Background: Recent studies suggest that the treatment of major depressive disorder (MDD) with newer antidepressant drugs that simultaneously enhance norepinephrine and serotonin neurotransmission might result in higher response and remission rates than the selective serotonin reuptake inhibitors (SSRIs). The goal of our work was to compare response rates among patients with MDD treated with either of these two broad categories of antidepressant drugs. Methods: Medline/Pubmed, EMBase, clinical trial registries, program syllabi from major psychiatric meetings held since 1995, and documents from relevant pharmaceutical companies were searched for double-blind, randomized trials comparing a newer serotonergic-noradrenergic antidepressant drug (venlafaxine, duloxetine, milnacipran, mirtazapine, mianserin, or moclobemide) with an SSRI for MDD. Results: Ninety-three trials (n = 17,036) were combined using a random-effects model. Treatment with serotonergic + noradrenergic antidepressant drugs was more likely to result in clinical response than the SSRIs (risk ratio [RR] = 1.059; response rates 63.6% versus 59.3%; p = .003). There was no evidence for heterogeneity among studies combined (p = 1.0). Excluding each individual agent did not significantly alter the pooled RR. With the exception of duloxetine (.985), RRs for response for each individual serotonergic + noradrenergic antidepressant drug were within the 95% confidence interval of the pooled RR (1.019-1.101). Conclusions: Serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage compared with SSRIs in MDD. With the Number Needed to Treat (NNT) statistic as one indicator of clinical significance, nearly 24 patients would need to be treated with dual-action antidepressant drugs instead of SSRIs in order to obtain one additional responder. This difference falls well below the mark of NNT = 10 suggested by the United Kingdom's National Institute of Clinical Excellence but nonetheless might be of public health relevance given the large number of depressed patients treated with SSRI /serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant drugs. Further research is needed to examine whether larger differences between classes of antidepressant drugs might exist in specific MDD sub-populations or for specific MDD symptoms. © 2007 Society of Biological Psychiatry.