title: Duloxetine for the treatment of major depressive disorder: a closer look at efficacy and safety data across the approved dose range.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. cmallinc@lilly.com
authors.forename: Craig H
authors.initials: CH
authors.lastname: Mallinckrodt
authors.forename: Apurva
authors.initials: A
authors.lastname: Prakash
authors.forename: Anne C
authors.initials: AC
authors.lastname: Andorn
authors.forename: John G
authors.initials: JG
authors.lastname: Watkin
authors.forename: Madelaine M
authors.initials: MM
authors.lastname: Wohlreich
mesh_terms: 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
chemical_list: D000068736:Duloxetine Hydrochloride; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes