Duloxetine for the treatment of major depressive disorder: a closer look at efficacy and safety data across the approved dose range.
OBJECTIVE
This analysis focuses on efficacy and safety data obtained from studies of duloxetine for the treatment of major depressive disorder (MDD) within the approved dose range of 40-60 mg/day.


METHODS
Efficacy and safety data were obtained from the acute phase portions of four randomized, double-blind, placebo-controlled clinical trials in patients meeting DSM-IV criteria for MDD. In Studies 1 and 2, patients were randomized to duloxetine 60 mg once daily (QD) (n=123 [Study 1]; n=128 [Study 2]) or placebo (n=122 [Study 1]; n=139 [Study 2]) for 9 weeks. In Studies 3 and 4, patients were randomized to duloxetine 20 mg twice daily (BID) (n=91 [Study 3]; n=86 [Study 4]) or placebo (n=90 [Study 3]; n=89 [Study 4]) for 8 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total score (primary outcome), HAMD17 subscales, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain. Safety assessments included rates of discontinuation due to adverse events, spontaneously reported treatment-emergent adverse events, and changes in vital signs.


RESULTS
In both studies of duloxetine 60 mg QD, mean change in HAMD17 total score was significantly greater in duloxetine-treated patients compared with placebo (Study 1, p<.001; Study 2, p=.024). At a dose of 20 mg BID, duloxetine demonstrated significant superiority over placebo on the HAMD17 total score in one of the two studies (Study 4, p=.034). Probabilities of remission among patients receiving duloxetine 60 mg QD were 44.2% in Study 1 (p<.001 vs. placebo) and 43.0% in Study 2 (NS), while for patients receiving duloxetine 20 mg BID the probabilities of remission were 27.2% in Study 3 (NS) and 36.1% in Study 4 (NS). Across the six assessed VAS measures of pain severity and interference, the main effect of treatment for duloxetine 60 mg QD was significantly superior to placebo on 7 of the 12 outcomes in Studies 1 and 2, while duloxetine 20 mg BID was not superior to placebo on any of the 12 outcomes in Studies 3 and 4. The rate of discontinuation due to adverse events was 13.1% among patients receiving duloxetine 60 mg QD, and 11.9% at a dose of 20 mg BID. The most frequently reported treatment-emergent adverse events at both doses included nausea, headache, dry mouth, dizziness, and insomnia. The incidence of treatment-emergent nausea among patients receiving duloxetine 60 mg QD was 37.8%, compared with 16.4% among patients receiving 20 mg BID.


CONCLUSIONS
Duloxetine provides safe and effective acute phase treatment of MDD at doses of 40-60 mg/day. Compared with placebo, the 60 mg QD dose was more consistently effective than the 20 mg BID dose. However, the incidence of certain treatment-emergent adverse events is likely to be lower at the 40 mg dose.
Mallinckrodt
Craig H
CH
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. cmallinc@lilly.com
Prakash
Apurva
A
Andorn
Anne C
AC
Watkin
John G
JG
Wohlreich
Madelaine M
MM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003865:Major Depressive Disorder / Q000175:diagnosis* / Q000188:drug therapy*; D004311:Double-Blind Method; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D013876:Thiophenes / Q000009:adverse effects* / Q000627:therapeutic use; D016896:Treatment Outcome
D000068736:Duloxetine Hydrochloride; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes