Controlling for drug dose in systematic review and meta-analysis: a case study of the effect of antidepressant dose

Med Decis Making. 2009 Jan-Feb;29(1):91-103. doi: 10.1177/0272989X08323298. Epub 2009 Jan 13.


Purpose: To describe a method for quantitatively dealing with drug dose in comparative effectiveness reviews. Second-generation antidepressants are used as an example to illustrate this method and to determine whether dose influences conclusions on comparative effectiveness.

Methods: Studies previously identified in a systematic review of second-generation antidepressants were included if data on drug dose were available. The usual dosing range for each drug was defined and then used to create 2- and 3-level dose categories. Placebo-controlled data were used to calculate overall effect sizes for the drug class and effect sizes stratified by drug dose. Meta-regression tested the impact of dose on effect size. Weighted mean differences and risk ratios were calculated for comparative studies, stratifying by whether compared doses were equivalent.

Results: The dose classification method was able to identify dose-response trends in the context of meta-analysis. Compared to low-dose studies, medium- and high-dose studies had a 1- to 2-point greater differential in mean Hamilton Depression Rating Scale (HAM-D) change (P < 0:001). Dose was not a statistically significant predictor of categorical HAM-D response. Among comparative trials with nonequivalent doses, trends favored higher dose categories but generally were not statistically significant.

Conclusions: A structured method for quantitatively dealing with drug dose in comparative effectiveness reviews is described, with application to the second-generation antidepressants. Dose-dependent reductions in HAM-D scores were identified, although differences did not translate into better response rates for higher doses. Dose equivalency was not a significant factor among comparative studies in second-generation antidepressants.

Publication types

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

MeSH terms

  • Antidepressive Agents, Second-Generation / administration & dosage*
  • Dose-Response Relationship, Drug
  • Humans
  • Psychiatric Status Rating Scales
  • Randomized Controlled Trials as Topic


  • Antidepressive Agents, Second-Generation