Duloxetine for the treatment of recurrent major depressive disorder in elderly patients: treatment outcomes in patients with comorbid arthritis.

BACKGROUND: Evaluation and treatment of major depression (MDD) in elderly patients is frequently complicated by the presence of comorbid medical conditions, which can reduce the effect of depression treatment, leading to lower rates of depressive-symptom improvement and higher rates of relapse. OBJECTIVE: The authors investigated results of antidepressant concurrent with arthritis pain treatment in elderly patients. METHOD: Patients age 65 and over with recurrent MDD were stratified by arthritis status and randomized to duloxetine (a dual reuptake-inhibitor of serotonin and norepinephrine) or placebo treatment for 8 weeks (duloxetine, N=117; placebo, N=55). RESULTS: Duloxetine significantly reduced MDD symptom severity in elderly patients with and without arthritis, and produced significant reduction in several pain measures in those patients with comorbid arthritis. DISCUSSION: The magnitude and time-course of depressive symptom improvement did not differ significantly between patients with and without arthritis. Some studies have suggested that the severity of pain in arthritis patients may be linked to depression severity.

Evidence for the efficacy of duloxetine in treating mild, moderate, and severe depression.

Clinicians need to know whether duloxetine is effective in patients across a broad range of depressive symptoms and depression severity. Data were pooled from nine randomized, double-blind, placebo-controlled studies in major depressive disorder (total N=2227) comparing duloxetine (40-120 mg/day) with placebo for 8-9 weeks. Patients were retrospectively stratified by baseline score on the HAMD17 into mild (< or =19; n=682), moderate (n=1099), or severe (> or =25; n=446) groups. Duloxetine produced significantly greater baseline-to-endpoint mean change than placebo in HAMD17 total score, Maier and retardation subscales, and the Clinical Global Impressions-Severity of Illness scale in all three cohorts. Significant improvement was seen in HAMD17 items 1 (depressed mood), 3 (suicide), 7 (work and activities), and 10 (psychic anxiety) regardless of severity. The HAMD17 anxiety subscale and items 13 (somatic symptoms-general) and 15 (hypochondriasis) showed significant improvement only in moderately and severely ill patients. Significant improvement in the HAMD17 Maier subscale was seen in all groups by week 1. In all three groups, placebo was significantly superior to duloxetine at early visits on HAMD17 item 12 (somatic symptoms-GI). Mildly and severely ill patients exhibited significant reduction in visual analog scale overall pain severity at the study endpoint. The studies contained fewer patients with very mild or very severe illness, limiting our ability to draw conclusions in these patient populations. Duloxetine demonstrated superior efficacy in the treatment of major depressive disorder, when compared with placebo, regardless of the baseline severity of depressive symptoms, although effect sizes were largest in the most severely depressed patients.

Duloxetine in the treatment of major depressive disorder: an open-label study.

BACKGROUND: Major depressive disorder (MDD) is a chronic and highly disabling condition. Existing pharmacotherapies produce full remission in only 30% to 40% of treated patients. Antidepressants exhibiting dual reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE) may achieve higher rates of remission compared with those acting upon a single neurotransmitter. In this study, the safety and efficacy of duloxetine, a potent dual reuptake inhibitor of 5-HT and NE, were examined. METHODS: Patients (N = 533) meeting DSM-IV criteria for MDD received open-label duloxetine (60 mg once a day [QD]) for 12 weeks during the initial phase of a relapse prevention trial. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD17) total score >or=18 and a Clinical Global Impression of Severity (CGI-S) score >or=4 at baseline. Efficacy measures included the HAMD17 total score, HAMD17 subscales, the CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQ-SS). Quality of life was assessed using the Sheehan Disability Scale (SDS) and the Quality of Life in Depression Scale (QLDS). Safety was evaluated by recording spontaneously-reported treatment-emergent adverse events, changes in vital signs and laboratory analytes, and the Patient Global Impression of Sexual Function (PGI-SF) scale. RESULTS: The rate of discontinuation due to adverse events was 11.3%. Treatment-emergent adverse events reported by >or=10% duloxetine-treated patients were nausea, headache, dry mouth, somnolence, insomnia, and dizziness. Following 12 weeks of open-label duloxetine therapy, significant improvements were observed in all assessed efficacy and quality of life measures. In assessments of depression severity (HAMD17, CGI-S) the magnitude of symptom improvement continued to increase at each study visit, while for painful physical symptoms the onset of improvement was rapid and reached a maximum after 2 to 3 weeks of treatment. CONCLUSION: In this open-label phase of a relapse prevention study, duloxetine (60 mg QD) was shown to be safe and effective in the treatment of MDD.

Duloxetine for the management of diabetic peripheral neuropathic pain: response profile.

OBJECTIVE: The current analysis examines the response profile in patients receiving duloxetine for the management of diabetic peripheral neuropathic pain (DPNP). PATIENTS/DESIGN: Data were pooled from three double-blind, randomized, placebo-controlled 12-week acute therapy trials of patients with DPNP of at least 6 months' duration. Study 1 (N = 457) had treatment groups of duloxetine 20 mg once daily (QD), 60 mg QD, 60 mg twice daily (BID), and placebo; Studies 2 (N = 334) and 3 (N = 348) compared duloxetine 60 mg QD and 60 mg BID with placebo. The primary efficacy measure in each study was the weekly mean score of the 24-hour average pain severity. Treatment response was defined as a 30% reduction in pain severity, although some analyses were repeated using alternative response criteria (50% reduction, or 2-point reduction, in pain severity). RESULTS: Consistently across the three studies, response rates at endpoint were significantly higher among patients receiving duloxetine (60 mg QD or 60 mg BID) than among those receiving placebo, regardless of the chosen response criterion (30% reduction, 50% reduction, or 2-point reduction in weekly mean of 24-hour average pain severity). The proportion of patients achieving pain relief in the duloxetine treatment groups was significantly greater than that in the placebo group at Week 1 and at all subsequent study visits to the end of acute phase therapy. Using diary data (24-hour average pain severity) from the first 7 days of treatment, the first significant separation from placebo in pain severity reduction for duloxetine 60 mg QD occurred at Day 1 (Study 1), Day 2 (Study 2), and Day 4 (Study 3), while significant separation in response rates first occurred at Day 3 when using pooled data. CONCLUSIONS: Patients with DPNP receiving duloxetine 60 mg QD or 60 mg BID had significantly higher rates of treatment response, when compared with patients receiving placebo, regardless of the chosen response criterion. Response to duloxetine treatment tended to occur early in therapy.

Duloxetine for the treatment of major depressive disorder: safety and tolerability associated with dose escalation.

Duloxetine has demonstrated efficacy for the treatment of major depressive disorder (MDD) at a dose of 60 mg/day (given once daily). Whereas the target dose for the majority of patients is 60 mg/day, higher duloxetine doses (up to 120 mg/day) have been studied using a twice-daily dosing schedule. To further investigate the pharmacological profile of duloxetine within a once-daily dosing regimen at doses above 60 mg, we examined the safety and tolerability of duloxetine during a dose escalation from 60 mg/day to 120 mg/day. This single-arm, non-placebo-controlled study incorporated a 7-week dose escalation phase, in which patients and investigators were blinded as to timing of dose increases, followed by an open-label extension phase of up to 2 years duration. Patients (age >or=18 years) meeting DSM-IV criteria for MDD (n=128) received placebo for 1 week, followed by duloxetine (60 mg/day) titrated after 1 week to 90 mg/day, and after a further week to 120 mg/day. The dose of 120 mg/day was then maintained for 4 weeks. The extension phase comprised an initial 6-week dose stabilization period, during which duloxetine was tapered to the lowest effective dose, followed by continuation therapy at the stabilized dose. We assessed safety using spontaneously reported treatment-emergent adverse events (TEAEs), changes in vital signs, electrocardiograms (ECGs), laboratory analytes, and visual analogue scales (VAS) for gastrointestinal (GI) disturbance. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and VAS assessments of pain severity and interference. The rate of discontinuation due to adverse events during the acute phase of the study was 15.6%. The most frequently reported TEAEs were nausea, headache, dry mouth, dizziness, and decreased appetite. The majority of TEAEs were associated with initial duloxetine dosing; further escalations in dose produced few additional adverse events. VAS measures of GI disturbance worsened significantly compared with baseline values after 1 week of duloxetine treatment. Subsequent assessments of GI disturbance, following dose escalation to 90 mg/day and 120 mg/day, showed either no significant difference or a significant improvement from baseline. Significant improvements (P<.001) were observed in all assessed depression efficacy measures, and in five of six VAS pain outcomes, during acute phase treatment. During 2 years of extension phase therapy, the rate of discontinuation due to adverse events was 11.9%, and the only TEAEs reported by >10% of patients were upper respiratory tract infection (13.1%), headache (10.7%), and insomnia (10.7%). Mean changes from baseline to the end of the extension phase in supine systolic and diastolic blood pressure were 3.8 and 0.5 mm Hg, respectively, and there were no reports of sustained hypertension. Mean increase in heart rate was 5.9 bpm, while patients exhibited a mean weight increase of 3.1 kg over 2 years of treatment. Results from this study suggest that rapid dose escalation of duloxetine (60 mg/day --> 90 mg/day --> 120 mg/day) is safe and tolerable. Despite weekly escalation, the majority of adverse events were mild and transient and occurred in the first week of duloxetine dosing (at 60 mg once daily). Long-term treatment at a stabilized duloxetine dose was associated with a relatively low incidence of TEAEs and treatment discontinuation due to adverse events. Time course profiles of body weight and heart rate showed modest increases during 2 years of treatment [ClinicalTrials.gov number, NC T000 42575].

Duloxetine in the treatment of major depressive disorder: comparisons of safety and efficacy in U.S. Hispanic and majority Caucasian patients.

OBJECTIVE: To evaluate new pharmacotherapies for the treatment of major depressive disorder (MDD) in Hispanic Americans, the largest ethnic minority group in the United States. METHOD: Efficacy and safety data were pooled from 7 double-blind, placebo-controlled clinical trials of duloxetine conducted from February 1999 through November 2002. English-speaking patients (aged > or = 18 years) meeting DSM-IV criteria for MDD received duloxetine (40-120 mg/ day; Hispanic, N = 58; Caucasian, N = 748) or placebo (Hispanic, N = 62; Caucasian, N = 594) for up to 9 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score, HAM-D-17 subscales, the Clinical Global Impressions-Severity of Illness scale, the Patient Global Impression of Improvement scale, and the Visual Analog Scales for pain. Safety was assessed using discontinuation rates, treatment-emergent adverse events, vital signs, and laboratory analyses. Three sets of data were analyzed using different pooling strategies, including exploratory analyses with 470 subjects (Hispanic, N = 51; Caucasian, N = 419) receiving the recommended dose of 60 mg. RESULTS: No evidence for a differential effect of duloxetine in Hispanic and Caucasian patients was found in efficacy outcomes. Discontinuation rates due to adverse events among duloxetine-treated patients were 14.0% for Hispanics and 17.0% for Caucasians, compared with 3.2% and 5.7%, respectively, for placebo-treated patients (p = .671). The type of adverse events and their individual rate of occurrence did not differ significantly between Hispanic and Caucasian patients. Mean changes from baseline for pulse, blood pressure, weight, and laboratory analytes were small and showed no significant differences between Hispanic and Caucasian patients. CONCLUSION: In this analysis of pooled data, no evidence for a differential effect of duloxetine in Hispanic and majority Caucasian patients was found in efficacy or safety outcomes.

Duloxetine efficacy for major depressive disorder in male vs. female patients: data from 7 randomized, double-blind, placebo-controlled trials.

OBJECTIVE: A number of studies have suggested potential gender differences in the efficacy of antidepressant medications. Pooled data from double-blind, placebo-controlled studies were utilized to compare the efficacy of duloxetine in the treatment of major depressive disorder (MDD) in male and female patients. METHOD: Efficacy data were pooled from 7 randomized, double-blind, placebo-controlled clinical trials of duloxetine. These studies represent all available data from U.S. acute-phase, placebo-controlled studies of duloxetine for the treatment of MDD. Patients (aged > or = 18 years) meeting DSM-IV criteria for MDD received duloxetine (40-120 mg/day; men, N = 318; women, N = 578) or placebo (men, N = 242; women, N = 484) for up to 9 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score, HAM-D17 subscales (core, Maier, anxiety, retardation, sleep), the Clinical Global Impressions-Severity of Illness scale (CGI-S) and Patient Global Impression of Improvement scale (PGI-I), the Quality of Life in Depression Scale (QLDS), and Visual Analog Scales (VAS) for pain. The first patient visit was February 1, 1999, and the last patient visit was November 27, 2002. RESULTS: In both male and female patients, duloxetine produced significantly greater improvement in HAM-D17, CGI-S, and PGI-I when compared with placebo (p < .05). Treatment-by-gender interactions did not reach statistical significance, indicating that the magnitude of duloxetine's treatment effects did not differ significantly between male and female patients. However, there was a trend for female patients to show a more robust response than male patients to both duloxetine and placebo. On the basis of VAS assessments of pain severity, duloxetine-treated female patients appeared to exhibit greater improvement than male patients, while women receiving placebo had smaller responses than placebo-treated men. Improvements in quality of life were significantly greater for both men (p = .006) and women (p = .001) receiving duloxetine than placebo and showed no significant difference by gender. CONCLUSION: In this analysis of pooled data, the efficacy of duloxetine did not differ significantly in male and female patients.

Duloxetine in the treatment of major depressive disorder: comparisons of safety and tolerability in male and female patients.

BACKGROUND: While some studies have suggested sex differences in the efficacy of antidepressant medications, there have been few investigations into potential sex differences related to safety and/or tolerability. Pooled data from double-blind, placebo-controlled studies were utilized to assess the safety and tolerability of duloxetine in the treatment of major depressive disorder (MDD) in male and female patients. METHODS: Safety data were pooled from seven double-blind, placebo-controlled clinical trials of duloxetine. Patients (aged >or=18 years) meeting DSM-IV criteria for MDD received duloxetine (40-120 mg/day, male: N=318, female: N=578) or placebo (male: N=242, female: N=484) for up to 9 weeks. Safety was assessed using discontinuation rates, spontaneously reported treatment-emergent adverse events, changes in vital signs and laboratory analyses. RESULTS: Discontinuation rates due to adverse events among duloxetine-treated patients were 18.6% for males and 13.5% for females. The most common treatment-emergent adverse events in both male and female patients included nausea, headache, dry mouth, diarrhea and constipation. The only event occurring at significantly different rates in male and female patients was nausea (Breslow Day p-value=0.008), and the significant difference was driven by a placebo nausea rate that was almost three times greater in females compared with males. No significant differential sex effects were found for pulse, blood pressure or weight. No laboratory analyte had an incidence of abnormal high or low values that differed significantly between male and female patients. LIMITATIONS: This was a post-hoc analysis of pooled data from acute phase clinical trials. Plasma concentrations of duloxetine were not obtained. Adverse event rates were based on spontaneous reports and differential dose-response effects were not evaluated. CONCLUSIONS: No evidence of clinically meaningful sex differences in the safety and tolerability of duloxetine were uncovered.

Duloxetine in the treatment of major depressive disorder: comparisons of safety and efficacy.

BACKGROUND: Pooled data from double-blind, placebo-controlled studies were utilized to compare the safety and efficacy of duloxetine in the treatment of major depressive disorder (MDD) in African-American and Caucasian patients. METHODS: Efficacy and safety data were pooled from seven double-blind, placebo-controlled clinical trials of duloxetine. Patients (aged > or =18 years) meeting DSM-IV criteria for MDD received duloxetine (40-120 mg/day; African Americans, N=69; Caucasians, N=748) or placebo (African Americans, N=59; Caucasians, N=594) for up to nine weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total score, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain. Safety was assessed using discontinuation rates, spontaneously reported treatment-emergent adverse events, vital signs and laboratory analyses, RESULTS: Based upon mean changes in HAMD17, CGI-S and PGI-I scales, the magnitude of duloxetine's treatment effects did not differ significantly between African-American and Caucasian patients. Discontinuation rates due to adverse events among duloxetine-treated patients were 13.0% for African Americans and 17.0% for Caucasians. No adverse event led to discontinuation in more than one African-American patient. The most common treatment-emergent adverse events in both ethnic groups included nausea, headache, constipation, dizziness and insomnia. The rate of occurrence of these events did not differ significantly between African-American and Caucasian patients. Mean changes from baseline for pulse, blood pressure, weight and laboratory analytes were small and showed no significant differences between African-American and Caucasian patients. CONCLUSION: In this analysis of data from seven clinical trials, no convincing evidence was found to suggest that the overall safety and tolerability profile or the efficacy profile for duloxetine in this cohort of African-American patients differed from that observed in a comparator group of Caucasian patients. The results from these analyses provide supportive evidence for the efficacy and safety of duloxetine in the treatment of MDD in African-American patients.

Comparing onset of antidepressant action using a repeated measures approach and a traditional assessment schedule.

BACKGROUND: It has been recommended that onset of antidepressant action be assessed using survival analyses with assessments taken at least twice per week. However, such an assessment schedule is problematic to implement. The present study assessed the feasibility of comparing onset of action between treatments using a categorical repeated measures approach with a traditional assessment schedule. METHOD: Four scenarios representative of antidepressant clinical trials were created by varying mean improvements over time. Two assessment schedules were compared within the simulated 8-week studies: (i) 'frequent' assessment--16 postbaseline visits (twice-weekly for 8 weeks); (ii) 'traditional' assessment--5 postbaseline visits (Weeks 1, 2, 4, 6, and 8). Onset was defined as a 20 per cent improvement from baseline, and had to be sustained at all subsequent assessments. Differences between treatments were analysed with a survival analysis (KM = Kaplan-Meier product limit method) and a categorical mixed-effects model repeated measures analysis (MMRM-CAT). RESULTS: More frequent assessments resulted in small reductions in empirical standard errors compared with traditional assessments for both analytic methods. More frequent assessments altered estimates of treatment group differences in KM such that power was increased when the difference between treatments was increasing over time, but power decreased when the treatment difference decreased over time. More frequent assessments had a minimal effect on estimates of treatment group differences in MMRM-CAT. The MMRM-CAT analysis of data from a traditional assessment schedule provided adequate control of type I error, and had power comparable to or greater than that with KM analyses of data from either a frequent or a traditional assessment schedule. CONCLUSION: In the scenarios tested in this study it was reasonable to assess treatment group differences in onset of action with MMRM-CAT and a traditional assessment schedule. Additional research is needed to assess whether these findings hold in data with drop-out and across definitions of onset.

Duloxetine for the treatment of major depressive disorder: a closer look at efficacy and safety data across the approved dose range.

OBJECTIVE: This analysis focuses on efficacy and safety data obtained from studies of duloxetine for the treatment of major depressive disorder (MDD) within the approved dose range of 40-60 mg/day. METHOD: Efficacy and safety data were obtained from the acute phase portions of four randomized, double-blind, placebo-controlled clinical trials in patients meeting DSM-IV criteria for MDD. In Studies 1 and 2, patients were randomized to duloxetine 60 mg once daily (QD) (n=123 [Study 1]; n=128 [Study 2]) or placebo (n=122 [Study 1]; n=139 [Study 2]) for 9 weeks. In Studies 3 and 4, patients were randomized to duloxetine 20 mg twice daily (BID) (n=91 [Study 3]; n=86 [Study 4]) or placebo (n=90 [Study 3]; n=89 [Study 4]) for 8 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total score (primary outcome), HAMD17 subscales, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain. Safety assessments included rates of discontinuation due to adverse events, spontaneously reported treatment-emergent adverse events, and changes in vital signs. RESULTS: In both studies of duloxetine 60 mg QD, mean change in HAMD17 total score was significantly greater in duloxetine-treated patients compared with placebo (Study 1, p<.001; Study 2, p=.024). At a dose of 20 mg BID, duloxetine demonstrated significant superiority over placebo on the HAMD17 total score in one of the two studies (Study 4, p=.034). Probabilities of remission among patients receiving duloxetine 60 mg QD were 44.2% in Study 1 (p<.001 vs. placebo) and 43.0% in Study 2 (NS), while for patients receiving duloxetine 20 mg BID the probabilities of remission were 27.2% in Study 3 (NS) and 36.1% in Study 4 (NS). Across the six assessed VAS measures of pain severity and interference, the main effect of treatment for duloxetine 60 mg QD was significantly superior to placebo on 7 of the 12 outcomes in Studies 1 and 2, while duloxetine 20 mg BID was not superior to placebo on any of the 12 outcomes in Studies 3 and 4. The rate of discontinuation due to adverse events was 13.1% among patients receiving duloxetine 60 mg QD, and 11.9% at a dose of 20 mg BID. The most frequently reported treatment-emergent adverse events at both doses included nausea, headache, dry mouth, dizziness, and insomnia. The incidence of treatment-emergent nausea among patients receiving duloxetine 60 mg QD was 37.8%, compared with 16.4% among patients receiving 20 mg BID. CONCLUSION: Duloxetine provides safe and effective acute phase treatment of MDD at doses of 40-60 mg/day. Compared with placebo, the 60 mg QD dose was more consistently effective than the 20 mg BID dose. However, the incidence of certain treatment-emergent adverse events is likely to be lower at the 40 mg dose.

An open-label study of duloxetine for the treatment of major depressive disorder: comparison of switching versus initiating treatment approaches.

This study compared the stabilized duloxetine dose through approximately 12 weeks of treatment in patients initiating duloxetine therapy with that in patients switching to duloxetine from selective serotonin reuptake inhibitors or venlafaxine. All patients met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depressive disorder. Patients (n = 112) exhibiting suboptimal response or poor tolerability to their current antidepressant medication (citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, or venlafaxine) were switched to duloxetine 60 mg once daily (QD) without intermediate tapering or titration ("switching" group). A comparator group (n = 137), comprising patients not currently receiving antidepressant medication, was randomized to receive duloxetine 30 or 60 mg QD ("initiating" group). At the end of week 1, patients receiving 30 mg QD had their dose increased to 60 mg QD. During the remainder of the study, each patient's duloxetine dose could be titrated on the basis of degree of response within a range from 60 to 120 mg QD, with 90 mg QD as an intermediate dose. At the study end point, approximately one third of the patients in each treatment group were stabilized at each of the 3 studied duloxetine doses (60, 90, and 120 mg QD), and the distribution of stabilized doses among patients initiating duloxetine therapy did not differ significantly from that observed in patients switching to duloxetine. The efficacy of duloxetine in patients switching from selective serotonin reuptake inhibitor/venlafaxine did not differ significantly from that observed in untreated patients initiating duloxetine therapy (baseline-to-end point mean changes: 17-Item Hamilton Rating Scale for Depression total score, -13.1 vs. -13.5; Hamilton Rating Scale for Anxiety, -10.6 vs. -10.3; and Clinical Global Impression of Severity, -2.22 vs. -2.38, respectively). The rate of discontinuation caused by adverse events among patients switched to duloxetine was significantly lower than that in patients initiating duloxetine therapy (6.3% vs. 16.1%, P = 0.018). Treatment-emergent adverse events occurring in more than 10% of patients in both treatment groups were nausea, headache, dry mouth, insomnia, diarrhea, and constipation. In the first week of therapy, patients switched to duloxetine reported significantly lower rates of headache and fatigue compared with patients initiating duloxetine. Thus, the efficacy of duloxetine in switched patients was comparable to that observed in patients initiating duloxetine therapy. Immediate switching from a selective serotonin reuptake inhibitor or venlafaxine to duloxetine (60 mg QD) was well tolerated.

Duloxetine for the treatment of major depressive disorder in women ages 40 to 55 years.

The efficacy of duloxetine in the treatment of major depressive disorder in women of approximately perimenopausal age (40-55 years; 62 placebo subjects and 55 subjects taking duloxetine, 60 mg/day) was compared with that observed in cohorts of younger (<40 years, 94 placebo subjects and 85 duloxetine subjects) and older (>55 years, 26 placebo subjects and 25 duloxetine subjects) women. Women (ages 40-55 years) receiving duloxetine demonstrated significantly greater improvement in total scores on the 17-item Hamilton Rating Scale for Depression compared with placebo at the study endpoint (week 9). Significant advantages for duloxetine over placebo were observed on 17-item Hamilton depression scale subscales (core, Maier, anxiety, retardation, and sleep), in addition to the Clinical Global Impression severity and Patient Global Impression of Improvement Scale, the Quality of Life in Depression Scale, and Visual Analog Scales assessing pain severity. The magnitude of duloxetine's treatment effect in women ages 40-55 years was similar to that observed in younger (age <40 years) and older (age >55 years) female patients. In the placebo treatment groups, however, mean changes differed substantially by age group with the smallest placebo responses observed in the 40-55 age group. Duloxetine (60 mg/day) was demonstrated to be an effective treatment for major depressive disorder in this cohort of women ages 40-55 years.

Sexual functioning assessed in 4 double-blind placebo- and paroxetine-controlled trials of duloxetine for major depressive disorder.

OBJECTIVE: The onset or worsening of sexual dysfunction is a common treatment-emergent side effect of antidepressant medications. Post hoc analyses of pooled data from placebo-controlled studies were utilized to assess sexual functioning in patients receiving duloxetine or paroxetine. METHOD: Acute-phase data were obtained from four 8-week, double-blind, placebo- and paroxetine-controlled trials of similar design in which patients meeting DSM-IV criteria for major depressive disorder were randomly assigned to receive placebo (N = 371), duloxetine (40-120 mg/day; N = 736), or paroxetine (20 mg/day; N = 359). Pooling of data from these studies was anticipated during study design. This represented all available data from duloxetine studies in which the Arizona Sexual Experience Scale (ASEX) was administered both at baseline and endpoint. Long-term data were available from extension phases in 2 of these trials in which acute treatment responders received placebo (N = 129), duloxetine (80-120 mg/day; N = 297), or paroxetine (20 mg/day; N = 140) for an additional 26 weeks. Data were collected between March 2000 and July 2002. RESULTS: The incidence of acute treatment-emergent sexual dysfunction was significantly lower among duloxetine-treated patients compared with those receiving paroxetine (p = .015), although both rates were significantly higher than placebo (p = .007 and p < .001 for duloxetine and paroxetine, respectively). Treatment group differences in the incidence of treatment-emergent dysfunction did not vary significantly by gender. In female patients, acute treatment-emergent sexual dysfunction was significantly lower in the duloxetine treatment group compared with the paroxetine treatment group (p = .032), with both rates being significantly higher than placebo (p = .049 and p < .001 for duloxetine and paroxetine, respectively). In the somewhat smaller group of male patients, acute treatment-emergent dysfunction did not differ significantly between duloxetine and placebo treatment groups, but the incidence was significantly higher in paroxetine-treated male patients compared with male placebo patients (p = .012). The long-term incidence of treatment-emergent dysfunction did not differ significantly between duloxetine-, paroxetine-, and placebo-treated patients. CONCLUSION: In this analysis of pooled data, patients receiving duloxetine (40-120 mg/day) or paroxetine (20 mg/day) had a significantly higher incidence of acute treatment-emergent sexual dysfunction when compared with placebo patients. However, the incidence of acute treatment-emergent dysfunction for duloxetine was significantly lower than that observed for paroxetine.

Safety and tolerability of duloxetine in the treatment of major depressive disorder: analysis of pooled data from eight placebo-controlled clinical trials.

OBJECTIVE: To examine the safety and tolerability of the antidepressant duloxetine across multiple studies for major depressive disorder (MDD). METHOD: Safety data were integrated from the acute phases of eight double-blind, placebo-controlled trials in which patients were randomized to duloxetine (40-120 mg/d; n = 1139) or placebo (n = 777) for up to 9 weeks. This data set included all acute-phase clinical trials that formed the basis of the New Drug Application (United States) or European Union submission package for duloxetine in the treatment of MDD. Two studies included continuation phases in which acute treatment responders received duloxetine or placebo for an additional 26 weeks. Safety assessments included serious adverse event reports, rates of discontinuation, spontaneously reported treatment-emergent adverse events, changes in vital signs and laboratory values, and electrocardiograms. RESULTS: The rates of serious adverse events for duloxetine- and placebo-treated patients were 0.3% and 0.6%, respectively (p = 0.282). Adverse events led to discontinuation in 9.7% of duloxetine-treated patients, compared with 4.2% of patients receiving placebo (p < 0.001). Treatment-emergent adverse events with an incidence for duloxetine > or = 5.0% and significantly greater than placebo were nausea, dry mouth, constipation, insomnia, dizziness, fatigue, somnolence, increased sweating and decreased appetite. Mean changes in blood pressure and heart rate were small, and the incidence of increases above normal ranges was low. Duloxetine-treated patients had a mean decrease in weight of 0.5 kg compared with an increase of 0.2 kg for patients receiving placebo (p < 0.001). No significant differences were found between duloxetine and placebo in the incidence of potentially clinically significant laboratory values at anytime while on treatment. CONCLUSION: These results are consistent with those obtained previously from smaller pooled data sets, and suggest that duloxetine is safe and well tolerated in patients with MDD.

Duloxetine for the treatment of major depressive disorder in older patients.

OBJECTIVE: The efficacy and safety of duloxetine, a dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), were evaluated in the treatment of major depressive disorder (MDD) and associated pain symptoms in patients age 55 and older. METHODS: Efficacy data were obtained from patients age > or =55 who participated in two identical, multicenter, double-blind studies in which patients with MDD were randomized to receive placebo (N=43) or duloxetine (60 mg/day; N=47) for 9 weeks. The primary efficacy measure was the mean change in Ham-D-17 total score. Pain symptoms were assessed with visual-analog scales. Safety data for patients age > or =55 were pooled from six randomized, 8- or 9-week, double-blind studies of duloxetine in which patients with MDD were randomized to receive placebo (N=90) or duloxetine (40 mg/day-120 mg/day; N=119). RESULTS: The combined results of these two investigations found that duloxetine was significantly superior to placebo for mean change in Ham-D-17 total score. The estimated probability of remission for duloxetine-treated patients (44.1%) was also significantly higher than that for placebo (16.1%). Reductions in overall pain, back pain, and pain while awake were also significantly greater for duloxetine than placebo. The rate of discontinuation due to adverse events was significantly higher for duloxetine-treated patients (21.0%) than placebo (6.7%). Abnormal elevations in vital signs at endpoint were not significantly different from placebo. CONCLUSIONS: In these two investigations, duloxetine 60 mg/day was an efficacious treatment for MDD and also alleviated pain symptoms in depression patients age 55 and older.

Duloxetine in the treatment of Major Depressive Disorder: a comparison of efficacy in patients with and without melancholic features.

BACKGROUND: The most prominent feature of melancholic depression is a near-total loss of the capacity to derive pleasure from activities or other positive stimuli. Additional symptoms can include psychomotor disturbances, anorexia, excessive guilt, and early awakening from sleep. Melancholic patients may exhibit treatment responses and outcomes that differ from those of non-melancholic patients. Pooled data from double-blind, placebo-controlled studies were utilized to compare the efficacy of duloxetine in depressed patients with and without melancholic features. METHODS: Efficacy data were pooled from 8 double-blind, placebo-controlled clinical trials of duloxetine. The presence of melancholic features (DSM-IV criteria) was determined using results from the Mini International Neuropsychiatric Interview (MINI). Patients (aged >or= 18 years) meeting DSM-IV criteria for major depressive disorder (MDD) received duloxetine (40-120 mg/d; melancholic, N = 759; non-melancholic, N = 379) or placebo (melancholic, N = 519; non-melancholic, N = 256) for up to 9 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total score, HAMD17 subscales (Maier, anxiety, retardation, sleep), the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain. RESULTS: In data from all 8 studies, duloxetine's advantage over placebo did not differ significantly between melancholic and non-melancholic patients (treatment-by-melancholic status interactions were not statistically significant). Duloxetine demonstrated significantly greater improvement in depressive symptom severity, compared with placebo, within both melancholic and non-melancholic cohorts (p

Duloxetine 60 mg once-daily in the treatment of painful physical symptoms in patients with major depressive disorder.

BACKGROUND: While emotional symptoms such as depressed mood and loss of interest have traditionally been considered to constitute the core symptoms of major depressive disorder (MDD), the prevalence and importance of painful physical symptoms such as back pain, abdominal pain, and musculoskeletal pain is becoming increasingly appreciated. Antidepressants possessing dual serotonin/norepinephrine (5-HT/NE) reuptake inhibition may demonstrate greater efficacy in the alleviation of pain. The efficacy of duloxetine, a balanced and potent dual reuptake inhibitor of 5-HT and NE, was evaluated within a cohort of depressed patients with associated painful physical symptoms. METHODS: In this multicenter, double-blind, placebo-controlled study, patients meeting DSM-IV criteria for MDD were randomized to receive placebo (N=141) or duloxetine 60 mg QD (N=141). Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD17) total score 15, a Clinical Global Impression of Severity (CGI-S) score 4, and a Brief Pain Inventory (BPI) Average Pain score 2 at baseline. The primary efficacy measure was the BPI Average Pain score, while secondary measures included other BPI items, the HAMD17 total score, CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQSS). Safety was evaluated by recording treatment-emergent adverse events (spontaneously reported), vital signs, and laboratory analytes. RESULTS: Mean changes in BPI Average Pain for duloxetine- and placebo-treated patients differed significantly at most visits, but only approached significance at endpoint p=0.066. For the main effect of treatment (pooling all visits), significant advantages for duloxetine-treated patients were found in 10 of 11 assessed BPI pain severity and pain interference items, in addition to VAS overall pain and back pain. Mean changes in pain measures for duloxetine-treated patients corresponded to improvements of 25-50%, compared with 19-39% for placebo. Mean changes at endpoint in depression rating scales (HAMD17, CGI-S, PGI-I) did not differ significantly between duloxetine and placebo treatment groups due to unusually high placebo response. The magnitude of placebo treatment effects (as measured by HAMD17 total score and Maier subscale) was significantly smaller in patients with 1 previous depressive episode, compared to those patients with no previous episodes. In patients with 1 previous depressive episode the advantage of duloxetine over placebo was similar to previous studies. Rates of discontinuation due to adverse events were 14.2% vs. 2.1% for duloxetine and placebo, respectively p<0.001. Treatment-emergent adverse events reported at a significantly higher rate by duloxetine-treated patients included nausea, dry mouth, fatigue, and decreased appetite. CONCLUSIONS: In this study, duloxetine (60 mg QD) was shown to be an effective treatment for the painful physical symptoms which are frequently associated with depression. Improvements in pain severity occurred independently of changes in depressive symptom severity.

Comparative effects of duloxetine and desipramine on sleep EEG in healthy subjects.

RATIONALE: Antidepressants are known to modify human sleep patterns. OBJECTIVES: Duloxetine is a new antidepressant with a mechanism of action involving reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE). In this study, the effects of two dosing regimens of duloxetine on sleep electroencephalography (EEG) were investigated at steady-state plasma concentrations in young, healthy, male subjects. METHODS: Placebo (n=12), desipramine (50 mg BID; n=12) and two regimens of duloxetine (80 mg QD, n=6; or 60 mg BID, n=6) were compared in a randomized, double-blind, three-period crossover study, each treatment being administered from day 1 to day 7. Sleep polygraphic recordings took place at baseline (day -1) and day 6 of each period. The Leeds sleep evaluation questionnaire (LSEQ) was also administered on the morning of day 7. RESULTS: Both regimens of duloxetine produced a significant increase in the onset latency of REM sleep as well as a significant mean decrease in total REM sleep duration. Desipramine exhibited comparable effects. When compared to placebo, sleep continuity was significantly reduced with desipramine and duloxetine 60 mg BID whereas a significant improvement was observed with duloxetine 80 mg QD. On the LSEQ, duloxetine 80 mg QD produced a significant improvement in the "getting to sleep" subscale compared to placebo, whereas desipramine demonstrated a significant reduction (worsening) in the "quality of sleep" score versus placebo. CONCLUSIONS: The two dose regimens of duloxetine (80 mg QD and 60 mg BID) produced a REM sleep pattern comparable to that of most antidepressant medications. Duloxetine 80 mg QD appeared to exhibit less impact upon sleep quality than duloxetine 60 mg BID in healthy subjects.

Onset of action for duloxetine 60 mg once daily: double-blind, placebo-controlled studies.

BACKGROUND: It is widely believed that most antidepressant medications exhibit a delay of 2-4 weeks before clinically relevant improvement can be observed among patients. During this latency period, patients continue to be symptomatic and functionally impaired. Thus, time to onset of effect is an important attribute of a new pharmacotherapy. We assessed the onset of effect for duloxetine, utilizing analytical methods previously recommended in the literature. METHOD: Efficacy data were pooled from two identical, but independent, randomized, double-blind, placebo-controlled, 9-week clinical trials of duloxetine (60 mg QD). Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD(17)), HAMD(17) subscales (Maier, core, and anxiety), and the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales. In each individual study, duloxetine demonstrated statistically significant advantages over placebo on multiple outcomes. The present analysis utilized pooled data to more accurately and fully characterize the onset of effect for duloxetine. RESULTS: Median times to sustained improvements of 10% and 20% in the HAMD(17) total score among duloxetine-treated patients were 14 days and 21 days, respectively, compared with 34 days and 49 days, respectively, for placebo-treated patients (p < 0.001 for both results). The median time to sustained 30% improvement in HAMD(17) total score was 35 days for duloxetine-treated patients, while the median time for placebo-treated patients was not estimable since less than half of the patients met this criterion by the end of the trial. For duloxetine-treated patients, median times to sustained 10%, 20%, and 30% improvements on the Maier subscale of the HAMD(17) were the same as those for the HAMD(17) total score: 14, 21, and 35 days, respectively. However, in other analyses, changes in core emotional symptoms as measured by subscales of the HAMD(17) were somewhat faster than changes in overall symptomatology. The probabilities of achieving a sustained 30% improvement (Maier subscale) at Week 1 for duloxetine- and placebo-treated patients were 16.2% vs. 4.8%, respectively (p < 0.001). The corresponding probabilities of sustained improvement at Weeks 2 and 3 for duloxetine were 32.5% and 45.4%, respectively, compared to 12.8% and 21.4% for placebo ((p < 0.001 for both comparisons). CONCLUSION: The absence of an active comparator limits the conclusions which can be drawn regarding the rapidity of onset of clinically meaningful improvement. However, results from the present investigation may be useful to clinicians in consideration of treatment options for individual patients.