A 1-year, open-label study assessing the safety and tolerability of vilazodone in patients with major depressive disorder.

Vilazodone, a selective serotonin (5-HT) reuptake inhibitor and 5-HT(1A) receptor partial agonist, was efficacious in two 8-week placebo-controlled studies in adults with major depressive disorder. This open-label, multicenter study assessed the long-term safety of vilazodone. Adult patients with a 17-item Hamilton Rating Scale for Depression score of 18 or greater received vilazodone according to a fixed-titration schedule to reach a dose of 40 mg/d continued up to 1 year. Safety assessments included adverse events (AEs), physical examinations, clinical chemistry, electrocardiograms, and the Changes in Sexual Functioning Questionnaire. Effectiveness was assessed with the Montgomery-Åsberg Depression Rating Scale and Clinical Global Impressions scales. The safety population comprised 599 patients; 254 patients completed 1 year of treatment. The most frequent AEs were diarrhea (35.7%), nausea (31.6%), and headache (20.0%); greater than 90% of these AEs were mild or moderate. Adverse events resulting in discontinuation in more than 1% of patients were nausea (1.3%) and diarrhea (1.2%). There were no clinically important changes in physical examinations, electrocardiograms, or clinical chemistries. Mean weight increased by 1.7 kg (observed cases). Changes in Sexual Functioning Questionnaire mean scores (observed cases) improved throughout treatment for both males and females. Montgomery-Åsberg Depression Rating Scale mean scores were 29.9 at baseline, 11.4 at week 8, and 7.1 at week 52 (observed cases). Vilazodone 40 mg/d for 1 year was safe and well tolerated by adults with major depressive disorder.

A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of patients with major depressive disorder.

BACKGROUND: Clinical trials assessing antidepressant therapies typically include separate assessments of efficacy (benefit) and adverse events (risk). Global benefit-risk (GBR) assessment allows the simultaneous evaluation of both efficacy and adverse events. The objective was to compare the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine using GBR assessment. METHODS: Data were combined from two similarly designed, multicenter, randomized, double-blind, parallel group studies in which patients with major depressive disorder were randomized to either duloxetine 60 mg/day or venlafaxine extended release (XR) 150 mg/day (75 mg/day for the first 2 weeks) for a 6-week fixed dosing period followed by an additional 6 weeks of treatment in which the dose could be increased up to 120 mg/day for duloxetine and 225 mg/day for venlafaxine. Patients completing the study (or receiving study drug for 2 weeks or more) were eligible to enter a taper period where the dose of study drug was gradually reduced over 1-2 weeks prior to drug discontinuation. The primary outcome measure (defined a priori) was the GBR comparison of duloxetine 60 mg/day and venlafaxine XR 150 mg/day after 6 weeks of treatment. In the GBR analysis, benefit was defined as remission at endpoint [17-item Hamilton Depression Rating Scale (HAMD17) 7]. Risk was defined by four categories: patients having either no adverse events (AEs), AEs with no severity rating greater than moderate, AEs with at least one severity rating of severe, or having discontinued with a reason of self-reported adverse event (regardless of any AE severity). Additional efficacy measures included HAMD17 total score and subscales, HAMA, CGI-S, and PGI-I. Safety and tolerability were assessed via analysis of reasons for discontinuation, treatment-emergent adverse events (TEAEs), discontinuation-emergent adverse events, and changes in vital signs, weight, and laboratory analytes. RESULTS: There were no significant differences between duloxetine 60 mg/day and venlafaxine 150 mg/day as measured by GBR assessment at the end of 6 weeks (-1.418 vs. -1.079, P = 0.217) or 12 weeks (-0.349 vs. -0.121, P = 0.440), nor were there significant differences between treatment groups on the majority of efficacy measures. Significantly more venlafaxine-treated patients (74.5%) completed 12 weeks of treatment compared with duloxetine-treated patients (64.8%, P =.006). Nausea was the most common treatment-emergent adverse event (TEAE) for both drugs, and was significantly higher with duloxetine 60 mg/day compared to venlafaxine 150 mg/day during the first 6 weeks of treatment (43.6% vs. 35.0%, P0.05). During the taper period, significantly more venlafaxine-treated patients reported discontinuation-emergent adverse events (DEAEs) than duloxetine-treated patients. From a safety perspective, significantly more venlafaxine-treated patients (n = 4) than duloxetine-treated patients (n=0, P =.047) experienced sustained elevations of systolic blood pressure during the fixed dosing period. Otherwise, there were few significant differences in safety measures found between treatment groups during 6 and 12 weeks of therapy. CONCLUSIONS: Duloxetine 60 mg/day and venlafaxine XR 150 mg/day have similar benefit-risk profiles on the basis of a comparison utilizing GBR assessment. The implications of the more subtle differences between these drugs, as well as for interpreting the GBR assessment, are discussed.

The significance of treating somatic symptoms on functional outcome improvement in patients with major depressive disorder: a post hoc analysis of 2 trials.

BACKGROUND: Functional impairment is associated with major depressive disorder (MDD), and patients with MDD often present with somatic symptoms. OBJECTIVE: To examine the relationships between improved global functioning and core depressive symptoms as well as painful and nonpainful somatic symptoms in patients with MDD. METHOD: This post hoc analysis of 2 identical trials compared the efficacy of duloxetine with that of paroxetine or placebo as treatment of MDD. In the trials, patients with DSM-IV-defined MDD received duloxetine 80 mg/day (N = 188), duloxetine 120 mg/day (N = 196), paroxetine 20 mg/day (N = 183), or placebo (N = 192) for 8 weeks. The Sheehan Disability Scale (SDS), Maier subscale of the 17-item Hamilton Rating Scale for Depression, 21-item Somatic Symptom Inventory, and Visual Analog Scale for overall pain were used to measure functional impairment, core symptoms of depression, and nonpainful and painful somatic symptoms, respectively. Baseline-to-endpoint mean changes in SDS total and subdomains were measured using analysis of variance with last-observation-carried-forward Pearson partial correlations, and path analysis was used to assess the significance of associations and relative contributions of improvement in global functional impairment, depression, and somatic symptoms. The trials were conducted from November 2000 to July 2002. RESULTS: The difference between antidepressant treatment and placebo in SDS total and subdomains was significant (p < .001). At baseline and in change from baseline to endpoint, associations between global functional impairment and core depressive and somatic symptoms were all significant (p < .05). Path analysis demonstrated improvement of functional impairment attributed to treatment effect as 37.0% (core depressive symptoms), 13.0% (nonpainful somatic symptoms), and 11.0% (painful somatic symptoms). CONCLUSION: In patients with MDD, over a third of functional improvement associated with antidepressant therapy was mediated through improvement in core depressive symptoms. In addition, a significant proportion of functional improvement, although to a lesser degree, was associated with the treatment of both nonpainful and painful somatic symptoms.

An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies.

BACKGROUND AND OBJECTIVE: In recent years, new classes of medication, such as the serotonin-noradrenaline reuptake inhibitors (SNRIs), have been developed for use in the treatment of major depressive disorder (MDD). For many years, treatment options were largely limited to the use of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, there have been published reports of orthostatic hypotension, arrhythmias and corrected QT (QTc) interval changes in patients treated with TCAs. As new medications become available, it is important to understand how their cardiovascular safety profile compares with that of more established agents to aid clinicians and patients in choosing the best treatment options. This study was designed to evaluate the cardiovascular safety profile of the SNRI duloxetine through evaluation of cardiovascular-related parameters and adverse events (AEs). METHODS: The cardiovascular safety of duloxetine was assessed using all placebo-controlled duloxetine clinical trial data as of December 2005. This consisted of data from 42 placebo-controlled clinical trials of 8504 patients who were treated with duloxetine. Additional information from a high-dose clinical pharmacology study and postmarketing safety surveillance are also presented. Of the placebo-controlled trials included in this analysis, clinical indications under investigation included MDD (15 studies), diabetic peripheral neuropathic pain (3 studies), fibromyalgia (2 studies), generalised anxiety disorder (3 studies) and lower urinary tract disorders (19 studies, all related to incontinence). Cardiovascular safety was evaluated based on vital signs, ECGs and the incidence of treatment-emergent AEs potentially related to cardiovascular safety. These safety parameters were analysed across all indications. To identify both serious and non-serious cardiovascular-related AEs, as well as AEs reported as the reason for discontinuation, a comprehensive list of terms derived from the Medical Dictionary for Regulatory Activities (version 8.0) was generated and used to search the duloxetine databases for cardiovascular-related events. RESULTS: Calculation of change from baseline to maximum in ECG parameters showed significant differences between treatment groups for all parameters, with decreases from baseline in RR, QRS and QT intervals for patients receiving duloxetine and increases from baseline for patients treated with placebo. These shifts were related to small heart rate changes, but the mean differences were not considered clinically relevant. Categorical analyses of shifts from normal to abnormal (or abnormal to normal) for heart rate and QT corrected for heart rate using Fridericia's formula (QTcF) values showed that most patients did not shift from their baseline category. Patients with MDD who were treated for up to 1 year with duloxetine had blood pressure changes early in treatment that then stabilised. Even in patients with elevated blood pressure at baseline in these clinical trials, no increased risk of sustained blood pressure elevation with duloxetine treatment was found. CONCLUSION: Overall, the findings presented here support our conclusions that use of duloxetine does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.

Duloxetine for the management of diabetic peripheral neuropathic pain: evidence-based findings from post hoc analysis of three multicenter, randomized, double-blind, placebo-controlled, parallel-group studies.

OBJECTIVE: This post hoc analysis was aimed to summarize the efficacy and tolerability of duloxetine as represented by number needed to treat (NNT) and number needed to harm (NNH) to provide a clinically useful assessment of the position of duloxetine among current agents used to treat diabetic peripheral neuropathic pain (DPNP). METHODS: Data were pooled from three 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in which patients received 60 mg duloxetine either QD or BID or placebo. NNT was calculated based on rates of response (defined as >or=30% and >or=50% reductions from baseline in the weekly mean of the 24-hour average pain severity scores); NNH was calculated based on rates of discontinuation due to adverse events (AEs). RESULTS: Patients receiving duloxetine 60 mg QD and 60 mg BID had NNTs (95% CI) of 5.2 (3.8-8.3) and 4.9 (3.6-7.6), respectively, based on last observation carried forward; NNTs of 5.3 (3.8-8.3) for 60 mg QD and 5.7 (4.1-9.7) for 60 mg BID were obtained based on baseline observations carried forward. The NNHs (95% CI) based on discontinuation due to AEs were 17.5 (10.2-58.8) in the duloxetine 60-mg QD group and 8.8 (6.3-14.7) in the 60-mg BID group. CONCLUSION: These post hoc results suggest that duloxetine was effective and well tolerated for the management of DPNP and further support the importance of duloxetine as a treatment option for clinicians and patients to assist with the management of DPNP.

Duloxetine for the treatment of fibromyalgia in women: pooled results from two randomized, placebo-controlled clinical trials.

BACKGROUND: To assess the efficacy (in particular, in pain, functional impairment, and quality of life) and safety and tolerability (incidence of adverse events, discontinuation rates, changes in laboratory findings, and vital signs) of duloxetine in female patients with fibromyalgia. METHODS: Data were pooled from two placebo-controlled clinical trials of similar design (randomized, 12-week, and double-blind), comparing duloxetine 60 mg a day (q.d.) or 60 mg twice daily (b.i.d.) (n = 326) with placebo (n = 212), in women who met the American College of Rheumatology criteria for primary fibromyalgia. RESULTS: Compared with the patients receiving placebo, duloxetine-treated female patients demonstrated a significantly greater improvement in the Brief Pain Inventory (BPI) average pain severity score and in the Fibromyalgia Impact Questionnaire (FIQ) total score, beginning at week 1 and continuing through week 12 (p < 0.001). Duloxetine was superior to placebo on all efficacy measures, including mean tender point threshold, Clinical Global Impression of Severity, Patient Global Impression of Improvement, and average interference from pain scores. The duloxetine-treated group was superior to placebo on all quality of life and functional measures, including each domain of the Medical Outcomes Study Short Form-36 (SF-36). A direct treatment effect of duloxetine on pain reduction was demonstrated and shown to be independent of secondary improvement in mood (based on BPI average pain score). Significantly more duloxetine-treated patients reported treatment-emergent adverse events (296 [90.8%] duloxetine-treated and 165 [77.8%] placebo-treated, p < 0.001). Rates of serious adverse events were similar between duloxetine-treated and placebo-treated patients. CONCLUSIONS: The pooled results of these studies demonstrate that duloxetine is a safe and efficacious treatment for both the pain and functional impairment associated with fibromyalgia in female patients, while significantly improving quality of life.

Dose-response relationship of duloxetine in placebo-controlled clinical trials in patients with major depressive disorder.

RATIONALE: The optimal dose for achieving the maximum antidepressive effect of selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenalin reuptake inhibitors (SNRIs) remains a controversial issue. The varying sensitivity of scales that measure the severity of depression is one of the many factors affecting the evaluation of the dose-response relationship with antidepressants. OBJECTIVES: To determine if the 6-item Hamilton rating scale for depression (HAM-D6) demonstrates a clearer association between dose and antidepressive effect compared with the 17-item Hamilton rating scale for depression (HAM-D17) for fixed doses of duloxetine hydrochloride (40, 60, 80, and 120 mg daily) from six double-blind, randomized, placebo-controlled clinical trials assessing safety and efficacy in the acute treatment of patients with DSM-IV-defined major depressive disorder (MDD). METHODS: Mantel-Haenszel adjusted effect sizes were determined by dose for change from baseline to endpoint in HAM-D6 and HAM-D17 scores from the six studies. To confirm, assessments were repeated on the subset of the population corresponding to the 70% of patients with the longest duration of treatment regardless of study, treatment, dose, geography, or completion status. RESULTS: For the majority of assessments, HAM-D6 effect sizes were numerically larger than those estimated from the HAM-D17. Findings support that duloxetine 60 mg daily is the best effective dose. CONCLUSIONS: In this assessment of patients with MDD, the HAM-D6 was shown to be more sensitive compared with the HAM-D17 at detecting treatment effects. These findings are consistent with published results of other effective antidepressants.

Treatment benefits of duloxetine in major depressive disorder as assessed by number needed to treat.

The efficacy of an antidepressant typically is assessed by comparing it with placebo using a validated rating scale. This type of analysis, however, does not translate well to the clinical settings. For clinicians, a more meaningful measure is the number needed to treat (NNT). The objective of this analysis is to assess the efficacy of duloxetine in terms of NNT. Data were obtained from nine clinical trials designed to assess the efficacy and safety of duloxetine as a treatment for major depressive disorder. These studies examined 8-9 weeks of acute treatment with duloxetine. NNT estimates were determined for duloxetine, selective serotonin reuptake inhibitor comparators from six multi-dose studies, and for duloxetine in patients > or =65 years of age. The NNT was based on the Hamilton Depression Rating Scale (HAMD17) for response and remission, and improvements defined by the Clinical Global Impression (CGI) were estimated and compared. The NNT was favorable for both duloxetine and selective serotonin reuptake inhibitor compared with placebo. The patients receiving duloxetine had NNT for HAMD17 response of 6.0, remission 7-9, and CGI-defined improvement 6-7 by 8 weeks. The NNTs for selective serotonin reuptake inhibitors (fluoxetine or paroxetine, 20 mg/day) were around 7 for response, 11 for remission, and 8 for CGI-defined improvement. The NNTs in the elderly were similar. The NNT for several measures of efficacy including remission consistently demonstrated the treatment benefits of duloxetine as well as of fluoxetine and paroxetine compared with placebo.

Duloxetine in the treatment of major depressive disorder: an assessment of the relationship between outcomes and episode characteristics.

Duloxetine, an inhibitor of serotonin and norepinephrine reuptake, has been approved for the treatment of major depressive disorder. In this analysis, data from eight, double-blind, placebo-controlled duloxetine trials were pooled, and the response to duloxetine treatment (40-120 mg/day) was compared between patients experiencing their first episode of depression (n=581) or a subsequent episode (n=1321), and between patients experiencing a depressive episode of short (n=596), medium (n=669), or long (n=649) duration based on tertile divisions. Treatment response was determined on the basis of changes from baseline in the 17-item Hamilton Rating Scale for Depression total score, the Clinical Global Impressions of Severity Scale, and painful physical symptoms (Somatic Symptom Inventory and Visual Analog Scales). Overall, changes on all outcome measures and response and remission rates were significantly greater in duloxetine-treated patients than in placebo-treated patients. Furthermore, the effect of duloxetine was similar across all episode characteristic groups (first/subsequent episode, short/medium/long episode duration). Only for the Somatic Symptom Inventory was the effect of duloxetine significantly different between groups (greater in the subsequent episode group than in the first episode group). Duloxetine was effective in the treatment of first and subsequent episodes of major depressive disorder, and regardless of duration of the current depressive episode.

Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder.

BACKGROUND: Discontinuation symptoms are common following antidepressant treatment. This report characterizes symptoms following duloxetine discontinuation. METHODS: Data were obtained from 9 clinical trials assessing the efficacy and safety of duloxetine in the treatment of major depressive disorder (MDD). RESULTS: In a pooled analysis of 6 short-term treatment trials, in which treatment was stopped abruptly, discontinuation-emergent adverse events (DEAEs) were reported by 44.3% and 22.9% of duloxetine- and placebo-treated patients, respectively (p<0.05). Among duloxetine-treated patients reporting at least 1 DEAE, the mean number of symptoms was 2.4. DEAEs reported significantly more frequently on abrupt discontinuation of duloxetine compared with placebo were dizziness (12.4%), nausea (5.9%), headache (5.3%), paresthesia (2.9%), vomiting (2.4%), irritability (2.4%), and nightmares (2.0%). Dizziness was also the most frequently reported DEAE in the analyses of 3 long-term duloxetine studies. Across the short- and long-term data sets, 45.1% of DEAEs had resolved in the duloxetine-treated populations by the end of the respective studies, and the majority of these (65.0%) resolved within 7 days. Most patients rated the severity of their symptoms as mild or moderate. A higher proportion of patients reporting DEAEs were seen with 120 mg/day duloxetine compared with lower doses. For doses between 40 and 120 mg/day duloxetine the proportion of patients reporting at least one DEAE differed significantly from placebo. Extended treatment with duloxetine beyond 8-9 weeks did not appear to be associated with an increased incidence or severity of DEAEs. CONCLUSIONS: Abrupt discontinuation of duloxetine is associated with a DEAE profile similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. It is recommended that, whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment. LIMITATIONS: The main limitation is the use of spontaneously reported DEAEs.

Is treatment-associated hypomania rare with duloxetine: secondary analysis of controlled trials in non-bipolar depression.

BACKGROUND: Selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) like duloxetine have the efficacy of tricyclic antidepressants (TCAs) with a more tolerable side-effect profile. Bipolar disorder is often undetected, with the most common misdiagnosis being unipolar depression. Studies have suggested that treatment of bipolar and unipolar depression with heterocyclic TCAs may increase the risk of switch rate to mania. Studies of antidepressants in unipolar major depression show a small risk of mania or hypomania, presumably because some bipolar depressives were mistakenly studied. This study investigated the rate of hypomania, mania, and hypomanic-like symptoms observed during treatment with duloxetine in patients with major depression. METHODS: This was a retrospective analysis of data from eight placebo-controlled, double-blind, randomized clinical trials of duloxetine in patients with non-bipolar major depression. LIMITATIONS: The studies were of limited duration. Manic or hypomanic symptoms were not elicited using standardized mania rating scale instruments. RESULTS: One case of mania occurred in the placebo group (0.1%), and two cases of hypomania were observed in the duloxetine-treated group (0.2%). Among hypomanic-like symptoms, only insomnia was significantly higher in the duloxetine group than in the placebo group (p<0.05). CONCLUSIONS: Duloxetine was associated with a low incidence of treatment-emergent hypomania, mania, or hypomanic-like symptoms in patients with major depressive disorder (MDD). The low incidence reported here may be due to greater diagnostic diligence on the part of the investigators. It is possible that the cases reported likely reflect inclusion of misdiagnosed bipolar II patients rather than true unipolar MDD cases. The effect of duloxetine in patients with bipolar depression is not known.

The efficacy profile of vilazodone, a novel antidepressant for the treatment of major depressive disorder.

OBJECTIVE: Vilazodone is a novel serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder (MDD). This evaluation presents side-by-side efficacy data from two randomized, double-blind, placebo-controlled, short-term 8-week trials (referred to as randomized controlled trial [RCT]-1 [N = 410] and RCT-2 [N = 481]); efficacy data for demographic and clinical subgroups (derived from pooled RCT data); and effectiveness data from a 52-week, open-label, long-term study (N = 616). The objective is to summarize the efficacy profile of vilazodone at its approved dose of 40 mg/day. METHODS: The main assessment in individual pivotal trials and pooled subgroup analyses was the change from baseline to end of treatment (EOT, 8 weeks) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Mixed-effects repeated-measures analyses were conducted in the placebo-controlled trials. Effectiveness analyses in the long-term study included mean MADRS score change over time. RESULTS: Vilazodone-treated patients in both short-term studies showed greater improvement from baseline to EOT in mean MADRS scores than placebo-treated patients (least-squares mean [LSM] treatment difference: -3.2 [p = 0.001], RCT-1; -2.5 [p = 0.009], RCT-2). Clinical Global Impressions-Improvement mean scores at EOT reflected greater improvement with vilazodone compared with placebo in both studies (LSM treatment difference: -0.4 [p = 0.001], RCT-1; -0.3 [p = 0.004], RCT-2). MADRS response rates were significantly greater among patients receiving vilazodone versus those receiving placebo (RCT-1: 40.4% versus 28.1%, respectively [p = 0.007]; RCT-2: 43.7% versus 30.3%, respectively [p = 0.002]). The greater efficacy of vilazodone versus placebo was consistent for the majority of demographic and MDD characteristic subgroups. In the long-term study, the mean MADRS score improved from 29.9 (baseline) to 11.4 (week 8), 8.2 (week 24), and 7.1 (week 52). CONCLUSION: Vilazodone 40 mg/day resulted in clinically meaningful, statistically significant improvement in MDD symptoms in two placebo-controlled, 8-week studies. Findings are supported by subgroup analysis and open-label, long-term effectiveness data. TRIAL REGISTRATION: Randomized controlled trial 1: ClinicalTrials.gov identifier: NCT00285376, http://ClinicalTrials.gov/ct2/show/NCT00285376 ; randomized controlled trial 2: ClinicalTrials.gov identifier: NCT00683592, http://ClinicalTrials.gov/ct2/show/NCT00683592 ; open-label, long-term study: ClinicalTrials.gov identifier: NCT00644358, http://ClinicalTrials.gov/ct2/show/NCT00644358 .

A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder.

OBJECTIVE: To evaluate the efficacy, and further establish the safety profile, of oral once-daily vilazodone, a potent and selective serotonin 1A receptor partial agonist and reuptake inhibitor, in the treatment of major depressive disorder (MDD). METHOD: This phase 3, randomized, double-blind, placebo-controlled, 8-week study (conducted March 2008-February 2009) enrolled 481 adults with DSM-IV-TR-defined MDD. Patients received vilazodone (titrated to 40 mg/d) or placebo. The primary efficacy endpoint was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to end of treatment. Secondary efficacy measures included MADRS and 17-item Hamilton Depression Rating Scale (HDRS-17) response and change in HDRS-17, HDRS-21, Hamilton Anxiety Rating Scale (HARS), Clinical Global Impressions-Severity of Illness (CGI-S), and Clinical Global Impressions-Improvement (CGI-I) scores. The Changes in Sexual Functioning Questionnaire (CSFQ) was administered at baseline and week 8. RESULTS: Vilazodone-treated patients had significantly greater improvement (P = .009) according to the MADRS than placebo patients (intent-to-treat; least-squares mean changes: -13.3, -10.8). MADRS response rates were significantly higher with vilazodone than placebo (44% vs 30%, P = .002). Remission rates for vilazodone were not significantly different based on the MADRS (vilazodone, 27.3% vs placebo, 20.3%; P = .066) or HDRS-17 (vilazodone, 24.2% vs placebo, 17.7%; P = .088). Vilazodone-treated patients had significantly greater improvements from baseline in HDRS-17 (P = .026), HDRS-21 (P = .029), HARS (P = .037), CGI-S (P = .004), and CGI-I (P = .004) scores than placebo patients. Rates of discontinuation due to adverse events were 5.1% (vilazodone) and 1.7% (placebo). The most common adverse events (vilazodone vs placebo) were diarrhea (31% vs 11%), nausea (26% vs 6%), and headache (13% vs 10%). Treatment-related effects on sexual function as measured by the CSFQ were small and similar to placebo. Effects on weight were no different from placebo. CONCLUSIONS: Vilazodone 40 mg/d was well tolerated and effective in adult patients with MDD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00683592.

The Safety and Tolerability Profile of Vilazodone, A Novel Antidepressant for the Treatment of Major Depressive Disorder.

OBJECTIVE: Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder (MDD). This report summarizes the safety and tolerability of vilazodone 40 mg/day during short- and long-term treatment of adult MDD. METHODS: Pooled data from two 8-week, double-blind studies of vilazodone (n = 436) vs placebo (n = 433) and data from one 52-week, open-label study (n = 616, vilazodone only) were analyzed. Patients aged 18-70 with DSM-IV-TR-defined MDD received vilazodone or placebo (8-week studies only) once daily, with food, titrated to 40 mg/day over 2 weeks. Safety and tolerability assessments included adverse events (AEs), laboratory tests, vital signs, electrocardiograms, and weight. RESULTS: The most common AEs in all studies were diarrhea, nausea, and headache. Vilazodone-associated AEs in the two 8-week studies, defined as an incidence rate of ≥5% in the vilazodone group and at least twice that for placebo, were diarrhea (28.0% vs 9.2%), nausea (23.4% vs 5.1%), and insomnia (6.0% vs 2.1%), with the majority reported as mild to moderate and <5% of those patients requiring concomitant (directed) treatment for these conditions. Discontinuation rates due to AEs were 7.1% (vilazodone) and 3.2% (placebo) in the 8-week studies and 20.7% in the 52-week study. Vilazodone had no clinically significant effects on vital signs, laboratory tests, or electrocardiograms. CONCLUSION: Vilazodone 40 mg/day was well tolerated during short- and long-term MDD treatment in these trials. Safety profiles associated with 8- and 52-week exposure were consistent.

Estimation of minimum clinically important difference for pain in fibromyalgia.

OBJECTIVE: To estimate the minimum clinically important difference (MCID) for several pain measures obtained from the Brief Pain Inventory (BPI) for patients with fibromyalgia. METHODS: Data were pooled across 12-week treatment periods from 4 randomized, double-blind, placebo-controlled studies designed to evaluate the safety and efficacy of duloxetine for the treatment of fibromyalgia. Each study enrolled subjects with American College of Rheumatology--defined fibromyalgia who presented with moderate to severe pain. The MCIDs for the BPI average pain item score and the BPI severity score (the mean of the BPI pain scale values: right now, average, least, and worst) were estimated by anchoring against the Patient's Global Impressions of Improvement scale. RESULTS: The anchor-based MCIDs for the BPI average pain item and severity scores were 2.1 and 2.2 points, respectively. These MCIDs correspond to 32.3% and 34.2% reductions from baseline in scores. CONCLUSION: In these analyses, the MCIDs for several pain measures obtained from the BPI were similar (∼2 points) and corresponded to a 30-35% improvement from baseline to end point. These findings may be beneficial for use in designing clinical trials in which the BPI is used to evaluate improvements in pain severity.

Long-term safety, tolerability, and efficacy of duloxetine in the treatment of fibromyalgia.

OBJECTIVES: To assess the long-term safety, tolerability, and efficacy of duloxetine in patients with fibromyalgia. METHODS: We report results from the 6-month extension phases of 2 randomized, double-blind, placebo-controlled clinical trials having 6-month placebo-controlled phases. In Study 1, all patients received duloxetine 120 mg/d after 28 weeks on placebo or duloxetine 60 or 120 mg/d. In Study 2, patients taking placebo were titrated to duloxetine 60 mg/d after 27 weeks on treatment, while duloxetine-treated patients remained on their dosages of 60 or 120 mg/d. Safety and tolerability were assessed via discontinuation rates, treatment-emergent adverse events (TEAEs), and changes in vital signs and laboratory measures. The primary efficacy measure was the Brief Pain Inventory average pain severity score. RESULTS: The percentage of patients entering and completing the extension phase was 56% (156/278) for Study 1 and 69% (140/204) for Study 2. Groups titrating from placebo to duloxetine showed the highest discontinuation rates due to an adverse event (Study 1, 25%; Study 2, 19%) and TEAE rates (Study 1, 82%; Study 2, 77%). The most common TEAEs were nausea and dry mouth. No significant within-group changes in blood pressure occurred in any group. Significant within-group mean increases in pulse (bpm) were observed in the placebo/duloxetine 120 mg group in Study 1 (3.7 [SD = 11.2], P

Safety and tolerability of duloxetine treatment of diabetic peripheral neuropathic pain between patients with and without cardiovascular conditions.

BACKGROUND: Diabetic patients are predisposed to cardiovascular (CV) disease and other chronic medical conditions. We compared the safety of duloxetine in patients with (CV-positive) and without (CV-negative) historical/comorbid cardiovascular conditions at study entry. METHODS: Data were pooled from three double-blind studies in which patients (age > or =18 years) with diabetic peripheral neuropathic pain (DPNP) were randomized to 12 weeks of duloxetine (DLX) 60 mg qd (n=344), 60 mg bid (n=341), or placebo (PBO, n=339). Safety assessments included discontinuation rates, spontaneously reported treatment-emergent adverse events (TEAEs), changes in vital signs, and changes in lab analytes. RESULTS: Mean age of CV-positive patients (n=762) vs. CV-negative patients (n=262) was 61.1 vs. 56.1 years. The most common historical or comorbid CV conditions were hypertension, coronary artery disease, and myocardial infarction. Discontinuation due to adverse events was higher for DLX than for PBO in both CV-positive and CV-negative patients (13.5% DLX, 6.0% PBO, and 14.3% DLX, 3.4% PBO, respectively). Rates of CV-related TEAEs in CV-positive (8.4% DLX; 9.9% PBO) and CV-negative (8.6% DLX; 5.7% PBO) patients were similar (P>.1). Mean changes in blood pressure for each DLX dose vs. PBO between CV-positive and CV-negative patients were not statistically significant (P>.1), nor were sustained hypertension rates between CV-positive (2.4% DLX; 2.8% PBO) and CV-negative (2.9% DLX; 4.7% PBO) patients. CONCLUSIONS: In this analysis, the safety of duloxetine in patients with DPNP was not found to be significantly different between patients with and without historical or comorbid CV conditions.

A 1-year safety and efficacy study of duloxetine in patients with fibromyalgia.

OBJECTIVES: Evaluate the efficacy and safety of duloxetine at doses up to 120 mg once daily in patients with fibromyalgia. METHODS: This was a phase 3, 60-week study, which included an 8-week open-label period followed by a 52-week, randomized, double-blind period. Patients received duloxetine 30 mg daily for 1 week and duloxetine 60 mg daily for 7 weeks and were then randomized to receive either 60 or 120 mg daily (1:2 ratio). RESULTS: Enrolled patients (N=350, 95.7% female) exhibited moderate disease symptoms at study entry (Brief Pain Inventory average pain=6.7, Clinical Global Impression of Severity=4.1, and Patient's Global Impression of Severity=4.1). Significant pain reduction in patients was observed during the open-label study phase. This pain reduction continued during the 52-week double-blind study phase, as demonstrated by additional mean decreases in the Brief Pain Inventory average pain score within both duloxetine groups. The most common (> or =15%) treatment-emergent adverse events (overall phase) were nausea, headache, insomnia, dizziness, constipation, and dry mouth. Seventy-four (21.1%) patients reported adverse events as a reason for discontinuation [most common (>1%) were insomnia, vomiting, diarrhea, dizziness, and nausea]. The mean change (SD) in sitting systolic blood pressure (mm Hg) was -0.1 (14.4), in sitting diastolic blood pressure was -0.2 (9.6), in sitting pulse rate was 1.9 (10.4) bpm, and in weight was 0.7 (4.3) kg. DISCUSSION: The profile of duloxetine for the long-term treatment of fibromyalgia was consistent with that seen in other indications for which the drug is currently marketed.

Comparisons of the efficacy and safety of duloxetine for the treatment of fibromyalgia in patients with versus without major depressive disorder.

OBJECTIVES: To investigate whether comorbid major depressive disorder (MDD) influenced the efficacy and safety of duloxetine in treating fibromyalgia (FM). METHODS: This was a post-hoc analysis using pooled data from 4 double-blind, placebo-controlled studies of patients with American College of Rheumatology-defined primary FM with or without MDD. Patients were randomized to duloxetine [60 or 120 mg/d (N=797)] or placebo (N=535) for approximately 3 months. Efficacy measures included the Brief Pain Inventory average pain score, 17-item Hamilton Depression Rating Scale, Fibromyalgia Impact Questionnaire, and Patient's/Clinician's Global Impressions of Improvement/Severity scales. RESULTS: At baseline, 26% of patients met diagnostic criteria for MDD. At endpoint (3 mo or last observation), duloxetine showed significantly (P<0.05) greater improvement versus placebo on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire, Patient's Global Impressions of Improvement scale, and Clinician's Global Impressions of Severity scale in patients with and without comorbid MDD. The effect of duloxetine on these efficacy measures was consistent across FM patients with or without MDD (P>0.1 for treatment-by-strata interaction). On the 17-item Hamilton Depression Rating Scale, duloxetine showed significantly (P<0.05) greater improvement versus placebo in patients with comorbid MDD. The safety profile of duloxetine versus placebo with respect to serious adverse events and discontinuation owing to adverse events was similar for FM patients with versus without MDD (P>0.1 treatment-by-strata interaction). DISCUSSION: Duloxetine was effective in reducing pain and other symptoms in FM patients with and without MDD and demonstrated a similar safety profile for both groups.

Safety and tolerability of duloxetine in the treatment of patients with fibromyalgia: pooled analysis of data from five clinical trials.

The purpose of this report is to describe the overall safety profile of both short- and longer-term duloxetine treatment of fibromyalgia. Data from four double-blind, randomized, placebo-controlled studies (two with 6-month open-label extension phases) and a 1-year, open-label safety study were included. Safety measures included treatment-emergent adverse events (TEAEs), adverse events leading to discontinuation, serious adverse events (SAEs), clinical laboratory tests, vital signs, and electrocardiograms. The most common TEAEs for short-term treatment with duloxetine were nausea (29.3%), headache (20.0%), dry mouth (18.2%), insomnia (14.5%), fatigue (13.5%), constipation (14.5%), diarrhea (11.6%), and dizziness (11.0%; all p < 0.05 vs. placebo). Most TEAEs emerged early and were mild to moderate in severity. The profile of adverse events in patients enrolled at least 6 months, and for patients in the 1-year study, was similar to that found in the short-term treatment studies, with no new adverse events emerging at a notable rate. About 20% of patients discontinued due to adverse events in the short-term treatment studies and in the 1-year study. SAEs were uncommon, and none occurred at a significantly higher frequency for duloxetine compared with placebo. Mean changes in vital signs and weight were small. Rates of treatment-emergent potentially clinically significant (PCS) vital sign, laboratory, and electrocardiogram measures were low, with only PCS rates of alanine aminotransferase being significantly higher for duloxetine compared with placebo in the placebo-controlled treatment studies. In the 1-year study, four patients (1.1%) had suicide-related behavior. The data provided here summarize short- and long-term safety from five clinical studies in patients treated with duloxetine for fibromyalgia. In addition, postmarketing surveillance continues for adverse events reported with duloxetine in fibromyalgia, as in other indications.