The safety and tolerability of duloxetine in depressed elderly patients with and without medical comorbidity.
ABSTRACT: The impact of medical comorbidity on the efficacy and tolerability of duloxetine in elderly patients with major depressive disorder (MDD) was investigated in this study. Data were obtained from a multicentre, randomised, double-blind, placebo-controlled study in 311 patients with MDD aged 65-89. The primary outcome measure was a prespecified composite cognitive score based on four cognitive tests: (i) Verbal Learning and Recall Test; (ii) Symbol Digit Substitution Test; (iii) 2-Digit Cancellation Test and (iv) Letter-Number Sequencing Test. Secondary measures included the Geriatric Depression Scale (GDS), 17-Item Hamilton Depression Scale (HAMD17), Clinical Global Impression-Severity (CGI-S) Scale, Visual Analogue Scale (VAS) for pain and 36-Item Short Form Health Survey (SF-36). Tolerability measures included adverse events reported as the reason for discontinuation and treatment-emergent adverse events (TEAEs). The consistency of the effect of duloxetine vs. placebo comparing patients with and without medical comorbidity (vascular disease, diabetes, arthritis or any of these) was investigated.Overall, duloxetine 60 mg/day demonstrated significantly greater improvement compared with placebo for the composite cognitive score, GDS and HAMD17 total scores, CGI-Severity, HAMD17 response and remission rates, and some of the SF-36 and VAS measures. There were few significant treatment-by-comorbidity subgroup interactions for these efficacy variables, or for adverse events reported as the reason for discontinuation and common TEAEs.The present analyses suggested that the efficacy of duloxetine on cognition and depression in elderly patients, and its tolerability, were not largely affected by the comorbidity status. These results further support the use of duloxetine in elderly patients with MDD.
Project description:OBJECTIVE:To compare the efficacy and tolerability of duloxetine 60mg/day versus placebo in treating elderly patients with major depressive disorder (MDD) and concurrent anxiety symptoms. METHODS:Patients (>/=65) were randomized to eight weeks of treatment with duloxetine 60mg/day (n=207) or placebo (n=104). Anxiety measures were analyzed for all patients, by age (<75 and >/=75), and in patients having concurrent high anxiety (HAMD(17), item 10; Psychic Anxiety baseline score of 2, 3, or 4). Psychic Anxiety, Somatic Anxiety item 11, and the Anxiety/Somatization subscale were analyzed for all patients and subgroups by mean change from baseline to endpoint and repeated measures. Tolerability was assessed via treatment-emergent adverse events (TEAEs), and adverse events were reported as the reason for discontinuation. The analyses presented are primarily post hoc in nature. RESULTS:Duloxetine produced significantly greater reductions than placebo in Psychic Anxiety (least-squares mean change: -0.62 vs. -0.18, p<0.001) and the Anxiety/Somatization subscale (-1.88 vs. -0.99, p=0.002). Repeated measures analyses showed separation between the treatment groups beginning at Week 1 for Psychic Anxiety and Week 4 for the Anxiety/Somatization subscale. Significant improvement occurred in the <75 and >/=75 age groups for Psychic Anxiety, but only the <75 group for the Anxiety/Somatization subscale. Duloxetine-treated patients with high anxiety showed significant improvement compared with placebo-treated patients on Psychic Anxiety, Anxiety/Somatization subscale, the 17-item Hamilton Depression Rating Scale (HAMD(17)) total score, and several other measures. Duloxetine and placebo had similar TEAE rates and discontinuation rates due to adverse events. CONCLUSION:Duloxetine (60mg/day) was efficacious and tolerable in elderly patients with MDD and concurrent anxiety symptoms.
Project description:This multicenter, randomized, double-blind, placebo-controlled, active-referenced (duloxetine 60 mg), parallel-group study evaluated the short-term efficacy and safety of vortioxetine (10-20 mg) on cognitive function in adults (aged 18-65 years) diagnosed with major depressive disorder (MDD) who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test (DSST)-number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire (PDQ) and physician-assessed clinical global impression (CGI) were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment (UPSA) (ANCOVA) to measure functionality, MADRS (MMRM) to assess efficacy in depression, and a prespecified multiple regression analysis (path analysis) to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST (P < 0.05), PDQ (P < 0.01), CGI-I (P < 0.001), MADRS (P < 0.05), and UPSA (P < 0.001). Path analysis indicated that vortioxetine's cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events (incidence ? 5%) for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated.
Project description:<h4>Rationale</h4>Vortioxetine has reduced depressive symptoms in adults with major depressive disorder (MDD) in multiple clinical trials.<h4>Objectives</h4>The aim of this study is to evaluate the efficacy, safety, and tolerability of vortioxetine 15 and 20 mg vs placebo in adults with MDD.<h4>Methods</h4>Patients were randomized 1:1:1:1 to vortioxetine 15 mg, vortioxetine 20 mg, duloxetine 60 mg (active reference), or placebo. The primary efficacy endpoint was mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 8 (MMRM). Safety/tolerability assessments included physical examinations, vital signs, laboratory evaluations, electrocardiograms, adverse events (AEs), Columbia-Suicide Severity Rating Scale, Arizona Sexual Experiences Scale, and Discontinuation-Emergent Signs and Symptoms checklist.<h4>Results</h4>Six hundred and fourteen patients were randomized. Mean changes in MADRS scores were -12.83 (±0.834), -14.30 (±0.890), -15.57 (±0.880), and -16.90 (±0.884) for placebo, vortioxetine 15 mg (P = .224), vortioxetine 20 mg (P = .023), and duloxetine 60 mg (P < .001) (P vs placebo), respectively. AEs reported by ≥5 % of vortioxetine patients included nausea, headache, diarrhea, dizziness, dry mouth, constipation, vomiting, insomnia, fatigue, and upper respiratory infection. Treatment-emergent sexual dysfunction, suicidal ideation or behavior, and discontinuation symptoms were not significantly different between vortioxetine and placebo.<h4>Conclusions</h4>Vortioxetine 20 mg significantly reduced MADRS total scores after 8 weeks of treatment. Both vortioxetine doses were well tolerated.<h4>Clinical trial registration</h4>ClinicalTrials.gov identifier NCT01153009; www.clinicaltrials.gov/ .
Project description:OBJECTIVE:Major depressive disorder (MDD) is a significant public health concern and challenges health care providers to intervene with appropriate treatment. This article provides an overview of efficacy and safety information for duloxetine 60 mg/day in the treatment of MDD, including its effect on painful physical symptoms (PPS). DESIGN:A literature search was conducted for articles and pooled analyses reporting information regarding the use of duloxetine 60 mg/day in placebo-controlled trials. SETTING:Placebo-controlled, active-comparator, short- and long-term studies were reviewed. PARTICIPANTS:Adult (?18 years) patients with MDD. MEASUREMENTS:Effect sizes for continuous outcome (change from baseline to endpoint) and categorical outcome (response and remission rates) were calculated using the primary measures of 17-item Hamilton Rating Scale for Depression (HAMD-17) or Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The Brief Pain Inventory and Visual Analogue Scales were used to assess improvements in PPS. Glass estimation method was used to calculate effect sizes, and numbers needed to treat (NNT) were calculated based on HAMD-17 and MADRS total scores for remission and response rates. Safety data were examined via the incidence of treatment-emergent adverse events and by mean changes in vital-sign measures. RESULTS:Treatment with duloxetine was associated with small-to-moderate effect sizes in the range of 0.12 to 0.72 for response rate and 0.07 to 0.65 for remission rate. NNTs were in the range of 3 to 16 for response and 3 to 29 for remission. Statistically significant improvements (p?0.05) were observed in duloxetine-treated patients compared to placebo-treated patients in PPS and quality of life. The safety profile of the 60-mg dose was consistent with duloxetine labeling, with the most commonly observed significant adverse events being nausea, dry mouth, diarrhea, dizziness, constipation, fatigue, and decreased appetite. CONCLUSION:These results reinforce the efficacy and tolerability of duloxetine 60 mg/day as an effective short- and long-term treatment for adults with MDD. The evidence of the independent analgesic effect of duloxetine 60 mg/day supports its use as a treatment for patients with PPS associated with depression. This review is limited by the fact that it included randomized clinical trials with different study designs. Furthermore, data from randomized controlled trials may not generalize well to real clinical practice.
Project description:OBJECTIVE:To conduct a post hoc evaluation of the prevalence of clinically significant pain and the efficacy of duloxetine in patients with generalized anxiety disorder (GAD) and concurrent pain. METHOD:Data from two 9- to 10-week double-blind, placebo-controlled, randomized clinical trials of duloxetine (60 to 120 mg) in DSM-IV-defined GAD were analyzed (study 1 was conducted from July 2004 to September 2005; study 2 was conducted from August 2004 to June 2005). Efficacy was assessed with the Hamilton Rating Scale for Anxiety (HAM-A), visual analog scales (VAS) for pain, the Hospital Anxiety Depression Scale (HADS), the Clinical Global Impressions-Improvement of Illness (CGI-I) scale, the Patient Global Impressions-Improvement (PGI-I) scale, and the Sheehan Disability Scale (SDS) global functional impairment scale. RESULTS:Of 840 patients randomly assigned to treatment, 61.3% (302 duloxetine, 213 placebo) had VAS scores ? 30 mm on at least 1 of the pain scales, indicating clinically significant pain. Among those patients with concurrent pain at baseline, change from baseline to endpoint in the HAM-A total score (42.9% change in mean scores for duloxetine, 31.4% for placebo), HADS anxiety scale (40.3% vs. 22.8%), HADS depression scale (36.1% vs. 20.5%), HAM-A psychic factor (45.9% vs. 29.9%), and SDS global functional improvement score (45.5% vs. 22.1%) was significantly (all p's < .001) greater for duloxetine compared with placebo. Improvement on the CGI-I (p = .003) and PGI-I (p < .001) was also significantly greater for duloxetine. Response (HAM-A total score decrease ? 50%) (49% vs. 29%) and remission (HAM-A total score ? 7 at endpoint) (29% vs. 18%) rates were significantly greater for duloxetine compared with placebo (p < .001 and p = .041, respectively). Duloxetine demonstrated statistically significantly greater reduction in pain on all 6 VAS pain scales (all p's < .001 except headaches with p < .002) (for duloxetine, percent change in means from baseline to endpoint ranged from 40.1% to 45.2% across the 6 VAS scales; for placebo, 22.0% to 26.3%). CONCLUSION:Duloxetine, relative to placebo, improves anxiety symptoms, pain, and functional impairment among patients with GAD with concurrent clinically significant pain. TRIAL REGISTRATION:clinicaltrials.gov Identifiers: NCT00122824 (study 1) and NCT00475969 (study 2).
Project description:Purpose:To assess long-term safety, tolerability, and efficacy of duloxetine in Japanese patients with chronic knee pain due to osteoarthritis. Methods:In this open-label extension study (NCT02335346), Japanese patients with knee osteoarthritis and pain (Brief Pain Inventory [BPI] - Severity average pain score ?4 at start of randomized trial) who had previously received duloxetine 60 mg/day or placebo for 14 weeks in a double-blind randomized trial entered the extension and received duloxetine 60 mg/day for 48 weeks. The primary outcome was safety/tolerability, secondary outcomes were change in BPI-Severity (BPI-S) average pain, BPI-Interference (BPI-I), Patient Global Impression-Improvement (PGI-I), Clinical Global Impression-Improvement (CGI-I), 36-item Short-Form Health Survey (SF36), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and exploratory outcomes were knee range of motion (efficacy outcome) and Kellgren-Lawrence grade (safety outcome). Results:Of 323 patients who completed the randomized trial, 93 (50 placebo, 43 duloxetine) entered the extension. Most patients (85, 91.4%) experienced an adverse event, most commonly constipation, nasopharyngitis, somnolence, and dry mouth (?10% of patients). There were eight serious adverse events in seven patients and no deaths. No obvious duloxetine-related changes were observed in laboratory tests, vital signs, or electrocardiograms. The change from baseline in BPI-S average pain score was significant throughout the extension. Significant reductions in BPI-I, PGI-I, CGI-I, WOMAC, and SF36 scores were also maintained through 52 weeks. There were no substantial changes in range of motion or Kellgren-Lawrence grade. Conclusion:In Japanese patients with chronic knee pain due to osteoarthritis, long-term treatment with duloxetine was well tolerated and associated with sustained improvements in pain and health-related quality of life without radiographic deterioration.
Project description:OBJECTIVE:In placebo-controlled clinical trials, duloxetine has been shown to be effective and well-tolerated in patients with major depressive disorder (MDD). However, patients in registration trials may not be representative of patients in clinical practice. This study sought to assess the effectiveness, safety, and tolerability of duloxetine in diverse populations of outpatients with MDD. METHOD:This open-label study recruited out-patients ? 18 years of age with DSM-IV MDD in primary care or psychiatric practice settings and treated them with duloxetine 60 mg q.d. for 7 weeks. Primary outcome measures were (1) the physicianrated Clinical Global Impressions-Severity of Illness scale, (2) the patient-rated 28-item Somatic Symptom Inventory (SSI-28) average, and (3) the patient-rated 16-item Quick Inventory of Depressive Symptomatology-Self Report. Quality of life, disability, and vital signs also were assessed. The first patient visit was August 16, 2004. The last patient visit was January 7, 2005. RESULTS:Of 3543 outpatients enrolled, 3431 received at least 1 dose of duloxetine, of whom 71.4% completed the study. Most patients were Caucasian (90.8%) and female (75.4%); mean age was 48 years. Duloxetine significantly (p < .001) improved all efficacy measures in all treated patients as well as in subgroups based on gender, ethnic origin, age, and patient care setting. Except for the SSI-28 average, all the efficacy measures were in favor of female gender and primary care subgroups. Overall, 10.8% of patients discontinued due to adverse events. CONCLUSION:Duloxetine 60 mg q.d. was effective, regardless of gender, ethnic origin, age, and patient care settings, in this 7-week open-label study and was well-tolerated in a diverse population of outpatients with MDD. CLINICAL TRIALS REGISTRATION:ClinicalTrials.gov identifier NCT00479726.
Project description:To review efficacy of duloxetine for physical symptoms and depressive illness in patients with at least mild to moderate major depressive disorder (MDD; DSM-IV) and clinically significant painful physical symptoms at baseline.Global database of duloxetine clinical trials (Eli Lilly and Company).All 11 acute, double-blind, placebo-controlled studies of duloxetine (7 with duloxetine 60-mg doses and 4 with non-60-mg doses) in the database that used a scale to measure painful physical symptoms and were completed before March 17, 2011.For each study, patients with clinically significant pain levels at baseline (Visual Analog Scale overall pain rating ? 30, Numerical Rating Scale score ? 3, or Brief Pain Inventory 24-hour average pain rating ? 3) were selected in order to determine the effect sizes of duloxetine (compared with placebo for each trial) on the pain and depression measures. Overall effect sizes for both painful physical symptoms and MDD were obtained from the mean of individual-trial effect sizes, and each effect size was weighted relative to the number of patients within each study.The overall mean effect sizes were as follows: painful physical symptoms-60-mg trials, 0.29 (95% CI, 0.06 to 0.52); non-60-mg trials, 0.13 (95% CI, -0.19 to 0.45); MDD-60-mg trials, 0.29 (95% CI, 0.18 to 0.40); non-60-mg trials, 0.16 (95% CI, 0.00 to 0.32). Across the 11 studies, the weighted effect size for painful physical symptoms was 0.26 (95% CI, 0.00 to 0.51) and for MDD, 0.25 (95% CI, 0.16 to 0.34).According to this meta-analysis, duloxetine 60 mg once daily is as effective in improving painful physical symptoms as it is for depression in patients with MDD and clinically significant painful physical symptoms. The results of this meta-analysis indicate that duloxetine has small effect sizes in reducing painful physical symptoms and depressive symptoms in patients with MDD and clinically significant pain levels at baseline. Thus, the results of the study permit one to conclude that duloxetine has a clinically significant impact on painful physical symptoms and in reducing the severity of depressive symptoms. However, the results do not address its efficacy compared to other alternatives, as in all studies the comparator was placebo.
Project description:BACKGROUND:Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of vortioxetine on cognition in patients with MDD. METHODS:Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of vortioxetine (5-20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen's d ) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only). RESULTS:Before adjustment for MADRS, vortioxetine separated from placebo on DSST score (SES 0.25-0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, vortioxetine maintained DSST improvement in one individual trial ( p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04). CONCLUSIONS:Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction.
Project description:OBJECTIVES:The objective of this study was to evaluate the long-term safety and tolerability of flexible-dose brexpiprazole adjunct to antidepressant treatment (ADT) in elderly patients with major depressive disorder (MDD). METHODS:Elderly patients (?65 years) with MDD and inadequate response to ?1 ADT during the current episode were recruited to a 26-week, interventional, open-label study (NCT02400346) at outpatient centers in the USA and Europe. All patients received brexpiprazole 1 to 3 mg/day adjunct to their current ADT. Safety outcomes included adverse events (AEs), movement disorder scales, and standard safety assessments (vital signs, laboratory safety parameters, physical examination, electrocardiograms). Exploratory efficacy outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impressions-Severity of Illness (CGI-S), and Social Adaptation Self-Evaluation Scale (SASS). RESULTS:Of the 132 treated patients, 88 (66.7%) completed the study and 44 (33.3%) withdrew, including 24 who withdrew because of AEs (18.2%). Overall, 102 patients (77.3%) experienced ?1 treatment-emergent AE (TEAE), which were mostly mild or moderate in severity. Treatment-emergent AEs with the highest incidence were fatigue (15.2%) and restlessness (12.9%). The most common TEAE leading to withdrawal was fatigue (3.0%). No consistent clinically relevant findings were seen with regard to movement disorder scales or standard safety assessments. Mean (standard error) efficacy score changes from baseline to week 26 were: MADRS total, -14.5 (0.9); CGI-S, -1.8 (0.1); and SASS, 3.2 (0.5). CONCLUSIONS:Long-term (26-week) treatment with adjunctive brexpiprazole was generally well tolerated in elderly patients with MDD and inadequate response to prior ADT. Improvements were observed in depressive symptoms and social functioning.