Are SNRIs more effective than SSRIs? A review of the current state of the controversy

Psychopharmacol Bull. 2008;41(2):58-85.


The selective serotonin reuptake inhibitors (SSRI) are widely considered to be the first choice for antidepressant therapy. There is evidence from inpatient studies dating to 1986, however, suggesting that the tricyclic antidepressant clomipramine, which inhibits reuptake of both serotonin and norepinephrine, may have greater efficacy than some SSRIs for severe depression. There is controversy whether the newer, better tolerated, and safer serotonin norepinephrine reuptake inhibitors (SNRIs; venlafaxine, duloxetine, and-in some countries-milnacipran and desvenlafaxine) are more efficacious than SSRIs. In addressing this controversy, this article first focuses on the limitations of randomized controlled trials (RCTs), including the factors that limit their sensitivity to detect differences between active antidepressants, and meta-analysis to examine results of large sets of RCTs. Next, the results of RCTs and meta-analyses are reviewed. Although few individual studies report significant differences, meta-analyses consistently suggest that venlafaxine may have greater efficacy than the SSRIs as a class. The magnitude of this advantage is modest (i.e., differences in remission rates of 5-10%) and no advantage has been demonstrated versus escitalopram. The advantage for duloxetine versus selected SSRIs is limited to patients with more severe depression and the RCTs are flawed by use of minimum therapeutic doses of SSRIs. No evidence of an advantage is found in RCTs of milnacipran versus SSRIs. Even a modest difference in antidepressant efficacy-if sustained-may have important public health implications for the common, disabling condition of depression. Nevertheless, differences in tolerability and cost also must be considered when choosing therapies.

Publication types

  • Review

MeSH terms

  • Adrenergic Uptake Inhibitors / therapeutic use*
  • Antidepressive Agents, Tricyclic / therapeutic use
  • Citalopram / therapeutic use
  • Cyclohexanols / therapeutic use
  • Depressive Disorder / drug therapy*
  • Humans
  • Meta-Analysis as Topic
  • Randomized Controlled Trials as Topic
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*
  • Venlafaxine Hydrochloride


  • Adrenergic Uptake Inhibitors
  • Antidepressive Agents, Tricyclic
  • Cyclohexanols
  • Serotonin Uptake Inhibitors
  • Citalopram
  • Venlafaxine Hydrochloride