Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review

Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux LJ, Van Noord M, Mager U, Gaynes BN, Thieda P, Strobelberger M, Lloyd S, Reichenpfader U, Lohr KN. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center, Contract No. 290-2007-10056-I.) AHRQ Publication No. 12-EHC012-EF. Rockville, MD: Agency for Healthcare Research and Quality. December 2011.




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Depressive disorders such as major depressive disorder (MDD), dysthymia, and subsyndromal depression may be serious disabling illnesses. MDD affects more than 16 percent of adults at some point during their lifetimes. Second-generation antidepressants dominate the medical management of depressive disorders. These drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other drugs with related mechanisms of action that selectively target neurotransmitters.


The objective of this report was to compare the benefits and harms of bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine for the treatment of depressive disorders, including variations of effects in patients with accompanying symptoms and patient subgroups.

Data Sources

We updated a comparative effectiveness review published in 2007 by the Agency for Healthcare Research and Quality searching PubMed, Embase, The Cochrane Library, and International Pharmaceutical Abstracts up to January 2011.

Review Methods

Two people independently reviewed the literature, abstracted data, and rated the risk of bias. If data were sufficient, we conducted meta-analyses of head-to-head trials of the relative benefit of response to treatment. In addition, we conducted mixed treatment comparisons to derive indirect estimates of the comparative efficacy among all second-generation antidepressants.


From a total of 3,722 citations, we identified 248 studies of good or fair quality. Overall, no substantial differences in efficacy could be detected among second-generation antidepressants for the treatment of acute-phase MDD. Statistically significant differences in response rates between some drugs are small and likely not clinically relevant. No differences in efficacy were apparent in patients with accompanying symptoms or in subgroups based on age, sex, ethnicity, or comorbidities, although evidence within these subpopulations was limited.

Differences exist in the incidence of specific adverse events and the onset of action. Venlafaxine leads to higher rates of nausea and vomiting, sertraline to higher rates of diarrhea, and mirtazapine to higher rates of weight gain than comparator drugs. Bupropion causes lower rates of sexual dysfunction than other antidepressants. The evidence is insufficient to draw conclusions about the comparative efficacy and effectiveness for the treatment of dysthymia and subsyndromal depression.


Our findings indicate that the existing evidence does not warrant the choice of one second-generation antidepressant over another based on greater efficacy and effectiveness. Differences with respect to onset of action and adverse events may be taken into consideration for the choice of a medication.