Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects

Summary As modern research continues to unravel the details of the placebo phenomenon in CNS disorders, uncertainty about therapeutic outcomes in trials of treatments for several neurological conditions is growing. Advances in understanding the mechanisms of different placebo effects have emphasised the substantial challenges inherent in interpreting the results of CNS clinical trials. In the past few years, new mechanisms and concepts have emerged in the study of placebo, nocebo, and Hawthorne effects in CNS clinical trials. For example, the mere step of recruitment in a trial or social interaction among trial participants can change the baseline conditions and therefore affect the interpretation of therapeutic outcomes. Moreover, different genotypes have been shown to respond differently to placebos—eg, in studies of social anxiety, depression, and pain. Increasing recognition of these factors in the general population raises the question of whether attempts should be made to reduce placebo responses in CNS clinical trials. Both clinical trial design and medical practice could benefit from further investigation of these effects across a range of neuropsychiatric disorders.