Meta-analysis of trials comparing antidepressants with active placebos.
BACKGROUND
Unblinding effects may introduce bias into clinical trials. The use of active placebos to mimic side-effects of medication may therefore produce more rigorous evidence on the efficacy of antidepressants.


METHODS
Trials comparing antidepressants with active placebos were located. A standard measure of effect was calculated for each trial and weighted pooled estimates obtained. Heterogeneity was examined and sensitivity analyses performed. A subgroup analysis of in-patient and out-patient trials was conducted.


RESULTS
Only two of the nine studies examined produced effect sizes which showed a consistent significant difference in favour of the active drug. Combining all studies produced pooled effect size estimates of between 0.41 (0.27-0.56) and 0.46 (0.31-0.60) with high heterogeneity due to one strongly positive trial. Sensitivity analyses excluding this and one other trial reduced the pooled effect to between 0.21 (0.03-0.38) and 0.27 (0.10-0.45).


CONCLUSIONS
Meta-analysis is very sensitive to decisions about exclusions. Previous general meta-analyses have found combined effect sizes in the range 0.4-0.8. The more conservative estimates produced here suggest that unblinding effects may inflate the efficacy of antidepressants in trials using inert placebos.
Moncrieff
J
J
Section of Epidemiology and General Practice, Institute of Psychiatry, London.
Wessely
S
S
Hardy
R
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000627:therapeutic use*; D015982:Bias; D002986:Clinical Trials as Topic / Q000592:standards; D003866:Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012680:Sensitivity and Specificity
D000928:Antidepressive Agents; D010919:Placebos