title: Controlling for drug dose in systematic review and meta-analysis: a case study of the effect of antidepressant dose.
abstract: OBJECTIVE
  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.
authors.affiliation: School of Pharmacy, Division of Pharmaceutical Outcomes and Policy, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA. rahansen@unc.edu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hansen
authors.forename: Charity G
authors.initials: CG
authors.lastname: Moore
authors.forename: Stacie B
authors.initials: SB
authors.lastname: Dusetzina
authors.forename: Brian I
authors.initials: BI
authors.lastname: Leinwand
authors.forename: Gerald
authors.initials: G
authors.lastname: Gartlehner
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Gaynes
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011569:Psychiatric Status Rating Scales; D016032:Randomized Controlled Trials as Topic
chemical_list: D018687:Antidepressive Agents, Second-Generation