Posted by inquisitive1 on December 25, 2005, at 11:29:28
In reply to New PDoc RX'd High Dose Cymbalta, posted by Phillipa on December 22, 2005, at 16:29:24
Clinical Trials of Duloxetine for Major Depression
Four randomized, placebo-controlled, clinical trials of duloxetine for major depression have been published.[44–47] The studies are reviewed separately below, and additional details are provided in Table 1 . Patient baseline characteristics, inclusion and exclusion criteria, and methodology were comparable. Unless stated otherwise, a response was defined as a 50% or greater decrease in the HAMD17 score and remission as a HAMD17 score of ≤7. Patients were excluded if they had a major depressive episode within the preceding four months. Prescription pain and antihypertensive medications were not allowed. Patients had to meet the criteria for depression as defined by DSM-IV and needed to have a baseline HAMD17 score of not less than 18. Patients who had failed to respond to at least two adequate courses of antidepressant therapy (i.e., received each drug for at least four weeks) were excluded. All studies were in accordance with the ethical standards of the institutions where they were conducted.All four of the placebo-controlled trials of duloxetine primarily analyzed data by using a mixed-effects model for repeated-measures approach. This approach has been described elsewhere, as has the authors' rationale for using it.[48,49] However, depression studies and comparisons have traditionally been done with outcomes based on last-observation-carried-forward (LOCF) analysis.[50,51] To adequately assess duloxetine in relation to outcomes as typically reported in studies of MDD, this review will focus primarily on LOCF analysis.
Goldstein et al.[44] conducted a randomized, placebo-controlled, double-blind trial in adults with MDD at eight sites over an eight-week treatment period. Patients were assigned to receive an escalating dosage of duloxetine, fluoxetine 20 mg daily, or placebo. In the duloxetine treatment group, dosages were initiated at 40 mg per day (administered as 20 mg twice daily) and increased to 120 mg per day (60 mg twice per day) by the third week. Dosage adjustments of duloxetine were required, but the investigators were allowed to withhold a dosage escalation if there were concerns about safety or tolerability. During the treatment phase, 34% of patients in both the duloxetine and placebo groups and 36% taking fluoxetine discontinued treatment and withdrew from the study. One third of those who discontinued duloxetine did so because of adverse events, but a significant number of patients taking placebo discontinued it because of lack of efficacy.
Detke et al.[45] conducted a randomized, multicenter, double-blind trial that assigned 245 patients to either duloxetine 60 mg once per day or placebo for nine weeks. Patients 18 years and older who met DSM-IV criteria for MDD were included in the study. Patients who could not tolerate 60 mg once per day were permitted to reduce the duloxetine dosage to 40 mg per day for a maximum of three weeks. Patients in the duloxetine group had a greater reduction in HAMD17 scores than patients in the placebo group and had significantly reduced scores of anxiety and pain on HAMD17 subscales compared with patients receiving placebo.
Another randomized, double-blind, placebo-controlled study evaluated duloxetine for the treatment of major depression in 267 patients at 21 U.S. sites over nine weeks.[46] Patients were initiated at 60 mg per day for duloxetine. If patients requested, the dosage could be reduced to 40 mg per day but had to be escalated back to 60 mg per day within three weeks. Patients with at least one postbaseline assessment were included in the efficacy analysis. Greater reductions from baseline in HAMD17 scores were observed in patients receiving duloxetine than in those receiving placebo at the end of the study period. On secondary endpoints, duloxetine showed reduced pain and anxiety by week 9, but this finding was not significant.
Goldstein et al.[47] conducted a prospective, randomized, double-blind study comparing duloxetine 40 mg per day (20 mg twice daily) or duloxetine 80 mg per day (40 mg twice daily) with placebo or paroxetine 20 mg per day. The primary comparison was between the duloxetine 80-mg/day and placebo groups. There was no dosage adjustment period; all patients were initiated at and remained on the assigned dosage throughout the study period. At week 8, rates of remission in patients receiving duloxetine 80 mg per day (50%) were significantly greater than in those receiving duloxetine 40 mg per day (35%) or placebo (30%). Only patients receiving duloxetine 80 mg per day had significant reductions in overall pain severity (47% reduction). Also, on the HAMD17 subscale of anxiety, only the duloxetine 80-mg/day group achieved a significant reduction in anxiety or somatization.
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