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Major depressive disorder

Abstract

Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective–salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic–pituitary–adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

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Figure 1: Average 12-month prevalence of MDD.
Figure 2: The somatic consequences of MDD.
Figure 3: Biological systems involved in the pathophysiology of MDD.
Figure 4: Model of gene–environment interactions that lead to MDD.
Figure 5: Structural brain alterations in MDD.
Figure 6: Stepped-care model in the management of MDD.
Figure 7: The mechanisms of action of antidepressant drugs.

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Introduction (C.O.); Epidemiology (B.W.P.); Mechanisms/pathophysiology (C.O., S.M.G., B.W.P., C.M.P. and A.E.); Diagnosis, screening and prevention (A.F.S.); Management (M.F. and D.C.M.); Quality of life (S.M.G.); Outlook (C.O. and A.F.S.); Overview of the Primer (C.O.).

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Correspondence to Christian Otte.

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Competing interests

C.O. has received honoraria for lectures from Lundbeck and Servier and for membership in a scientific advisory board from Lundbeck and Neuraxpharm. S.M.G. has received honoraria from Novartis and travel reimbursements from Novartis, Merck Serono and Biogen Idec and has received in-kind research support for conducting clinical trials from GAIA AG, a commercial developer and vendor of health care management and eHealth interventions. B.W.P. has received research funding from Jansen Research and is supported by a VICI grant from the Dutch Scientific Organization. C.M.P. was supported by the National Institute for Health Research Mental Health Biomedical Research Centre in Mental Health at South London, Maudsley NHS Foundation Trust and King's College London, the grants ‘Persistent fatigue induced by interferon-α: A New Immunological Model for Chronic Fatigue Syndrome’ (MR/J002739/1), and ‘Immuno-psychiatry: a consortium to test the opportunity for immunotherapeutics in psychiatry’ (MR/L014815/1) from the Medical Research Council (UK), research funding from the Medical Research Council (UK) and the Wellcome Trust for research on depression and inflammation as part of two large consortia that also include Johnson & Johnson, GSK, Lundbeck and Pfizer, and research funding from Johnson & Johnson as part of a programme of research on depression and inflammation. In addition, C.M.P. has received a speaker's fee from Lundbeck. A.E. has received research funding from Brain Resource, Inc. and honoraria for consulting from Otsuka, Acadia and Takeda. M.F. reports the following research support: Abbot Laboratories; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Cerecor; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; FORUM Pharmaceuticals; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante; Methylation Sciences Inc.; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Coordinating Center for Integrated Medicine (NiiCM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC; PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Takeda Pharmaceuticals; Tal Medical; Wyeth-Ayerst Laboratories; Advisory Board/ Consultant: Abbott Laboratories; Acadia; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; Auspex Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; Biogen and BioMarin Phar. D.C.M. has received honoraria for lectures and for membership in a scientific advisory board from Otsuka. A.F.S. has, since 2015, served as a consultant for Alkermes, Cervel, Clintara, Forum Pharmaceuticals, McKinsey and Company, Myriad Genetics, Neurontics, Naurex, One Carbon, Pfizer, Takeda, Sunovion and X-Hale and as a speaker for Pfizer; he holds equity in Amnestix, Cervel, Corcept (co-founder), Delpor, Gilead Incyte, Merck, Neurocrine, Seattle Genetics, Titan and X-Hale; and he is listed as an inventor on pharmacogenetic and antiglucocorticoid use patents on prediction of antidepressant response.

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Otte, C., Gold, S., Penninx, B. et al. Major depressive disorder. Nat Rev Dis Primers 2, 16065 (2016). https://doi.org/10.1038/nrdp.2016.65

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