A New Paradigm Shift in Antidepressant Therapy: From Dual-action to Multitarget-directed Ligands

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 made, with very little disease course changing from a pharmacological perspective. Moreover, since the negative efficacy of novel molecules is frequently reported in studies, many pharmaceutical companies have put new studies on hold. Fortunately, relevant clinical studies are currently being performed extensively, developing immense interest among 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, occurring a paradigm shift, such as the multi-target approach beyond monoamines. In this review, we summarize antidepressant drug discovery aiming to shed some light on the current state-of-the-art clinical and preclinical advances to face this increasingly devastating disease.