or pursuing an education at study entry and the full analysis set. RESULTS: In study NCT00744627, the effect of vortioxetine versus placebo on HAM-A total score was -4.3 (p=0.0005) in working subjects (60% of total), while the effect in the total population was -3.8 (p=0.0001). The effect was greatest in subjects in professional (-4.5, p=0.0130) and associate professional positions (-7.6, p=0.0086). Greater effects in terms of response, remission, and the SDS and SF-36 were also observed. In NCT00788034, working subjects (69% of total) randomized to placebo were significantly more likely to relapse than subjects treated with vortioxetine (hazard ratio=2.9; p<0.001), while the hazard ratio in the total population was 2.7 (p<0.0001). CONCLUSIONS: The beneficial effects of vortioxetine on anxiety symptoms, functioning, and quality of life are greater in adults with GAD who are working and/or pursuing an education versus the full GAD study population.

Vortioxetine improves symptomatic and functional outcomes in major depressive disorder: A novel dual outcome measure in depressive disorders.

BACKGROUND: With symptomatic remission and functional recovery as the overarching therapeutic objectives of antidepressant therapy, composite endpoint measures that conjointly consider both aspects of treatment are needed. This analysis evaluated the combined effect of vortioxetine on depressive symptoms and functional capacity in adults with MDD. METHODS: NCT01564862, a multinational, double-blind, placebo-controlled, duloxetine-referenced study, conducted between April 2012 and February 2014, in 602 adult outpatients (18-65 years) with moderate-to-severe MDD (Montgomery-Åsberg Depression Rating Scale (MADRS) ≥ 26), a major depressive episode of ≥ 3 months' duration, and self-reported cognitive symptoms were randomized to once-daily vortioxetine (10 or 20mg), duloxetine (60mg), or placebo for 8 weeks. Assessments included the University of California San Diego Performance-based Skills Assessment (UPSA) and the MADRS. Two versions of UPSA were utilized; UPSA â€’Validation of Intermediate Measures and UPSA Brief form. An aligned UPSA-B (communication and finance items) was examined for sensitivity analysis. Efficacy was analyzed versus placebo according to the dual response (change from baseline in UPSA ≥ 7 and ≥ 9 and reduction in MADRS total score from baseline ≥ 50%). RESULTS: Significantly more vortioxetine-treated patients were classified as dual responders for change in MADRS total score and UPSA score of ≥ 7 (clinically important difference [CID]) (27.4% vs 14.5%; P = 0.004), and change above CID (≥ 9) (23.4% vs 13.9%; P = 0.025). Duloxetine did not differ significantly from placebo for these dual response criteria. Sensitivity analysis using the aligned UPSA-B confirmed these results for vortioxetine. LIMITATIONS: An exploratory analysis of a new dual outcome measure in patients with MDD. CONCLUSIONS: Vortioxetine, but not duloxetine, demonstrated a robust combined effect on depressive symptoms and functional capacity in patients with MDD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01564862; European Clinical Trials Database [EudraCT] Number 2011-005298-22.

Factors associated with failure to achieve remission and with relapse after remission in patients with major depressive disorder in the PERFORM study.

BACKGROUND: The Prospective Epidemiological Research on Functioning Outcomes Related to Major Depressive Disorder (PERFORM) study has been initiated to better understand the course of a depressive episode and its impact on patient functioning. This analysis aimed to identify sociodemographic and clinical factors associated with failure to achieve remission at month 2 after initiating or switching antidepressant monotherapy and with subsequent relapse at month 6 for patients in remission at month 2. MATERIALS AND METHODS: This was a 2-year observational cohort study in 1,159 outpatients aged 18-65 years with major depressive disorder initiating or undergoing the first switch of antidepressant monotherapy. Factors with P<0.20 in univariate logistic regression analyses were combined in a multiple logistic regression model to which backward variable selection was applied (ie, sequential removal of the least significant variable from the model and recomputation of the model until all remaining variables have P<0.05). RESULTS: Baseline factors significantly associated with lower odds of remission at month 2 were body-mass index ≥30 kg/m2 (OR 0.51), depressive episode >8 weeks (OR 0.51), being in psychotherapy (OR 0.51), sexual dysfunction (OR 0.62), and severity of depression (OR 0.87). Factors significantly associated with relapse at month 6 were male sex (OR 2.47), being married or living as a couple (OR 2.73), residual patient-reported cognitive symptoms at 2 months (OR 1.12 per additional unit of Perceived Deficit Questionnaire-5 score) and residual depressive symptoms at 2 months (OR 1.27 per additional unit of Patient Health Questionnaire-9 score). CONCLUSION: Different factors appear to be associated with failure to achieve remission in patients with major depressive disorder and with subsequent relapse in patients who do achieve remission. Patient-reported cognitive dysfunction is an easily measurable and treatable characteristic that may be associated with an increased likelihood of relapse at 6 months in patients who have achieved remission.

Effectiveness of long-term vortioxetine treatment of patients with major depressive disorder.

To investigate the effectiveness, safety, and tolerability of vortioxetine in patients treated at therapeutic doses (5-20mg/day) for both acute and maintenance treatment, patient-level data were pooled from 5 long-term (52-week), open-label extension studies of major depressive disorder. The mean (±standard deviation) MADRS total score improved from 17.1±10.2 at the start of maintenance therapy to 7.6±8.2 (observed cases [OC]) or 10.3±9.9 (last observation carried forward [LOCF]) at week 52. The mean HAM-A total scores improved from 11.3±6.9 to 6.0±6.0 (OC) or 7.5±6.7 (LOCF) and the mean CGI-S score improved from 3.11±1.20 to 1.94±1.08 (OC) or 2.27±1.26 (LOCF) at week 52. Response and remission rates increased over time. At week 52, the total response rate was 75.4% (n=916/1215, LOCF) and the total remission rate was 60.7% (n=738/1215, LOCF). There were no differences in effectiveness as assessed by MADRS total scores at week 52 in subgroups based on gender, age (<55 vs ≥55 years), baseline HAM-A total score (<20 vs ≥20), baseline MADRS total score (<30 vs ≥30), previous major depressive episodes (MDEs) (<3 vs ≥3) or current MDE duration (<6 vs ≥6 months) at the start of the lead-in studies, or response status (≥50% decrease in MADRS total score during the lead-in study). The most commonly reported adverse event during the maintenance period was nausea.

The effect of vortioxetine on overall patient functioning in patients with major depressive disorder.

BACKGROUND: The objectives of this meta-analysis of data from randomized, placebo-controlled studies were to assess the effect of vortioxetine on overall functioning (primary) and functional remission (secondary) using the Sheehan Disability Scale (SDS) in adults with major depressive disorder (MDD). METHODS: Data from nine short-term (6/8 weeks) pivotal studies that included patient functioning assessments were included in this random-effects meta-analysis, which used aggregated study-level data for all therapeutic vortioxetine doses and a mixed-effect model for repeated measures using the full analysis set. RESULTS: A total of 4,216 patients received ≥1 dose of study treatment (1,522 placebo, 2,694 vortioxetine 5-20 mg/day). At study end, the meta-analysis showed improvement for vortioxetine versus placebo (n = 911) in SDS total score (vortioxetine 5 mg, n = 564, change from baseline versus placebo [Δ] -0.24, p = NS; 10 mg, n = 445, Δ -1.68, p ≤ .001; 15 mg, n = 204, Δ -0.91, p = NS; 20 mg, n = 340, Δ -1.94, p ≤ .01). Functional remission (SDS total score ≤6) was observed with vortioxetine 10 mg (n = 170/573; odds ratio [OR] relative to placebo 1.7, p < .001) and 20 mg (n = 144/447; OR 1.6, p < .05), but not 5 mg (n = 207/757; OR 1.1, p = NS) or 15 mg (n = 92/295; OR 1.3, p = NS). CONCLUSION: Vortioxetine 5-20 mg for 6/8 weeks improved overall patient functioning in patients with MDD. Relative to placebo, vortioxetine 10 and 20 mg demonstrated significant improvement in SDS total score and functional remission.

Efficacy of Vortioxetine on Cognitive Functioning in Working Patients With Major Depressive Disorder.

OBJECTIVE: This post hoc analysis investigates the effect of vortioxetine on cognitive functioning and depressive symptoms in working adults with major depressive disorder (MDD). METHODS: Population data from FOCUS, a double-blind, randomized, placebo-controlled study investigating the efficacy of vortioxetine versus placebo on cognitive functioning and depression in patients with MDD, were used to analyze mean change from baseline scores for the Digit Symbol Substitution Test (DSST), Trail Making Test A/B (TMT-A/B), Stroop, and Perceived Deficits Questionnaire (PDQ). FOCUS, conducted from December 2011 through May 2013, included adult patients with recurrent MDD according to DSM-IV-TR criteria. Change in depression severity (Montgomery-Asberg Depression Rating Scale [MADRS] total score) was analyzed using data from 3 additional short-term placebo-controlled studies (2 of which included duloxetine) and 1 relapse prevention study. Analyses were done according to patients' working status at baseline and workplace position. All analyses were made versus placebo. RESULTS: In FOCUS, the effect versus placebo on the DSST was 5.6 for 10 mg and 5.0 for 20 mg (P < .001 for both doses) in working patients; the effect was 4.0 (P < .001 for both doses) in total study population. The effect remained significant when adjusting for change in MADRS. In patients with "professional" positions, the effect was 9.2 for 10 mg (P = .006) and 9.0 for 20 mg (P = .001). A similar pattern of results was also observed for TMT-A/B, Stroop, PDQ, and MADRS total score. The efficacy of duloxetine was not different in working patients (MADRS). CONCLUSIONS: The beneficial effects of vortioxetine on objective and subjective measures of cognitive functioning are greater in working patients with MDD; the observed benefits were independent of improvement in depressive symptoms. TRIAL REGISTRATION: This study is a secondary analysis of data from 5 registered trials: ClinicalTrials.gov identifiers: NCT01422213, NCT00635219, NCT00735709, NCT01140906, NCT00596817​.

A meta-analysis of randomized, placebo-controlled trials of vortioxetine for the treatment of major depressive disorder in adults.

The efficacy and safety of vortioxetine, an antidepressant approved for the treatment of adults with major depressive disorder (MDD), was studied in 11 randomized, double-blind, placebo-controlled trials of 6/8 weeks׳ treatment duration. An aggregated study-level meta-analysis was conducted to estimate the magnitude and dose-relationship of the clinical effect of approved doses of vortioxetine (5-20mg/day). The primary outcome measure was change from baseline to endpoint in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Differences from placebo were analyzed using mixed model for repeated measurements (MMRM) analysis, with a sensitivity analysis also conducted using last observation carried forward. Secondary outcomes included MADRS single-item scores, response rate (≥50% reduction in baseline MADRS), remission rate (MADRS ≤10), and Clinical Global Impressions scores. Across the 11 studies, 1824 patients were treated with placebo and 3304 with vortioxetine (5mg/day: n=1001; 10mg/day: n=1042; 15mg/day: n=449; 20mg/day: n=812). The MMRM meta-analysis demonstrated that vortioxetine 5, 10, and 20mg/day were associated with significant reductions in MADRS total score (Δ-2.27, Δ-3.57, and Δ-4.57, respectively; p<0.01) versus placebo. The effects of 15mg/day (Δ-2.60; p=0.105) were not significantly different from placebo. Vortioxetine 10 and 20mg/day were associated with significant reductions in 9 of 10 MADRS single-item scores. Vortioxetine treatment was also associated with significantly higher rates of response and remission and with significant improvements in other depression-related scores versus placebo. This meta-analysis of vortioxetine (5-20mg/day) in adults with MDD supports the efficacy demonstrated in the individual studies, with treatment effect increasing with dose.

A Population Pharmacokinetic-Pharmacodynamic Meta-Analysis of Vortioxetine in Patients with Major Depressive Disorder.

Vortioxetine is approved for the treatment of major depressive disorder (MDD). This analysis aimed to develop pharmacokinetic (PK) and PK/Efficacy models to evaluate the exposure-response relationship for vortioxetine in patients with MDD. PK data from 10 MDD and two generalized anxiety disorder studies of vortioxetine (3160 patients), and efficacy data [Montgomery-Åsberg Depression Rating Scale (MADRS)] from seven MDD studies (2537 patients), were used for the development of PK and PK/Efficacy models. One- and two-compartment models were evaluated as structural PK models, and linear and nonlinear (Emax) models were used to describe the relationship between average vortioxetine concentration at steady-state (Cav) and change in MADRS score from baseline (ΔMADRS). The impact of selected covariates on the PK and efficacy parameters of vortioxetine was also investigated. PK of vortioxetine was best characterized by a two-compartment model with first-order absorption and elimination. Mean estimates for oral clearance (CL/F) and volume of distribution for the central compartment of vortioxetine were 42 L/hr and 2920 L. Creatinine clearance, height and geographic region had statistically significant effects on vortioxetine CL/F, but the effect of each of these covariates was not considered clinically relevant, as they lead to ±26% change in area under the curve or Cmax of vortioxetine. An Emax model best described the relationship between ΔMADRS and Cav. Half-maximal effective concentration (EC50) and Emax estimates were 24.9 ng/mL and 7.0. No identified covariates, except region, had clinically meaningful effects on vortioxetine efficacy. These PK/Efficacy models adequately characterized the vortioxetine exposure-response relationship.