Quality of life in children and adolescents with bipolar I depression treated with olanzapine/fluoxetine combination.

BACKGROUND: We examined the efficacy of olanzapine/fluoxetine combination (OFC) in improving health-related quality of life (QoL) in the treatment of bipolar depression in children and adolescents. METHODS: Patients aged 10-17 years with bipolar I disorder, depressed episode, baseline children's depression rating scale-revised (CDRS-R) total score ≥40, Young Mania Rating Scale (YMRS) total score ≤15, and YMRS-item 1 ≤ 2 were randomized to OFC (6/25-12/50 mg/day olanzapine/fluoxetine; n = 170) or placebo (n = 85) for up to 8 weeks of double-blind treatment. Patients and parents completed the revised KINDL questionnaire for measuring health-related QoL in children and adolescents (KINDL-R) at baseline and endpoint. The mean change in CDRS-R total and item scores were used to compare improvement in symptomatology in patients taking OFC and placebo. Tests were 2-sided using a Type I error cutoff of 0.05, and no adjustments for multiple comparisons were made. RESULTS: Baseline QoL as measured by the KINDL-R was substantially impaired relative to published norms for a healthy school-based sample. OFC-treated patients demonstrated an improvement over placebo at endpoint with respect to mean change from baseline in the patient-rated KINDL-R Self-esteem subscale score (p = 0.028), and in the parent KINDL-R ratings of emotional well-being (p = 0.020), Self-esteem (p = 0.030), and Family (p = 0.006). At endpoint, OFC-treated patients still had a lower QoL compared to the normative population. OFC showed significant improvement (p ≤ 0.05) versus placebo on the CDRS-R total score and on 7 of the 17 CDRS-R items. CONCLUSIONS: Patients aged 10-17 years with an acute episode of bipolar depression and their parents reported greater improvements (parents noticed improvements in more areas than did their offspring) on some aspects of QoL when treated with OFC compared with placebo. However, after 8 weeks of treatment, KINDL-R endpoint scores remained lower than those of the, presumably healthy, control population. Clinical trial registration information A Study for Assessing Treatment of Patients Ages 10-17 with Bipolar Depression; http://www.clinicaltrials.gov; NCT00844857.

Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a CNS disorder that has its onset in childhood, but often persists into adulthood. There is growing recognition that adult ADHD can result in multiple negative consequences for individuals. ADHD is also often associated with a number of comorbid psychiatric disorders. Atomoxetine (ATX), a nonstimulant, selective noradrenergic reuptake inhibitor, was approved in the United States in 2002 for the treatment of ADHD in children and adolescents, as well as adults. We review here the safety and efficacy of ATX in adults with ADHD, including data in special populations, functional outcomes, as well as provider and patient real-world perceptions. METHODS: We searched the databases Embase, MEDLINE and PsycINFO using the terms 'ADHD' and 'adult' and 'ATX' capturing publications from January 1, 1998, to March 27, 2014. Only publications in English were considered. RESULTS: ATX demonstrated significantly greater improvement than placebo (PBO) on the Conners Adult ADHD Rating Scale-Investigator rated:Screening Version (CAARS-Inv:SV) in all trials (N = 6; total score difference ranged from -3.5 to -5.5). For long-term trials using the CAARS-Inv:SV, ATX demonstrated significantly greater improvement than PBO in three of four trials (total score differences ranged from -0.1 to -6.0). In short-term studies, ATX showed significantly greater improvement than PBO on the Adult ADHD Quality-of-Life scale total score in three of three studies, but results were mixed on the Sheehan Disability Scale. Three studies of ATX have reported statistically significant improvement (compared with PBO) on the Behavior Rating Inventory of Executive Function-Adult Version Self Report scale. The most common adverse events (occurring in ≥ 10% of patients taking ATX) were nausea, dry mouth, decreased appetite, insomnia and fatigue. CONCLUSIONS: ATX is an important treatment option for the right patient. ATX can provide long-term, consistent symptom relief and functional improvement for adults with ADHD.

The potential for misuse and abuse of medications in ADHD: a review.

This article reviews the literature concerning attention-deficit/hyperactivity disorder (ADHD) medication misuse, abuse, dependence, diversion, and malingering. The review covers nonmedical use (NMU) of both stimulant (methylphenidate and amphetamine) and nonstimulant (α-adrenergic agonists and atomoxetine) prescription medications, and provides a discussion on the relevance for ADHD treatment today. The neural basis for ADHD medication mechanisms of action (increased norepinephrine and dopamine signaling) and their neurobiochemical relationship to the abuse potential is explored. Regionally-specific, stimulant-induced elevations in brain dopamine appear to be integral to both efficacy in ADHD and potential for abuse. In addition to the prevalence of misuse and diversion, additional topics discussed include the potential safety concerns associated with NMU of prescription ADHD medications and the cost to payers of prescription drug diversion (eg, increased emergency department visits associated with misuse). The evidence describing the difficulty in detecting malingering for the purpose of illicit access to ADHD medications for subsequent misuse or diversion is also summarized. Moreover, the effect of ADHD medications in patients with comorbid substance use disorder and the controversial potential linkage of stimulant prescription use with subsequent substance use disorder are explored. Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study. Stimulant effectiveness and speed of action are deemed desirable to enhance attention and focus performance for activities like studying, but stimulants are also misused recreationally. Conversely, the data suggest a lack of abuse potential and lack of actual medication misuse for the nonstimulant medications. Although they can be efficacious for the treatment of ADHD, the nonstimulants lack a mechanism of action linked to the abuse potential and they lack the desirable effects (speed of action, stimulant feel) that make stimulants susceptible to NMU. In light of these findings, the data suggest a need for close screening and therapeutic monitoring of ADHD medication use. In addition, nonstimulants might be an appropriate alternative for patients with concern about abuse and physicians concerned with general misuse and diversion.

Impact of pretreatment with antidepressants on the efficacy of duloxetine in terms of mood symptoms and functioning: an analysis of 15 pooled major depressive disorder studies.

OBJECTIVE: This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. METHOD: Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. RESULTS: Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. CONCLUSIONS: Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change differences on efficacy measures among the 4 subgroups were inconsistent. Duloxetine showed a similar therapeutic effect independent of episode frequency and antidepressant pretreatment.

Adverse events in healthy subjects exposed to single and multiple doses of LY2140023 monohydrate: pooled results from 10 phase 1 studies.

Ten phase 1 studies of LY2140023 monohydrate (LY2140023), an mGlu2/3 receptor agonist, in healthy male and female subjects were pooled to evaluate the adverse event profile. These studies included both single-dose (5-200 mg) and multiple-dose (20-160 mg 2 times a day) treatment groups. The percentage of subjects reporting treatment-emergent adverse events (TEAEs) were assessed in placebo and LY2140023 dose groups: 5 to 20, 40, 60 to 80, and more than 80 mg (120-200 mg). The severity and duration of TEAEs were also determined. Electroencephalograms were performed in 1 study to detect if there were any prodromal signs of convulsions or seizures. Subjects who received either placebo or LY2140023 and participated in the single-dose (n = 159) and multiple-dose (n = 102) treatment groups were included in these analyses. No clear trends for increased TEAE incidence occurred with higher doses of LY2140023 in both the single-dose and multiple-dose treatment groups. The TEAEs with the highest incidence were gastrointestinal and nervous system events. No serious adverse events occurred in any of the 10 studies, and most TEAEs were mild in severity and transient in nature. There were no clinically significant changes in electroencephalograms in subjects receiving LY2140023 (n = 26). LY2140023 was generally well tolerated in healthy subjects.

Predictors of relapse in a study of duloxetine treatment for patients with generalized anxiety disorder.

OBJECTIVE: Data from a relapse prevention study of duloxetine treatment for adults with generalized anxiety disorder (GAD) were examined to identify predictors of relapse. METHODS: Patients responding to 6 months of open-label duloxetine treatment were randomized to continuation with duloxetine or withdrawal to placebo for a 6-month double-blind continuation phase (duloxetine, N= 216; placebo, N= 213). Post hoc analyses compared time to GAD relapse during continuation phase by using predictor variables that included patient demographics, symptom severity measures (Hamilton Anxiety Scale Scores [HAMA], Hospital Anxiety and Depression Scale), functional outcomes, and visual analogue scale (VAS) pain measures. Univariate and multivariate analyses were performed using predictor variables from time of randomization into the continuation, withdrawal phase. RESULTS: Severity of anxiety symptoms, degree of functional impairment, and severity of pain at time of randomization were significantly predictive of likelihood of relapse during the continuation phase. Multivariate backwards elimination analysis of significant univariate predictors identified HAMA item one (anxious mood) ≥ 1 and severity of pain while awake (≥ 30 on VAS) as the strongest predictors of GAD relapse. CONCLUSIONS: For patients with GAD responding to open-label treatment with duloxetine, residual symptoms related to anxious mood, pain severity, and psychosocial function were associated with increased relapse risk, although the greatest risk was associated with anxious mood and increased severity of pain while awake.

Weight gain and changes in metabolic variables following olanzapine treatment in schizophrenia and bipolar disorder.

Antipsychotic therapy forms the cornerstone of treatment for people with severe mental illness. Second-generation (atypical) antipsychotics are associated with a significantly lower incidence of extrapyramidal symptoms than the typical, first-generation agents; however, changes in metabolic variables -- including impaired glucose metabolism, diabetes mellitus, weight gain and dyslipidaemia -- have been reported during treatment with second-generation antipsychotics. Understanding any potential link between antipsychotic treatment and the incidence of these events is complicated by the increasing prevalence of obesity and diabetes occurring in the general population and the increased risk of diabetes and changes in metabolic variables in people with schizophrenia. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose level appears to fall on a continuum, with olanzapine appearing to have a greater association than some other atypical antipsychotics. The PubMed database was used to search for publications that included any information on measures of changes in weight, body mass index (BMI) and/or metabolic variables in randomized studies of olanzapine published between 1992 and 2010. In long-term (≥48 weeks) studies of olanzapine, the mean weight gain was 5.6 kg (last observation carried forward; median exposure 573 days). The proportions of patients who gained at least 7%, 15% or 25% of their baseline weight with long-term exposure were 64%, 32% and 12%, respectively. Some studies have suggested that weight gain early during the course of olanzapine treatment may predict clinically significant weight gain following long-term exposure to the drug. Changes in metabolic variables, such as elevated indices of glucose metabolism and triglyceride level, have also been observed during treatment with olanzapine. Consensus guidelines emphasize the importance of appropriate baseline screening and ongoing monitoring of weight gain and metabolic variables for people receiving all antipsychotic treatments. Long-term weight management programmes have been shown to reduce weight gain in some patients.

Estimation of minimum clinically important difference for pain in fibromyalgia.

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

Sexual function during long-term duloxetine treatment in patients with recurrent major depressive disorder.

INTRODUCTION: Sexual dysfunction (SD) is frequently associated with major depressive disorder (MDD) in the untreated state and may be worsened by antidepressant treatment. AIM: We evaluated SD in duloxetine-treated patients during an MDD recurrence prevention study. METHOD: Patients (N = 514) received open-label duloxetine 60-120 mg/day for up to 34 weeks. Responders (N = 288) were randomly assigned to duloxetine or placebo during a further 52-week double-blind maintenance phase. MAIN OUTCOME MEASURES: The Arizona Sexual Experience Scale (ASEX) was used to assess sexual functioning. RESULTS: At study entry, 73.4% of patients met ASEX criteria for SD. After open-label duloxetine treatment, the probability of continued SD was 77.9% for nonresponders and 53.2% for responders. In patients without SD at study entry, the probability of emergent SD was 49.6% (nonresponders) and 33.2% (responders). In the double-blind maintenance phase, there was no significant difference (P = 0.105) in the probability of emergent SD between placebo-treated (49.2%) and duloxetine-treated (27.9%) patients without SD at baseline, with no significant treatment-by-gender interaction. In patients with a recurrence of MDD, the probability of emergent SD was similar between placebo- (71.3%) and duloxetine-treated (82.7%) patients. However, in patients with no recurrence of MDD, the probability of emergent SD in placebo patients (40.0%) was numerically higher than in duloxetine patients (12.9%). Spontaneous reports of adverse events related to sexual function were infrequent and no patients discontinued due to these events. CONCLUSIONS: In patients with MDD, the probability of continued or emergent SD after up to 34 weeks of open-label duloxetine treatment was associated with the response status of the patients. In patients who responded to duloxetine treatment, after up to a further 52 weeks of double-blind treatment either with duloxetine or placebo, the probability of continued or emergent SD appeared to be more related to MDD itself than the treatments that the patients received.

Evaluation of duloxetine for chronic pain conditions.

Summary Duloxetine hydrochloride (duloxetine) is used as a nonopioid analgesic for the treatment of certain chronic pain conditions. It is a serotonin and norepinephrine reuptake inhibitor and has been approved in the USA for the management of both diabetic peripheral neuropathic pain and fibromyalgia. In addition, based on several studies demonstrating that duloxetine was efficacious in the management of chronic low back pain and chronic pain caused by osteoarthritis, duloxetine was approved for the management of chronic musculoskeletal pain. Effect sizes in studies of each of the aforementioned chronic pain conditions are comparable with other commonly used pain medications. Treatment-emergent adverse events are generally mild to moderate in severity, and tend to occur early and transiently.

Maintenance of effect of duloxetine in patients with chronic low back pain: a 41-week uncontrolled, dose-blinded study.

OBJECTIVE: To assess the maintenance of the effect of duloxetine in the treatment of chronic low back pain. METHODS: Patients (N = 181) with chronic low back pain entered a 41-week extension phase after completing a 13-week placebo-controlled treatment phase. The maintenance of the effect was assessed in patients taking duloxetine 60/120 mg/day who met the response criteria (> or = 30% reduction in Brief Pain Inventory average pain) at the end of the placebo-controlled phase. In addition, physical function was evaluated using the Roland-Morris Disability Questionnaire, the Clinical Global Impressions-Severity of Illness, and the Brief Pain Inventory Pain Severity and Interference ratings. Quality of life, safety, and tolerability outcomes were also assessed. Finally, placebo-treated patients were switched to duloxetine 60 mg/day at the beginning of the extension phase and their response to treatment is also reported. RESULTS: Initial responders to duloxetine treatment demonstrated further significant improvement (within-group) in pain, physical function, and quality of life. Significant within-group improvements were also observed in the extension phase for placebo-treated patients who were switched to duloxetine. Duloxetine was well tolerated with no new safety findings reported. CONCLUSIONS: In this study, the analgesic effect of duloxetine in patients with chronic low back pain was not only maintained for 41 weeks, but additional statistically significant improvement in pain and function was observed.

Profile of adverse events with duloxetine treatment: a pooled analysis of placebo-controlled studies.

BACKGROUND: The serotonin and noradrenaline (norepinephrine) reuptake inhibitor duloxetine has been approved in the US and elsewhere for a number of indications, including psychiatric illnesses and chronic pain conditions. Because the patient populations are diverse within these approved indications, and duloxetine is not yet approved for treatment of other conditions, we wanted to determine if adverse event profiles would differ among patients being treated for these various conditions. OBJECTIVE: To provide detailed information on the adverse events associated with duloxetine and to identify differences in the adverse event profile between treatment indications and patient demographic subgroups. METHODS: Data were analysed from all placebo-controlled trials of duloxetine completed as of December 2008. The 52 studies included 17,822 patients (duloxetine n = 10,326; placebo n = 7496) with major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, osteoarthritis knee pain (OAKP), chronic lower back pain and lower urinary tract disorders. The main outcome measures were rates of treatment-emergent adverse events (TEAEs) and adverse events reported as the reason for discontinuation. RESULTS: The overall TEAE rate was 57.2% for placebo-treated patients and 72.4% for duloxetine-treated patients (p < or = 0.001). Patients with OAKP had the lowest TEAE rate (placebo 36.7% vs duloxetine 50.2%, p < or = 0.01), while patients with fibromyalgia had the highest rate (placebo 80.0% vs duloxetine 89.0%, p < or = 0.001). The most common TEAE for all indications was nausea (placebo 7.2% vs duloxetine 23.4%, p < or = 0.001), which was predominantly mild to moderate in severity. No statistically significant treatment-by-subgroup interactions for age were found between placebo and duloxetine treatment for the most common TEAEs. The rates of duloxetine-associated dry mouth and fatigue were greater in women than in men (13.1% vs 10.4%, interaction p = 0.004; and 9.4% vs 7.6%, interaction p = 0.03, respectively). Duloxetine-associated dry mouth incidence was higher in Caucasians than non-Caucasians (13.2%, 11.0%, interaction p = 0.04). CONCLUSIONS: Duloxetine treatment is associated with significantly higher rates of common TEAEs versus placebo, regardless of indication or demographic subgroup. Differences across indications are likely to be attributable to the underlying condition rather than duloxetine, as suggested by the similar trends observed in placebo- and duloxetine-treated patients.

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

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

Duloxetine in the prevention of depressive recurrences: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy of duloxetine 60-120 mg once daily in the prevention of depressive recurrence in outpatients with recurrent major depressive disorder (MDD). METHOD: Eligible patients with at least 3 episodes of MDD (DSM-IV diagnosis) in the past 5 years received open-label duloxetine 60-120 mg/day for up to 34 weeks. Patients meeting response criteria were then randomly assigned to either duloxetine or placebo for up to 52 weeks of double-blind maintenance treatment. The primary outcome measure was time to recurrence of a major depressive episode. Safety and tolerability were assessed via analysis of treatment-emergent adverse events (TEAEs), vital signs, weight, and laboratory measures. Patients were recruited from 43 study centers in 5 European countries (France, Germany, Italy, Russia, and Sweden) and the United States. The study was conducted from March 2005 to January 2008. RESULTS: A total of 288 patients were randomly assigned to duloxetine or placebo. Time to a depressive recurrence was significantly longer in duloxetine-treated patients compared with placebo-treated patients (p < .001). During the double-blind maintenance phase, 33.1% of placebo-treated patients experienced a depressive recurrence compared with 14.4% of duloxetine-treated patients (p < .001). There were no significant differences between treatment groups in TEAEs, discontinuations due to adverse events, vital signs, or weight. CONCLUSIONS: Treatment with duloxetine was associated with a longer time to depressive recurrence and a significantly lower recurrence rate compared with placebo. TRIALS REGISTRATION: (ClinicalTrials.gov) Identifier: NCT00105989.

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

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

Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: Results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial.

The primary objectives of this study were to assess the efficacy and safety of duloxetine for reducing pain severity in fibromyalgia patients with or without current major depressive disorder. This was a 6-month, multicenter, randomized, double-blind, placebo-controlled study. In total, 520 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to duloxetine (20 mg/day, 60 mg/day, or 120 mg/day) or placebo, administered once daily, for 6 months (after 3 months, the duloxetine 20-mg/day group titrated to 60 mg/day). The co-primary outcome measures were the Brief Pain Inventory (BPI) average pain severity score and Patient Global Impressions of Improvement (PGI-I) score. Safety was assessed via treatment-emergent adverse events, and changes in vital sign, laboratory, and ECG measures. Compared with placebo-treated patients, those patients treated with duloxetine 120 mg/day improved significantly more on the co-primary outcome measures at 3 months (change in BPI score [-2.31 vs -1.39, P<0.001] and PGI-I [2.89 vs 3.39, P=0.004]) and at 6 months (change in BPI [-2.26 vs -1.43, P=0.003] and PGI-I [2.93 vs 3.37, P=0.012]). Compared with placebo, treatment with duloxetine 60 mg/day also significantly improved the co-primary measures at 3 months and BPI at 6 months. Duloxetine was efficacious in patients both with and without major depressive disorder. There were no clinically significant differences between treatment groups in changes in vital signs, laboratory measures, or ECG measures. Study results demonstrated that duloxetine at doses of 60 mg/day and 120 mg/day appears to be safe and efficacious in patients with fibromyalgia.

Safety and tolerability of duloxetine at 60 mg once daily in elderly patients with major depressive disorder.

OBJECTIVE: To compare the safety and tolerability profile of duloxetine versus placebo in elderly (> or = 65 years) patients with major depressive disorder (MDD). METHODS: Patients were randomized (2:1) to duloxetine 60 mg/d (once daily) (n = 207) or placebo (n = 104) for 8 weeks. Safety and tolerability measures were analyzed in the total cohort of patients, as well as in subgroups defined by age and preexisting hypertension. RESULTS: Patients had a median age of 72 years (65-90 years). No deaths occurred in the study. Discontinuation rates due to adverse events were similar for duloxetine and placebo (9.7% vs 8.7%). Treatment-emergent dry mouth, nausea, and diarrhea occurred significantly (P < or = 0.05) more frequently with duloxetine compared with placebo. Changes in supine and standing blood pressure (BP) and pulse and in corrected QT (QTc) interval were not significantly different between duloxetine and placebo, except for change in orthostatic systolic BP (-2.45 vs 0.93 mm Hg; P = .017). Incidences of sustained elevation in BP and treatment-emergent orthostatic hypotension were similar for duloxetine compared with placebo (0.5% vs 1.0% and 15.6% vs 20.5%, respectively). The duloxetine group showed significant weight loss compared with the placebo group (-0.73 kg vs -0.13 kg; P = 0.009). Of 5 hepatic analytes, the only significant difference was an increase in alkaline phosphatase in duloxetine compared with placebo (P = 0.017); this difference was not considered clinically relevant. The incidence of 1 or more discontinuation-emergent adverse events was not significantly different between the duloxetine and placebo groups (17.3% vs 11.3%). CONCLUSIONS: This study suggests that duloxetine is safe and well tolerated in elderly patients with major depressive disorder.

A randomized, controlled trial of duloxetine alone vs. duloxetine plus a telephone intervention in the treatment of depression.

OBJECTIVE: We hypothesized that combining antidepressant medication with a standardized telephone adherence support intervention would lead to superior outcomes in the treatment of depression compared with antidepressant medication alone. METHOD: Patients with depression were randomized to receive the antidepressant duloxetine alone (DLX), or duloxetine plus a standardized telephone intervention (DLX+TI), for 12 weeks of open-label treatment. The primary outcome measure was remission (HAMD 17 total score 90% at every visit) in both groups. CONCLUSIONS: A telephone intervention in combination with antidepressant medication (duloxetine) did not improve depression outcomes compared with antidepressant alone in this clinical trial, perhaps due to high drug adherence in both treatment groups. Addition of a telephone intervention was, however, associated with increased reporting of AEs.

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

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

Tadalafil for treatment of erectile dysfunction in men on antidepressants.

OBJECTIVE: The objective of this post hoc analysis was to evaluate tadalafil, a treatment indicated for erectile dysfunction (ED), in men on antidepressants. METHOD: A retrospective, pooled analysis of 19 double-blind, placebo-controlled trials (N = 3864) identified 205 men with ED, mean age of 55 years (range, 27-79 years) receiving antidepressants and tadalafil 10 mg (n = 38), tadalafil 20 mg (n = 113), or placebo (n = 54). Efficacy was measured by the International Index of Erectile Function erectile function domain score, the Sexual Encounter Profile diary, and a Global Assessment Question. Tolerability was assessed via collection and analysis of treatment-emergent adverse events. RESULTS: Patients on antidepressants who were treated with tadalafil showed significantly greater baseline-to-end point improvement on the International Index of Erectile Function score compared with placebo (end point: tadalafil 10 mg, 21.7; tadalafil 20 mg, 21.8; placebo, 14.5; both P < 0.01). The mean per-patient percent successful intercourse postbaseline was also greater with tadalafil 10 mg (54%) and tadalafil 20 mg (59%) than placebo (29%, both P < 0.05). Patients taking tadalafil 10 (72%) and 20 (76%) mg both reported significant improvement in erections on the Global Assessment Question compared with placebo (33%, both P < 0.01). The incidence of treatment-emergent adverse events was low in all treatment groups with the most common being headache, dyspepsia, and back pain. CONCLUSION: Tadalafil was well tolerated and improved erectile function in patients taking antidepressant medications.