Send Orders for Reprints to reprints@benthamscience.net Current Medicinal Chemistry, 2021, 28, 1-0 1 0929-8673/21 $65.00+.00 © 2021 Bentham Science Publishers REVIEW ARTICLE Research Domain Criteria (RDoC): A Perspective to Probe the Biolog- ical Background Behind Treatment Efficacy in Depression Marco Calabrò 1 , Chiara Fabbri 2,3 , Siegfried Kasper 4 , Joseph Zohar 5 , Daniel Souery 6 , Stuart Montgomery 7 , Diego Albani 8 , Gianluigi Forloni 8 , Panagiotis Ferentinos 9 , Dan Rujescu 10 , Julien Mendlewicz 11 , Roberto Colombo 12 , Diana De Ronchi 2 , Alessandro Serretti 2,* and Con- cetta Crisafulli 1 1 Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Ita- ly; 2 Department of Biomedical and NeuroMotor Sciences, University of Bologna, Italy; 3 Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom; 4 Department of Psychiatry and Psychotherapy, Medical University Vienna, Aus- tria; 5 Department of Psychiatry, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Israel; 6 Laboratoire de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels; 7 Imperial College School of Medicine, Lon- don, UK; 8 Laboratory of Biology of Neurodegenerative Disorders, Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; 9 Department of Psychiatry, Athens University Medical School, Athens, Greece; 10 University Clinic for Psychiatry, Psychotherapy and Psychosomatic, Martin-Luther-University Halle-Wittenberg, Germany; 11 Universite´ Libre de Bruxelles; 12 Fondazione Poli- clinico Universitario “A. Gemelli” - IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy. ARTICLE HISTORY Received: July 22, 2020 Revised: October 27, 2020 Accepted: November 03, 2020 DOI: 10.2174/0929867328666210104104938 Abstract: Background: Major Depressive Disorder(MDD) and its frequent partial re- sponse to antidepressants are a major health concern and therefore an important focus of research. Despite the efforts, MDD pathogenesis and the mechanisms of antidepressant action are only partially understood. In the last few years, the need of rethinking the clas- sification of depressive disorders and psychiatric disorders, in general, has been suggest- ed, in order to provide a nosology that reflects more closely the biological background as- sociated with disease pathogenesis and its role/significance in treatment. The classifica- tion proposed by the National Institute of Mental Health (NIMH), namely the research do- main criteria (RDoC), may represent a key framework to guide research in this direction. Methods: A literature search was performed on PubMed and Google Scholar databases in order to retrieve data regarding Antidepressants effects on specific RDoC constructs. Further, the targets of drugs of interest were identified through the Drug bank database, and their possible function within RDoC constructs was discussed. Discussion: In this review, we summarize and discuss the significance of the results of pre-clinical and clinical studies investigating specific RDoC paradigms relevant to depres- sive phenotypes and antidepressant effects. Keywords: Research domain criteria, major depressive disorder, antidepressant, behavioral paradigm, RDoC Con- structs, drugs targets. 1. INTRODUCTION Major Depressive Disorder(MDD) is a common and severe mental disorder with relevant consequences * Address correspondence to this author at the Department of Biomedical and NeuroMotor Sciences, University of Bologna, Ita- ly; Tel: +39 0902213371, Fax: +39 090692449; E-mail: alessandro.serretti@unibo.it for society as well as for the affected individual [ 1]. MD D represents a heavy burden for health care sys- tems [2], being responsible for a quarter of psychiatric hospitalizations [3], with high direct and indirect costs [2, 4]. More than 300 million people worldwide suffer from depression, with a variable range of severity. In the most severe cases, MDD can lead to suicide, with a lifetime risk between 3% and 8% [5]. These numbers