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

Abstract

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.

Introduction

Major depressive disorder (MDD) affects an estimated 18 million people in the United States and 340 million worldwide. In the U.S. and Europe, MDD has a lifetime prevalence of approximately 17% Kessler et al., 1994, Lepine et al., 1997. MDD represents a major social and economic burden (Davidson and Meltzer-Brody, 1999) and, by 2020, is expected to be the second leading cause of mortality and disability worldwide Murray and Lopez, 1996, Greden, 2001, Rosenbaum and Hylan, 1999. Although antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs), remain the first-line treatment for MDD, several important limitations, including limited efficacy, delayed onset of action, and side-effects, suggest that improved therapies may provide substantial clinical benefit in the treatment of depression Fawcett and Barkin, 1997, Gumnick and Nemeroff, 2000.

MDD is a recurring chronic condition and continuation treatment with antidepressants is now recommended for at least 9 months Montgomery and Kasper, 1998, Reimherr et al., 1998. Indeed, approximately one-third of patients who stabilize following acute treatment will relapse if medication is discontinued (Hirschfeld, 2001). Moreover, long-term antidepressant treatment may lead to the emergence of adverse events, including weight gain and sexual dysfunction (Gumnick and Nemeroff, 2000).

As many as 80% of patients with MDD present with physical complaints Fishbain et al., 1997, Kirmayer et al., 1993, with up to 60% of these patients having pain complaints, including headache, back pain, stomach aches, and poorly localized musculoskeletal pain (Kroenke and Price, 1993). Treatment and resolution of the painful physical symptoms that frequently accompany MDD Fishbain et al., 1997, Kirmayer et al., 1993, Kroenke and Price, 1993, Simon et al., 1999 are necessary to achieve an optimal therapeutic outcome (Fava, 2002). In addition to their key role in the neurobiology of depression, serotonin (5-HT) and norepinephrine (NE) also modulate descending inhibitory pain pathways of the brain and spinal cord (Millan, 2002). Furthermore, antidepressants that influence the neurotransmission of both 5-HT and NE have been reported to demonstrate greater analgesic efficacy compared with reuptake inhibitors of 5-HT alone Ansari, 2000, Lynch, 2001, Sindrup and Jensen, 1999. A growing body of evidence suggests that therapies with combined 5-HT and NE activity may have a broader spectrum of action, compared with SSRIs, and demonstrate greater efficacy in the treatment of both emotional and painful physical symptoms of depression Anderson, 2000, Faravelli et al., 2003, Nelson et al., 1991, Stahl et al., 2002, Steffens et al., 1997, Thase et al., 2001, Tran et al., 2003.

Duloxetine is a balanced and potent reuptake inhibitor of both 5-HT and NE, and lacks significant affinity for other receptors (Wong and Bymaster, 2002). The safety and efficacy of duloxetine in the acute treatment of MDD have been established in double-blind, placebo-controlled studies Detke et al., 2002a, Detke et al., 2002b, Goldstein et al., 2002, Goldstein et al., 2004, Nemeroff et al., 2002. It was proposed that the relatively high probabilities of remission observed in these studies (ranging from 43% to 57%) may result from duloxetine's efficacy in both emotional and physical symptom domains. Moreover, results from a 52-week open-label study indicated that duloxetine was efficacious, safe, and well tolerated in the long-term treatment of MDD (Raskin et al., 2003). However, the lack of a placebo group limited the conclusions that could be drawn from this study.

For the present study, several study objectives were determined a priori. Firstly, to investigate the efficacy of duloxetine (120 mg/day) compared with placebo. This duloxetine dose was selected such that results could be consolidated with those from other acute trials employing duloxetine 40, 60, and 80 mg/day Detke et al., 2002a, Detke et al., 2002b, Goldstein et al., 2002, Goldstein et al., 2004 to fully characterize the dose range. Secondly, to compare the safety of duloxetine (80 and 120 mg/day), paroxetine (at an approved and commonly prescribed dose of 20 mg QD (Dunner and Dunbar, 1992)), and placebo during acute and continuation phase treatment. And thirdly, to evaluate maintenance of efficacy during long-term treatment with duloxetine (80 and 120 mg/day), paroxetine (20 mg QD), or placebo in patients responding to acute-phase therapy. Results from this study were to be combined with those from a second identical, but independent, study to establish non-inferiority for duloxetine versus paroxetine. However, the present study was not, by itself, specifically designed or powered to facilitate head-to-head comparisons of efficacy between paroxetine (20 mg QD) and duloxetine (80 or 120 mg/day).