Benefits and burdens of placebos in psychiatric research.

RATIONALE: The debate over the use of placebos in clinical trials when proven treatments exist continues to be lively, especially in psychiatric research. Current practice permits placebos in such settings, as long as the benefits outweigh the risks and burdens.
OBJECTIVES: To examine in depth the risk-benefit framework typically used to justify placebo controls in psychiatric drug development, by making explicit the implicit ethical tradeoffs.
METHODS: Analysis informed by a review of currently available data on the benefits and burdens of exposing psychiatric research subjects to placebos.
RESULTS: Various risk/burden thresholds for limiting placebo controls have been proposed, ranging from the currently used standards of no increased mortality or permanent morbidity to more recent proposals of 'serious but reversible harm' and 'severe discomfort.' Placebo exposure in antidepressant and antipsychotic trials appears not to increase mortality by suicide. Direct data on long-term effects are lacking. Symptom-related burdens of placebos need to be better quantified and more integrated into the ethical analysis of placebos. While the perspective of those who benefit from the practice of using placebo controls is well represented, virtually no data from the perspective of potential subjects exist.
CONCLUSIONS: The ethical analysis of placebos in psychiatric research has an important but limited evidence base. Suggestions for areas of further inquiry to increase that evidence base are given.