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The importance of irritability as a symptom of major depressive disorder: results from the National Comorbidity Survey Replication


Irritability is a diagnostic symptom of major depressive disorder (MDD) in children and adolescents but not in adults in both the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) and International Classification of Diseases (ICD-10) systems. We explore the importance of irritability for subtyping adult DSM-IV MDD in the National Comorbidity Survey Replication (NCS-R), a national US adult household survey. The WHO Composite International Diagnostic Interview (CIDI) was used to assess prevalence of many DSM-IV disorders in the lifetime and in the year before interview (12-month prevalence). MDD was assessed conventionally (that is, requiring either persistent sadness or loss of interest), but with irritability included as one of the Criterion A symptoms. We also considered the possibility that irritability might be a diagnostic symptom of adult MDD (that is, detect cases who had neither sad mood nor loss of interest). Twelve-month MDD symptom severity was assessed with the Quick Inventory of Depressive Symptomatology and role impairment with the Sheehan Disability Scale. After excluding bipolar spectrum disorders, irritability during depressive episodes was reported by roughly half of respondents with lifetime DSM-IV MDD. Irritability in the absence of either sad mood or loss of interest, in comparison, was rare. Irritability in MDD was associated with early age of onset, lifetime persistence, comorbidity with anxiety and impulse-control disorders, fatigue and self-reproach during episodes, and disability. Irritability was especially common in MDD among respondents in the age range 18–44 and students. Further investigation is warranted of distinct family aggregation, risk factors and treatment response. Consideration should also be given to including irritability as a nondiagnostic symptom of adult MDD in DSM-V and ICD-11.

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The National Comorbidity Survey Replication (NCS-R) was supported by the National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the National Institute of Drug Abuse, the Substance Abuse and Mental Health Services Administration, the Robert Wood Johnson Foundation (Grant No. 044780) and the John W Alden Trust. Collaborating NCS-R investigators include Ronald C Kessler (Principal Investigator, Harvard Medical School), Kathleen Merikangas (Co-principal Investigator, NIMH), James Anthony (Michigan State University), William Eaton (The Johns Hopkins University), Meyer Glantz (NIDA), Doreen Koretz (Harvard University), Jane McLeod (Indiana University), Mark Olfson (Columbia University College of Physicians and Surgeons), Harold Pincus (University of Pittsburgh), Greg Simon (Group Health Cooperative), T Bedirhan Ustun (World Health Organization), Michael Von Korff (Group Health Cooperative), Philip Wang (Harvard Medical School), Kenneth Wells (UCLA), Elaine Wethington (Cornell University) and Hans-Ulrich Wittchen (Max Planck Institute of Psychiatry). The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies or US Government. A complete list of NCS publications and the full text of all NCS-R instruments can be found at Send correspondence to The NCS-R is carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centers for assistance with instrumentation, fieldwork and consultation on data analysis. These activities were supported by the John D and Catherine T MacArthur Foundation, the Pfizer Foundation, the US Public Health Service (R13MH066849, R01-MH069864 and R01 DA016558), Eli Lilly and Company, GlaxoSmithKline, Ortho-McNeil Pharmaceutical Inc. and the Pan American Health Organization. A complete list of WMH publications and instruments can be found at (

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Correspondence to R C Kessler.

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Dr Fava has research support from Abbott Laboratories, Alkermes, Aspect Medical Systems, AstraZeneca, Bristol-Myers Squibb Company, Cephalon, Eli Lilly and Company, Forest Pharmaceuticals Inc., GlaxoSmithKline, Johnson & Johnson Pharmaceuticals, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis, Organon Inc., PamLab LLC, Pfizer Inc., Pharmavite, Roche, Sanofi-Synthelabo, Solvay Pharmaceuticals Inc. and Wyeth-Ayerst Laboratories. He has served as an advisor/consultant for Aspect Medical Systems, AstraZeneca, Bayer AG, Biovail Pharmaceuticals Inc., BrainCells Inc., Bristol-Myers Squibb Company, Cephalon, Comellas, Cypress Pharmaceuticals, DOV Pharmaceuticals, Eli Lilly and Company, EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals Inc., Forest Pharmaceuticals Inc., GlaxoSmithKline, Grunenthal GmbH, Janssen Pharmaceutica, Jazz Pharmaceuticals Inc., Johnson & Johnson Pharmaceuticals, Knoll Pharmacuetical Company, Lundbeck, MedAvante Inc., Merck, Neuronetics, Novartis, Nutrition 21, Organon Inc., PamLab LLC, Pfizer Inc., PharmaStar, Pharmavite, Roche, Sanofi-Synthelabo, Sepracor, Solvay Pharmaceuticals Inc., Somaxon, Somerset Pharmaceuticals and Wyeth-Ayerst Laboratories. He has been on speaker bureaus for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb Company, Cephalon, Eli Lilly and Company, Forest Pharmaceuticals Inc., GlaxoSmithKline, Novartis, Organon Inc., Pfizer Inc., PharmaStar and Wyeth-Ayerst Laboratories. He holds equity in Compellis and MedAvante. Dr Kessler has been a consultant for GlaxoSmithKline Inc., Pfizer Inc., Wyeth-Ayerst, Sanofi-Aventis, Kaiser Permanente and Shire Pharmaceuticals; has served on advisory boards for Eli Lilly and Company and Wyeth-Ayerst; and has had research support for his epidemiological studies from Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Johnson & Johnson Pharmaceuticals, Ortho-McNeil Pharmaceuticals Inc., Pfizer Inc. and Sanofi-Aventis. Dr Rush has provided scientific consultation to or served on Advisory Boards for Advanced Neuromodulation Systems Inc., AstraZeneca, Best Practice Project Management Inc., Bristol-Myers Squibb Company/Otsuka, Cyberonics Inc., Forest Pharmaceuticals, GlaxoSmithKline, Jazz Pharmaceuticals, Eli Lilly and Company, Magellan Health Services, Merck & Co. Inc., Neuronetics, Novartis, Ono Pharmaceutical, Organon Inc., Pamlab Pfizer Inc. and Transcept Pharmaceuticals. He has received royalties from Guilford Press and Healthcare Technology Systems and research/grant support from the National Institute of Mental Health and the Stanley Medical Research Institute; has been on speaker bureaus for Cyberonics Inc., Forest Pharmaceuticals Inc. and GlaxoSmithKline; and owned stock in Pfizer Inc.

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Fava, M., Hwang, I., Rush, A. et al. The importance of irritability as a symptom of major depressive disorder: results from the National Comorbidity Survey Replication. Mol Psychiatry 15, 856–867 (2010).

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  • epidemiology
  • irritability
  • major depressive disorder
  • National Comorbidity Survey Replication
  • adult

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