Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression
Introduction
It is estimated that major depressive disorder (MDD) affects 18 million people in the United States and 340 million people worldwide (Greden, 2001) and is projected to be the second leading cause of disability in the world by the year 2020 (Murray and Lopez, 1996). Currently, MDD is the third most costly and disabling illness in the United States (Davidson and Meltzer-Brody, 1999, Thompson et al., 1996). Although antidepressant medications remain the first-line treatment for MDD, approximately 50% stop treatment after 3 months (Lin et al., 1995) due in part to lack of efficacy. Indeed, only about 30–40% of patients achieve full remission of symptoms with their initially selected antidepressant (Greden, 2001, Richelson, 1993).
Despite the recent introduction of several new antidepressant medications with significant improvements in side-effect profiles, little improvement in efficacy has been achieved. For example, as a class, the selective serotonin reuptake inhibitors (SSRIs) have not demonstrated improved efficacy relative to tricyclic antidepressant (TCA) drugs (Anderson and Tomenson, 1994, Steffens et al., 1997) with only ∼35% of SSRI-treated patients exhibiting symptom remission (Thase et al., 2001). Combined norepinephrine (NE) and serotonin (5-HT) reuptake inhibition may offer greater efficacy in the treatment of depression. Studies examining the effect of the combination of the SSRI fluoxetine and desipramine, a relatively selective NE reuptake inhibitor, were found to have a more robust therapeutic effect than desipramine alone (Nelson et al., 1991). Moreover, the Danish University Antidepressant Group demonstrated that clomipramine, which inhibits 5-HT and NE reuptake, has greater clinical efficacy than the SSRIs citalopram (Anderson et al., 1986) and paroxetine (Danish Univeristy Antidepressant Group, 1990). These findings support the view that combined 5-HT and NE enhancement has greater therapeutic efficacy compared with the enhancement of either neurotransmitter alone. Indeed, in a recent pooled analysis, remission rates achieved with venlafaxine, which inhibits the reuptake of both 5-HT and NE at higher doses, exceed those observed with SSRIs and placebo (Thase et al., 2001).
Approximately 70% of patients with major depression present with physical complaints (Simon et al., 1999, Fava, 2002), and 60% of patients presenting with multiple physical complaints, including headache, back pain, stomach aches, and poorly localized musculoskeletal pains, have depression (Kroenke and Price, 1993). In addition to their effect on depression, both 5-HT and NE also modulate descending pain pathways (Jones, 1991, Richardson, 1990, Zhou and Gebhart, 1992). Hence, medications that interact with 5-HT and NE would be predicted to be efficacious in alleviating both the emotional and painful physical symptoms associated with depression (Ansari, 2000).
Duloxetine hydrochloride (Cymbalta™) is a potent and balanced dual reuptake inhibitor of both 5-HT and NE and lacks significant affinity for muscarinic, histamine1, α1adrenergic, dopamine, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, and opioid receptors (Bymaster et al., 2001). Duloxetine demonstrates potent inhibition of both 5-HT and NE reuptake, with similar affinities in several preparations, including cloned human transporters (Ki ratio: 9.4) (Bymaster et al., 2001). Duloxetine also produces simultaneous increases in extracellular 5-HT and NE in rat hypothalamus and frontal cortex (Bymaster et al., 2001). In healthy humans, duloxetine 60 mg once daily inhibited platelet 5-HT uptake (Turcotte et al., 2001), and 80–120 mg/d decreased urinary excretion of NE metabolites similar in magnitude to desipramine 100 mg, indicating NE uptake inhibition in vivo (Chalon et al., 2000).
Duloxetine, administered in divided doses (BID), has previously been shown to be efficacious in the treatment of MDD (Goldstein et al, 2002). While duloxetine has a peripheral plasma half-life of approximately 12 h, Yyldyz and Sachs (2001) have recently shown that antidepressants, even with short half-lives, have comparable efficacy when dosed once daily or multiple times per day. Given the improved patient compliance with simpler daily dosing regimens (Claxton et al., 2001) the present study compared a fixed once daily dose (60 mg/day) of duloxetine with placebo in the treatment of the emotional and painful physical symptoms in patients with MDD.
Section snippets
Study design
The protocol (F1J-MC-HMBH-B) for this study was filed with the United States Food and Drug Administration prior to study initiation. It included all of the methodology presented here as well as a complete statistical analysis plan.
This was a randomized, double-blind, parallel-group, placebo-controlled study conducted at 21 sites (psychiatric clinical settings) in the United States. The study design incorporated double-blind, variable-duration placebo lead-in and lead-out periods to blind
Baseline patient characteristics
A total of 367 patients entered the screening phase of the study. Of these, a total of 100 patients failed to meet entry criteria or declined to participate in the study. The remaining 267 patients were randomized to placebo (N=139) or duloxetine 60 mg once daily (N=128). There were no statistically significant differences between the treatment groups in baseline demographics or psychiatric profile (Table 1). Of the randomized patients, a total of 61% of duloxetine and 65% placebo-treated
Discussion
In the present randomized, double-blind placebo-controlled trial, duloxetine 60 mg once daily was significantly more effective in reducing the severity of depression in outpatients with MDD. Patients treated with duloxetine 60 once daily showed a significantly greater decrease in the HAMD17 total score (the primary outcome measure) than did patients treated with placebo. In addition, duloxetine 60 mg once daily was significantly greater than placebo on several secondary measures of depression
Disclosure
At the time of this study, all of the authors were employed by Eli Lilly & Co., and accept full responsibility for the conduct of this trial. The authors had full access to all data from the trial and participated in the decision to publish the data.
Acknowledgements
The authors thank the many patients who generously agreed to participate in this clinical trial, and the clinical staff and principle investigators including: C. Bailey, M.D., M. Bari, M.D., C. Casat, M.D., S. Cheren, M.D., E. Cherlin, M.D., L. Ginsberg, M.D., D. Hellerstein, M.D., S. Ishaque, M.D., R. Landbloom, M.D., T. Lefton, M.D., P. Beighley, M.D., H. Logue, M.D., D. Margolin, M.D., W. McEntee, M.D., D. Mitchell, M.D., W. Privitera, M.D., M. Rapaport, M.D., M. Rynn, M.D., F. Schaerf,
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Current address: Wyeth-Ayerst Pharmaceuticals, St. Davids, PA 19087, USA.