Duloxetine-treated Patients Research Articles

Duloxetine in the Management of Diabetic Peripheral Neuropathic Pain: Response Profile

Introduction Analyses examine the response rate at endpoint, as well as time course of response, in patients receiving duloxetine for management of diabetic peripheral neuropathic pain (DPNP). Methods Data were pooled from 3 double-blind, randomized, placebo-controlled 12-week trials in patients with DPNP ≥ 6 months duration, and without depression. Study 1 ( N = 457) compared 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. Ethics committees approved the study protocol in accordance with Declaration of Helsinki principles. Patients provided written informed consent prior to study participation. Treatment response was defined a priori as 30% reduction in the primary efficacy measure, 24-hour average pain severity. Analysis was replicated using alternative criteria (50% reduction or 2-point reduction). Results Endpoint response rates were significantly higher among patients receiving duloxetine (60 mg QD or 60 mg BID) than those receiving placebo, regardless of chosen response criterion. The proportion of patients responding (30% reduction in 24-hour average pain severity) to duloxetine was statistically greater than to placebo Week 1 and all subsequent visits. Similar results were obtained for the visitwise sustained response rate. Within the group with a sustained response at Week 12, the proportion of patients first exhibiting a response at Weeks 1 or 2 was higher in the duloxetine groups (60 mg QD, 65.0%; 60 mg BID, 62.0%) when compared with the placebo group (40.2%). Conclusion Patients with DPNP receiving duloxetine 60 mg QD or 60 mg BID had significantly higher treatment response rates compared with patients receiving placebo, regardless of response criterion. Response to duloxetine treatment tended to occur early, with approximately 30% of patients responding at Week 1. Among duloxetine-treated patients with a sustained treatment response at Week 12, over 60% had maintained responder status for 10 to 11 weeks.

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 ≥ 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: a placebo- and paroxetine-controlled trial

Objective Duloxetine doses of 80 and 120 mg/day were assessed for efficacy and safety in the treatment of major depressive disorder (MDD). Methods In this randomized, double-blind trial, patients age ≥ 18 meeting DSM-IV criteria for MDD were randomized to placebo ( N = 99), duloxetine 80 mg/day ( N = 93), duloxetine 120 mg/day ( N = 103), or paroxetine 20 mg/day ( N = 97). The primary outcome measure was mean change from baseline in the 17-item Hamilton rating scale for depression (HAMD 17) total score after 8 weeks of treatment; a number of secondary efficacy measures also were assessed. Safety and tolerability were assessed via collection and analysis of treatment–emergent adverse events (TEAEs), vital signs, and weight. The Arizona sexual experiences scale was used to assess sexual functioning. Patients who had a ≥ 30% reduction from baseline in the HAMD 17 total score at the end of the acute phase entered a 6-month continuation phase where they remained on the same treatment as they had taken during the acute phase; efficacy and safety/tolerability outcomes were assessed during continuation treatment. Results More than 87% of patients completed the acute phase in each treatment group. Duloxetine-treated patients (both doses) showed significantly greater improvement ( P < 0.05) in the HAMD 17 total score at week 8 compared with placebo. Paroxetine was not significantly different from placebo ( P = 0.089) on mean change on the HAMD 17. Duloxetine 120 mg/day also showed significant improvement on most secondary efficacy measures (six of nine) compared with placebo while duloxetine 80 mg/day (three of nine) and paroxetine (three of nine) were significantly superior to placebo on fewer secondary measures. HAMD 17 mean change data from this study and an identical sister study were pooled as defined a priori for the purposes of performing a non-inferiority test versus paroxetine. Both duloxetine doses met statistical criteria for non-inferiority to paroxetine. TEAE reporting rates were low in all treatment groups and no deaths occurred in the acute or continuation phases. Conclusions The efficacy of duloxetine at doses of 80 and 120 mg/day in the treatment of MDD was demonstrated. Tolerability, as measured by TEAEs, and safety were similar to paroxetine 20 mg/day and consistent with previous published data on duloxetine in the treatment of MDD.

Safety and tolerability of duloxetine – adverse events and how to handle them

The efficacy and side effect profile of antidepressants are important issues to consider when selecting an antidepressant for a patient. Duloxetine is a serotonin (5HT) and noradrenalin (NE) reuptake inhibitor (SNRI) that has recently been licensed for the treatment of depression. This presentation concerns duloxetine’s side effect profile. Before considering side effects seen in clinical studies it is helpful to consider the pharmacokinetic and pharmacodynamic properties of duloxetine. Duloxetine is 96% protein bound and has an elimination half-life of about 12 hours. Food has no clinically significant effect on its absorption. Duloxetine is metabolized by CYP2D6 and CYP1A2. Duloxetine does not inhibit CYP1A2 or CYP3A4 but it is a moderate inhibitor of cytochrome CYP2D6. According to published data, duloxetine is a less potent inhibitor of CYP2D6 than paroxetine, but a more potent inhibitor of CYP2D6 than sertraline. Duloxetine has no major active metabolites. Studies in rats show that following a dose of duloxetine, there are dose dependent increases in both 5HT and NE in the frontal cortex as measured by microdialysis. Even at lower doses there were measurable increases in both neurotransmitters. The similarity of the 5HT and NE curves suggests that effects on both neurotransmitters were present at all doses and rose according to the dose given. In clinical trials most side effects seen with duloxetine are mild and transitory. Side effects that occur in duloxetine-treated patients at a rate of >5% and twice the rate for placebo are (in descending order of incidence) nausea, dry mouth, constipation, fatigue, somnolence, increased sweating and decreased appetite. Nausea, the most common side effect, is usually mild and resolves within one week. After the first week of duloxetine treatment, the percentage of patients reporting new cases of nausea is similar to patients who receive placebo. Unlike venlafaxine, duloxetine is not associated with dose dependent hypertension. Duloxetine has no clinically relevant effect on the QT interval. In short-term trials (8–9 week trials) there is a small but significant amount of weight loss with Duloxetine. In a 6 month trial the mean weight gain for Duloxetine 60 mg/day is no different from placebo. Recent years has seen increasing interest in discontinuation symptoms i.e. symptoms that result from stopping medication. To investigate this phenomenon several trials had a design that included duloxetine being stopped abruptly, without taper, after which patients were followed up for 2 weeks. Discontinuation symptoms after stopping duloxetine were mild and transient with the most common symptom being dizziness. In summary duloxetine appears well tolerated. Its side effects appear similar to those seen with SSRIs and venlafaxine. Preliminary data suggests that in some areas duloxetine may have a more favorable side effect profile than these comparators.

A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder

This was a 12-week, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, in 354 female patients with primary fibromyalgia, with or without current major depressive disorder. Patients (90% Caucasian; mean age, 49.6 years; 26% with current major depressive disorder) received duloxetine 60 mg once daily (QD) ( N=118), duloxetine 60 mg twice daily (BID) ( N=116), or placebo ( N=120). The primary outcome was the Brief Pain Inventory average pain severity score. Response to treatment was defined as ≥30% reduction in this score. Compared with placebo, both duloxetine-treated groups improved significantly more ( P<0.001) on the Brief Pain Inventory average pain severity score. A significantly higher percentage of duloxetine-treated patients had a decrease of ≥30% in this score (duloxetine 60 mg QD (55%; P<0.001); duloxetine 60 mg BID (54%; P=0.002); placebo (33%)). The treatment effect of duloxetine on pain reduction was independent of the effect on mood and the presence of major depressive disorder. Compared with patients on placebo, patients treated with duloxetine 60 mg QD or duloxetine 60 mg BID had significantly greater improvement in remaining Brief Pain Inventory pain severity and interference scores, Fibromyalgia Impact Questionnaire, Clinical Global Impression of Severity, Patient Global Impression of Improvement, and several quality-of-life measures. Both doses of duloxetine were safely administered and well tolerated. In conclusion, both duloxetine 60 mg QD and duloxetine 60 mg BID were effective and safe in the treatment of fibromyalgia in female patients with or without major depressive disorder.

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 (HAMD 17) total score (primary outcome), HAMD 17 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 HAMD 17 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 HAMD 17 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.

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.

Sexual Functioning Assessed in 4 Double-Blind Placebo- and Paroxetine-Controlled Trials of Duloxetine for Major Depressive Disorder

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. 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. 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. 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

To examine the safety and tolerability of the antidepressant duloxetine across multiple studies for major depressive disorder (MDD). 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. 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. 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

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.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).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.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 for the Treatment of Major Depressive Disorder in Older Patients

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. 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). 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. 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.

Time course of depression-symptom improvement during treatment with duloxetine

The aim of this study was to examine the longitudinal response for overall and individual symptoms during the treatment of major depressive disorder. Data were pooled from two 9-week trials, which compared duloxetine 60-mg QD (n=251) with placebo (n=261) in the treatment of MDD. Changes from baseline in the 17-item Hamilton Depression Rating Scale (HAMD17) and in the Visual Analog Scales for pain were analyzed. Compared to placebo-treated patients, duloxetine-treated patients experienced greater improvement (P<.05) in the HAMD17 total score at Week 2. The individual symptoms showing the most rapid improvements (Week 1) were depressed mood, guilt, suicidal ideation, work/activities, and psychic anxiety as well as VAS back pain and shoulder pain. At subsequent visits, significant improvements were observed in retardation (Week 2); hypochondriasis (Week 3); general somatic symptoms (Week 5); middle and late insomnia (Week 7); and gastrointestinal (GI) symptoms, genital symptoms (level of sexual interest or ease of sexual arousal), insight, and early insomnia (Week 9). Significant advantages for duloxetine were not achieved at any visit for agitation, somatic anxiety, or weight loss. At Weeks 1 and 2, placebo-treated patients had significantly lower GI symptoms and reported less weight loss compared with duloxetine-treated patients; however, differences were not significant at subsequent visits. Furthermore, duloxetine was superior to placebo on GI symptoms at endpoint compared to placebo-treated patients; duloxetine-treated patients had a significantly higher response rate at Week 2 and a higher remission rate at Week 5. These results may help clinicians establish more accurate expectations regarding treatment with duloxetine.

Stress Urinary Incontinence in Women: Efficacy and Safety of Duloxetine

Stress urinary incontinence (SUI), the complaint of involuntary loss of urine on effort or exertion, or on sneezing, coughing or laughing, is a common condition affecting millions of women world wide. SUI is a medical condition which can have a significant impact on the psychosocial, social and economic well-being of the sufferers and their family, thus significantly impairing their Quality of Life (QoL). Currently, women with SUI who wish to have their problem solved can choose between treatments like pelvic floor muscle training, which usually has poor compliance over time, or surgical procedures which are mainly an option for more severely affected patients with the risk of complications. To date, no pharmacological treatment for women with SUI has been widely approved. Duloxetine, a potent and relatively balanced serotonin and noradrenaline reuptake inhibitor, has been evaluated in a clinical trial program of one phase II and three phase III trials world wide, and proven efficacious and safe in the treatment of women with SUI. Significant improvements in various parameters were reported with duloxetine compared to placebo in all trials. Half of the women experienced a median decrease in incontinence episode frequency (IEF) of 50–58%. Concurrent increases in incontinence Quality of Life scores (I-QOL) in the range of 5.5–11.1 points indicated that these improvements in IEF were sufficient for the women to feel noticeably better. Between 56% and 74% of the women treated with duloxetine stated that they felt better after treatment. Nausea was the most common side effect reported in the duloxetine-treated patients; it was usually mild to moderate and transient as it resolved in the majority of the cases in one to four weeks. Overall, duloxetine was well tolerated and efficacious. This drug has the potential to become the first widely approved pharmacological treatment for women with SUI.

Incidence and duration of antidepressant-induced nausea: duloxetine compared with paroxetine and fluoxetine

Objective: This analysis assessed the incidence, severity, onset, and duration of nausea among patients with major depressive disorder (MDD) treated with the new antidepressant duloxetine. Methods: Data were pooled from 8 double-blind, randomized, placebo- and active comparator-controlled trials employing patients with MDD that were submitted to the US Food and Drug Administration to support duloxetine's new drug application for treatment of MDD. Results: The numbers of patients receiving each regimen were as follows: placebo, n = 777; duloxetine 40 mg/d, n = 177; duloxetine 60 mg/d, n = 251; duloxetine 80 mg/d, n = 363; duloxetine 120 mg/d, n = 348; paroxetine 20 mg/d, n = 359; and fluoxetine 20 mg/d, n = 70. In acute placebo-controlled trials of duloxetine 40 to 120 mg/d, treatment-emergent nausea was reported by more duloxetine-treated patients than those receiving placebo (19.9% [227/1139] vs 6.9% [l54/777], respectively; P <). Among duloxetine-treated patients, the median time to onset of nausea was 1 day, and the median duration of nausea was 7 days. The incidence of nausea was similar to placebo rates after 1 week. In paroxetine-controlled studies, the incidence of treatment-emergent nausea in patients receiving duloxetine did not differ significantly from paroxetine (14.4% vs 12.0%, respectively). In head-to-head studies, the incidence of treatment-emergent nausea with duloxetine did not differ significantly from that with fluoxetine (17.1% vs 15.7%, respectively). Most duloxetine-treated patients reported nausea to be mild (52.9%) or moderate (41.4%). Treatment discontinuation secondary to nausea occurred in more duloxetine-treated patients than those receiving placebo (1.4% [16/1139] vs 0.1% [1/777], respectively; P = 0.002). Following abrupt discontinuation after acute treatment, 5.9% of duloxetine-treated patients exhibited nausea compared with 0.3% of patients receiving placebo ( P < 0.001). The incidence of treatment-emergent nausea during 6-month continuation of duloxetine treatment (80 mg/d, 2.1%; 120 mg/d, 1.3%) was similar to placebo (1.6%). Following abrupt discontinuation after 8 months of treatment, nausea was reported by 1.6% of patients receiving duloxetine 120 mg/d compared with 0% for those receiving duloxetine 80 mg/d and 0% for placebo. Conclusions: Duloxetine induced mild to moderate nausea in a subset of patients with MDD during treatment initiation. Nausea resolved rapidly with continued treatment. The incidence of duloxetine-induced nausea resembled that produced by paroxetine and fluoxetine.

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.

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 (HAMD 17) 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 HAMD 17 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 (HAMD 17, 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 HAMD 17 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.

Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial

Background: Duloxetine is a balanced and potent dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) that has previously been shown to be effective in the acute treatment of major depressive disorder (MDD). This placebo-controlled study assesses the safety and efficacy of duloxetine (80 or 120 mg/day) and paroxetine (20 mg QD) during an initial 8-week acute phase and subsequent 6-month continuation phase treatment of MDD. Method: In this randomized, double-blind, placebo-controlled trial, adult outpatients (age ≥18 years) meeting DSM-IV criteria for MDD received placebo ( n=93), duloxetine 80 mg/day (40 mg BID; n=95), duloxetine 120 mg/day (60 mg BID; n=93), or paroxetine (20 mg QD; n=86) for 8 weeks. Patients who had a ≥30% reduction from baseline in HAMD 17 total score during the acute phase were allowed to continue on the same (blinded) treatment for a 6-month continuation phase. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD 17) total score, HAMD 17 subscales, the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAMA), Visual Analog Scales (VAS) for pain, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, the 28-item Somatic Symptom Inventory (SSI), and the Sheehan Disability Scale (SDS). Safety and tolerability were assessed using treatment-emergent adverse events, discontinuations due to adverse events, vital signs, ECGs, laboratory tests, and the Arizona Sexual Experiences Scale (ASEX). Results: During the acute phase, patients receiving duloxetine 80 mg/day, duloxetine 120 mg/day, or paroxetine 20 mg QD had significantly greater reductions in HAMD 17 total score compared with placebo. Both duloxetine (80 and 120 mg/day) and paroxetine treatment groups had significantly greater improvement, compared with placebo, in MADRS, HAMA, CGI-S, and PGI-I scales. Estimated probabilities of remission at week 8 for patients receiving duloxetine 80 mg/day (51%), duloxetine 120 mg/day (58%), and paroxetine (47%) were significantly greater compared with those receiving placebo (30%). The rate of discontinuation due to adverse events among duloxetine-treated patients (80 and 120 mg/day) did not differ significantly from the rate in the placebo group. Treatment-emergent adverse events reported significantly more frequently by duloxetine-treated patients than by patients receiving placebo were constipation (80 and 120 mg/day), increased sweating (120 mg/day), and somnolence (120 mg/day). The incidence of acute treatment-emergent sexual dysfunction in duloxetine- and paroxetine-treated patients was 46.5% and 62.8%, respectively. During the 6-month continuation phase, duloxetine (80 and 120 mg/day) and paroxetine treatment groups demonstrated significant improvement in HAMD 17 total score. Treatment-emergent adverse events occurring most frequently in each active treatment group during the continuation phase were viral infection (duloxetine 80 mg/day), diarrhea (duloxetine 120 mg/day), and headache (paroxetine 20 mg QD). Conclusion: These data support previous findings that duloxetine is safe, efficacious, and well tolerated in the acute treatment of MDD. Furthermore, these data provide the first demonstration under double-blind, placebo-controlled conditions that the efficacy and tolerability of duloxetine are maintained during chronic treatment.

P.1.211 Burden of manic vs depressive symptoms in subjects with bipolar disorder

Existing therapies for major depressive disorder (MDD) have either limited efficacy and/or poor tolerability. The present study examined the effects of duloxetine, a potent and balanced dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), in patients with MDD. Adult patients (N=267) with MDD were randomly assigned to receive duloxetine (60 mg/day) or placebo in this 9-week, multi-center, double-blind, parallel-group clinical trial. Efficacy was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD17), Visual Analog Scales (VAS) for pain, Clinical Global Impression of Severity (CGI-S), Patient's Global Impression of Improvement (PGI-I), and Quality of Life in Depression Scale (QLDS). Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. Duloxetine (60 mg QD) significantly reduced the HAMD17 total score compared with placebo at the end of 9-week therapy. Estimated probabilities of response and remission were 65 and 43%, respectively, for duloxetine compared with 42 and 28% for placebo. Duloxetine also reduced overall pain, back pain, shoulder pain and time in pain while awake significantly more than placebo. Global measures of improvement, including PGI-I and QLDS, were significantly improved by duloxetine compared with placebo. Discontinuations due to adverse events were more frequent for duloxetine-treated patients (12.5%) than for placebo-treated patients (4.3%). Nausea, dry mouth, dizziness, and constipation were more frequent for duloxetine than placebo. There was no significant incidence of hypertension, nor any other safety issues. Duloxetine 60 mg administered once daily appears to be a safe and effective treatment for MDD.

Duloxetine: A New Treatment for the Emotional and Physical Symptoms of Depression.

BACKGROUND: Depression is underdiagnosed in the primary care setting. Physical symptoms such as aches, pains, and gastrointestinal disturbance are frequently associated with major depressive disorder (MDD) and are often the presenting symptoms. Duloxetine, a dual-reuptake inhibitor of serotonin and norepinephrine, may have a positive effect on physical symptoms in addition to efficacy in treating emotional symptoms of depression. METHOD: Efficacy was evaluated in 6 double-blind, placebo- and/or active comparator-controlled trials of duloxetine for patients with MDD (DSM-IV criteria). Efficacy in depression was determined primarily using the 17-item Hamilton Rating Scale for Depression (HAM-D-17). Secondary efficacy measures included subscales of the HAM-D-17 and assessment of physical symptoms. Safety evaluations included adverse events, vital signs, laboratory analyses, and electrocardiograms. Safety was evaluated by pooling the data from the MDD trials and a study of duloxetine in nondepressed patients. RESULTS: Duloxetine demonstrated significant differences from placebo on core mood symptoms, physical symptoms (e.g., back pain), and global functioning as early as week 1 of treatment. The estimated probabilities of remission in the studies that demonstrated efficacy ranged from 43% to 57%. The most frequently observed adverse events for duloxetine-treated patients included nausea, dizziness, insomnia, fatigue, and somnolence. Duloxetine did not prolong corrected QT intervals, and the rate of sustained elevations of blood pressure did not differ significantly from placebo. CONCLUSION: In these studies, duloxetine was safe and effective in the treatment of both emotional and physical symptoms of MDD. Based on dose assessments, 60 mg q.d. appears to be the optimum starting and therapeutic dose.

Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression

Existing therapies for major depressive disorder (MDD) have either limited efficacy and/or poor tolerability. The present study examined the effects of duloxetine, a potent and balanced dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), in patients with MDD. Adult patients ( N=267) with MDD were randomly assigned to receive duloxetine (60 mg/day) or placebo in this 9-week, multi-center, double-blind, parallel-group clinical trial. Efficacy was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD 17), Visual Analog Scales (VAS) for pain, Clinical Global Impression of Severity (CGI-S), Patient's Global Impression of Improvement (PGI-I), and Quality of Life in Depression Scale (QLDS). Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. Duloxetine (60 mg QD) significantly reduced the HAMD 17 total score compared with placebo at the end of 9-week therapy. Estimated probabilities of response and remission were 65 and 43%, respectively, for duloxetine compared with 42 and 28% for placebo. Duloxetine also reduced overall pain, back pain, shoulder pain and time in pain while awake significantly more than placebo. Global measures of improvement, including PGI-I and QLDS, were significantly improved by duloxetine compared with placebo. Discontinuations due to adverse events were more frequent for duloxetine-treated patients (12.5%) than for placebo-treated patients (4.3%). Nausea, dry mouth, dizziness, and constipation were more frequent for duloxetine than placebo. There was no significant incidence of hypertension, nor any other safety issues. Duloxetine 60 mg administered once daily appears to be a safe and effective treatment for MDD.