ORIGINAL ARTICLE Heterogeneity of DSM-IV Major Depressive Disorder as a Consequence of Subthreshold Bipolarity Petra Zimmermann, PhD; Tanja Brückl, PhD; Agnes Nocon, MSc; Hildegard Pfister, Dipl-Inf; Roselind Lieb, PhD; Hans-Ulrich Wittchen, PhD; Florian Holsboer, MD, PhD; Jules Angst, MD Context: There is growing evidence that major depres- Results: Among 488 respondents with MDD, 286 (58.6%) sive disorder (MDD) might be overdiagnosed at the ex- had pure MDD and 202 (41.4%) had subthreshold BPD pense of bipolar disorder (BPD). (cumulative incidence, 9.3%). Compared with respon- dents who had pure MDD, respondents with subthresh- Objectives: To identify a subgroup of subthreshold BPD old BPD were found to have a significantly increased fam- among DSM-IV MDD, which is distinct from pure MDD ily history of mania, considerably higher rates of nicotine regarding a range of validators of bipolarity, and to ex- dependence and alcohol use disorders, rates of panic dis- amine the pattern of these validators among different order that were twice as high, and a tendency toward higher groups with affective disorders. rates of criminal acts. Prospective analyses showed that sub- threshold BPD converted more often into BPD during fol- low-up, with DSM-IV criterion D (symptoms observable Design: Ten-year prospective longitudinal and family by others) being of critical predictive relevance. With in- study including 3 follow-up waves. Data were assessed creasing severity of the manic component, rates for di- with the DSM-IV Munich Composite International Di- verse validators accordingly increased (eg, alcohol use dis- agnostic Interview. orders, parental mania) or decreased (harm avoidance). Setting: Community sample in Munich, Germany. Conclusions: Data suggest that MDD is a heteroge- neous concept including a large group with subthreshold Participants: A total of 2210 subjects (aged 14-24 years BPD, which is clinically significant and shares similari- at baseline) who completed the third follow-up. ties with BPD. Findings might support the need for a broader concept and a more comprehensive screening of Main Outcome Measures: Cumulative incidence of bipolarity, which could be substantial for future research pure MDD, BPD, and subthreshold BPD (defined as ful- and adequate treatment of patients with bipolarity. filling criteria for MDD plus having manic symptoms but never having met criteria for [hypo]mania). Arch Gen Psychiatry. 2009;66(12):1341-1352 HE DIAGNOSTIC CONCEPT OF manic episode, and they also noted that major depressive disorder some MDD cases might be better reclassi- (MDD) was adopted in the fied as bipolar.13-18 This could particularly DSM-III1 in 1980 and sub- pertain to young adults, when the disor- sequently refined in the der is in its early stages. Additionally, it must Author Affiliations: Molecular DSM-III-R2 and the DSM-IV.3 Since then, be questioned whether the current DSM- Psychology Unit, Max Planck T Institute of Psychiatry, Munich, MDD has been described as the most fre- IV–based instruments are sufficiently sen- 19,20 Germany (Drs Zimmermann, quent mood disorder, with rates up to 16%, sitive for detecting hypomania. Sup- Brückl, Lieb, Wittchen, and and as highly comorbid with anxiety and port comes from epidemiological and Holsboer and Mss Nocon and substance use disorders (SUDs).4-6 In con- clinical studies dealing with wider con- Pfister); Department of trast as shown by large community stud- cepts of bipolarity, which showed that sub- Epidemiology and Health ies, the prevalence of bipolar disorders threshold BPD not recognized with the cur- Psychology, University of Basel, (BPDs) is 2%, considerably lower.7-10 rent DSM-IV criteria is common and Basel, Switzerland (Dr Lieb); However, concerns about the reliabil- clinically significant.8,14,16,21,22 In the Na- Technische Universität Dresden, ity of the hypomania diagnosis were tional Comorbidity Survey Replication, the Institut für Klinische 11,12 Psychologie und Psychotherapie, raised. Several investigators noted that overall prevalence of BPD increased from Dresden, Germany bipolarity might be underdiagnosed by the 2.1% to 4.4% if subthreshold BPD was con- (Dr Wittchen); and Zurich DSM-IV criteria as the diagnosis of bipolar sidered, and the clinical validity of this sub- University Psychiatric Hospital, II disorder (BP-II) requires the presence of threshold group was clearly demonstrated Zurich, Switzerland (Dr Angst). a major depressive episode plus a hypo- in terms of role impairment or comorbid- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 66 (NO. 12), DEC 2009 WWW.ARCHGENPSYCHIATRY.COM 1341 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 ity.8 In the small prospective Zurich Study,14 a stepwise 1.99) and any illegal SUD (OR=1.71; 95% CI, 1.10-2.47), there broadening of the criteria for hypomania allocated almost was no selective attrition between baseline and the third fol- half of the subjects with major depressive episodes to a low-up due to mental syndromes and disorders. broadly defined bipolar group. The frequently reported as- Our investigation is based on the 2210 respondents who com- sociation between alcohol use disorders (AUDs) and MDD pleted the final 10-year follow-up (ie, the third follow-up). The EDSP study was approved by the Ethics Committee of the Medi- disappeared in favor of a high association with BP-II.14,23 19 cal Faculty of the Technische Universität Dresden and the Bay- Benazzi and Akiskal found that 61% of 168 outpatients erische Landesärztekammer Munich. All participants pro- with MDD were classified as bipolar when the strict Struc- vided informed consent. tured Clinical Interview for DSM Disorders criteria for hy- pomania were broadened. DIAGNOSTIC ASSESSMENT Overall, there is still a lack of large-scale epidemio- logical studies that systematically examine the question At each wave participants were interviewed with the computer- of whether DSM-IV MDD might be overdiagnosed at the assisted Munich Composite International Diagnostic Inter- expense of BPD owing to a too restrictive threshold for view (M-CIDI),30 which allows for the standardized assess- DSM-IV hypomania. Taking the considerable burden and ment of symptoms, syndromes, and diagnoses of DSM-IV clinical implications of BPD into account9,10,24-26 as com- disorders along with information about onset, duration, and pared with MDD, the identification of cases with “hid- severity.3 It is supplemented by a respondents’ booklet includ- den” bipolarity might be highly important. ing disorder-specific questionnaires, symptom lists, and cog- Our investigation uses data from the prospective lon- nitive aids. Test-retest reliability and validity have been re- ported elsewhere.31-33 The M-CIDI is highly sensitive for detecting gitudinal Early Developmental Stages of Psychopathol- 32 ogy (EDSP) study and has 3 goals. We examine how many any BPD and MDD (sensitivity, 93%-100%). Clinical inter- viewers, mostly graduated psychologists, who had received the cases previously classified as DSM-IV MDD would be re- standardized M-CIDI training according to the World Health classified as bipolar by broadening the criteria for mania/ Organization protocol carried out face-to-face interviews mainly hypomania and to what degree such subthreshold BPD in the respondents’ homes. All interviewers were regularly su- cases are distinct from pure MDD regarding a broad range pervised. At baseline, lifetime and 12-month disorders were as- of validators that were previously found to differentiate sessed. At the first through third follow-ups, the M-CIDI cov- between BPD and unipolar depression.14,27 Further, we ex- ered the interval since the respective last interview. amine the pattern of these validators among different groups of affective disorders with respect to clinical significance. ASSESSMENT OF MENTAL DISORDERS METHODS Depressive and manic symptoms, syndromes, and disorders were assessed using the DSM-IV M-CIDI sections E (depression) and F (mania). We built 8 mutually exclusive categories. Accord- DESIGN AND SAMPLE ing to the DSM-IV M-CIDI criteria, the spectrum of major mood disorders comprises threshold bipolar I disorder (BP-I), BP-II, Data come from the prospective longitudinal EDSP study28,29 and MDD. To establish a pure depression group, we split MDD comprising a baseline investigation and 3 follow-up waves that into MDD without any manic features (pure MDD) and MDD cover an overall period of about 10 years. The baseline sample with subthreshold hypomania (subthreshold BPD). Subthresh- was drawn randomly from the 1994 government registries of old hypomania means that the person reported a period of at all residents with German nationality aged 14 to 24 years in least 4 days with the following: (1) elated or expansive mood Munich and surrounding counties. The 14- to 15-year-olds were that created troubles or was noticed by others as a change in sampled at twice the probability of the individuals aged 16 to functioning, but DSM-IV hypomania criterion B (meeting the 21 years, and the 22- to 24-year-olds were sampled at half the required minimum number of symptoms) was not fulfilled, or probability of the individuals aged 16 to 21 years. A total of 3021 (2) unusually irritable mood expressed as starting arguments, respondents were interviewed at baseline (response rate, 71.3%), shouting at or hitting people, and having at least 3 manic symp- of whom 36.2% were students at secondary level, 26.4% were toms, but criterion D (symptoms observable by others) was not students at university, and 21.7% were employed. Among the met. Together these syndromes are labeled as the major affec- participants, 62.4% were living with their parents, 22.7% were tive spectrum because in each group DSM-IV criteria for major living alone, and 12.1% were living with their partner or spouse. depressive episodes were fulfilled. The other categories incor- The first follow-up (approximately 20 months after base- porated a subthreshold definition of depressive disorders.