A new paradigm shift in antidepressant therapy? From dual-action to multitarget-directed ligands.

Overview

Major Depressive Disorder is a chronic, recurring, and potentially fatal disease affecting up to 20% of the global population. Since the monoamine hypothesis was proposed more than 60 years ago, only a few relevant advances have been achieved, with very little disease course changing, from a pharmacological perspective. Moreover, since negative efficacy studies with novel molecules are frequent, many pharmaceutical companies have put new studies on hold. Fortunately, relevant clinical studies are currently being performed, and extensive striving is being developed by universities, research centers, and other public and private institutions. Depression is no longer considered a simple disease but a multifactorial one. New research fields are emerging in what could be a paradigm shift: the multitarget approach beyond monoamines. In this review, we summarize the present and the past of antidepressant drug discovery, with the aim to shed some light on the current state of the art in clinical and preclinical advances to face this increasingly devastating disease.