Treatment of SSRI-resistant depression: a meta-analysis comparing within- versus across-class switches

Biol Psychiatry. 2008 Apr 1;63(7):699-704. doi: 10.1016/j.biopsych.2007.08.010. Epub 2007 Oct 24.


Background: Two broad treatment options exist for switching antidepressants for depressed patients who fail to respond to a selective serotonin reuptake inhibitor (SSRI): either a second course of SSRI therapy or a different class of antidepressants. The goal of the present work was to conduct a meta-analysis of studies comparing these two switch strategies.

Methods: Several sources were searched for randomized clinical trials comparing these two switch strategies.

Results: Data from four clinical trials (n = 1496) were combined using a random-effects model. Patients randomized to switch to a non-SSRI antidepressant (bupropion, mirtazapine, venlafaxine) were more likely to experience remission than patients switched to a second SSRI (risk ratio = 1.29, p = .007). Pooled remission rates were 28% (for non-SSRIs) and 23.5% (for SSRIs). There was also a nonsignificant trend (p = .1) in the rate of discontinuation due to intolerance favoring the within-class switch strategy (risk ratio = 1.23). There was no difference in response rates between the two treatment groups.

Conclusions: These results suggest a modest yet statistically significant advantage in remission rates when switching patients with SSRI-resistant depression to a non-SSRI rather than an SSRI antidepressant. With the number needed to treat (NNT) statistic as one indicator of clinical significance, nearly 22 SSRI nonresponders would need to be switched to a non-SSRI rather than a second SSRI antidepressant to obtain one additional remitter. 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 SSRI-resistant patients switched to an SSRI versus a non-SSRI antidepressant.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • Bupropion / therapeutic use
  • Cyclohexanols / therapeutic use
  • Depressive Disorder, Major / drug therapy*
  • Drug Resistance*
  • Humans
  • Mianserin / analogs & derivatives
  • Mianserin / therapeutic use
  • Mirtazapine
  • Randomized Controlled Trials as Topic
  • Selective Serotonin Reuptake Inhibitors / classification*
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*
  • Venlafaxine Hydrochloride


  • Cyclohexanols
  • Serotonin Uptake Inhibitors
  • Bupropion
  • Mianserin
  • Venlafaxine Hydrochloride
  • Mirtazapine