High placebo response rates have been a major source of difficulty in many neuroscience clinical trials and their effects have been difficult to overcome in developing new compounds. This difficulty has led to high failure rates in mood disorder trials, among others, even in trials with known effective drugs. To address this issue, this talk will offer insights into new enrichment design strategies, as well as approaches to reducing investigator and subject expectation bias. The concepts of enrichment, bias, and adaptation in clinical trials will be discussed. A newly proposed design will be introduced and its benefits examined relative to existing approaches in the literature.