Practising evidence-based medicine in an era of high placebo response: number needed to treat reconsidered.

The number needed to treat (NNT) statistic was developed to facilitate the practice of evidence-based medicine. Placebo was assumed to be therapeutically inert when the NNT was originally conceived, but more recent data for conditions such as major depressive disorder (MDD) suggest that the placebo control condition can have considerable therapeutic effects. Complications arise because the NNT calculated from randomised controlled trials (RCTs) reflects a comparison between medication plus clinical management and placebo plus clinical management, whereas, in the clinical setting, physicians choose between prescribing open medication, observing a patient over time with a supportive approach, and doing nothing. Thus, NNTs derived from clinical trials are not directly relevant to clinical decision-making, because they are based on control conditions that do not exist in standard practice. Additional difficulties may arise when using NNTs to compare alternative treatments for MDD, such as medication and psychotherapy, since these comparisons require the control conditions upon which the respective NNTs are based to be similar.Whereas pill placebo conditions include intensive clinical management and elicit expectations of improvement, attention control conditions for psychotherapy research are less well developed. Often the effects of psychotherapy are gauged against a wait-list control condition, which has substantially fewer therapeutic components than a pill placebo control condition. To improve the clinical utility of NNTs for the treatment of MDD, we advocate effectiveness studies that include treatment conditions resembling actual clinical practice, rather than using placebo-controlled RCTs for this purpose. Until such studies are performed, the effect of bias in comparing NNTs across treatments can be controlled by ensuring that the RCT control conditions upon which the NNTs are based are comparable.