Maier Subscale Research Articles

Venlafaxine extended-release for depression following spinal cord injury: a randomized clinical trial.

Depression is prevalent and associated with negative outcomes in individuals with spinal cord injury (SCI). Antidepressants are used routinely to treat depression, yet no placebo-controlled trials have been published in this population to our knowledge. To determine the efficacy and tolerability of venlafaxine hydrochloride extended-release (XR) for major depressive disorder (MDD) or dysthymic disorder in persons with chronic SCI. Multisite, randomized (1:1), double-blind, placebo-controlled Project to Improve Symptoms and Mood After SCI (PRISMS) trial. All research staff conducting screening, intervention, and outcome procedures were blinded to randomization status. We screened 2536 patients from outpatient clinics at 6 SCI treatment centers in the United States and randomized 133 participants into the trial. Participants were 18 to 64 years old and at least 1 month after SCI, with MDD or dysthymic disorder. Seventy-four percent of participants were male, and participants were on average 40 years old and 11 years after SCI. Forty-seven percent had cervical injuries, 53.4% had American Spinal Injury Association injury severity A (complete injury) SCI, 24.1% had at least 2 prior MDD episodes, and 99.2% had current MDD. Common comorbidities included chronic pain (93.9%), significant anxiety (57.1%), and history of substance dependence (44.4%). Twelve-week trial of venlafaxine XR vs placebo using a flexible-dose algorithm. The Hamilton Depression Rating Scale (HAM-D 17-item version and Maier subscale, which focuses on core depression symptoms and excludes somatic symptoms) over 12 weeks. Mixed-effects models revealed a significant difference between the venlafaxine XR and placebo groups in improvement on the Maier subscale from baseline to 12 weeks (treatment effect, 1.6; 95% CI, 0.3-2.9; P = .02) but not on the HAM-D 17-item version (treatment effect, 1.0; 95% CI, -1.4 to 3.4; P = .42). Participants receiving venlafaxine XR reported significantly less SCI-related disability on the Sheehan Disability Scale at 12 weeks compared with placebo (treatment effect, 4.7; 95% CI, 1.5-7.8; P = .005). Blurred vision was the only significantly more common new or worsening adverse effect in the venlafaxine XR group compared with the placebo group over 12 weeks. Venlafaxine XR was well tolerated by most patients and an effective antidepressant for decreasing core symptoms of depression and improving SCI-related disability. Further research is needed to determine the optimal treatment and measurement approaches for depression in chronic SCI. clinicaltrials.gov Identifier: NCT00592384.

More Options for Geriatric Pain, Depression

ORLANDO – Duloxetine for the treatment of late-life depression missed its primary endpoint in a recent large randomized trial, but it did result in consistently significant clinical improvement, compared with placebo across numerous secondary outcome measures. The results overall provide a suggestion of antidepressant efficacy along with evidence of a meaningful reduction in pain in this elderly patient population, Dr. David C. Steffens observed at the annual meeting of the American Association for Geriatric Psychiatry. This was a multicenter, double-blind, placebo-controlled 24-week study. It included 296 patients age 65 years or older with major depressive disorder, a Montgomery-Asberg Depression Rating Scale score of 20 or above indicative of at least moderately severe depression, and a Mini-Mental Status Examination score of 20 or more. Participants were randomized 2-to-1 to duloxetine (Cymbalta) at either 60 mg/day or 120 mg/day, or placebo. The primary endpoint was change in the Maier subscale of the 17-item Hamilton Depression Rating Scale (HAMD-17) at week 12, compared with placebo. The difference fell short of statistical significance at week 12, which was surprising given that the difference was significant at weeks 4, 8, 16, and 20. Moreover, significantly greater improvement in depressive symptoms as measured by the Geriatric Depression Scale was seen in the duloxetine group at weeks 2, 4, 8, 16, 20, and 24 – but once again, not at week 12, which was the point when the study allowed for dose adjustment from 60 mg/day to 120 mg/day, noted Dr. Steffens, professor and chairman of the department of psychiatry at the University of Connecticut, Farmington. Participants had baseline mild to moderate pain as reflected in their scores on the Brief Pain Inventory and Pain Numeric Rating Scale. The duloxetine-treated group showed significant improvement in pain severity and interference, compared with controls. That's an important finding given that close to two-thirds of patients with geriatric depression have comorbid pain that typically compounds their mood disorder. Prior trials of duloxetine have been shorter. In this one, the remission rate, as defined by a HAMD-17 score of 7 or less among patients on duloxetine at 60 mg/day for the full 24 weeks, was 66% by week 12 and 65% at week 24. Thus, if a patient wasn't in remission after 12 weeks at 60 mg/day, it was unlikely to happen with another 12 weeks on that regimen, and a dose increase to 120 mg/day may be warranted. Five patients discontinued duloxetine for serious adverse events, compared with one placebo-treated control. The most prominent duloxetine-related side effects were diarrhea and dizziness. Duloxetine-treated patients showed a small increase in heart rate and a modest decrease in blood pressure, issues that need to be considered in an elderly population at increased cardiovascular risk. One patient on duloxetine fell and sustained a hip fracture (Am J Geriatr Psychiatry 2014;22[1]:34-45). Dr. Steffens, who didn't participate in the duloxetine trial, highlighted another encouraging development in the treatment of late-life depression: a pooled subgroup analysis he and other investigators conducted using the data from three similar 14-week, prospective, randomized, double-blind trials of adjuvant aripiprazole (Abilify), compared with second-line antidepressant therapy in patients with major depressive disorder who had an incomplete response to standard antidepressant therapy. Their analysis included 679 patients younger than 50 years of age and 409 others aged 50–67 years. The older group was further subdivided by age: 50–55, 56–60, and 61–67 years. “Our goal was to generate some preliminary data. Industry has been less and less interested in thinking about atypical antipsychotics in the elderly because of the black box warnings. Our reasoning was any data that we can get that might support further study in this population of older adults makes sense,” the psychiatrist explained. Older patients on aripiprazole showed significantly greater improvement on the Montgomery-Asberg Depression Rating Scale at week 14 than placebo-treated controls. Their remission rate was 33%, compared with 27% in younger aripiprazole-treated patients (Int J Geriatr Psychiatry 2011;26[6]:564-72). These data are “as good as we have in terms of this particular research issue. We showed people are not keeling over from this therapy. We can at least say that among the few elderly patients we have here, we have preliminary data that this may be helpful and can be tolerated. There are some signals here. Subsequent studies looking at the older population are needed,” according to Dr. Steffens. In response to an audience question, Dr. Steffens said that in the 10 or 12 patients with late-life depression where he has tried using aripiprazole off-label at a starting dose of 1 or 2 mg/day he has had a fair degree of success. Dr. Steffens reported having no financial conflicts.

Acute and Long-term Treatment of Late-Life Major Depressive Disorder: Duloxetine Versus Placebo

To compare the efficacy of duloxetine with placebo on depression in elderly patients with major depressive disorder. Multicenter, 24-week (12-week short-term and 12-week continuation), randomized, placebo-controlled, double-blind trial. United States, France, Mexico, Puerto Rico. Age 65 years or more with major depressive disorder diagnosis (one or more previous episode); Mini-Mental State Examination score≥20; Montgomery-Asberg Depression Rating Scale total score≥20. Duloxetine 60 or 120 mg/day or placebo; placebo rescue possible. Primary-Maier subscale of the 17-item Hamilton Depression Rating Scale (HAMD-17) at week 12. Secondary-Geriatric Depression Scale, HAMD-17 total score, cognitive measures, Brief Pain Inventory (BPI), Numeric Rating Scales (NRS) for pain, Clinical Global Impression-Severity scale, Patient Global Impression of Improvement in acute phase and acute plus continuation phase of treatment. Compared with placebo, duloxetine did not show significantly greater improvement from baseline on Maier subscale at 12 weeks, but did show significantly greater improvement at weeks 4, 8, 16, and 20. Similar patterns for Geriatric Depression Scale and Clinical Global Impression-Severity scale emerged, with significance also seen at week 24. There was a significant treatment effect for all BPI items and 4 of 6 NRS pain measures in the acute phase, most BPI items and half of the NRS measures in the continuation phase. More duloxetine-treated patients completed the study (63% versus 55%). A significantly higher percentage of duloxetine-treated patients versus placebo discontinued due to adverse event (15.3% versus 5.8%). Although the antidepressant efficacy of duloxetine was not confirmed by the primary outcome, several secondary measures at multiple time points suggested efficacy. Duloxetine had significant and meaningful beneficial effects on pain.

Assessment of depressive symptoms and functional outcomes in patients with major depressive disorder treated with duloxetine versus placebo: primary outcomes from two trials conducted under the same protocol

Return of functional ability is a central goal in the treatment of major depressive disorder. We conducted two trials with the same protocol that was designed to assess functioning after 8 Weeks of treatment with duloxetine. The a priori primary outcome was improvement in the Hamilton Depression Rating Scale (HAMD) item 7 (work/activities). Secondary outcomes included improvement in depressive symptoms assessed by the HAMD Maier subscale, and improvement in functioning assessed by the Sheehan Disability Scale (SDS), and the Social Adaptation Self-evaluation Scale (SASS). Patients were randomly assigned to duloxetine 60 mg/day (Trial I, n = 257; Trial II, n = 261) or placebo (Trial I, n = 127; Trial II, n = 131). Changes from baseline were analyzed using a mixed-effects model repeated measures approach. At Week 8, duloxetine was superior to placebo in improving HAMD work/activities (p < 0.001) in Trial II, but not Trial I (p = 0.051), and Maier scores (p < 0.01) in both trials. At Week 12, duloxetine was superior to placebo on improving SASS scores in both trials, and the SDS in Trial II. Treatment with duloxetine was associated with significant improvement in depressive symptoms compared with placebo, but improvement in HAMD work/activities was inconsistent at 8 weeks.

Attributes of response in depressed patients switched to treatment with duloxetine

Background:This study was designed to assess clinical and functional outcomes associated with switching to duloxetine treatment in patients with major depressive disorder (MDD) experiencing emotional and painful physical symptoms in their current episode.Methods:In this 8-week, multinational, multicentre, single-arm, open-label clinical trial, 242 MDD patients were switched to duloxetine 60 mg/day after selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) treatment. The primary analysis compared mean change from baseline in Brief Pain Inventory – Modified Short Form (BPI-SF) interference score between initial responders [≥ 50% reduction from baseline on the 17-item Hamilton Depression Rating Scale (HAMD17) Maier subscale] and initial non-responders after 4 weeks. Initial responders continued with duloxetine 60 mg/day. Initial non-responders received duloxetine 120 mg/day for the remaining 4 weeks. Depression, pain, anxiety and functional outcomes were also compared after 8 weeks.Results:BPI-SF interference decreased from baseline in initial responders (n = 108) and initial non-responders (n = 85) after 4 weeks of duloxetine treatment, with greater reductions in initial responders [BPI-SF mean difference in reduction: 1.01 (95% CI 0.42–1.61); p < 0.001]. Reductions in pain interference favouring initial responders were also apparent after 8 weeks [0.68 (95% CI: 0.03–1.33); p = 0.042]. Depression, pain, anxiety and function improved over 8 weeks across patient groups.Conclusions:Elements of core mood and pain are important residual symptoms following poor treatment response in MDD. Early improvement in these symptoms after switching to duloxetine indicated an increased chance of functional recovery.

The Effect of Pain on Outcomes in a Trial of Duloxetine Treatment of Major Depressive Disorder

Patients with major depressive disorder (MDD) frequently report one or more pain symptoms. To explore the relationship between improvement in pain symptoms and MDD treatment outcomes, we conducted a secondary analysis of an approximately 12-week, open label trial of duloxetine in MDD. The primary objective was to test the hypothesis that a greater reduction in pain was associated with a higher probability of MDD remission. Adults with DSM-IV MDD were enrolled in the study if they had a Hamilton Depression Scale (HAMD-17) total score of 15 or more and a Clinical Global Impression of Severity (CGI-S) score of 4 or more. The duloxetine dose of patients could be titrated on the basis of the degree of response within the range from 60 to 120 mg given QD, with 90 mg QD as an intermediate dose. Remission of major depressive disorder was defined as a HAMD-17 total score of < or = 7. Core emotional symptoms of depression were determined by the HAMD-17 Maier subscale. Pain was assessed using a 100 mm visual analog scale (VAS) of overall pain severity over the last week (0 = no pain, 100 = pain as severe as I can imagine). For the primary analysis, mean change in VAS overall pain score over time was compared between remitters and non-remitters at endpoint using a mixed model repeated measures approach. Two hundred forty nine patients were included in the analysis. A greater reduction in pain was associated with a significantly higher probability of remission of MDD, after accounting for changes in the core emotional symptoms. Greater pain reduction was associated with significant improvement in MDD core emotional symptoms. A greater improvement in pain was also associated with improvements in patient and clinician-rated global assessments. The effective treatment of pain symptoms in patients with major depressive disorder was associated with higher remission rates. The results underscore the importance of effectively treating painful symptoms associated with depression.

Clinical impact of duloxetine treatment on sleep in patients with major depressive disorder

The objective of this study was to conduct a meta-analysis of the clinical impact of duloxetine treatment on sleep in adults with major depressive disorder. Data were pooled from 11 placebo-controlled, double-blind studies of duloxetine treatment (8-9 weeks acute therapy, modal dose 60 mg/day). Sleep outcome was assessed by the Hamilton Depression Rating Scale-17 (HAMD(17)) sleep items (onset latency, middle awakening, and early awakening) and their sum (insomnia subscale) and by occurrence of sleep-related treatment-emergent adverse events (TEAEs). Efficacy was measured by HAMD(17) Maier subscale scores. Adult outpatients (mean age: 45.4 years; 65.8% women) were assigned randomly to duloxetine (N=1760) or placebo (N=1159). Duloxetine-treated patients improved more on the HAMD(17) sleep subscale compared with placebo-treated patients (mean=-1.2 vs. -1.1, P< or =0.05). Sleep-related TEAEs that occurred more frequently for patients treated with duloxetine, compared with placebo, were insomnia (8.9 vs. 5.9%, P< or =0.001), middle insomnia (1.4 vs. 0.3%, P=0.001), and hypersomnia (1.0 vs. 0.3%, P< or =0.01). Patients with sleep-related TEAEs demonstrated similar mean improvement in Maier subscale score as patients without sleep-related TEAEs (P=0.223). Compared with placebo, duloxetine treatment was associated with a positive, but negligible, benefit on clinical ratings of insomnia and with more frequent sleep-related TEAEs that did not negatively impact overall efficacy for major depressive disorder.

The Significance of Treating Somatic Symptoms on Functional Outcome Improvement in Patients With Major Depressive Disorder

Functional impairment is associated with major depressive disorder (MDD), and patients with MDD often present with somatic symptoms. To examine the relationships between improved global functioning and core depressive symptoms as well as painful and nonpainful somatic symptoms in patients with MDD. This post hoc analysis of 2 identical trials compared the efficacy of duloxetine with that of paroxetine or placebo as treatment of MDD. In the trials, patients with DSM-IV-defined MDD received duloxetine 80 mg/day (N = 188), duloxetine 120 mg/day (N = 196), paroxetine 20 mg/day (N = 183), or placebo (N = 192) for 8 weeks. The Sheehan Disability Scale (SDS), Maier subscale of the 17-item Hamilton Rating Scale for Depression, 21-item Somatic Symptom Inventory, and Visual Analog Scale for overall pain were used to measure functional impairment, core symptoms of depression, and nonpainful and painful somatic symptoms, respectively. Baseline-to-endpoint mean changes in SDS total and subdomains were measured using analysis of variance with last-observation-carried-forward Pearson partial correlations, and path analysis was used to assess the significance of associations and relative contributions of improvement in global functional impairment, depression, and somatic symptoms. The trials were conducted from November 2000 to July 2002. The difference between antidepressant treatment and placebo in SDS total and subdomains was significant (p < .001). At baseline and in change from baseline to endpoint, associations between global functional impairment and core depressive and somatic symptoms were all significant (p < .05). Path analysis demonstrated improvement of functional impairment attributed to treatment effect as 37.0% (core depressive symptoms), 13.0% (nonpainful somatic symptoms), and 11.0% (painful somatic symptoms). In patients with MDD, over a third of functional improvement associated with antidepressant therapy was mediated through improvement in core depressive symptoms. In addition, a significant proportion of functional improvement, although to a lesser degree, was associated with the treatment of both nonpainful and painful somatic symptoms.

The impact of analytic method on interpretation of outcomes in longitudinal clinical trials

AimsVarious analytical strategies for addressing missing data in clinical trials are utilised in reporting study results. The most commonly used analytical methods include the last observation carried forward (LOCF), observed case (OC) and the mixed model for repeated measures (MMRM). Each method requires certain assumptions regarding the characteristics of the missing data. If the assumptions for any particular method are not valid, results from that method can be biased. Results based on these different analytical methods can, therefore, be inconsistent, thereby making interpretation of clinical study results confusing. In this investigation, we compare results from MMRM, LOCF and OC in order to illustrate the potential biases and problems in interpretation.MethodsData from an 8-month, double-blind, randomised, placebo-controlled (placebo; n= 137), outpatient depression clinical trial comparing a serotonin-noradrenalin reuptake inhibitor (SNRI; n= 273) with a selective serotonin reuptake inhibitor (SSRI; n= 274) were used. The study visit schedule included efficacy and safety assessments weekly to week 4, bi-weekly to week 8, and then monthly. Visitwise mean changes for the 17-item Hamilton Depression Rating Scale (HAMD17) Maier subscale (primary efficacy outcome), blood pressure, and body weight were analysed using LOCF, MMRM and OC.ResultsLast observation carried forward consistently underestimated within-group mean changes in efficacy (benefit) and safety (risk) for both drugs compared with MMRM, whereas OC tended to overestimate within-group changes.ConclusionsInferences are based on between-group comparisons. Therefore, whether or not underestimating (overestimating) within-group changes was conservative or anticonservative depended on the relative magnitude of the bias in each treatment and on whether within-group changes represented improvement or worsening. Preference should be given in analytic plans to methods whose assumptions are more likely to be valid rather than relying on a method based on the hope that its results, if biased, will be conservative.

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

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

P.2.c.016 Comparative efficacy of escitalopram and duloxetine in the acute treatment of major depressive disorder

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 (HAMD17), HAMD17 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 HAMD17 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 HAMD17 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 HAMD17 were the same as those for the HAMD17 total score: 14, 21, and 35 days, respectively. However, in other analyses, changes in core emotional symptoms as measured by subscales of the HAMD17 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.

Patterns of depressive symptom response in duloxetine-treated outpatients with mild, moderate or more severe depression

This was a post hoc analysis to determine whether baseline severity of depression influenced the efficacy of duloxetine in treating major depressive disorder (MDD) and to better characterise the symptom response profile for duloxetine in patients with mild, moderate or more severe depression. Data were pooled from four double-blind, placebo-controlled studies in which outpatients with MDD were randomised to duloxetine (60 mg/day) or placebo for 8-9 weeks. Patients were retrospectively stratified according to baseline 17-item Hamilton Depression Rating scale (HAMD17) total scores: mild=total score<or=19 (duloxetine, n=246; placebo, n=184); moderate=20-24 (duloxetine, n=333; placebo, n=217); severe=25+ (duloxetine, n=127; placebo, n=87). Duloxetine produced significantly greater baseline-to-end-point improvement vs. placebo (p<0.05) on the HAMD17 total score, Maier and retardation subscales, HAMD17 items 1 (depressed mood), 7 (work and activities) and 10 (psychic anxiety) in all three patient cohorts. The largest effect sizes were observed in assessments of core emotional depressive symptoms. A significant improvement for duloxetine vs. placebo was not observed for sleep-related symptoms at end-point or genital symptoms at any time point during acute treatment. With respect to the time course of depressive symptom improvement, the data show that regardless of baseline severity, the most rapid and consistent improvement for duloxetine compared with placebo was observed in the core symptoms of MDD (measured by the Maier subscale). Regardless of baseline MDD severity, duloxetine at one dose (60 mg/day) produced a significant improvement compared with placebo on the core emotional symptoms of MDD.

Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action, a non-inferiority study

ABSTRACTObjective: The goal of a non-inferiority study is to test whether a new treatment has at least as much efficacy as an established treatment1. The purpose of this non-inferiority study was to compare the speed of onset of antidepressant efficacy for duloxetine (a dual serotonin and norepinephrine reuptake inhibitor) and escitalopram (a selective serotonin reuptake inhibitor).Research design and methods: This was a randomized, double-blind, placebo- and active comparator-controlled study, in which patients (≥ 18 years) meeting DSM‑IV criteria for Major Depressive Disorder (MDD) received duloxetine 60 mg once daily (QD; N = 273), escitalopram 10 mg QD (N = 274), or placebo (N = 137) for 8 weeks. The primary objective was to compare the onset of antidepressant efficacy, by testing the hypothesis that the percentage of duloxetine-treated patients achieving onset criteria at Week 2 was not inferior to that in the escitalopram group.Main outcome measures: Onset of efficacy was defined as a 20% decrease from baseline on the 17‑item Hamilton Rating Scale for Depression (HAMD17) Maier subscale that was maintained or exceeded at all subsequent visits.Results: Probabilities of meeting onset criteria at Week 2 for duloxetine- and escitalopram-treated patients were 42.6% versus 35.2%, respectively (treatment difference = 7.4%; 95% confidence interval, –1.3% to 16.2%; p = 0.097). Both drugs showed significant improvement compared with placebo ( p ≤ 0.05) on the primary efficacy measure (Maier subscale) at Week 1 and endpoint (Week 8). No differences were found between duloxetine, escitalopram, and placebo rates of remission or response at 8 weeks. Adverse events that occurred significantly more frequently among duloxetine-treated patients when compared with those receiving escitalopram were nausea, dry mouth, vomiting, yawning, and irritability. The rate of discontinuation due to adverse events did not differ significantly between treatment groups.Limitations: Given the difficulties in constructing appropriate dose comparisons, the results of this study should be interpreted specific to the doses tested and not extrapolated to the drug as a whole. This study employed a fixed-dose design; flexible-dose designs are more likely to find a difference between antidepressants and placebo.Conclusion: In this study, both duloxetine and escitalopram showed significantly greater improvement on the primary efficacy measure than placebo over the 8‑week acute treatment period, while no differences were observed between drugs or between drugs and placebo on response and remission rates at 8 weeks. Escitalopram at a starting dose of 10 mg QD was better tolerated than duloxetine at a starting dose of 60 mg QD. This study met its pre-defined primary objective of assessing if duloxetine was non-inferior to escitalopram in antidepressant onset efficacy, and the results show that duloxetine is at least as fast as (non-inferior to) escitalopram.Trial registration: ClinicalTrials.gov identifier: NCT00073411.

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.