Ecopipam for Tourette Syndrome: A Randomized Trial.

BACKGROUND AND OBJECTIVES: All US Food and Drug Administration-approved medications for Tourette syndrome are antipsychotics, and their use is limited by the risk of weight gain, metabolic changes, and drug-induced movement disorders. Several small trials suggest that ecopipam, a first-in-class, selective dopamine 1 receptor antagonist, reduces tics with a low risk for these adverse events. This trial sought to further evaluate the efficacy, safety, and tolerability of ecopipam in children and adolescents with moderate to severe Tourette syndrome. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, phase 2b trial. Subjects aged ≥6 to <18 years with a baseline Yale Global Tic Severity Score Total Tic Score of ≥20 were randomly assigned 1:1 to ecopipam (n = 76) or placebo (n = 77). The primary endpoint was mean change over 12 weeks in the Yale Global Tic Severity Score Total Tic Score. The Clinical Global Impression of Tourette Syndrome Severity was the secondary endpoint. Safety and tolerability were evaluated at each study visit. RESULTS: Total tic scores were significantly reduced from baseline to 12 weeks in the ecopipam group compared with placebo (least squares mean differences -3.44, 95% confidence interval -6.09 to -0.79, P = .01). Improvement in Clinical Global Impression of Tourette Syndrome Severity was also greater in the ecopipam group (P = .03). More weight gain was seen in subjects assigned to placebo. No metabolic or electrocardiogram changes were identified. Headache (15.8%), insomnia (14.5%), fatigue (7.9%), and somnolence (7.9%) were the most common adverse events. CONCLUSIONS: Among children and adolescents with TS, ecopipam reduces tics to a greater extent than placebo, without observable evidence of common antipsychotic-associated side effects.

Suicidal ideation and behavior in adults with major depressive disorder treated with vortioxetine: post hoc pooled analyses of randomized, placebo-controlled, short-term and open-label, long-term extension trials.

OBJECTIVES: This study aimed to evaluate the risk of suicidal ideation and behavior associated with vortioxetine treatment in adults with major depressive disorder (MDD). METHODS: Suicide-related events were evaluated post hoc using 2 study pools: one short-term pool of 10 randomized, placebo-controlled studies (6-8 weeks) and another long-term pool that included 3 open-label extension studies (52 weeks). Evaluation of suicide-related events was performed using Columbia-Suicide Severity Rating Scale (C-SSRS) scores and treatment-emergent adverse events (TEAEs) data. RESULTS: At baseline, the percentage of patients reporting any C-SSRS ideation or behavior events in short-term studies was similar between placebo (14.7%), vortioxetine (19.8%, 13.0%, 11.2%, and 13.7% for 5-, 10-, 15-, and 20-mg groups, respectively), and duloxetine active reference (13.2%) and did not change throughout the 6- to 8-week treatment period for placebo (17.0%), vortioxetine (19.3%, 13.5%, 12.6%, and 15% for 5-, 10-, 15-, and 20-mg groups, respectively), or duloxetine (11.3%). The incidence of suicide-related events for TEAEs in the short-term pool was 0.4% for placebo, 0.2% or 1.0% for vortioxetine 5 mg or 10 mg, and 0.7% each for vortioxetine 15 mg and 20 mg, as well as duloxetine. After 52-week treatment with vortioxetine, suicidal ideation based on C-SSRS was 9.8%, C-SSRS suicidal behavior was 0.2%, and the incidence of suicide-related events based on TEAEs was <1%. There were no completed suicides in any study. CONCLUSIONS: Vortioxetine is not associated with increased risk of suicidal ideation or behavior in MDD patients.

A phase 2, randomized, placebo-controlled study of the efficacy and safety of TAK-063 in subjects with an acute exacerbation of schizophrenia.

INTRODUCTION: TAK-063 is a potent, selective inhibitor of phosphodiesterase 10A, an enzyme selectively expressed in medium spiny neurons of the striatum. This randomized, parallel-group study evaluated the efficacy and safety of 20-mg daily TAK-063 versus placebo in subjects with acutely exacerbated symptoms of schizophrenia (NCT02477020). METHODS: Adults aged 18 to 65 with diagnosed schizophrenia and psychotic symptoms that exacerbated within 60 days before screening were included. Subjects who discontinued psychotropic medications before screening were randomized 1:1 to 6 weeks of placebo (n = 81) or 20-mg TAK-063 (n = 83). Weekly efficacy visits were conducted during the treatment period, and dose de-escalation was allowed (blinded) to 10-mg TAK-063 for intolerability. RESULTS: The primary endpoint, change from baseline in the Positive and Negative Syndrome Scale total score at week 6, was not achieved (least-squares mean difference vs placebo [standard error] = -5.46 [3.44]; p = 0.115). Secondary endpoints were generally supportive of antipsychotic efficacy. Consistent with previous phase 1 studies, TAK-063 was safe and well tolerated, and most adverse events were mild or moderate in severity and did not result in discontinuation. No deaths occurred, and the incidence of akathisia and dystonia, categories of extrapyramidal syndromes, was more frequent in the TAK-063 group than placebo. CONCLUSIONS: Although the study did not meet the primary endpoint (effect size = 0.308), the effects of TAK-063 on the primary and secondary endpoints may be suggestive of antipsychotic activity. Interpretation of these results is confounded by a relatively high placebo effect and a lack of dose-ranging or active reference.

What is the overlap between subjective and objective cognitive impairments in MDD?

BACKGROUND: Cognitive impairments, such as memory deficits and executive impairment, are common among patients with major depressive disorder (MDD) and can be captured with objective or subjective assessments. The aim of this post-hoc analysis of the CONNECT study was to assess the degree of overlap between subjective and objective cognitive impairment among MDD patients, and to evaluate associated clinical characteristics. METHODS: The study was conducted from April 2012 to February 2014 and enrolled a total of 602 patients with MDD who reported subjective cognitive impairment. Efficacy was assessed using a battery of objective tests of cognitive function representing multiple domains: Digit Symbol Substitution Test performance, Trail Making Test A, Trail Making Test B, Congruent and Incongruent Stroop Test, Groton Maze Learning Test, Detection Task, Identification Task, and One-Back Task. The Cognitive and Physical Functioning Questionnaire (CPFQ) was used to capture patient-reported assessments of cognitive function. RESULTS: Although 48% of patients with MDD met our conservative criteria for subjectively defined marked cognitive impairment, 64% of patients with MDD met our conservative criteria for objectively defined cognitive impairment. Therefore, the proportion of patients defined as having impaired cognition was somewhat similar regardless of methodology. Overall, 80% of patients with MDD in this study reported either subjective or objective cognitive impairment per subjective and objective scales. However, the proportion of patients meeting criteria for both subjectively and objectively defined cognitive impairment was only 31%. This could be explained by the fact that the CPFQ total score was only modestly-although significantly-correlated with all but one of the objective tests. CONCLUSIONS: This post-hoc study shows that approximately 80% of patients with MDD participating in an antidepressant trial reported either subjective or objective cognitive impairment.

Randomized, double-blind, placebo-controlled 8-week trial of the efficacy, safety, and tolerability of 5, 10, and 20 mg/day vortioxetine in adults with major depressive disorder.

AIM: This study assessed the efficacy and safety of vortioxetine in adults with major depressive disorder. METHODS: In this double-blind, placebo-controlled study, 600 patients with major depressive disorder were randomly assigned (1:1:1:1) to receive vortioxetine 5, 10, or 20 mg, or placebo once daily for 8 weeks. The primary end-point was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 8, evaluated by the last-observation-carried-forward method. Secondary end-points included response (≥ 50% decrease in the MADRS total score from baseline) and remission (MADRS total score ≤ 10), Clinical Global Impression Scale-Improvement, and change from baseline in Sheehan Disability Scale. Adverse events were summarized. RESULTS: Vortioxetine failed to show significant differences from placebo in the primary end-point. Nominally significant improvements over placebo were observed for vortioxetine doses of 10 and 20 mg when the primary end-point was evaluated using the mixed model for repeated measures as the secondary analysis, and 10 mg in secondary measures of response and patient functioning. Vortioxetine was well tolerated. Nausea, constipation, dry mouth, dizziness, and insomnia each occurred at a >twofold higher rate than placebo. Discontinuation symptom scores were comparable between all groups after 1 and 2 weeks following withdrawal of the study drug. CONCLUSION: While vortioxetine failed to meet significance versus placebo in the primary efficacy analysis, there was evidence of efficacy for the 10- and 20-mg doses in secondary analyses. Vortioxetine was safe and well tolerated. Additional studies appear warranted.

Efficacy and safety of sublingual ramelteon as an adjunctive therapy in the maintenance treatment of bipolar I disorder in adults: A phase 3, randomized controlled trial.

BACKGROUND: The optimal long-term management strategy for bipolar I disorder patients is not yet established. Evidence supports the rationale for circadian rhythm regulation to prevent mood episode relapse in bipolar patients. This study evaluated the efficacy and safety of a new sublingual formulation of the melatonin receptor agonist ramelteon (ramelteon SL) as adjunctive therapy in the maintenance treatment of bipolar I patients. METHODS: In a double-blinded trial in the United States and Latin America, adult bipolar I disorder patients stable for ≥ 8 weeks before baseline and with a mood episode 8 weeks to 9 months before screening, were randomized to once-daily ramelteon SL 0.1mg (n = 164), 0.4mg (n = 160), or 0.8mg (n = 154), or placebo (n = 164), in addition to their existing treatment. The primary endpoint was time from randomization to relapse of symptoms. The prespecified futility criterion in a planned, unblinded, independent interim analysis was the failure of all ramelteon SL doses to achieve a conditional power ≥ 30% compared with placebo. RESULTS: No significant differences between any dose of ramelteon SL and placebo were observed. The study was terminated after meeting the futility criteria. Ramelteon SL was well tolerated, with a safety profile consistent with that for oral ramelteon. LIMITATIONS: A low rate of relapse events precluded detection of any statistically significant difference between groups. CONCLUSIONS: The study failed to demonstrate the efficacy of ramelteon SL as adjunctive maintenance therapy for bipolar disorder. Interim analyses for futility in clinical studies are valuable in preventing unnecessary exposure of subjects to interventions.

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.

Treatment-emergent sexual dysfunction in randomized trials of vortioxetine for major depressive disorder or generalized anxiety disorder: a pooled analysis.

OBJECTIVE: Antidepressants are frequently associated with treatment-emergent sexual dysfunction (TESD). Vortioxetine, which was approved for patients with major depressive disorder (MDD), has a receptor profile that suggests limited impact on sexual functioning. METHODS: Arizona Sexual Experiences Scale (ASEX) patient-level data were pooled from 7 short-term vortioxetine trials (6 in MDD, 1 in generalized anxiety disorder) and analyzed for incidence of TESD at any post-baseline visit in patients without sexual dysfunction at baseline (defined as ASEX total score ≥19; individual ASEX item score ≥5; or a score ≥4 on any 3 ASEX items). The primary objective was to confirm the non-inferiority of vortioxetine 5-20 mg/day to placebo on the incidence of TESD. Comparisons were based on the common risk difference (95% confidence interval). Additional analyses compared vortioxetine to duloxetine and duloxetine to placebo. A sensitivity analysis, defined as TESD at 2 consecutive post-baseline visits, was conducted. RESULTS: TESD incidence, relative to placebo, generally increased with vortioxetine dose with vortioxetine 5 mg non-inferior to placebo. Vortioxetine 10, 15, and 20 mg did not meet the non-inferiority criterion, but no dose had a significantly higher risk of developing TESD versus placebo. Changes in ASEX individual item scores supported the similarity of vortioxetine doses to placebo. Significantly higher TESD risk occurred with duloxetine 60 mg/day versus placebo and versus vortioxetine 5 or 10 mg. The sensitivity analysis was generally consistent with the primary analysis. Rates of spontaneously reported sexual adverse events were low. CONCLUSIONS: Vortioxetine was associated with rates of TESD that were not significantly different from placebo in short-term clinical trials.

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.

Effect of Vortioxetine vs. Escitalopram on Sexual Functioning in Adults with Well-Treated Major Depressive Disorder Experiencing SSRI-Induced Sexual Dysfunction.

INTRODUCTION: Sexual dysfunction is common with serotonergic antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and does not resolve in most patients. Vortioxetine, an antidepressant with a multimodal mechanism of action, has shown low rates of sexual dysfunction in previous major depressive disorder (MDD) trials. AIM: This study compared the effects of vortioxetine and escitalopram on sexual functioning in adults with well-treated MDD experiencing treatment-emergent sexual dysfunction (TESD). METHODS: Participants treated with, and responding to, citalopram, paroxetine, or sertraline were randomized to switch to either vortioxetine (10/20 mg; n = 225) or escitalopram (10/20 mg; n = 222) for 8 weeks. Sexual function was assessed using the Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14), and antidepressant efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impressions (CGI) scale, and Profile of Mood States brief form (POMS-brief). Safety and tolerability were also assessed. MAIN OUTCOME MEASURES: The primary endpoint was change from baseline in the CSFQ-14 total score after 8 weeks of treatment. The MADRS, CGI, and POMS-brief were used to assess antidepressant efficacy. Safety was assessed via adverse events, vital signs, electrocardiograms, laboratory values, weight, and physical examination findings. RESULTS: Vortioxetine showed significantly greater improvements in CSFQ-14 total score (8.8 ± 0.64, mean ± standard error) vs. escitalopram (6.6 ± 0.64; P = 0.013). Benefits vs. escitalopram were significant on four of five dimensions and all three phases of sexual functioning assessed by the CSFQ-14 (P < 0.05). Antidepressant efficacy continued in both groups, with similar, but slight, improvements in MADRS and CGI scores. Vortioxetine and escitalopram had similar clinical efficacy profiles in this study, with safety profiles similar to previous trials. Nausea (n = 9, 4.0%) was the most common treatment-emergent adverse event leading to discontinuation of vortioxetine. CONCLUSION: Switching antidepressant therapy to vortioxetine may be beneficial for patients experiencing sexual dysfunction during antidepressant therapy with SSRIs.

Association Between Cognitive Function and Health Care Costs 3 Months and 6 Months After Initiating Antidepressant Medication for Depressive Disorders.

BACKGROUND: Major depressive disorder is one of the most common and disabling mental health disorders and is associated with substantial costs in terms of direct health care utilization and workplace productivity. Cognitive dysfunction, which alone substantially increases health care costs, is commonly associated with major depressive disorder. However, the health care costs of cognitive dysfunction in the context of depressive disorder are unknown. Recovery from mood symptoms is not always associated with resolution of cognitive dysfunction. Thus, cognitive dysfunction may contribute to health care burden even with successful antidepressant therapy.  OBJECTIVE: To compare health care utilization and costs for patients with a depressive disorder with and without cognitive dysfunction, at 3 and 6 months after initiation of antidepressant medication.  METHODS: This was an observational study, combining a cross-sectional patient survey, administered during a telephone interview, with health care claims data from a large, geographically diverse U.S. health plan. Included patients had at least 1 pharmacy claim for an antidepressant medication between August 1 and September 30, 2012, and no claim for any antidepressant during the 6 months prior to the index date. In addition to other criteria assessed in the claims data, patients confirmed a diagnosis of depression or major depressive disorder and the absence of any exclusionary neurological diagnoses possibly associated with cognitive impairment. Eligible patients were administered validated cognitive function assessments of verbal episodic memory (Hopkins Verbal Learning Test-Revised, Delayed and Total); attention (Digit Span Forward Maximum Sequence Length); working memory (Digit Span Backward Maximum Sequence Length); and executive function (D-KEFS-Letter Fluency Test). Based on comparison of scores with normative data, patients were assigned to cognitive dysfunction or cognitive normal cohorts. All-cause (all diagnoses) and depressive disorder-related health care utilization and costs (all from a payer perspective) were assessed 6 months prior (baseline) to antidepressant initiation and 3 months and 6 months after (follow-up) initiation of antidepressant medication. Health care utilization and costs included ambulatory (office and hospital outpatient), emergency room, inpatient hospital, pharmacy, other medical (e.g., laboratory and diagnostics), and total (all categories combined). All-cause and depressive disorder-related total costs during the 3- and 6-month follow-up periods were modeled with generalized linear modeling with gamma distribution and log link, while adjusting for potential confounders (age, race, gender, education, employment, and comorbidities). RESULTS: Of the 13,537 patients who were mailed an invitation, 824 (6%) were eligible and agreed to participate. Of these, 563 patients provided informed consent, completed the interview, maintained eligibility, and were included in the 3-month calculations. Among these, 255 (45%) were classified as having cognitive dysfunction. Mean patient age was 41.3 (± 12.5) years; 80% were female. Most patients were white and employed. More patients in the cognitive normal cohort were white (P less than 0.001) and employed full time (P = 0.029), had higher education attainment (P less than 0.001), and had fewer comorbidities (P = 0.007) than those in the cognitive dysfunction cohort. Over the first 3 months, patients with cognitive dysfunction had higher adjusted all-cause costs ($3,309 vs. $2,157, P = 0.002) and higher adjusted depressive disorder-related costs ($718 vs. $406, P less than 0.001) than patients without cognitive dysfunction. At 6 months, data from 4 patients were removed from the analysis because of exclusionary diagnoses. Over 6 months, patients with cognitive dysfunction had higher adjusted all-cause costs ($4,793) than patients without cognitive dysfunction ($3,683, P = 0.034). Over 6 months, depressive disorder-related costs did not significantly differ between patients with ($771) and without cognitive dysfunction ($594, P = 0.071). The main drivers of all-cause costs were office visits, outpatient hospital visits, and inpatient costs, and the main driver of depressive disorder-related costs was inpatient costs. CONCLUSIONS: Cognitive dysfunction was associated with higher adjusted all-cause and depressive disorder-related costs 3 months after initiation of an antidepressant medication. This difference persisted for all-cause costs through 6 months. Identification and treatment of cognitive dysfunction in patients with depressive disorder might reduce health care costs.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of vortioxetine 10 mg and 20 mg in adults with major depressive disorder.

CONTEXT: Vortioxetine (Lu AA21004) is an antidepressant with a mechanism of action thought to be related to a combination of 2 pharmacologic actions: direct modulation of several receptors and inhibition of the serotonin transporter. OBJECTIVE: To evaluate the efficacy of vortioxetine 10 and 20 mg once daily in outpatients with major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS: This 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted from July 2010 to January 2012 among adults with a primary diagnosis of recurrent major depressive disorder (DSM-IV-TR). INTERVENTION: Eligible subjects were randomized in 1:1:1 ratio to 1 of 3 treatment arms: vortioxetine 10 mg, vortioxetine 20 mg, or placebo once daily for 8 weeks. Subjects who completed the 8-week trial entered a 2-week blinded discontinuation period to assess potential discontinuation symptoms. MAIN OUTCOME MEASURE: The primary endpoint was the least squares mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline. Key secondary outcomes were analyzed in the following prespecified sequential order: MADRS response (≥ 50% decrease from baseline in total score), Clinical Global Impressions-Improvement score, change from baseline in MADRS total score in subjects with baseline Hamilton Anxiety Rating Scale score ≥ 20, MADRS remission (total score ≤ 10), and change from baseline in Sheehan Disability Scale total score (all at week 8). RESULTS: A total of 462 subjects were randomized to placebo (n = 157), vortioxetine 10 mg (n = 155), and vortioxetine 20 mg (n = 150). Mean (SE) reductions from baseline in MADRS total score (week 8) were -10.77 (± 0.807), -12.96 (± 0.832), and -14.41 (± 0.845) for the placebo, vortioxetine 10 mg (P = .058 vs placebo), and vortioxetine 20 mg (P = .002 vs placebo) groups. MADRS response/remission was achieved in 28.4%/14.2%, 33.8%/21.4%, and 39.2%/22.3% of subjects, respectively, in the 3 groups. Only MADRS response for vortioxetine 20 mg significantly separated from placebo (P = .044). Treatment was well tolerated, with the most frequently reported adverse events consisting of nausea, headache, diarrhea, and dizziness. CONCLUSIONS: Vortioxetine 20 mg significantly reduced MADRS total score at 8 weeks in this study population. Overall, vortioxetine was well tolerated in this study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01163266.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of 2 doses of vortioxetine in adults with major depressive disorder.

BACKGROUND: This 8-week, randomized, double-blind, placebo-controlled study, conducted August 2010-May 2012 in the United States, evaluated the safety and efficacy of vortioxetine 10 mg and 15 mg in patients with major depressive disorder (MDD). The mechanism of action of vortioxetine is thought to be related to direct modulation of serotonin (5-HT) receptor activity and inhibition of the serotonin transporter. METHOD: Adults aged 18-75 years with MDD (DSM-IV-TR) and Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 26 were randomized (1:1:1) to receive vortioxetine 10 mg or 15 mg or placebo once daily, with the primary efficacy end point being change from baseline at week 8 in MADRS analyzed by mixed model for repeated measures. Adverse events were recorded during the study, suicidal ideation and behavior were assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), and sexual dysfunction was assessed using the Arizona Sexual Experience (ASEX) scale. RESULTS: Of the 1,111 subjects screened, 469 subjects were randomized: 160 to placebo, 157 to vortioxetine 10 mg, and 152 to vortioxetine 15 mg. Differences from placebo in the primary efficacy end point were not statistically significant for vortioxetine 10 mg or vortioxetine 15 mg. Nausea, headache, dry mouth, constipation, diarrhea, vomiting, dizziness, and flatulence were reported in ≥ 5% of subjects receiving vortioxetine. Discontinuation due to adverse events occurred in 7 subjects (4.4%) in the placebo group, 8 (5.2%) in the vortioxetine 10 mg group, and 12 (7.9%) in the vortioxetine 15 mg group. ASEX total scores were similar across groups. There were no clinically significant trends within or between treatment groups on the C-SSRS, laboratory values, electrocardiogram, or vital sign parameters. CONCLUSIONS: In this study, vortioxetine did not differ significantly from placebo on MADRS total score after 8 weeks of treatment in MDD subjects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01179516.

Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible-dose, 52-week extension study.

Vortioxetine is approved for the treatment of adults with major depressive disorder. This open-label extension (OLE) study evaluated the safety and tolerability of vortioxetine in the long-term treatment of major depressive disorder patients, as well as evaluated its effectiveness using measures of depression, anxiety, and overall functioning. This was a 52-week, flexible-dose, OLE study in patients who completed one of three randomized, double-blind, placebo-controlled, 8-week vortioxetine trials. All patients were switched to 10 mg/day vortioxetine for week 1, then adjusted between 15 and 20 mg for the remainder of the study, but not downtitrated below 15 mg. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), vital signs, laboratory values, physical examination, and the Columbia-Suicide Severity Rating Scale. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Impression Scale-Severity of Illness, and the Sheehan Disability Scale. Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs. Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (≥10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery-Åsberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Δ-4.2), the Clinical Global Impression Scale-Severity of Illness (Δ-1.2), and the Sheehan Disability Scale (Δ-4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20 mg vortioxetine were safe and well tolerated. After entry into this study, patients continued to show improvement in depression and anxiety symptoms, as well as overall functioning, throughout the treatment period.

A Randomized, Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder.

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.

A randomized, double-blind, duloxetine-referenced study comparing efficacy and tolerability of 2 fixed doses of vortioxetine in the acute treatment of adults with MDD.

RATIONALE: Vortioxetine has reduced depressive symptoms in adults with major depressive disorder (MDD) in multiple clinical trials. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Vortioxetine 20 mg significantly reduced MADRS total scores after 8 weeks of treatment. Both vortioxetine doses were well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01153009; www.clinicaltrials.gov/ .

Prospective assessment of suicidal ideation and behavior: an internet survey of pharmaceutical sponsor practices.

OBJECTIVE: To survey the current approaches of clinical trial sponsors in prospective suicidal ideation and behavior assessments and challenges encountered. DESIGN: An internet-based survey. SETTING: Inclusion of prospective assessments of suicidal ideation and behavior in industry-sponsored clinical studies were required following the release of the September 2010 United States Federal Drug Administration draft guidance. The International Society for CNS Clinical Trials and Methodology Suicidal Ideation and Behavior Assessment Workgroup conducted an online survey to understand industry practices and experiences in implementing suicidal ideation and behavior assessments in clinical trials. PARTICIPANTS: The survey was sent to 1,447 industry employees at 178 pharmaceutical companies. A total of 89 evaluable responses, representing 39 companies, were obtained. MEASUREMENTS: A 30-item internet survey was developed asking about potential challenges and issues in implementing prospective suicidal ideation and behavior assessments. RESULTS: Common factors in deciding whether to include suicidal ideation and behavior assessments in a clinical trial were psychiatric or neurologic drug product (95%); central nervous system activity (78%); disease (74%) and patient population (71%); and regulatory announcements and policies (74%). The most common challenges in implementing suicidal ideation and behavior assessments included cross-cultural differences in acceptance of SIB assessments (40%); obtaining adequate baseline history (36.8%); obtaining translations (35%); investigator/rater discomfort with asking about suicidal ideation and behavior (32%); and inadequate training of raters to administer suicidal ideation and behavior ratings (30%). CONCLUSION: Among sponsors surveyed, the implementation rate of suicidal ideation and behavior assessment in central nervous systems studies is very high. Most have used the Columbia-Suicide Severity Rating Scale. Challenges regarding standardization of retrospective assessment timeframes and differing approaches to summarizing and analyzing suicidal ideation and behavior-related study data were frequently reported. These results suggest that inconsistent reports of suicidal ideation and behavior within study datasets may occur and that integration of data across studies remains a concern.

A randomized, double-blind, fixed-dose study comparing the efficacy and tolerability of vortioxetine 2.5 and 10 mg in acute treatment of adults with generalized anxiety disorder.

BACKGROUND: Vortioxetine is a recently approved multimodal antidepressant with anxiolytic properties in preclinical studies. OBJECTIVE: This double-blind, placebo-controlled study assessed the efficacy and tolerability of vortioxetine in subjects with a primary diagnosis of generalized anxiety disorder. METHODS: Subjects (n = 457) were randomized 1:1:1 to treatment with placebo or vortioxetine 2.5 or 10 mg once daily. The primary efficacy endpoint was reduction in Hamilton Anxiety Scale (HAM-A) total scores from baseline after 8 weeks of treatment. Key secondary outcomes were changes from baseline in HAM-A total scores for the 2.5 and 10 mg dose, Hospital Anxiety and Depression anxiety subscore, 36-Item Short-Form Health Survey, Sheehan Disability Scale, and Clinical Global Impression-Improvement Scale score, as well as HAM-A response rate at week 8. RESULTS: Neither vortioxetine dose achieved a statistically significant improvement over placebo on the primary endpoint (least-squares mean difference ± standard error from placebo: -0.87 ± 0.803 [p = 0.279] for 2.5 mg and -0.81 ± 0.791 [p = 0.306] for 10 mg vortioxetine) or on any secondary efficacy endpoints. Common adverse events (≥5% in either vortioxetine group) were nausea, dry mouth, headache, diarrhea, constipation, and vomiting. CONCLUSIONS: Vortioxetine 2.5 and 10 mg treatment did not significantly improve generalized anxiety disorder symptoms versus placebo. Vortioxetine was safe and well tolerated in this patient population.

Safety, tolerability, and efficacy of vortioxetine (Lu AA21004) in major depressive disorder: results of an open-label, flexible-dose, 52-week extension study.

Patients with major depressive disorder often experience relapse after responding to treatment; therefore, maintenance therapy with antidepressants is recommended for maintaining response or remission. This multicenter, open-label, flexible-dose, 52-week extension study evaluated the long-term safety, tolerability, and maintenance of efficacy in study participants who had completed one of two randomized, double-blind, placebo-controlled, 8-week dose-ranging vortioxetine trials in study participants with major depressive disorder. At the open-label baseline, all study participants were switched to vortioxetine 5 mg/day for the first week, with subsequent dose adjustments from 2.5 to 10 mg/day on the basis of response and tolerability. Treatment with vortioxetine for 52 weeks was well tolerated, with no new safety signals identified. Among the 834 evaluable study participants, treatment-emergent adverse events were reported in 70.6%, with the most common in the combined (all doses) population of nausea (15.2%), headache (12.4%), nasopharyngitis (9.8%), diarrhea (7.2%), and dizziness (6.8%). The rate of adverse events related to sexual dysfunction was low and weight gain was minimal. Laboratory values, vital signs, ECGs, physical examinations, and Columbia-Suicide Severity Rating Scale results showed no trends of clinical concern. The change in the severity of depressive and anxiety symptoms was maintained throughout the study as reflected by a 24-item Hamilton Depression Scale total score of 8.2 at week 52 (from 17.6 at open-label baseline) in the observed case data set.