^{1 Exciva GmbH, Heidelberg, Germany. anton.bespalov@exciva.com.
2 Evotec, Göttingen, Germany.
3 Janssen Pharmaceutica, Beerse, Belgium.}

In this article, we explore the challenges in translating preclinical findings into clinical efficacy within neuroscience drug discovery. Disappointments in this area have led us to shift research strategies, moving away from relying too heavily on efficacy claims from preclinical models. Instead, we propose a reverse engineering approach, focusing on pharmacodynamic activity as a common denominator, to improve translation from clinically validated phenomena to preclinical models and back to human applications. By emphasizing research rigor, openness, and transparency, we aim to develop more effective and safe medications for patients in need.