Molecular Psychiatry (2010) 15, 856–867 & 2010 Macmillan Publishers Limited All rights reserved 1359-4184/10 www.nature.com/mp ORIGINAL ARTICLE The importance of irritability as a symptom of major depressive disorder: results from the National Comorbidity Survey Replication M Fava1, I Hwang2, AJ Rush3,4, N Sampson2, EE Walters2 and RC Kessler2 1Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; 2Department of Health Care Policy, Harvard Medical School, Boston, MA, USA; 3Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA and 4Department of Clinical Sciences, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA 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. Molecular Psychiatry (2010) 15, 856–867; doi:10.1038/mp.2009.20; published online 10 March 2009 Keywords: epidemiology; irritability; major depressive disorder; National Comorbidity Survey Replication; adult Introduction fact that irritability is commonly found in clinical samples of adults with MDD.3–5 The clinical literature Clinical studies of depressed children and adoles- also suggests that irritability might be a meaningful cents have shown that the most frequently reported subtyping variable in MDD, with irritable cases more 1,2 symptom in moderate depression is irritability, likely than nonirritable cases to be women, young, which is consistent with the Diagnostic and Statis- unemployed, more severely depressed, lower in tical Manual of Mental Disorders, fourth edition functional status and quality of life, and to have a (DSM-IV) stipulation that irritability is a diagnostic history of at least one suicide attempt.4 These symptom of major depression in children and differences could be of considerable importance, adolescents (that is, it detects subjects not detected because irritability with anger attacks might be by sad mood or loss of interest). However, DSM-IV present in more than one-third of patients with does not include irritability as a symptom of major MDD,6–8 although the robustness of these results is depressive disorder (MDD) among adults, despite the difficult to assess due to the fact that irritability was not assessed consistently in these studies. Correspondence: Dr R Kessler, Department of Health Care Policy, The above results all come from clinical samples. Harvard Medical School, 180 Longwood Ave, Boston, MA 2115, No study, to our knowledge, has investigated the USA. prevalence or correlates of irritability as a symptom of E-mail: [email protected] Received 24 June 2008; revised 27 January 2009; accepted 28 MDD in a general population sample. The current January 2009; published online 10 March 2009 report presents such results from the National Irritability as a symptom of MDD M Fava et al 857 Comorbidity Survey Replication (NCS-R),9 with the the syndrome level. The CIDI assessment of major goal of exploring the importance of irritability as a depressive episode (MDE) asked about symptoms in symptomatic subtyping distinction in a general the worst lifetime episode and included a number of population sample of people with a lifetime history symptoms in addition to those specified in DSM-IV. of MDD. One of these was irritability, which was assessed with a simple yes–no question about whether the respon- dent was ‘irritable, grouchy or in a bad mood’ most Materials and methods every day during the worst 2 weeks of the index Sample episode. In retrospect, the decision to assess irrit- The NCS-R is a nationally representative survey of ability with only a single question was unfortunate, as mental disorders among English-speaking household we could have evaluated the sensitivity of results to residents ages 18 and older in the continental United different definitions if multiple items had been used. States.9 Interviews were conducted with 9282 respon- Furthermore, inclusion of the term ‘bad mood’ in the dents between February 2001 and April 2003. Verbal irritability question might have led to some false informed consent was obtained before data collection. positives, to the extent that respondents interpreted Consent was verbal rather than written to maintain this term to mean a sad mood, but our impression consistency with the baseline NCS.10 The Human from subsequent debriefing interviews is that this was Subjects Committees of Harvard Medical School and not a common interpretation in the context of the the University of Michigan both approved the earlier terms ‘irritable’ and ‘grouchy’. Other symp- recruitment and consent procedures. Respondents toms included in the assessment were euphoria, were paid $50 for participation. The response rate extreme irritability and several other symptoms of was 70.9%. A probability subsample of respondents mania–hypomania that were included to distinguish that oversampled Composite International Diagnostic depressive episodes from mixed episodes. CIDI–SCID Interview (CIDI) cases was administered the lifetime concordance was found to be good for lifetime nonpatient version of the Structured Clinical Inter- diagnoses of MDE (k = 0.59) and excellent for diag- view for DSM-IV (SCID)11 to validate CIDI diagnoses. noses of BP spectrum disorder, including BP-I, BP-II These clinical reappraisal study respondents were and subthreshold BP disorder (k = 0.94). given a $50 incentive. A probability subsample of In addition to diagnosing threshold MDD, the CIDI nonrespondents was administered a brief telephone included an assessment of subthreshold cases, mak- survey and results were used to weight the main ing it possible to calculate how much the estimated sample for nonresponse bias. Nonrespondent survey prevalence of MDD would increase, if irritability participants were given a $100 incentive. could substitute for sad mood if the latter was not The main NCS-R interview was administered in present. Furthermore, in an effort to explore the two parts. Part I included a core diagnostic assess- implications of including irritability as a core symp- ment of all respondents (n = 9282). Part II included tom of MDD (that is, as a symptom that could questions about correlates and additional disorders substitute for the requirement of either sad mood or administered to all Part I respondents who met loss of interest if neither of the latter was present) lifetime criteria for any core disorder plus a roughly among adults rather than only among children and one-in-three probability subsample of other respon- adolescents, a separate assessment of all other dents (n = 5692). A more detailed discussion of NCS-R symptoms of MDD was made for episodes of irrit- sampling and weighting procedures is presented ability in the absence of either depressed mood or loss elsewhere.12 of interest. Respondents who met DSM-IV/CIDI criteria life- Diagnostic assessment time MDD and reported having an episode in the year Diagnoses were based on Version 3.0 of the World before the interview (12-month MDD) were adminis- Health Organization CIDI,13 a fully structured instru- tered the Quick Inventory of Depressive Symptoma- ment designed for use by trained lay interviewers tology Self-Report (QIDS-SR)15 to assess symptom who do not have clinical experience. Diagnoses are severity in the worst month of the past year. The based on DSM-IV criteria.14 Diagnostic hierarchy QIDS-SR is a fully structured measure that is strongly rules were applied in making diagnoses. The core related both to the clinician-administered Inventory disorders assessed in the survey include mood of Depressive Symptomatology (IDS-C)16 and to the disorders (MDD, dysthymia and bipolar (BP) I and II Hamilton Rating Scale of Depression (HRSD).17 disorders), anxiety disorders (panic