February 3, 2009 — When balancing benefits, acceptability, and cost, sertraline may be the best initial treatment option for moderate to severe major depression in adults, according to the results of a meta-analysis of 12 new-generation antidepressants reported in the January 28 Online First issue of The Lancet.
"Conventional meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants," write Andrea Cipriani, PhD, from the University of Verona, in Verona, Italy, and colleagues.
"We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirect comparisons, to assess the effects of 12 new-generation antidepressants on major depression."
This systematic review included 117 randomized controlled trials, enrolling a total of 25,928 participants, from 1991 up to November 30, 2007. Inclusion criteria for the review were comparison of any of the following antidepressants at therapeutic dose range for the acute treatment of unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The primary outcome measures were the percentages of patients who responded to or withdrew from the assigned treatment, with analysis by intent-to-treat.
Efficacy was significantly better for mirtazapine, escitalopram, venlafaxine, and sertraline vs duloxetine (odds ratios [ORs], 1.39, 1.33, 1.30, and 1.27, respectively), fluoxetine (ORs, 1.37, 1.32, 1.28, and 1.25, respectively), fluvoxamine (ORs, 1.41, 1.35, 1.30, and 1.27, respectively), paroxetine (ORs 1.35, 1.30, 1.27, and 1.22, respectively), and reboxetine (ORs, 2.03, 1.95, 1.89, and 1.85, respectively).
Compared with all of the other antidepressants tested, reboxetine was significantly less effective. Acceptability profile was best for escitalopram and sertraline, with significantly fewer discontinuations than were observed with duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine.
"Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline," the study authors write. "Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost."
Limitations of this meta-analysis include lack of comparison of adverse effects, toxic effects, discontinuation symptoms, and social functioning; applicability only to acute-phase treatment (8 weeks) of depression; lack of adequate information about randomization and allocation concealment in most included studies; presence of sponsorship bias; and lack of cost-effectiveness analysis.
In an accompanying comment, Sagar V. Parikh, from the University of Toronto and University Health Network in Toronto, Ontario, Canada, notes the "enormous implications" of these findings, but he recommends further meta-analysis to compare 6-month outcomes.
"Intriguingly, Cipriani and colleagues also challenge the field of clinical trials to use sertraline as a benchmark in the development of new compounds; by raising the efficacy bar beyond 'beating placebo,' they hope to discourage the development of drugs of routine efficacy and also side-step the ethically challenging position of using placebos in an era of multiple proven treatments for depression," Dr. Parikh writes. "With such a host of clinical and research implications, this pivotal meta-analysis of antidepressant efficacy and acceptability will surely change the tune of psychiatrists."