Relapse prevention in adults with major depressive disorder treated with vilazodone: a randomized, double-blind, placebo-controlled trial.

This randomized withdrawal study assessed relapse prevention with vilazodone in adults with major depressive disorder. After 20 weeks of open-label treatment with vilazodone 40 mg/day, responders were randomized (1 : 1 : 1) to 28 weeks of double-blind, fixed-dose treatment with vilazodone 20 mg/day, vilazodone 40 mg/day, or placebo. The primary efficacy endpoint was time to first relapse, defined as Montgomery-Åsberg Depression Rating Scale total score of at least 18 and meeting major depressive episode criteria, Montgomery-Åsberg Depression Rating Scale total score of at least 18 at two consecutive visits, or discontinuation for an insufficient therapeutic response. Of 1204 patients who received open-label treatment, 564 completed treatment and were randomized (placebo=192, vilazodone 20 mg/day=185, vilazodone 40 mg/day=187). No significant difference was detected in time to relapse during the double-blind period (P>0.05). The crude percentage of patients that relapsed was similar between treatment groups (placebo=12.6%; vilazodone 20 mg/day=11.4%; vilazodone 40 mg/day=13.4%). The most common treatment-emergent adverse events were diarrhea (29.6%), nausea (24.0%), and headache (14.0%) during open-label treatment and headache (8.9%), nasopharyngitis (8.4%), and diarrhea (7.5%) during double-blind treatment in the combined vilazodone groups (20 and 40 mg/day). In conclusion, time to relapse with vilazodone was not statistically different from placebo. Vilazodone was generally well tolerated in adults with major depressive disorder.

Vilazodone efficacy in subgroups of patients with major depressive disorder: a post-hoc analysis of four randomized, double-blind, placebo-controlled trials.

The efficacy of antidepressants to treat major depressive disorder (MDD) varies by patient characteristics. This post-hoc analysis evaluated the effects of vilazodone across patient subgroups in adults with MDD. Data were pooled from four trials of vilazodone (NCT00285376, NCT00683592, NCT01473394, and NCT01473381). Mean change from baseline to week 8 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, MADRS response (≥50% total score improvement), and MADRS remission (total score≤10) were analyzed in the pooled intent-to-treat population (vilazodone=1254, placebo=964) and in subgroups of patients categorized by sex, age, MDD duration, recurrent episodes, baseline MADRS total score, and current episode duration. MADRS total score improvement was significantly greater with vilazodone versus placebo in the intent-to-treat population and in all patient subgroups (P<0.001). MADRS response and remission rates significantly separated from placebo (P<0.05) regardless of age, sex, MDD duration, recurrent MDD, and baseline symptom severity [except remission in patients with very severe baseline symptoms (MADRS score≥35)] and in patients with a shorter current episode duration (≤12 months). Despite the limitations associated with analyzing uncommon outcomes (e.g. MADRS remission) in small subgroups, vilazodone was an effective treatment in multiple patient populations, including those where reduced efficacy has previously been reported: males, older individuals, patients with a longer duration of MDD, and patients with recurrent depression.

Measures of suicidality in phase 3 clinical trials of levomilnacipran ER in adults with major depressive disorder.

OBJECTIVE: To evaluate the effects of levomilnacipran extended-release (ER) on suicidal ideation and behavior in adults with major depressive disorder (MDD). METHODS: Post hoc analyses were conducted in patients from 4 randomized, double-blind, placebo-controlled trials and a long-term, open-label extension study of levomilnacipran ER (40-120 mg/d) in adults with MDD. Analyses included incidence of suicide-related treatment-emergent adverse events (TEAEs); incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation (score=1-5) and behavior (score=6-10); percent of patients who shifted from no C-SSRS suicidal ideation/behavior at baseline to suicidal ideation during treatment (worsened from score=0 to score=1-5), or vice-versa (improved from score=1-5 to score=0). RESULTS: Suicide-related TEAEs occurred in<1% of patients in the levomilnacipran ER studies. The incidence of C-SSRS suicidal ideation was 22.2%, 23.9%, and 21.7% for placebo, short-term levomilnacipran ER, and long-term levomilnacipran ER, respectively; C-SSRS suicidal behavior was<1% in all of these groups. In the short-term studies, the percentage of patients with C-SSRS shifts were as follows: worsening from score=0 to score=1-5 (placebo, 8.6%; levomilnacipran ER, 11.0%); improvement from score=1-5 to score=0 (placebo, 24.0%; levomilnacipran ER, 27.7%). CONCLUSION: In adult MDD patients, the incidence of suicidal ideation and behavior was similar between placebo and short-term levomilnacipran ER as indicated by TEAE reports and C-SSRS scores. Worsening in C-SSRS scores was also similar between placebo and levomilnacipran ER. There was no indication of increased suicidality during longer courses of continued therapy. Together, these findings suggest that this medication is not associated with increased risks of suicidal ideation or behavior.

Effects of vilazodone on suicidal ideation and behavior in adults with major depressive disorder or generalized anxiety disorder: post-hoc analysis of randomized, double-blind, placebo-controlled trials.

Treatment-emergent suicidal ideation and behavior are ongoing concerns with antidepressants. Vilazodone, currently approved for the treatment of major depressive disorder (MDD) in adults, has also been evaluated in generalized anxiety disorder (GAD). Post-hoc analyses of vilazodone trials were carried out to examine its effects on suicidal ideation and behavior in adults with MDD or GAD. Data were pooled from vilazodone trials in MDD (four studies) and GAD (three studies). The incidence of suicide-related events was analyzed on the basis of treatment-emergent adverse event reporting and Columbia-Suicide Severity Rating Scale (C-SSRS) monitoring. Treatment-emergent suicidal ideation was analyzed on the basis of a C-SSRS category shift from no suicidal ideation/behavior (C-SSRS=0) at baseline to suicide ideation (C-SSRS=1-5) during treatment. In pooled safety populations (MDD, n=2233; GAD, n=1475), suicide-related treatment-emergent adverse events occurred in less than 1% of vilazodone-treated and placebo-treated patients. Incidences of C-SSRS suicidal ideation were as follows: MDD (vilazodone=19.9%, placebo=24.7%); GAD (vilazodone=7.7%, placebo=9.4%). Shifts from no suicidal ideation/behavior at baseline to suicidal ideation during treatment were as follows: MDD (vilazodone=9.4%, placebo=10.3%); GAD (vilazodone=4.4%, placebo=6.1%). Data from placebo-controlled studies indicate little or no risk of treatment-emergent suicidal ideation or behavior with vilazodone in adults with MDD or GAD. Nevertheless, all patients should be monitored for suicidal thoughts and behaviors during antidepressant treatment.

Effects of levomilnacipran ER on noradrenergic symptoms, anxiety symptoms, and functional impairment in adults with major depressive disorder: Post hoc analysis of 5 clinical trials.

OBJECTIVE: To evaluate the effects of levomilnacipran extended-release (LVM-ER; 40-120mg/day) on noradrenergic (NA) and anxiety-related symptoms in adults with major depressive disorder (MDD) and explore the relationship between these symptoms and functional impairment. METHODS: Data were pooled from 5 randomized, double-blind, placebo-controlled trials (N=2598). Anxiety and NA Cluster scores were developed by adding selected item scores from the Montgomery-Åsberg Depression Rating Scale (MADRS) and 17-item Hamilton Depression Rating Scale (HAMD17). A path analysis was conducted to estimate the direct effects of LVM-ER on functional impairment (Sheehan Disability Scale [SDS] total score) and the indirect effects through changes in NA and Anxiety Cluster scores. RESULTS: Mean improvements from baseline in NA and Anxiety Cluster scores were significantly greater with LVM-ER versus placebo (both P<0.001), as were the response rates (≥50% score improvement): NA Cluster (44% vs 34%; odds ratio=1.56; P<0.0001); Anxiety Cluster (39% vs 36%; odds ratio=1.19; P=0.041). Mean improvement in SDS total score was also significantly greater with LVM-ER versus placebo (-7.3 vs -5.6; P<0.0001). LVM-ER had an indirect effect on change in SDS total score that was mediated more strongly through NA Cluster score change (86%) than Anxiety Cluster score change (18%); the direct effect was negligible. LIMITATIONS: NA and Anxiety Cluster scores, developed based on the face validity of individual MADRS and HAMD17 items, were not predefined as efficacy outcomes in any of the studies. CONCLUSION: In adults with MDD, LVM-ER indirectly improved functional impairment mainly through improvements in NA symptoms and less so via anxiety symptoms.

Effects of vilazodone on sexual functioning in healthy adults: results from a randomized, double-blind, placebo-controlled, and active-controlled study.

The aim of this study is to evaluate the effects of vilazodone on sexual functioning in healthy, sexually active adults and assess the impact of medication nonadherence in this type of trial. Participants were randomized to vilazodone (20 or 40 mg/day), paroxetine (20 mg/day), or placebo for 5 weeks of double-blind treatment. The primary endpoint was change from baseline to day 35 in Change in Sexual Functioning Questionnaire (CSFQ) total score in the intent-to-treat (ITT) population. Post-hoc analyses were carried out in modified intent-to-treat (mITT) populations that excluded participants in the active-treatment groups with undetectable plasma drug concentrations at all visits (mITT-I) or at least one visit (mITT-II). In the ITT population (N=199), there were no statistically significant differences between any treatment groups for CSFQ total score change: placebo, -1.0; vilazodone 20 mg/day, -1.4; vilazodone 40 mg/day, -1.9; and paroxetine, -3.5. In mITT-I (N=197) and mITT-II (N=159), CSFQ total score change was not significantly different between vilazodone (either dose) versus placebo; the CSFQ total score decreased significantly (P<0.05) with paroxetine versus both placebo and vilazodone 20 mg/day, but not versus vilazodone 40 mg/day. Vilazodone exerted no significant effect on sexual functioning in healthy adults. Medication nonadherence can alter study results and may be an important consideration in trials with volunteer participants.

Effects of levomilnacipran extended-release on major depressive disorder patients with cognitive impairments: post-hoc analysis of a phase III study.

Performance-based cognitive data were collected using the Cognitive Drug Research System in a study of levomilnacipran extended-release (ER) 40-120 mg/day (NCT01034462) in adults with major depressive disorder. These data were analyzed post-hoc to explore the relationship between cognitive measures, depression symptoms (Montgomery-Åsberg Depression Rating Scale, MADRS), and self-reported psychosocial functioning (Sheehan Disability Scale; SDS). Changes from baseline were analyzed in the intent-to-treat population and subgroups with impaired attention, as indicated by baseline Cognitive Drug Research System scores for Power of Attention and Continuity of Attention. Path analyses evaluated the direct and indirect effects of levomilnacipran ER on SDS total score change. Significantly greater improvements were observed for levomilnacipran ER versus placebo for Power of Attention, Continuity of Attention, MADRS, and SDS score changes; the mean differences were larger in the impaired subgroups than in the overall intent-to-treat population. Path analyses showed that the majority of SDS total score improvement (≥50%) was attributable to an indirect treatment effect through MADRS total score change; some direct effect of levomilnacipran ER on SDS total score improvement was also observed. In adults with major depressive disorder, levomilnacipran ER effectively improved measures of depression and cognition, which contributed toward reductions in self-reported functional impairment.

Categorical improvements in disease severity in patients with major depressive disorder treated with vilazodone: post hoc analysis of four randomized, placebo-controlled trials.

BACKGROUND: In three 8-week studies of vilazodone 40 mg/d (NCT00285376, NCT00683592, and NCT01473394) and a 10-week study of vilazodone 20 or 40 mg/d (NCT01473381), adults with major depressive disorder (MDD) showed significantly greater improvement with vilazodone versus placebo in global disease severity as measured by mean change from baseline in Clinical Global Impression of Severity (CGI-S) score. To assess the proportion of patients achieving clinically meaningful improvement, a post hoc pooled analysis was conducted using categorical shifts in disease severity based on CGI-S scores at baseline and end of treatment (EOT). METHODS: Analyses were conducted in the pooled intent-to-treat population (N=2,218). Definitions of categorical shifts included CGI-S ≥4 (moderately ill or worse) at baseline to CGI-S ≤2 (normal or borderline ill) at EOT; CGI-S ≥5 (markedly ill or worse) at baseline to CGI-S ≤2 at EOT; and CGI-S ≥6 (severely ill or worse) at baseline to CGI-S ≤3 (mildly ill or better) at EOT. RESULTS: At baseline, 2,217 patients were moderately ill or worse. The percentage who improved to normal or borderline ill was significantly higher with vilazodone than with placebo (40.0% versus 27.8%; odds ratio [OR] =1.7, P<0.001; number needed to treat [NNT] =9). In the 979 patients who were markedly ill or worse at baseline, the percentage who improved to normal or borderline ill was significantly higher with vilazodone than with placebo (36.8% versus 25.5%; OR =1.7, P<0.001; NNT =9). The small number of severely ill patients at baseline (n =43) provided inadequate power to detect statistically significant between-group differences, but an NNT =5 was found for improvement to mildly ill or better. CONCLUSION: Categorical shift analyses, defined using baseline and EOT CGI-S scores, showed that significantly higher proportions of patients had clinically meaningful improvements in global disease severity with vilazodone 20-40 mg/d versus placebo. This type of analysis may be useful for evaluating the effects of antidepressant treatment in adults with MDD.

Post Hoc Analyses of Anxiety Measures in Adult Patients With Generalized Anxiety Disorder Treated With Vilazodone.

OBJECTIVE: To investigate vilazodone, currently approved for major depressive disorder in adults, for generalized anxiety disorder (GAD). METHOD: Three randomized, double-blind, placebo-controlled studies showing positive results for vilazodone (2,040 mg/d) in adult patients with GAD (DSM-IV-TR) were pooled for analyses; data were collected from June 2012 to March 2014. Post hoc outcomes in the pooled intent-to-treat population (n = 1,462) included mean change from baseline to week 8 in Hamilton Anxiety Rating Scale (HARS) total score, psychic and somatic anxiety subscale scores, and individual item scores; HARS response (≥ 50% total score improvement) and remission (total score ≤ 7) at week 8; and category shifts, defined as HARS item score ≥ 2 at baseline (moderate to very severe symptoms) and score of 0 at week 8 (no symptoms). RESULTS: The least squares mean difference was statistically significant for vilazodone versus placebo in change from baseline to week 8 in HARS total score (-1.83, P < .0001) and in psychic anxiety (-1.21, P < .0001) and somatic anxiety (-0.63, P < .01) subscale scores; differences from placebo were significant on 11 of 14 HARS items (P < .05). Response rates were higher with vilazodone than placebo (48% vs 39%, P < .001), as were remission rates (27% vs 21%, P < .01). The percentage of patients who shifted to no symptoms was significant for vilazodone on several items: anxious mood, tension, intellectual, depressed mood, somatic-muscular, somatic-sensory, cardiovascular, respiratory, and autonomic symptoms (P < .05). CONCLUSIONS: Treatment with vilazodone versus placebo was effective in adult GAD patients, with significant differences between treatment groups found on both psychic and somatic HARS items. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01629966, NCT01766401, NCT01844115.

Effects of levomilnacipran extended-release on motivation/energy and functioning in adults with major depressive disorder.

The objective of this post-hoc analysis was to investigate the relationship between motivation/energy and functional impairment in patients with major depressive disorder (MDD). Data were taken from a phase 3 trial of levomilnacipran extended-release (ER) in adults with MDD (NCT01034462; N=429) that used the 18-item Motivation and Energy Inventory (MEI) to assess motivation/energy. Two subgroups with lower and higher motivation/energy were defined using baseline MEI total scores (≤28 and >28, respectively). Change from baseline in the Sheehan Disability Scale (SDS) total score was analyzed in the intent-to-treat (ITT) population and both subgroups. Path analyses were carried out in the ITT population and a lower MEI subgroup to assess the direct and indirect effects of levomilnacipran ER on SDS total score change. In the ITT population and the lower MEI subgroup, significant differences were found between levomilnacipran ER and placebo for changes in the SDS total score (-2.6 and -3.9, both P<0.01), but not in the higher MEI subgroup. The indirect effect of levomilnacipran ER on SDS total score improvement, as mediated by MEI total score change, was 79.9% in the lower MEI subgroup and 67.2% in the ITT population. Levomilnacipran ER was previously shown to improve motivation/energy in adults with MDD. The current analysis indicates that improvements in functional impairment were considerably mediated by improvements in motivation/energy, particularly in patients with lower motivation/energy at baseline.

Characterizing sexual function in patients with generalized anxiety disorder: a pooled analysis of three vilazodone studies.

BACKGROUND: Vilazodone has been shown to reduce core symptoms of generalized anxiety disorder (GAD) in three randomized, double-blind, placebo-controlled trials. Since sexual dysfunction (SD) is not well characterized in GAD, a post hoc analysis of these trials was conducted to evaluate the effects of vilazodone on sexual functioning in GAD patients. MATERIALS AND METHODS: Data were pooled from one fixed-dose trial of vilazodone 20 and 40 mg/day (NCT01629966) and two flexible-dose studies of vilazodone 20-40 mg/day (NCT01766401, NCT01844115) in adults with GAD. Sexual functioning was assessed using the Changes in Sexual Functioning Questionnaire (CSFQ). Outcomes included mean change from baseline to end of treatment (EOT) in CSFQ total score and percentage of patients shifting from SD at baseline (CSFQ total score ≤47 for males, ≤41 for females) to normal functioning at EOT. Treatment-emergent adverse events related to sexual functioning were also analyzed. RESULTS: A total of 1,373 patients were included in the analyses. SD at baseline was more common in females (placebo, 46.4%; vilazodone, 49%) than in males (placebo, 35.1%; vilazodone, 40.9%). CSFQ total score improvement was found in both females (placebo, +1.2; vilazodone, +1.6) and males (placebo, +2.1; vilazodone, +1.0), with no statistically significant differences between treatment groups. The percentage of patients who shifted from SD at baseline to normal sexual functioning at EOT was higher in males (placebo, 40.6%; vilazodone, 35.7%) than in females (placebo, 24.9%; vilazodone, 34.9%); no statistical testing was performed. Except for erectile dysfunction and delayed ejaculation in vilazodone-treated males (2.4% and 2.1%, respectively), no treatment-emergent adverse events related to sexual functioning occurred in ≥2% of patients in either treatment group. CONCLUSION: Approximately 35%-50% of patients in the vilazodone GAD studies had SD at baseline. Vilazodone and placebo had similar effects on CSFQ outcomes in both females and males, indicating a limited adverse impact on sexual functioning with vilazodone.

The efficacy of levomilnacipran ER across symptoms of major depressive disorder: a post hoc analysis of 5 randomized, double-blind, placebo-controlled trials.

OBJECTIVE: A post hoc analysis evaluated the effects of levomilnacipran ER on individual symptoms and symptom domains in adults with major depressive disorder (MDD). METHODS: Data were pooled from 5 Phase III trials comprising 2598 patients. Effects on depression symptoms were analyzed based on change from baseline in individual Montgomery-Åsberg Depression Rating Scale (MADRS) item scores. A1dditional evaluations included resolution of individual symptoms (defined as a MADRS item score ≤1 at end of treatment) and concurrent resolution of all 10 MADRS items, all MADRS6 subscale items, and all items included in different symptom clusters (Dysphoria, Retardation, Vegetative Symptoms, Anhedonia). RESULTS: Significantly greater mean improvements were found on all MADRS items except Reduced Appetite with levomilnacipran ER treatment compared with placebo. Resolution of individual symptoms occurred more frequently with levomilnacipran ER than placebo for each MADRS item (all P<.05), with odds ratios (ORs) ranging from 1.26 to 1.75; resolution of all 10 items was also greater with levomilnacipran ER (OR=1.57; P=.0051). Significant results were found for the MADRS6 subscale (OR=1.73; P<.0001) and each symptom cluster (OR range, 1.39 [Vegetative Symptoms] to 1.84 [Retardation]; all clusters, P<.01). CONCLUSION: Adult MDD patients treated with levomilnacipran ER improved across a range of depression symptoms and symptom domains.

Efficacy and Safety of Vilazodone in Patients With Generalized Anxiety Disorder: A Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Trial.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of vilazodone as an acute treatment for generalized anxiety disorder (GAD). Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder in adults. METHODS: This was a randomized, placebo-controlled, parallel-group, multicenter, flexible-dose study conducted from May 2013-March 2014. Adult patients (18-70 years, inclusive) who met DSM-IV-TR criteria for GAD were randomized (1:1) to placebo or vilazodone 20-40 mg/d for 8 weeks of double-blind treatment. Primary and secondary efficacy parameters were change from baseline to week 8 in the Hamilton Anxiety Rating Scale (HARS) total score and in the Sheehan Disability Scale (SDS) total score, respectively, analyzed using a mixed-effects model for repeated measures approach on a modified intent-to-treat population. Safety outcomes were summarized descriptively. RESULTS: Efficacy analyses were based on 400 patients (placebo = 200, vilazodone = 200); 76% completed the study (placebo = 81%, vilazodone = 71%). The least squares mean difference (95% CI) in total score change from baseline to week 8 was statistically significant for vilazodone versus placebo on the HARS (-2.20 [-3.72 to -0.68]; P = .0048) and on the SDS (-1.89 [-3.52 to -0.26]; P = .0236). Treatment-emergent adverse events reported in ≥ 5% of vilazodone patients and at least twice the rate of placebo were nausea, diarrhea, dizziness, fatigue, delayed ejaculation, and erectile dysfunction. CONCLUSION: Statistically significant differences in favor of vilazodone 20-40 mg/d versus placebo were seen on all measures of anxiety and functional impairment in patients with GAD. Vilazodone was generally well tolerated, and no new safety concerns were noted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01844115.

The effects of levomilnacipran ER in adult patients with first-episode, highly recurrent, or chronic MDD.

BACKGROUND: Major depressive disorder (MDD) can be challenging to manage due its variable and episodic nature. Post hoc analyses were conducted on five studies (NCT00969709, NCT01377194, NCT00969150, NCT01034462, EudraCT:2006-002404-34) to evaluate the efficacy of levomilnacipran extended-release (ER) in patients with different MDD episode histories. METHODS: Adults with MDD were randomized to double-blind treatment with levomilnacipran ER (40-120mg/d) or placebo. Three subgroups were identified: first-episode (n=494); highly recurrent (≥3 major depressive episodes; n=1954); and chronic (current episode duration ≥2 years; n=218). Mean changes from baseline to end of study (Week 8 [US studies], Week 10 [non-US study]) in Montgomery-Åsberg Depression Rating Scale (MADRS), 17-item Hamilton Depression Rating Scale (HAMD17), and Sheehan Disability Scale (SDS) total scores were analyzed in each subgroup. MADRS response, defined as ≥50% total score improvement from baseline to Week 8/10, was also analyzed. RESULTS: Least squares mean differences (LSMDs) between treatment groups indicated significantly greater improvements with levomilnacipran ER versus placebo in MADRS (first-episode, -2.5; highly recurrent, -3.0; chronic, -4.9; all P<.05) and HAMD17 (first-episode, -2.1; highly recurrent, -1.6; chronic, -2.6; all P<.05) total scores. LSMDs for SDS total score were statistically significant in the first-episode and highly recurrent MDD subgroups (both subgroups, -2.3; P<.01). MADRS response rate was significantly higher with levomilnacipran ER versus placebo in all three subgroups (first-episode, 44.5% versus 35.0%; highly recurrent, 44.3% versus 33.5%; 36.8% versus 22.0%; all P<.05). LIMITATIONS: MDD subgroups were defined post hoc; none of the studies were prospectively designed to evaluate outcomes in these subgroups. Other limitations include lack of active comparators and variability of dose/duration due to data being pooled from multiple clinical trials. CONCLUSIONS: Results suggest that levomilnacipran ER improves depression symptoms and functional impairment in adult patients with different histories of MDD episodes.

Effects of levomilnacipran ER on fatigue symptoms associated with major depressive disorder.

The aim of this study was to evaluate the effects of levomilnacipran extended-release (ER) on depression-related fatigue in adults with major depressive disorder. Post-hoc analyses of five phase III trials were carried out, with evaluation of fatigue symptoms based on score changes in four items: Montgomery-Åsberg Depression Rating Scale (MADRS) item 7 (lassitude), and 17-item Hamilton Depression Rating Scale (HAMD17) items 7 (work/activities), 8 (retardation), and 13 (somatic symptoms). Symptom remission was analyzed on the basis of score shifts from baseline to end of treatment: MADRS item 7 and HAMD17 item 7 (from ≥2 to ≤1); HAMD17 items 8 and 13 (from ≥1 to 0). The mean change in MADRS total score was analyzed in patients with low and high fatigue (MADRS item 7 baseline score <4 and ≥4, respectively). Patients receiving levomilnacipran ER had significantly greater mean improvements and symptom remission (no/minimal residual fatigue) on all fatigue-related items: lassitude (35 vs. 28%), work/activities (43 vs. 35%), retardation (46 vs. 39%), somatic symptoms (26 vs. 18%; all Ps<0.01 versus placebo). The mean change in MADRS total score was significantly greater with levomilnacipran ER versus placebo in both low (least squares mean difference=-2.8, P=0.0018) and high (least squares mean difference=-3.1, P<0.0001) fatigue subgroups. Levomilnacipran ER treatment was effective in reducing depression-related fatigue in adult patients with major depressive disorder and was associated with remission of fatigue symptoms.

Levomilnacipran Extended-Release Treatment in Patients With Major Depressive Disorder: Improvements in Functional Impairment Categories.

OBJECTIVE: In this post hoc analysis, improvement in functional impairment in patients with major depressive disorder (MDD) treated with levomilnacipran extended release (ER) was evaluated by assessing shifts from more severe to less severe functional impairment categories on individual Sheehan Disability Scale (SDS) subscales. METHOD: SDS data were pooled from 5 phase II/III studies conducted between December 2006 and March 2012 of levomilnacipran ER versus placebo in adult patients with MDD (DSM-IV-TR criteria). Proportions of patients shifting from moderate-extreme baseline impairment (score ≥ 4) to mild-no impairment (score ≤ 3) at end of treatment were assessed for each SDS subscale. Proportions of patients shifting from marked-extreme (score ≥ 7) baseline impairment to moderate-no (score ≤ 6) or mild-no impairment (score ≤ 3) at end of treatment, and shifts in which patients worsened from moderate-no to marked-extreme impairment, were also evaluated. RESULTS: A significantly higher proportion of patients treated with levomilnacipran ER than placebo-treated patients improved from more severe categories of functional impairment at baseline to less severe impairment categories across all SDS subscales: work/school, social life, and family life/home responsibilities (P < .01). Depending on the SDS subscale, 48%-55% of levomilnacipran ER-treated patients with moderate-extreme impairment at baseline improved to mild or no impairment, compared with no more than 40% of placebo patients on any subscale. Almost half (42%-47%) of levomilnacipran ER-treated patients versus only about one-third (29%-34%) of placebo patients improved from marked-extreme to mild or no impairment across functional domains. CONCLUSIONS: These results suggest that functional improvement was observed across the SDS functional domains. To our knowledge, this is the first such categorical analysis of functional improvement, as measured by the SDS, for an antidepressant. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00969709, NCT01377194, NCT00969150, and NCT01034462 and EudraCT identifier: 2006-002404-34.

Levomilnacipran Pharmacokinetics in Healthy Volunteers Versus Patients with Major Depressive Disorder and Implications for Norepinephrine and Serotonin Reuptake Inhibition.

PURPOSE: Levomilnacipran, a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor, is approved for the treatment of major depressive disorder (MDD) in adults. The objectives of this investigation were to characterize the pharmacokinetic (PK) parameters of levomilnacipran in healthy subjects and in patients with MDD and to compare the plasma concentrations observed at clinically effective doses (40-120 mg daily) in MDD patients versus in vitro inhibitory concentration values for NE and 5-HT transporters. METHODS: Data from 2 trials were analyzed: a Phase I trial (healthy volunteers received a single dose of levomilnacipran extended-release capsule [ER; 25, 50, or 100 mg], escalating multiple doses of levomilnacipran ER [25-300 mg once daily], or placebo); and a Phase III trial (adults with MDD received a fixed dose of levomilnacipran ER [40, 80, or 120 mg once daily for 8 weeks]). Plasma samples of participants were assayed to determine levomilnacipran concentrations, and PK analyses were performed. Unbound plasma concentrations of levomilnacipran in MDD patients were estimated, and inhibitory concentration values were determined by curve fitting of the in vitro data. FINDINGS: Cmax and AUC were dose proportional after single dosing (25-100 mg) and multiple dosing (across the 25-300 mg dose range) of levomilnacipran ER in healthy subjects. Dose-proportional steady-state Cmax (93, 180, and 297 ng/mL) and AUC0-τ (1520, 2935, and 4799 ng*h/mL) were also observed in patients with MDD who received levomilnacipran ER (40, 80, and 120 mg daily). Tmax was ~6 hours and was similar after single and multiple oral doses of levomilnacipran ER. Estimates of levomilnacipran concentration at 50%, 80%, and 90% inhibition were 19, 91, and 237 nM, respectively, for the 5-HT transporter, and 10, 41, and 92 nM for the NE transporter. Average unbound plasma concentrations for levomilnacipran in MDD patients treated with levomilnacipran ER 40, 80, or 120 mg daily exceeded the estimated concentration at 80% and 90% inhibition for 5-HT and NE. IMPLICATIONS: Levomilnacipran PK was dose proportional after single and multiple dosing and was similar between healthy subjects and patients with MDD. Steady-state unbound plasma concentrations of levomilnacipran across the approved dose range (40, 80, and 120 mg daily) in MDD patients were estimated to be comparable or greater than the concentrations that inhibited reuptake of NE and 5-HT by >90% and >80%, respectively, in vitro.

Vilazodone in patients with generalized anxiety disorder: a double-blind, randomized, placebo-controlled, flexible-dose study.

Vilazodone is a selective serotonin reuptake inhibitor and a 5-HT1A receptor partial agonist that is approved for treatment of major depressive disorder in adults in the USA and Mexico. The efficacy, safety, and tolerability of vilazodone for generalized anxiety disorder (GAD) were investigated in a clinical trial (NCT01766401 ClinicalTrials.gov). Participants (18-70 years, inclusive) who met Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision, criteria for GAD were randomized (1:1) to placebo or flexible-dose vilazodone (20-40 mg/day) for 8 weeks of double-blind treatment. Primary and secondary efficacy parameters were changes from baseline to week 8 in Hamilton Rating Scale for Anxiety and Sheehan Disability Scale total scores, respectively. Analysis was based on a mixed-effects model for repeated measures approach on the intent-to-treat population. The intent-to-treat population comprised 395 patients (placebo=197, vilazodone=198); 77% completed the study. The least squares mean difference in change from baseline to week 8 in the Hamilton Rating Scale for Anxiety total score was statistically significant for vilazodone versus placebo [-1.50 (-2.96, -0.04), P=0.0438]. The mean change from baseline to week 8 in the Sheehan Disability Scale total score for vilazodone versus placebo was not statistically significant. Adverse events were reported in 60% of placebo-treated and 83% of vilazodone-treated patients. This was a positive clinical trial of 20-40 mg/day vilazodone versus placebo in the treatment of GAD.

Sexual dysfunction during treatment of major depressive disorder with vilazodone, citalopram, or placebo: results from a phase IV clinical trial.

Sexual dysfunction commonly occurs with major depressive disorder (MDD). Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist antidepressant approved for the treatment of MDD in adults, was evaluated to determine its effects on sexual function. The primary study was a double-blind, randomized, controlled trial comparing vilazodone 20 and 40 mg/day with placebo; citalopram 40 mg/day was an active control (NCT01473381; http://www.clinicaltrials.gov). Post-hoc analyses evaluated change from baseline to week 10 on the Changes in Sexual Functioning Questionnaire (CSFQ); no inferential statistics were performed. CSFQ scores increased for women [1.2 (citalopram) to 3.0 (vilazodone 40 mg)] and men [1.2 (vilazodone 40 mg) to 3.5 (placebo)] in all treatment groups. Greater changes in CSFQ scores were seen in responders [women: 2.33 (citalopram) to 5.06 (vilazodone 40 mg); men: 2.26 (vilazodone 40 mg) to 4.35 (placebo)] versus nonresponders. CSFQ change from baseline was small for patients with normal baseline sexual function; in patients with baseline sexual dysfunction, CSFQ scores improved across groups [women: 2.35 (citalopram) to 4.52 (vilazodone 40 mg); men 2.83 (vilazodone 40 mg) to 6.43 (placebo)]. Across treatment groups, baseline sexual function improved in women and men, MDD responders, and patients with baseline sexual dysfunction.

A double-blind, randomized, placebo-controlled, fixed-dose phase III study of vilazodone in patients with generalized anxiety disorder.

BACKGROUND: Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is approved for treating major depressive disorder in adults. This study (NCT01629966 ClinicalTrials.gov) evaluated the efficacy and safety of vilazodone in adults with generalized anxiety disorder (GAD). METHODS: A multicenter, double-blind, parallel-group, placebo-controlled, fixed-dose study in patients with GAD randomized (1:1:1) to placebo (n = 223), or vilazodone 20 mg/day (n = 230) or 40 mg/day (n = 227). Primary and secondary efficacy parameters were total score change from baseline to week 8 on the Hamilton Rating Scale for Anxiety (HAMA) and Sheehan Disability Scale (SDS), respectively, analyzed using a predefined mixed-effect model for repeated measures (MMRM). Safety outcomes were presented by descriptive statistics. RESULTS: The least squares mean difference (95% confidence interval) in HAMA total score change from baseline (MMRM) was statistically significant for vilazodone 40 mg/day versus placebo (-1.80 [-3.26, -0.34]; P = .0312 [adjusted for multiple comparisons]), but not for vilazodone 20 mg/day versus placebo. Mean change from baseline in SDS total score was not significantly different for either dose of vilazodone versus placebo when adjusted for multiplicity; significant improvement versus placebo was noted for vilazodone 40 mg/day without adjustment for multiplicity (P = .0349). The incidence of adverse events was similar for vilazodone 20 and 40 mg/day (∼71%) and slightly lower for placebo (62%). Nausea, diarrhea, dizziness, vomiting, and fatigue were reported in ≥5% of patients in either vilazodone group and at least twice the rate of placebo. CONCLUSIONS: Vilazodone was effective in treating anxiety symptoms of GAD. No new safety concerns were identified.