Third-generation antidepressants: do they offer advantages over the SSRIs?

CNS Drugs. 2001;15(12):941-54. doi: 10.2165/00023210-200115120-00004.


Third-generation antidepressants are a group of antidepressant agents of variable action, not confined to serotonin reuptake inhibition. These agents include venlafaxine, reboxetine, nefazodone and mirtazapine. Claims have been made for these agents in terms of improved efficacy, faster speed of onset of effect and greater safety in the treatment of depression compared with previous medications, such as the selective serotonin reuptake inhibitors (SSRIs). This article reviews the evidence for these improvements. Thirty active comparator studies were reviewed involving the third-generation antidepressant agents. While there were isolated reports of improvements over comparator agents for venlafaxine, reboxetine and mirtazepine, there were no convincing differences between third-generation agents and comparators in terms of overall efficacy, relapse prevention and speed of onset. The third-generation antidepressants were, however, of equivalent safety to SSRIs and maintained improvements in safety over first-generation agents.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antidepressive Agents / adverse effects
  • Antidepressive Agents / pharmacokinetics
  • Antidepressive Agents / therapeutic use*
  • Clinical Trials as Topic
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / prevention & control
  • Humans
  • Secondary Prevention
  • Selective Serotonin Reuptake Inhibitors / adverse effects
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*


  • Antidepressive Agents
  • Serotonin Uptake Inhibitors