Major depressive disorder (MDD) is a common, chronic illness associated with substantial
disability and economic burden. Although a number of effective antidepressants are
available, the need for new medications that are effective and well tolerated remains.
The aim of this study was to compare the efficacy and tolerability of fixed-dose desvenlafaxine
50 and 100 mg/d with placebo for MDD. A post hoc pooled analysis was conducted to
evaluate this study in the context of all similarly designed, completed studies with
the 2 doses.
This was an 8-week, Phase III, randomized, double-blind, duloxetine-referenced, placebo-controlled,
parallel-group trial conducted in 21 centers across the United States. Duloxetine
was included for assay sensitivity as a positive control; the study was not designed
or powered to compare desvenlafaxine with duloxetine. Participants were outpatients
aged > or =18 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition-defined MDD and a 17-item Hamilton Rating Scale for Depression (HAM-D(17))
score > or =20. Patients were randomly assigned at baseline to fixed-dose desvenlafaxine
(50 or 100 mg/d), fixed-dose duloxetine (60 mg/d), or placebo. The primary outcome
measure was HAM-D(17) total score at the final evaluation. Additional measures included
the Clinical Global Impressions-Improvement (CGI-I) score, Montgomery Asberg Depression
Rating Scale (MADRS) score, Clinical Global Impressions-Severity (CGI-S) score, and
6-item Hamilton Rating Scale for Depression, Bech version (HAM-D(6)). Tolerability
assessments included discontinuation rates, adverse events (AEs), vital signs, and
laboratory tests. The post hoc pooled analysis was performed using data from the current
study and 2 previously published, positive studies that compared the efficacy and
tolerability of desvenlafaxine 50 and 100 mg/d with placebo for MDD. The design and
methodologies of the 2 studies were similar to the methodology of the current trial,
other than not including a reference compound.
Of the 925 patients who were screened, 287 did not meet entry criteria, and 638 patients
enrolled in the study; the intent-to-treat (ITT) population included 615 patients
who were evaluated for efficacy (mean [SD] age range, 38.8-40.7 [12.1-13.2] years;
mean weight range, 83.3-87.0 [22.8-23.9] kg; female sex, 398 [64.7%]; white race,
458 [74.5%]). The primary end point did not reach significance based on the global
F test for controlling multiplicity of the desvenlafaxine doses. Based on pairwise
comparison, significantly greater improvements on the HAM-D(17) were observed in the
desven-lafaxine 100 mg/d (-10.5; P = 0.028, unadjusted for multiple comparisons) and
duloxetine 60 mg/d groups (-10.3; P = 0.047) compared with placebo (-8.7). Desvenlafaxine
100 mg/d and duloxetine 60 mg/d were associated with significantly better scores compared
with placebo on the CGI-I, MADRS, CGI-S, and HAM-D(6). No significant differences
were observed in any scale between the desvenlafaxine 50 mg/d and placebo groups.
Discontinuation rates due to AEs were 5%, 7%, 13%, and 6% for the desvenlafaxine 50-mg/d,
desvenlafaxine 100-mg/d, duloxetine 60-mg/d, and placebo groups, respectively. The
ITT population from all 3 studies in the pooled analysis consisted of 1388 patients
(mean [SD] age range, 38.8-45.7 [12.1-12.6] years; mean weight range, 73.1-87.0 [17.6-23.9]
kg; female sex, 896 [64.6%]; white race, 1136 [81.8%]). Significantly greater improvements
on the HAM-D(17) were observed for desvenlafaxine 50 mg/d (-11.5; P < 0.001) and 100
mg/d (-11.8; P < 0.001) versus placebo (-9.6). Both doses were significantly better
than placebo on the CGI-I, MADRS, and HAM-D(6).
The current study failed to meet its primary efficacy end point based on the a priori
analysis plan. Desvenlafaxine was generally well tolerated. A post hoc pooled analysis
of this trial and 2 previously published trials with both desvenlafaxine 50 and 100
mg/d found both doses to be effective for MDD compared with placebo. ClinicalTrials.gov
Identifier: 00384033.