Tricyclic antidepressants compared with active placebos for depression

This review examined trials which compared antidepressants with 'active' placebos, that is placebos containing active substances which mimic side effects of antidepressants. Small differences were found in favour of antidepressants in terms of improvements in mood. This suggests that the effects of antidepressants may generally be overestimated and their placebo effects may be underestimated.

Authors' conclusions: 

The more conservative estimates from the present analysis found that differences between antidepressants and active placebos were small. This suggests that unblinding effects may inflate the efficacy of antidepressants in trials using inert placebos. Further research into unblinding is warranted.

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Background: 

Although there is a consensus that antidepressants are effective in depression, placebo effects are also thought to be substantial. Side effects of antidepressants may reveal the identity of medication to participants or investigators and thus may bias the results of conventional trials using inert placebos. Using an 'active' placebo which mimics some of the side effects of antidepressants may help to counteract this potential bias.

Objectives: 

To investigate the efficacy of antidepressants when compared with 'active' placebos.

Search strategy: 

CCDANCTR-Studies and CCDANCTR-References were searched on 12/2/2008. Reference lists from relevant articles and textbooks were searched.

Selection criteria: 

Randomised and quasi randomised controlled trials comparing antidepressants with active placebos in people with depression.

Data collection and analysis: 

Since many different outcome measures were used a standard measure of effect was calculated for each trial. A subgroup analysis of inpatient and outpatient trials was conducted. Two reviewers independently assessed whether each trial met inclusion criteria.

Main results: 

Nine studies involving 751 participants were included. Two of them produced effect sizes which showed a consistent and statistically significant difference in favour of the active drug. Combining all studies produced a pooled estimate of effect of 0.39 standard deviations (confidence interval, 0.24 to 0.54) in favour of the antidepressant measured by improvement in mood. There was high heterogeneity due to one strongly positive trial. Sensitivity analysis omitting this trial reduced the pooled effect to 0.17 (0.00 to 0.34). The pooled effect for inpatient and outpatient trials was highly sensitive to decisions about which combination of data was included but inpatient trials produced the lowest effects.

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