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Predicting treatment outcomes of major depressive disorder by early improvement in painful physical symptoms: a pooled analysis of double-blind, placebo-controlled trials of duloxetine.

ABSTRACT: OBJECTIVE:We determined if early improvement in painful physical symptoms (PPS) can be a predictor of remission in the treatment of major depressive disorder (MDD). METHODS:We included randomized, double-blind, parallel-group clinical trials of duloxetine (40-60 mg/day) versus placebo for the acute treatment of MDD with associated PPS. Only those studies using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Brief Pain Inventory - Short Form (BPI-SF) were included. Three studies met all criteria and included male or female outpatients aged ?18 years who met the diagnostic criteria for MDD, had a MADRS total score ?20, and had at least moderate pain (BPI-SF average pain score ?3). Positive predictive values (PPVs) and negative predictive values (NPVs) of early improvement in PPS for remission were analyzed. PPVs were the proportion of patients with remission (MADRS total score ?10) at week 8 out of patients who experienced early improvement in BPI-SF average pain score (?30% decrease from baseline at week 1, 2, or 4). NPVs were the proportion of patients without remission (MADRS total score >10) at week 8 out of patients who did not experience early improvement in PPS. RESULTS:Data from 1,320 patients were analyzed (duloxetine N=641 and placebo N=679). The overall remission (MADRS total score ?10 at week 8) rate for the duloxetine group was significantly higher than the placebo group (38.5% vs 21.8%; P<0.0001). For both treatment groups, PPVs of early improvement in BPI-SF (30% improvement from baseline) were higher than the overall remission rate for all weeks examined (weeks 1, 2, and 4); in general, NPVs of early improvement in BPI-SF for nonremission were higher than the overall nonremission rate. CONCLUSION:Early improvement in PPS can be a useful clinical indicator of subsequent treatment outcome for MDD patients with associated PPS.

SUBMITTER: Tokuoka H

PROVIDER: S-EPMC5626379 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Predicting treatment outcomes of major depressive disorder by early improvement in painful physical symptoms: a pooled analysis of double-blind, placebo-controlled trials of duloxetine.

Tokuoka Hirofumi H Nishihara Makoto M Fujikoshi Shinji S Yoshikawa Aki A Kuga Atsushi A

Neuropsychiatric disease and treatment 20170925

<h4>Objective</h4>We determined if early improvement in painful physical symptoms (PPS) can be a predictor of remission in the treatment of major depressive disorder (MDD).<h4>Methods</h4>We included randomized, double-blind, parallel-group clinical trials of duloxetine (40-60 mg/day) versus placebo for the acute treatment of MDD with associated PPS. Only those studies using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Brief Pain Inventory - Short Form (BPI-SF) were included. Th ...[more]

PMID: 29026309

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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:BackgroundDuloxetine hydrochloride is a reuptake inhibitor of 5-hydroxytryptamine and norepinephrine used to treat depression, generalized anxiety disorder, neuropathic pain, and stress incontinence in women. We investigated the efficacy of duloxetine in painful diabetic neuropathy and fibromyalgia to allow comparison with other antidepressants.MethodsWe searched PubMed, EMBASE (via Ovid), and Cochrane CENTRAL up to June 2008 for randomised controlled trials using duloxetine to treat neuropathic pain.ResultsWe identified six trials with 1,696 patients: 1,510 were treated with duloxetine and 706 with placebo. All patients had established baseline pain of at least moderate severity. Trial duration was 12 to 13 weeks. Three trials enrolled patients with painful diabetic neuropathy (PDN) and three enrolled patients with fibromyalgia. The number needed to treat (NNT) for at least 50% pain relief at 12 to 13 weeks with duloxetine 60 mg versus placebo (1,211 patients in the total comparison) was 5.8 (95% CI 4.5 to 8.4), and for duloxetine 120 mg (1,410 patients) was 5.7 (4.5 to 5.7). There was no difference in NNTs between PDN and fibromyalgia. With all doses of duloxetine combined (20/60/120 mg) there were fewer withdrawals for lack of efficacy than with placebo (number needed to treat to prevent one withdrawal 20 (13 to 42)), but more withdrawals due to adverse events (number needed to harm (NNH) 15 (11 to 25)). Nausea, somnolence, constipation, and reduced appetite were all more common with duloxetine than placebo (NNH values 6.3, 11, 11, and 18 respectively). The results for duloxetine are compared with published data for other antidepressants in neuropathic pain.ConclusionDuloxetine is equally effective for the treatment of PDN and fibromyalgia, judged by the outcome of at least 50% pain relief over 12 weeks, and is well tolerated. The NNT of 6 for 50% pain relief suggests that this is likely to be a useful drug in these difficult-to-treat conditions, where typically only a minority of patients respond. Comparing duloxetine with antidepressants for pain relief in DPN shows inadequacies in the evidence for efficacy of antidepressants, which are currently recommended in PDN care pathways.

Project description:INTRODUCTION:Duloxetine has demonstrated efficacy in chronic low back pain (CLBP). We examined the predictors of response to duloxetine for CLBP. PATIENTS AND METHODS:This was a post hoc analysis of pooled data from 4 double-blind, ran-domized, placebo-controlled trials of duloxetine (60 mg/day for 12-14 weeks) in adult patients with CLBP. Primary outcome was proportion of patients with ?30% reduction in Brief Pain Inventory (BPI) average pain ("pain reduction") at 12-14 weeks. The proportion of patients with ?30% and ?50% (secondary outcome) pain reduction in duloxetine and placebo groups was compared. Variables for responder analyses were early improvement (?15% pain reduction at Week 2), sex, age, baseline BPI average pain score, duration of CLBP, and number of painful body sites according to the Michigan Body Map (?2 vs 1 [isolated CLBP]; 1 trial); relative risk (RR) and 95% confidence interval (CI) were calculated. RESULTS:Compared with placebo (n = 653), a greater proportion of duloxetine-treated patients (n = 642) achieved ?30% (59.7% vs 47.8%; P < 0.001) and ?50% pain reduction (48.6% vs 35.1%; P < 0.001). Among duloxetine-treated patients, early improvement was associated with greater likelihood of ?30% (RR [95% CI], 2.91 [2.30-3.67]) or ?50% (3.24 [2.44-4.31]) pain reduction. Women were slightly more likely than men to achieve ?30% (RR [95% CI], 1.14 [1.00-1.30]) or ?50% (1.17 [0.99-1.38]) pain reduction. Response rates were similar between age, CLBP duration, and baseline BPI average pain score subgroups. Patients with ?2 painful sites were more likely to respond to duloxetine 60 mg relative to placebo than patients with isolated CLBP (RR, duloxetine vs placebo [95% CI]: ?30% reduction, ?2 painful sites 1.40 [1.18-1.66], isolated CLBP 1.07 [0.78-1.48]; ?50% reduction, ?2 painful sites 1.51 [1.20-1.89], isolated CLBP 1.23 [0.81-1.88]). CONCLUSION:Early pain reduction was indicative of overall response. Patients with multiple painful sites had more benefit from duloxetine than patients with isolated CLBP.

Project description:The objective of this study was to assess the effectiveness of duloxetine monotherapy, in comparison with selective serotonin reuptake inhibitor (SSRI) monotherapy, in the treatment of painful physical symptoms (PPS) in Japanese patients with major depressive disorder (MDD) in real-world clinical settings.This was a multicenter, 12-week prospective, observational study. This study enrolled MDD patients with at least moderate PPS, defined as a Brief Pain Inventory-Short Form (BPI-SF) average pain score (item 5) ≥3. Patients were treated with duloxetine or SSRIs (escitalopram, sertraline, paroxetine, or fluvoxamine) for 12 weeks, and PPS were assessed by BPI-SF average pain score. The primary outcome was early improvement in the BPI-SF average pain score at 4 weeks post-baseline.A total of 523 patients were evaluated for treatment effectiveness (duloxetine N=273, SSRIs N=250). The difference in BPI-SF average pain score between the two groups was not statistically significant at 4 weeks post-baseline, the primary endpoint (least-squares mean change from baseline [95% confidence interval]: duloxetine, -2.8 [-3.1, -2.6]; SSRIs, -2.5 [-2.8, -2.3]; P=0.166). There was a numerical advantage for duloxetine in improvement from 4 to 12 weeks post-baseline, and the difference was statistically significant at 8 weeks post-baseline (least-squares mean change from baseline [95% confidence interval]: duloxetine, -3.6 [-3.9, -3.3]; SSRIs, -3.1 [-3.4, -2.8]; P=0.023). The 30% and 50% responder rates were significantly higher in patients treated with duloxetine at 4 and 8 weeks post-baseline. There were no serious adverse events experienced by duloxetine-treated patients. The rate of discontinuations due to adverse events was similar for duloxetine and the SSRIs (1.0% and 0.8% of patients, respectively).In this observational study, BPI-SF improvement was not significantly different at 4 weeks, the primary endpoint; however, patients treated with duloxetine tended to show better improvement in PPS compared to those treated with SSRIs.

Project description:INTRODUCTION:Valbenazine is a novel vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults. OBJECTIVE:Using data from double-blind, placebo-controlled trials, analyses were conducted to evaluate the cardiovascular effects of once-daily valbenazine in patients with a psychiatric disorder who developed tardive dyskinesia after exposure to a dopamine-blocking medication. METHODS:Data were pooled from three 6-week, double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Data from the 42-week valbenazine extension period of KINECT 3 were also analyzed. Outcomes of interest included cardiovascular-related treatment-emergent adverse events, vital sign measurements, and electrocardiogram parameters. RESULTS:The pooled safety population included 400 participants (placebo, n = 178; valbenazine 40 mg/day, n = 110; valbenazine 80 mg/day, n = 112). A history of cardiac disorders was present in 11.8% of participants, and 74.3% were taking a concomitant medication with known potential for QT prolongation. Mean changes from baseline to week 6 in supine vital signs and QTcF (Fridericia correction) were as follows for placebo, valbenazine 40 mg/day, and valbenazine 80 mg/day, respectively: systolic blood pressure (0.2, - 2.1, - 1.8 mmHg), diastolic blood pressure (- 0.1, - 1.6, - 1.2 mmHg), heart rate (- 1.7, - 2.2, - 1.7 bpm), QTcF interval (1.2, 1.1, 2.1 ms); all p > 0.05 for valbenazine vs. placebo. No statistically significant differences were observed between placebo and valbenazine in cardiovascular-related, treatment-emergent adverse events. No notable additional effects on cardiovascular outcomes were found with up to 48 weeks of valbenazine treatment. CONCLUSIONS:Results from double-blind, placebo-controlled trials showed no apparent difference between valbenazine and placebo on cardiovascular outcomes. No additional cardiovascular risk was detected during a longer extension study with valbenazine.

Dataset Information

Predicting treatment outcomes of major depressive disorder by early improvement in painful physical symptoms: a pooled analysis of double-blind, placebo-controlled trials of duloxetine.

Publications

Predicting treatment outcomes of major depressive disorder by early improvement in painful physical symptoms: a pooled analysis of double-blind, placebo-controlled trials of duloxetine.

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