Role of pill-taking, expectation and therapeutic alliance in the placebo response in clinical trials for major depression.

BACKGROUND Pill-taking, expectations and therapeutic alliance may account for much of the benefit of medication and placebo treatment for major depressive disorder (MDD). Aims To examine the effects of medication, placebo and supportive care on treatment outcome, and the relationships of expectations and therapeutic alliance to improvement. METHOD A total of 88 participants were randomised to 8 weeks of treatment with supportive care alone or combined with double-blind treatment with placebo or antidepressant medication. Expectations of medication effectiveness, general treatment effectiveness and therapeutic alliance were measured (trial registration at ClinicalTrials.gov: NCT00200902). RESULTS Medication or placebo plus supportive care were not significantly different but had significantly better outcome than supportive care alone. Therapeutic alliance predicted response to medication and placebo; expectations of medication effectiveness at enrolment predicted only placebo response. CONCLUSIONS Pill treatment yielded better outcome than supportive care alone. Medication expectations uniquely predicted placebo treatment outcome and were formed by time of enrolment, suggesting that they were shaped by prior experiences outside the clinical trial.