Major depressive disorder (MDD) represents one of the most serious challenges faced by healthcare providers throughout the world, affecting some 18 million people in the United States and 340 million people globally 1. The negative impact of MDD upon patient well-being and functioning is comparable to that of major chronic medical conditions such as diabetes, hypertension, coronary artery disease, and arthritis 2. Given the enormous impact of depression upon both the individual patient and the healthcare system as a whole, the need for effective treatment is clear.

Antidepressant medications, in particular the selective serotonin reuptake inhibitors (SSRIs), currently represent the first line of treatment for MDD. SSRIs attained clinical acceptance over tricyclic antidepressants (TCAs) in part due to their improved tolerability profile, including lower rates of anticholinergic events, orthostatic hypotension, sedation, and lower toxicity in overdose 34. However, SSRIs have not demonstrated superior efficacy when compared with TCAs 5, and up to half of all depressed patients fail to respond to SSRI therapy 6. Thus, the need for alternative safe and effective treatments for MDD is clear.

The antidepressant duloxetine is a potent dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) 7, but lacks significant affinity for muscarinic, histaminergic, α-adrenergic, dopaminergic, serotonergic, and opioid receptors 8. Previous double-blind, placebo-controlled studies have established the safety and efficacy of duloxetine in the treatment of MDD 91011121314. For licensing purposes, the European Committee for Proprietary Medicinal Products (CPMP) requires that an antidepressant's short-term effect be maintained for a longer duration. For this reason, a randomized withdrawal study, also called a relapse prevention study, was considered the best design. The study included an initial 12-week, open-label treatment phase followed by a 26-week, double-blind, randomized withdrawal phase. The primary results of the relapse prevention study have been published elsewhere 15. Here we present results from the initial open-label acute phase of a relapse prevention study, in which a cohort of over 500 patients received duloxetine (60 mg once-daily) for 12 weeks.

The results of the current investigation are based on the initial 12-week, open-label acute treatment phase of a randomized withdrawal study of duloxetine in the prevention of relapse of MDD. Results of the parent study have been published and show that patients receiving duloxetine 60 mg/d had significantly longer times to relapse than patients receiving placebo 15. The current analysis utilized data from an open-label setting to assess the safety and efficacy of a once-daily 60 mg duloxetine dose during acute phase treatment of MDD. Although the study yielded data from a cohort of over 500 patients receiving duloxetine at the target therapeutic dose for up to 12 weeks, interpretation of results from an open-label study should be approached cautiously. The absence of placebo or active comparator treatment arms limits our ability to draw firm conclusions from the current results, especially with regard to efficacy outcomes. Patients in an open-label study will exhibit the combined benefits of both drug and placebo responses, and therefore efficacy results such as response and remission rates may be more favorable than those obtained from double-blind, placebo-controlled studies. Furthermore, the statistical significance of treatment outcomes can only be assessed relative to baseline values rather than a comparator group. However, an open-label setting does provide a more realistic approximation of clinical practice when compared with a double-blind study, and a large study such as this can yield a substantial body of safety and tolerability data. In certain areas, such as rates of discontinuation and the incidence of spontaneously-reported adverse events, results from an open-label study may be especially relevant for practicing clinicians. With these limitations in mind, we discuss in general terms the principal findings from this study. Wherever possible, comparisons with data from previous double-blind, placebo-controlled studies are utilized to provide context for the current results.

The rate of discontinuation due to adverse events in this study (11.3%) was similar to that observed in double-blind, placebo-controlled studies of duloxetine, 60 mg once-daily (13.8% 9 and 12.5% 10) and is also broadly consistent with the reported rates of discontinuation due to adverse events presented in the full prescribing information for other antidepressants (6% escitalopram 28, 10% paroxetine controlled release 29, 11% venlafaxine extended release 30). Furthermore, the incidence and pattern of treatment-emergent adverse events was also consistent with previously published data. In an analysis of pooled data from placebo-controlled studies of duloxetine (40–120 mg/d), adverse events occurring in ≥5% of duloxetine-treated patients, and at twice the rate for placebo, were nausea, dry mouth, fatigue, dizziness, constipation, somnolence, decreased appetite, and increased sweating 14. The incidence of treatment-emergent nausea in the present study (35.8%) was similar to that reported in 2 placebo-controlled studies of duloxetine 60 mg QD 910. Although patients could request a reduction of the duloxetine dose from 60 mg QD to 30 mg QD at any point during the first 4 weeks of therapy, 85% of patients tolerated the starting dose of 60 mg QD without the need for downward titration.

The incidence of spontaneously-reported adverse events related to sexual functioning was relatively low. However, spontaneous reports frequently under-represent the actual incidence of sexual side-effects, and more accurate estimates may be elicited using validated, structured questionnaires. In the present study, the Patient Global Impression of Sexual Function (PGI-SF) questionnaire was utilized to assess treatment-emergent impairment of sexual functioning. Female patients experienced significant within-group mean improvements on all 4 items of the PGI-SF, while male patients experienced improvement on Item 1 (sexual interest/desire). While results from an open-label study should be viewed with a degree of caution, these results suggest that duloxetine does not have a substantial adverse impact upon patient's perception of sexual functioning. By way of comparison, in four double-blind, placebo- and paroxetine-controlled studies of up to 9 months duration, the Arizona Sexual Experience (ASEX) scale was utilized to compare the incidence of sexual dysfunction in patients receiving duloxetine with the corresponding rates in paroxetine- and placebo-treated patients. Results of an analysis of pooled data from these studies showed that the incidence of acute-phase sexual dysfunction in patients receiving duloxetine (40–120 mg/d) was significantly lower than that for patients receiving paroxetine (20 mg QD) 31.

Consistent with duloxetine's pharmacological profile as a reuptake inhibitor of NE, a mean increase in heart rate was observed (1.7 bpm from baseline to endpoint). The magnitude of this increase is similar to that observed in an analysis of pooled data from acute-phase, placebo-controlled studies of duloxetine (1.4 bpm vs. -0.6 bpm for placebo) 32. Modest increases in HR have also been observed during treatment of depressed patients with the NE reuptake inhibitor reboxetine (increase in HR of approximately 8% during 3 weeks of treatment at 4–8 mg/d) 33 and the 5-HT and NE reuptake inhibitor venlafaxine (increase of 3.8 bpm during 8 weeks of treatment at 225 mg/d) 34. Duloxetine also produced small (less than 2 mm Hg) mean increases in blood pressure – in the case of supine systolic BP the mean change to endpoint (1.4 mm Hg) was statistically but not clinically significant when compared with the baseline value. These mean changes are consistent with those observed in acute-phase, placebo controlled studies of duloxetine (40–120 mg/d) 32. Thus, in an analysis of pooled data, mean change in supine systolic BP was 0.8 mm Hg for duloxetine vs. -1.4 mm Hg for placebo (p < .001), while mean change in supine diastolic BP was 0.9 mm Hg for duloxetine vs. 0.4 mm Hg for placebo (p = .099) 32.

In the present study, duloxetine lacked significant effects on the QT interval. None of the 402 patients providing ECG data had a PCS prolongation of corrected QT interval. These data are consistent with results obtained from placebo-controlled studies of duloxetine, which found no evidence for prolongation of QTc intervals in duloxetine-treated patients when compared with those receiving placebo 32.

During the course of this 12-week study, patients receiving duloxetine had a small (0.1 kg) decrease in mean body weight. In the absence of a placebo comparator, no definitive conclusions can be drawn concerning the significance of this mean change. However, in an analysis of pooled data from acute-phase, placebo-controlled trials of up to 12 weeks duration, patients receiving duloxetine (40–120 mg/d) exhibited a mean change in weight of -0.46 kg, compared with 0.23 kg for those receiving placebo (p < .001) 32. Furthermore, results from a long-term (52-week) open-label study of duloxetine (80–120 mg/d) demonstrated that mean body weight decreased slightly in the first few weeks of treatment, returned to baseline levels at intermediate visits, and showed an increase of 1.1 kg at the study endpoint 35.

In a large study with many measures, small clinically insignificant mean changes in laboratory values commonly achieve statistical significance. Thus, in this large study, mean changes in some laboratory values were statistically significant, but small in magnitude and of doubtful clinical relevance. However, definitive evidence of non-causality is problematic in the absence of placebo control. In the present study, the incidence of ALT and AST values greater than 1×, but less than 3× the ULN, were 9.8% and 9.4%, respectively, while 1 patient (0.2%) had an ALT elevation greater than 3× the ULN. These results are consistent with observations from controlled studies of duloxetine. Within the primary placebo-controlled database (pooled data from 8 studies), the incidence of abnormal (high) values for ALT (duloxetine 9.5% vs. placebo 7.4%; p = .146) and AST (duloxetine 8.1% vs. placebo 6.0%; p = .122) did not differ significantly from the placebo rate 3236), while elevations of ALT greater than 3× the ULN occurred in 0.9% (8/930) of duloxetine-treated patients compared with 0.3% (2/652) of those receiving placebo 36. Analyses from another long-term (52-week), open-label clinical study of duloxetine (N = 2109) showed that duloxetine use was associated with a mild, transient, self-limited rise in ALT and AST, and these changes did not appear to be of clinical significance 3536.

The efficacy of duloxetine (40–120 mg/d) in the acute treatment of MDD has been established in a number of acute phase, double-blind, placebo-controlled studies, in addition to a long-term open-label study 9101112131435. Efficacy results obtained in this study are consistent with those obtained previously at a 60 mg once daily dose 910, although double-blind, placebo-controlled studies should be regarded as the primary source of efficacy data, with open-label studies such as this playing a supporting role. The time course of improvement in individual symptom domains is noteworthy. In assessments of depression severity (HAMD₁₇, CGI-S) the magnitude of improvement continued to increase at each study visit, while for painful physical symptoms the onset of improvement was rapid and reached a maximum after 2 to 3 weeks of treatment. With regard to duloxetine's effect on overall pain severity improvement, our observations are consistent with experimental data indicating that both 5-HT and NE exert analgesic effects via descending pain pathways 373839. The effects on painful symptoms observed in this study are consistent with data from other duloxetine studies demonstrating analgesic effects in depressed patients 40, and the results from the current study are also supportive of those obtained previously from double-blind, placebo-controlled studies which suggest that duloxetine's effect upon painful physical symptoms is, to some extent, independent of its effects upon core emotional symptoms of depression. Thus, in a path analysis of pooled data from 2 placebo-controlled clinical trials, 50% of duloxetine's total effect on overall pain severity was found to be independent of changes in depressive symptom severity 41.

In the current study, the rate of treatment response (≥50% reduction in HAMD₁₇ total score from baseline) was 67.9%, while the remission rate (HAMD₁₇ total score ≤7) was 52.8% (LOCF analysis). In two previously-published placebo-controlled, 9-week studies of duloxetine (60 mg once-daily), estimated probabilities of response (MMRM analysis) were 62% 9 and 65% 10 while probabilities of remission were 44% 9 and 43% 10. In other placebo-controlled studies of duloxetine at doses up to 120 mg/d probabilities of remission (MMRM) of up to 57% have been observed 14. The remission rate in the present study is somewhat higher than that observed in the two placebo-controlled trials involving duloxetine 60 mg once-daily dosing 910. As discussed previously, this may be a result of the more favorable treatment outcomes often observed in patients participating in an open-label study. However, other confounding factors also preclude any detailed between-study comparisons, including differing treatment periods (12 weeks in this study vs. 9 weeks in the placebo-controlled studies), somewhat higher baseline severity of depression in the present study (HAMD total score of 23.7 vs. 20–21 in the placebo-controlled studies), and differing analytical methods (LOCF in the current study vs. MMRM in the placebo-controlled studies).

In summary, both safety and efficacy results from this open-label study are supportive of those obtained from more rigorous double-blind, placebo-controlled trials. The cohort of 533 patients in this study was the largest patient group to receive the recommended therapeutic dose of 60 mg once daily in any duloxetine study to date. Despite the limited utility of efficacy data obtained under open-label conditions, it is hoped that the results described here will provide clinically relevant information for practicing clinicians, especially with regard to the safety and tolerability of duloxetine.

A number of study limitations should be considered when interpreting the present results. As mentioned previously, the principal limitation is the open-label nature of the study and the lack of placebo or active comparator treatment arms. Secondly, the study was of 12 weeks duration and therefore the results are applicable only to acute phase treatment of MDD. Thirdly, patients received a fixed 60 mg dose of duloxetine throughout the study, although the option of a temporary downward titration to 30 mg QD was available at the beginning of the treatment period. Outcomes may have differed if dosing regimens had been optimized on an individual patient basis. Fourthly, patients with serious or unstable medical illnesses were excluded from the study, which limits the generalizability of the current results to a general population of depressed patients.

In this open-label study of over 500 patients with a diagnosis of MDD, duloxetine (60 mg QD) was safe and efficacious in the treatment of both emotional and painful physical symptoms of depression. Safety and tolerability results were consistent with those observed previously in double-blind, placebo-controlled studies.

DP, IG, FW, JW, and MD were employees of Eli Lilly and Company at the time this manuscript was drafted. DP, IG, FW, and MD own Eli Lilly and Company stock. JH has consulted for Eli Lilly and Company and Ortho-McNeil Pharmaceutical, Inc.; and has received research grants from Eli Lilly and Company, Ortho-McNeil Pharmaceutical, Inc., and Forest Laboratories. The article-processing charge for this manuscript is being paid by Eli Lilly and Company.

DP, IG, and MD conceived of the study, participated in its design and coordination, interpreted the data, and helped to draft the manuscript. FW performed the statistical analysis and interpreted the data. JH participated as a site principal investigator in the study and helped interpret the data. JW interpreted the data and drafted the manuscript. All authors critically reviewed and approved the final manuscript.