Controlling for Drug Dose in Systematic Review and Meta-Analysis: A Case Study of the Effect of Antidepressant Dose

Abstract

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.