Comparative risk for harms of second-generation antidepressants : a systematic review and meta-analysis

Drug Saf. 2008;31(10):851-65. doi: 10.2165/00002018-200831100-00004.


Background: Evidence indicates that only minor differences in efficacy exist among second-generation antidepressants for the treatment of major depressive disorder (MDD). However, a comprehensive assessment of both benefits and harms is crucial to evaluate the net benefit.

Objective: To review systematically the comparative harms of second-generation antidepressants for the treatment of MDD in adults by including both experimental and observational evidence.

Data sources: We searched MEDLINE, EMBASE, PsychLit, The Cochrane Library and the International Pharmaceutical Abstracts from 1980 to April 2007. We manually searched reference lists of pertinent review articles and explored the Center for Drug Evaluation and Research database to identify unpublished research.

Study selection: Eligible study designs were trials and observational studies comparing one drug of interest with another.

Data extraction: Two persons independently reviewed abstracts and full-text articles. One investigator extracted relevant data. A senior reviewer checked data for completeness and accuracy.

Data synthesis: We included 104 experimental and observational studies. If data were sufficient, we conducted meta-analyses of randomized controlled trials on the relative risk of specific adverse events. Findings indicate that the spectrum of adverse events is similar. The frequency of specific adverse events, however, differed across drugs. Venlafaxine was associated with a significantly higher rate of nausea and vomiting than selective serotonin reuptake inhibitors. Compared with other drugs, paroxetine frequently led to more sexual adverse effects and bupropion to fewer such effects; mirtazapine and paroxetine was associated with more weight gain and sertraline with a higher rate of diarrhoea. Overall, however, these differences did not lead to different discontinuation rates. The evidence is insufficient to draw conclusions about rare but severe adverse events.

Conclusions: Adverse event profiles are similar among second-generation antidepressants. However, different frequencies of specific adverse events might be clinically relevant and influence the choice of a treatment.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Antidepressive Agents, Second-Generation / adverse effects*
  • Antidepressive Agents, Second-Generation / therapeutic use
  • Blood Pressure / drug effects
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Humans
  • Nausea / chemically induced
  • Risk Assessment / methods
  • Risk Assessment / statistics & numerical data
  • Seizures / chemically induced
  • Sexual Dysfunction, Physiological / etiology
  • Sexual Dysfunctions, Psychological / etiology
  • Treatment Outcome
  • Vomiting / chemically induced


  • Antidepressive Agents, Second-Generation