title: Allowing for non-adherence to treatment in a randomized controlled trial of two antidepressants (citalopram versus reboxetine): an example from the GENPOD trial.
abstract: BACKGROUND
  Meta-analyses suggest that reboxetine may be less effective than other antidepressants. Such comparisons may be biased by lower adherence to reboxetine and subsequent handling of missing outcome data. This study illustrates how to adjust for differential non-adherence and hence derive an unbiased estimate of the efficacy of reboxetine compared with citalopram in primary care patients with depression.
  
  
  METHODS
  A structural mean modelling (SMM) approach was used to generate adherence-adjusted estimates of the efficacy of reboxetine compared with citalopram using GENetic and clinical Predictors Of treatment response in Depression (GENPOD) trial data. Intention-to-treat (ITT) analyses were performed to compare estimates of effectiveness with results from previous meta-analyses.
  
  
  RESULTS
  At 6 weeks, 92% of those randomized to citalopram were still taking their medication, compared with 72% of those randomized to reboxetine. In ITT analysis, there was only weak evidence that those on reboxetine had a slightly worse outcome than those on citalopram [adjusted difference in mean Beck Depression Inventory (BDI) scores: 1.19, 95% confidence interval (CI) -0.52 to 2.90, p = 0.17]. There was no evidence of a difference in efficacy when differential non-adherence was accounted for using the SMM approach for mean BDI (-0.29, 95% CI -3.04 to 2.46, p = 0.84) or the other mental health outcomes.
  
  
  CONCLUSIONS
  There was no evidence of a difference in the efficacy of reboxetine and citalopram when these drugs are taken and tolerated by depressed patients. The SMM approach can be implemented in standard statistical software to adjust for differential non-adherence and generate unbiased estimates of treatment efficacy for comparisons of two (or more) active interventions.
authors: School of Social and Community Medicine,University of Bristol,UK.
authors: N J
authors: NJ
authors: Wiles
authors: Estonian Genome Centre,University of Tartu,Estonia.
authors: K
authors: K
authors: Fischer
authors: Department of Psychiatry,University of Oxford,UK.
authors: P
authors: P
authors: Cowen
authors: Department of Neuropsychopharmacology,Imperial College London,UK.
authors: D
authors: D
authors: Nutt
authors: School of Clinical Sciences,University of Bristol,UK.
authors: T J
authors: TJ
authors: Peters
authors: Mental Health Sciences Unit,University College London,UK.
authors: G
authors: G
authors: Lewis
authors: MRC Biostatistics Unit,Cambridge,UK.
authors: I R
authors: IR
authors: White
mesh_terms: D000328:Adult; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D005260:Female; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D014179:Neurotransmitter Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016032:Randomized Controlled Trials as Topic / Q000592:standards*; D000077593:Reboxetine; D016896:Treatment Outcome
chemical_list: D009025:Morpholines; D014179:Neurotransmitter Uptake Inhibitors; D015283:Citalopram; D000077593:Reboxetine