Comparative Safety of Pharmacologic Treatments for Persistent Depressive Disorder: A Systematic Review and Network Meta-Analysis

PLoS One. 2016 May 17;11(5):e0153380. doi: 10.1371/journal.pone.0153380. eCollection 2016.


We aimed to compare the safety of antidepressants for the treatment of persistent depressive disorder (PDD) with each other and with placebo. We conducted a systematic electronic search and included randomized controlled trials that investigated antidepressants for the treatment of PDD in adults. Outcomes were the incidence of experiencing any adverse event, specific adverse events and related treatment discontinuations. We analyzed the data using traditional and network meta-analyses. Thirty-four studies that comprised 4,769 patients and examined 20 individual agents in nine substance classes were included. Almost all analyzed substance classes were associated with higher discontinuation rates than placebo including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), antipsychotics, and the serotonin antagonist and reuptake inhibitor (SARI) trazodone. The odds of experiencing any adverse event were significantly higher for TCAs and serotonin noradrenaline reuptake inhibitors (SNRIs) compared to placebo. Pairwise comparisons among the substance classes revealed that more patients receiving TCAs or SNRIs experienced any adverse event and that more patients receiving TCAs or the SARI trazodone discontinued treatment. The complementary treatment with acetyl-l-carnitine showed lower rates of experiencing any adverse event and related discontinuations than all other comparators. TCAs were primarily associated with (anti-)cholinergic and sedating adverse events. SSRIs primarily showed gastrointestinal adverse events. Patients treated with the antipsychotic amisulpride were more likely to manifest weight gain and endocrine adverse events. The comparative evidence for further agents was insufficient or lacking. The identified safety differences may be used to inform the selection among the antidepressants.

Publication types

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

MeSH terms

  • Antidepressive Agents / adverse effects
  • Antidepressive Agents / therapeutic use*
  • Depression / drug therapy*
  • Humans


  • Antidepressive Agents

Grants and funding

The present study was funded by an internal fund of the University Medical Center Hamburg-Eppendorf ("Forschungsförderungsfond der Medizinischen Fakultät", FFM; grant no. NWF-14/06). The sponsor had no further role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.