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

ABSTRACT

Objective: 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.     

A comparative study of the efficacy of acute and continuation treatment with escitalopram versus duloxetine in patients with major depressive disorder

ABSTRACT

Objective: This study evaluated the efficacy and tolerability of escitalopram and duloxetine in the treatment of major depressive disorder (MDD).

Research design and methods: Patients were randomised to 24 weeks of double-blind treatment with fixed doses of escitalopram (20?mg) (n = 143) or duloxetine (60?mg) (n = 151). The primary analysis of efficacy was an analysis of covariance (ANCOVA) of change from baseline to endpoint (week 24) in MADRS total score (last observation carried forward).

Main outcome measures; Results: At week 8, the mean change from baseline in total MADRS score was –19.5 for patients treated with escitalopram (n = 141) and –17.4 for patients treated with duloxetine (n = 146), a difference of 2.1 points (?p < 0.05). At week 8, the proportion of responders (≥?50% decrease in MADRS) was 69% (escitalopram) and 58% (duloxetine) (?p < 0.05) and remission (MADRS ≤?12) rates were 56% (escitalopram) and 48% (duloxetine) (NS). For the primary endpoint, the mean change from baseline in total MADRS score at week 24 was –23.4 for patients treated with escitalopram and –21.7 for patients treated with duloxetine, a difference of 1.7 points (?p = 0.055, one-sided). The difference in mean change from baseline in MADRS total score favoured escitalopram at weeks 1, 2, 4, 8, 12 and 16 (?p < 0.05). The overall withdrawal rates were 22% (escitalopram) and 25% (duloxetine) (NS). The withdrawal rate due to adverse events was lower for escitalopram (9%) compared to duloxetine (17%) (?p < 0.05) and significantly more patients treated with duloxetine reported insomnia (12.6% vs. 4.9%) and constipation (8.6% vs. 2.8%).

Conclusion: Escitalopram was superior to duloxetine in acute treatment and at least as efficacious and better tolerated in long-term treatment of MDD.     

A Markov cost-utility analysis of escitalopram and duloxetine for the treatment of major depressive disorder

ABSTRACT

Objective: To estimate the costs and quality-adjusted life weeks of duloxetine and escitalopram.

Research design: A probabilistic Markov cost-utility analysis with a time horizon of 1 year using data from placebo controlled randomized clinical trials for both products.

Methods: Efficacy was defined as remission of depressive symptoms and converted to utilities. Side effects were incorporated using rates from clinical trials and converted to utilities to define treatment effective­ness. The effectiveness outcome was quality adjusted life weeks (QALWs). Estimates of effectiveness (efficacy and side effects) used beta distributions and costs used gamma distributions. Using a managed care perspective, medication costs and physician office visits were included in the model, along with costs associated with treatment failure. Antidepressant costs were obtained using average wholesale price minus 20%. Physician visit costs were obtained from the 2006 US Medicare fee schedule for physician services. A Monte Carlo simulation was conducted using 1000 trials with both first- and second-order sampling.

Results: Over 1 year, the estimated mean quality-adjusted life weeks was 41.0 (95% confidence interval [CI]: 40.7–41.3) for escitalopram and 38.2 (95% CI: 37.9–38.4) for duloxetine. The mean annual total medical cost for escitalopram was $907 (95% CI: $894–$919) and $1633 (95% CI: $1614–$1654) for duloxetine. Limitations to this analysis include using separate studies examining the efficacy and adverse events of either escitalopram or duloxetine, assuming the switch, augmentation, and titration rates for duloxetine to be similar to escitalopram, and using utility estimates from published literature for the antidepressant adverse events.

Conclusion: This analysis suggests that escitalopram was more effective in terms of QALWs and less costly than duloxetine for treatment of depression.     

Duloxetine versus placebo in the treatment of major depressive disorder and associated painful physical symptoms: a replication study

Abstract

Objective:

Painful physical symptoms are common in patients with major depressive disorder (MDD) and can negatively affect patient outcomes. Duloxetine has demonstrated efficacy in treating MDD and other certain painful conditions; this study specifically evaluated patients with both MDD and MDD-associated pain.     

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

Background: Duloxetine is a balanced and potent dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) that has previously been shown to be effective in the acute treatment of major depressive disorder (MDD). This placebo-controlled study assesses the safety and efficacy of duloxetine (80 or 120 mg/day) and paroxetine (20 mg QD) during an initial 8-week acute phase and subsequent 6-month continuation phase treatment of MDD. Method: In this randomized, double-blind, placebo-controlled trial, adult outpatients (age ≥18 years) meeting DSM-IV criteria for MDD received placebo (n=93), duloxetine 80 mg/day (40 mg BID; n=95), duloxetine 120 mg/day (60 mg BID; n=93), or paroxetine (20 mg QD; n=86) for 8 weeks. Patients who had a ≥30% reduction from baseline in HAMD₁₇ total score during the acute phase were allowed to continue on the same (blinded) treatment for a 6-month continuation phase. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD₁₇) total score, HAMD₁₇ subscales, the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAMA), Visual Analog Scales (VAS) for pain, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, the 28-item Somatic Symptom Inventory (SSI), and the Sheehan Disability Scale (SDS). Safety and tolerability were assessed using treatment-emergent adverse events, discontinuations due to adverse events, vital signs, ECGs, laboratory tests, and the Arizona Sexual Experiences Scale (ASEX). Results: During the acute phase, patients receiving duloxetine 80 mg/day, duloxetine 120 mg/day, or paroxetine 20 mg QD had significantly greater reductions in HAMD₁₇ total score compared with placebo. Both duloxetine (80 and 120 mg/day) and paroxetine treatment groups had significantly greater improvement, compared with placebo, in MADRS, HAMA, CGI-S, and PGI-I scales. Estimated probabilities of remission at week 8 for patients receiving duloxetine 80 mg/day (51%), duloxetine 120 mg/day (58%), and paroxetine (47%) were significantly greater compared with those receiving placebo (30%). The rate of discontinuation due to adverse events among duloxetine-treated patients (80 and 120 mg/day) did not differ significantly from the rate in the placebo group. Treatment-emergent adverse events reported significantly more frequently by duloxetine-treated patients than by patients receiving placebo were constipation (80 and 120 mg/day), increased sweating (120 mg/day), and somnolence (120 mg/day). The incidence of acute treatment-emergent sexual dysfunction in duloxetine- and paroxetine-treated patients was 46.5% and 62.8%, respectively. During the 6-month continuation phase, duloxetine (80 and 120 mg/day) and paroxetine treatment groups demonstrated significant improvement in HAMD₁₇ total score. Treatment-emergent adverse events occurring most frequently in each active treatment group during the continuation phase were viral infection (duloxetine 80 mg/day), diarrhea (duloxetine 120 mg/day), and headache (paroxetine 20 mg QD). Conclusion: These data support previous findings that duloxetine is safe, efficacious, and well tolerated in the acute treatment of MDD. Furthermore, these data provide the first demonstration under double-blind, placebo-controlled conditions that the efficacy and tolerability of duloxetine are maintained during chronic treatment.     

艾司西酞普兰与度洛西汀对抑郁症患者主观睡眠质量的影响

目的比较艾司西酞普兰与度洛西汀治疗抑郁症患者的疗效以及对主观睡眠质量的影响。方法将80例抑郁症患者随机分为艾司西酞普兰组42例和度洛西汀组38例,疗程均为8周。采用汉密尔顿抑郁量表（HAMD）减分率评定抗抑郁疗效,HAMD睡眠障碍因子和匹兹堡睡眠指数（PSQI）评定睡眠改善效果,不良反应量表（TESS）评定用药的安全性。结果 2种药物的抗抑郁疗效相仿。度洛西汀组治疗后1、2周未HAMD睡眠障碍因子和PSQI评分低于艾司西酞普兰组,差异均有统计学意义（P〈0.05）;但2组治疗4周后比较差异均无统计学意义（P〉0.05）。结论艾司西酞普兰抗抑郁症总体疗效与度洛西汀相当,但治疗早期度洛西汀对患者主观睡眠的改善优于艾司西酞普兰。     

甲磺酸瑞波西汀与氢溴酸西酞普兰治疗迟缓性抑郁的随机双盲对照研究

目的 比较甲磺酸瑞波西汀与氢溴酸西酞普兰治疗迟缓性抑郁症的疗效和安全性.方法 将59例迟缓性抑郁症患者随机分为Ⅰ组(n=29)和Ⅱ组(n=30).Ⅰ、Ⅱ组治疗分别使用甲磺酸瑞波西汀和氢溴酸西酞普兰,两组疗程均为6周.使用汉密尔顿抑郁量表(HAMD)于治疗前及治疗第1、2、4、6周末各评定1次临床疗效;通过不良反应量表(TESS)、实验室检查、生命体征等观察药物安全性.结果 治疗6周后,甲磺酸瑞波西汀组HAMD总分减分值为(18.48±6.38),氢溴酸西酞普兰组为(11.60±4.46),两组差异有统计学意义(P＜0.001).两组总有效率差异有统计学意义(82.8%与56.7%,P＜0.05),而不良反应差异无统计学意义.结论 甲磺酸瑞波西汀治疗迟缓性抑郁症的疗效优于氢溴酸西酞普兰,是一种安全有效的抗抑郁药物.     

Remission of major depressive disorder without adverse events: a comparison of escitalopram versus serotonin norepinephrine reuptake inhibitors

Abstract

Objective:

An antidepressant’s tolerability, generally captured as the frequency and severity of adverse events (AEs), is often as important as its efficacy in determining treatment success. This study used a composite outcome – remission of major depressive disorder (MDD) without AEs?– to compare the benefit–risk profiles of escitalopram versus the norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine extended release (XR).     

度洛西汀与帕罗西汀治疗抑郁症的多中心双盲对照研究

目的:以帕罗西汀为对照,评价度洛西汀治疗抑郁症的疗效和安全性.方法:采用随机双盲多中心对照研究方法,244例患者纳入研究,度洛西汀组121例(60 mg·d-1),帕罗西汀组123例(20 mg·d-1),疗程8周.以汉密尔顿抑郁评定量表17项作为主要疗效评价指标.结果:度洛西汀组与帕罗西汀组的有效率分别为71.1%和...     

Escitalopram versus sertraline in the treatment of major depressive disorder: a randomized clinical trial*

ABSTRACT

Objective: This trial was conducted to compare the efficacy and tolerability of a fixed dose of escitalopram 10?mg/day with sertraline optimally dosed within its recommended dose range (50–200?mg/day) for the treatment of major depressive disorder.

Methods: In this multicenter trial, depressed patients (DSM?IV defined; baseline Montgomery–Asberg Depression Rating Scale [MADRS] ≥ 22) aged 18–80 years were randomly assigned to 8 weeks of double-blind treatment with escitalopram (10?mg/day) or sertraline (50–200?mg/day) following a 1?week single-blind placebo lead-in period. There was no placebo comparison arm. Sertraline was initiated at 50?mg/day, and could be increased by 50?mg/day at weekly intervals based on clinical need and tolerability at the lower dose level. The blind was maintained with matching double-blind placebo capsules for the escitalopram group. Change from baseline to endpoint in MADRS total score (last observation carried forward) was the primary efficacy measure.

Results: A total of 212 patients received double-blind medication. At week 8, the mean sertraline dosage was 144?mg/day (median = 150?mg/day). Mean changes from baseline to endpoint in MADRS scores were –19.1 and –18.4 for the escitalopram and sertraline groups, respectively. At endpoint, 75% and 70% of escitalopram- and sertraline-treated patients, respectively, were responders (≥ 50% improvement from baseline in mean MADRS scores). Both treatments were generally well tolerated; only 2% and 4% of patients prematurely discontinued escitalopram and sertraline treatment, respectively, due to adverse events.

Conclusion: No differences in efficacy were observed for fixed-dose escitalopram 10?mg/day and sertraline flexibly dosed from 50–200?mg/day. At these doses, both escitalopram and sertraline were generally well tolerated.     

Cost-effectiveness analysis of escitalopram: a new SSRI in the first-line treatment of major depressive disorder in Austria

SUMMARY

Objectives: To compare the cost-effectiveness of escitalopram, a new selective serotonin reuptake inhibitor (SSRI), with (generic) citalopram in the first-line treatment of major depressive disorder (MDD) in Austria.

Methods: A two-path decision analytic model with a 6-month horizon was adapted to the Austrian setting using Austrian clinical guidelines. All patients (aged ≥ 18?years) started at the primary care path and were referred to specialist care in the secondary care path in case of insufficient response. Model inputs included drug-specific probabilities from head-to-head trial data, literature and expert opinion. The main outcome measure was success (i.e., remission defined as Montgomery–Åsberg Depression Rating Scale (MADRS) score ≤ 12) and costs of treatment (i.e., drug costs and medical care). The analysis was performed from the Austrian societal and Social Healthcare Insurance System (SHIS) perspectives. The Human Capital approach was used to estimate the societal costs of lost productivity.

Results: Treatment with escitalopram yielded lower expected cost and greater effectiveness compared with citalopram. The expected success rate was higher for escitalopram (64.5%) compared to citalopram (59.1%). From the SHIS perspective, the total expected cost per successfully treated patient was lower (€115) for escitalopram (€608) compared with citalopram (€723). From the societal perspective, these expected costs were €3034 and €3269 respectively. Sensitivity analyses on unit costs and probabilities demonstrated the robustness of the results. From the societal perspective, escitalopram remained the dominant treatment option, even at a cost of €0 for (generic) citalopram.

Conclusion: Escitalopram is a cost-effective alternative compared to (generic) citalopram in the first-line treatment of MDD in Austria.     

A randomized placebo-controlled trial of duloxetine in patients with major depressive disorder and associated painful physical symptoms

Abstract

Objective:

Painful physical symptoms are common in patients with major depressive disorder (MDD) and may predict poorer treatment outcomes. Duloxetine has demonstrated efficacy in treating both MDD and certain other painful conditions. This randomized, double-blind clinical trial assessed the effects of duloxetine in patients with both MDD and MDD-associated physical pain.     

Duloxetine added to oral nonsteroidal anti-inflammatory drugs for treatment of knee pain due to osteoarthritis: results of a randomized,double-blind,placebo-controlled trial

Abstract

Objective:

To determine the efficacy, tolerability, and safety of duloxetine when added to oral nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with osteoarthritis (OA) of the knee with pain of moderate or greater severity.     

A randomized,double-blind,placebo-controlled study of escitalopram in patients with social anxiety disorder in Japan

Objective This randomized, double-blind placebo-controlled study compared the efficacy and tolerability of escitalopram (10 and 20?mg/day) in Japanese patients with social anxiety disorder (SAD).

Research design and methods Patients aged 18–64 years with a primary diagnosis of DSM-IV-TR defined SAD, a Liebowitz Social Anxiety Scale Japanese version (LSAS-J) total score ≥60 and a Clinical Global Impression–Severity (CGI-S) score ≥4 at baseline were randomly assigned (1:1:1) to placebo, escitalopram 10?mg or escitalopram 20?mg. The primary endpoint was change from baseline to Week 12 in the LSAS-J total score for both escitalopram 10?mg and 20?mg versus placebo (ANCOVA, FAS, LOCF), using a hierarchical testing procedure. Pre-specified secondary endpoints included LSAS-J sensitivity analyses.

Clinical trial registration This study has the www.japic.or.jp identifier: JapicCTI-121842.

Results For the primary efficacy endpoint, the difference from placebo in the LSAS-J was ?3.9 (p?=?0.089) for escitalopram 10?mg. Since the superiority of escitalopram 10?mg over placebo was not confirmed, an analysis without multiplicity adjustment was made, which showed a difference for escitalopram 20?mg versus placebo of ?9.8 (p?<?0.001). In pre-specified sensitivity analyses, the difference versus placebo was ?4.9 (p?=?0.035) (ANCOVA, FAS, OC) and ?5.0 (p?=?0.028) (MMRM, FAS) (escitalopram 10?mg) and ?10.1 (p?<?0.001) (ANCOVA, FAS, OC) and ?10.6 (p?<?0.001) (MMRM, FAS) (escitalopram 20?mg). Common adverse events (incidence ≥5% and significantly different from placebo) were somnolence, nausea and ejaculation disorder.

Conclusion Escitalopram was efficacious, safe and well tolerated by patients with SAD in Japan. Study limitations are discussed including patient characteristics.