Overview Stress and Depression: Preclinical Research and Clinical Implications Alessandro Bartolomucci1*, Rosario Leopardi2* 1 Department of Evolutionary and Functional Biology, University of Parma, Parma, Italy, 2 Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Major depression (MD) is a severe, life- threatening, and highly prevalent psychiat- ric disorder, predicted to soon become one of the major causes of death worldwide. Despite extensive investigations, the exact mechanisms responsible for MD have not been identified. This Overview focuses on the role of stress in depression. It discusses current advancements in biological psychi- atry, neuroscience, and neuroendocrinolo- gy, highlighting key findings presented in the research papers included in the Special Collection ‘‘Stress-Induced Depression and Comorbidities: From Bench to Bedside,’’ published in this issue of PLoS ONE. The Overview encompasses the problematic diagnosis of MD, as well as preclinical evidences linking genetic predisposition, early life events and social factors, imbal- anced HPA axis, molecular pathways within the central nervous system, and metabolic comorbidities with depression- like disorders. It is emphasized how the link between stress and depression can be deeper than previously recognized, follow- ing the description of a potentially common depression subtype, named tentatively ‘‘stress-induced depression’’ (STRID). Due to the inherent biological perspective un- derlying the STRID concept, both preclin- ical and clinical research will be pivotal in clarifying the validity of this new subtype of MD and in improving predictors for treatment response, and will provide a better basis for genetic studies as well as stimulating new drug discovery programs. Introduction Major depression (MD) is a severe, life- threatening, and widespread psychiatric disorder having an incidence of about 340 million cases worldwide. MD ranks fifth among leading causes of global disease burden including developing countries, and by year 2030 it is predicted to represent one of the three leading causes of burden of disease worldwide [1,2]. MD is also a risk factor for cardiovascular and metabolic diseases, and a major risk factor for suicide [3]. Despite extensive investigations, the exact mechanisms responsible for MD have not been identified, and current therapeutics are based on serendipitous discoveries rather than on bench-to-bedside, targeted drug discovery [4]. In addition, although clinically efficient antidepressant drugs do exist, the situation is in many cases far from ideal. Shortcomings such as low remission and/or high treatment-resistance rates, slow onset of action, side effects, and drug–drug interac- tions merit the exploration of all plausible agents that are effective, tolerable, and safe, and that improve maintenance of wellness [5–8]. Accordingly, there is an enormous need for joint experimental efforts between preclinical and clinical scientists. Understanding MD in its etiology and biological phenomenological characteristics could improve its recognition and treat- ment [8–11]. The present Overview high- lights current trends in modern biological psychiatry, neuroscience, and neuroendo- crinology by discussing key aspects present- ed in research papers included in the Special Collection ‘‘Stress-Induced Depression and Comorbidities: From Bench to Bedside,’’ published in this issue of PLoS ONE. The Problematic Diagnosis of Major Depression Presently accepted diagnostic criteria for MD [12] are five (or more) specific symptoms having been present during the same two-week period and representing a change from previous functioning; at least one of the symptoms should be either depressed mood or loss of interest or pleasure. Although their definition fol- lowed rigorous statistical validating criteria and years-long investigations, they are often criticized as being subjective–quali- tative rather than objective–quantitative [13,14]. The current Diagnostic and Statisti- cal Manual (DSM-IV) classification ignores etiology, and distinguishes between bipolar and unipolar conditions, and within the unipolar group between cases with and without melancholia, or with and without psychotic symptoms, as well as atypical depression. In addition, the current diag- nostic criteria represent clusters of symp- toms and characteristics of clinical courses that do not necessarily describe homoge- nous disorders and may rather reflect common final pathways of different path- ological processes [15]. MD is also a highly heterogeneous disease. Subtypes of de- pression may differ not only in etiology and clinical picture, but also in clinical response to medical treatments [15]. However, no past or present classification includes biological criteria except for changes in body weight or sleep parame- ters [16]. Therefore, there is an urgent need for neurological, biological, and genetic data in future DSM classifications [17]. Inclusion of biological diagnostic criteria requires extensive investigation on the biological correlates of MD as well as on the implementation of mechanistic- based investigations. In this respect, A˚s- berg and coworkers [18] and Schu¨ le and coworkers [19] add to the current discus- sion important biological correlates in MD patients. Increased plasma monocyte che- moattractant protein-1 (MCP-1), epider- mal growth factor (EGF), and vascular endothelial growth factor (VEGF) are increased in a population of women under prolonged psychosocial stress and can thus be considered potential biomarkers for screening and early interventions [18]. These data are particularly intriguing because they extend a growing body of evidence linking increased plasma concen- tration of signaling molecules such as Citation: Bartolomucci A, Leopardi R (2009) Stress and Depression: Preclinical Research and Clinical Implications. PLoS ONE 4(1): e4265. doi:10.1371/journal.pone.0004265 Editor: Bernhard Baune, James Cook University, Australia Received December 5, 2008; Accepted January 7, 2009; Published January 30, 2009 Copyright: 2009 Bartolomucci, Leopardi. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: alessandro.bartolomucci@unipr.it (AB); Rosario.Leopardi@ki.se (RL) PLoS ONE | www.plosone.org 1 January 2009 | Volume 4 | Issue 1 | e4265