Quality of Evidence Supporting Major Psychotropic Drug-Drug Interaction Warnings: A Systematic Literature Review

Pharmacotherapy. 2020 May;40(5):455-468. doi: 10.1002/phar.2382. Epub 2020 Mar 23.


Among pharmacodynamic and pharmacokinetic drug-drug interactions (DDIs), psychotropic drug-drug interactions (pDDIs) are of particular interest because psychopharmacologic agents mark one of the fastest growing therapeutic drug classes over the past 2 decades, and prescribing multiple psychotropic drugs has become increasingly prevalent in clinical practice. However, the documentation of pDDIs across drug references has lacked consistency. Thus we set out to review the primary evidence directly supporting 58 pDDIs that were uniformly reported as "major" or "contraindicated" in three prominent drug references: Clinical Pharmacology, Micromedex, and Lexicomp. We identified 134 citations from Micromedex in December 2017 and 4251 citations from Medline in March 2018 involving any of the 58 pDDIs. The included articles directly observed a clinical adverse effect or effects on drug plasma concentrations from the concomitant use of the two listed drugs in each pDDI. These articles were classified as controlled studies (e.g., randomized controlled trials, clinical trials, or observational studies) or uncontrolled studies (case reports). A total of 124 studies with 2716 patients were included in this review. Commonly evaluated adverse effects related to the studied pDDIs included decreased effectiveness, central nervous system depression, neurotoxicity, QT-interval prolongation, and serotonin syndrome. Among the 58 pDDIs, 18 (31%) were not supported by any primary studies. Among the remaining 35 pDDIs supported by studies on clinical adverse effects, only 14 (40%) included evidence from controlled study designs. Only 7 (12.1%) of the 58 pDDIs had evidence from studies with a combined sample size of more than 100 patients. This literature review highlights the poor quality of evidence supporting major or contraindicated psychotropic DDI warnings. Most DDIs lacked support from controlled studies that evaluated clinically significant adverse effects, leaving uncertainty about the clinical relevance of the warning. More postmarketing studies are needed to evaluate the safety of psychotropic combination therapy.

Keywords: adverse drug reactions; drug interaction; psychiatry.

Publication types

  • Systematic Review

MeSH terms

  • Drug Interactions
  • Drug Labeling
  • Drug-Related Side Effects and Adverse Reactions
  • Humans
  • Psychotropic Drugs / adverse effects*


  • Psychotropic Drugs