Under-reporting bipolar disorder in large-scale epidemiologic studies

Journal of Affective Disorders 159 (2014) 147–154

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Research report

Under-reporting bipolar disorder in large-scale epidemiologic studies Elie G. Karam a,b,n, Nancy Sampson c, Lynn Itani a, Laura Helena Andrade d, Guilherme Borges e, Wai Tat Chiu c, Silvia Florescu f, Itsuko Horiguchi g, Zahari Zarkov h, Hagop Akiskal i a

Institute for Development, Research, Advocacy and Applied Care (IDRAAC), Beirut, Lebanon Department of Psychiatry and Clinical Psychology, Saint George Hospital University Medical Center, Balamand University, Faculty of Medicine, Beirut, Lebanon c Department of Health Care Policy, Harvard Medical School, Boston, MA, USA d Institute of Psychiatry, University of Sao Paulo Medical School, São Paulo, Brazil e Division of Epidemiological and Psychosocial Research, National Institute of Psychiatry (Mexico) and Metropolitan Autonomous University, Mexico City, Mexico f National School of Public Health, Management and Professional Development, Bucharest, Romania g Faculty of Medicine, Juntendo University, Tokyo, Japan h National Center of Public Health and Analyses, Department Mental Health, Sofia, Bulgaria i International Mood Center, University of California at San Diego, La Jolla, CA, USA b

art ic l e i nf o

a b s t r a c t

Article history: Received 1 October 2013 Received in revised form 31 December 2013 Accepted 16 January 2014 Available online 28 January 2014

Background: To investigate if the prevalence of bipolar disorder in epidemiologic studies is an underestimate, as suggested by clinical studies. Methods: We analyzed data from 8 countries that participated in the World Mental Health Survey Initiative (n ¼47,552). We identified 6.8% and 18.9% of the sample who we think were screened out inappropriately (SCI) from the euphoric and irritable bipolar sections respectively. We compared them to those who were allowed to continue the section (CONT, 2.6% of the sample for euphoric; 1.0% for irritable) and to the reference group (REF, 69.5% of the sample). Results: The SCI group had consistently higher rates of major depression (29.1% vs. 6.4%), earlier age of onset (24.3 y vs. 32.4 y), more suicide attempts (13.3% vs. 5.9%), and more episodes (4.2 vs. 2.7) than the REF for the euphoric group. Similar findings exist for the irritable group. Also, comorbidity with anxiety, disruptive behavior disorders and substance use were much higher than the REF. Limitations: As with all epidemiologic studies, recall bias cannot be ruled out. Conclusions: The findings above suggest that a number of the SCI subjects belong to the bipolar group. A revision of instruments used in epidemiologic research will probably prove what clinical studies have been showing that bipolar disorder is more common than has been reported. & 2014 Elsevier B.V. All rights reserved.

Keywords: Bipolar disorder Diagnosis Composite International Diagnostic Interview

1. Introduction Epidemiologic studies are of major importance not only in shaping policies on national and international levels but also in complementing, inspiring and often directing clinical and basic research. The impact of epidemiology has been essential to define disorders, unravel their etiology, describe their complications and offer insights on various aspects of their treatment, and this is in various environmental and individual settings. What constitutes a

n Correspondence to: Institute for Development Research, Advocacy, and Applied Care (IDRAAC), Department of Psychiatry and Clinical Psychology, Saint George Hospital University Medical Center, Faculty of Medicine, Balamand University, P.O. Box: 166227, Ashrafieh, Beirut 1100 2110, Lebanon. Tel.: þ 961 1 583583; fax: þ961 1 587190. E-mail address: [email protected] (E.G. Karam).

0165-0327/$ - see front matter & 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2014.01.011

mental disorder, although still a challenge in the absence of the more objective data found in other areas of biological sciences, has continued to advance and today relies on what is commonly called “diagnostic criteria”; these have been constantly evolving in the two classificatory systems (DSM and the ICD) since the early work by the Washington University group in the US almost 50 years ago (Feigner et al., 1972). These criteria conceptualize observations and report on behavior, thought, mood and affect. Skills in helping patients and other informants detect and identify symptoms in the clinical setting usually require several years of training. In addition, and not infrequently, diagnosis is modified in the course of the regular re-assessment process inherent in clinical work. By contrast, assessment of mental disorders in large general epidemiologic studies typically relies on information collected from subjects on a single occasion by lay interviewers using fully-structured questions in the absence of informant reports.

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These reports are based on constantly evolving tools, better known as structured interviews (Robins et al., 1988; Kessler and Ustun, 2004). They are regularly evaluated for the reliability and the validity of the gathered data to minimize the differences between the data obtained in the fieldwork and those within the more ideal clinical setting (Wittchen, 1994; Kessler et al., 1998; Haro et al., 2006). The most commonly used structured interviews in epidemiologic studies of bipolar disorders, the DIS (Diagnostic Interview Schedule) (Robins et al., 1988) and the CIDI (Composite International Diagnostic Interview) (Kessler and Ustun., 2004) have been built around the diagnostic criteria of the DSM and the ICD diagnostic systems (Waraich et al., 2004). The questions in the successive versions of the DIS and the CIDI have evolved progressively with the changes in the DSM and ICD classificatory systems. There are a few others such as the SCL90 (Symptom Checklist), which have been designed specifically to the study of bipolar disorders (Angst et al., 2003). A cross-national review of community studies, conducted from the year 1988 to the year 1992, in 6 countries that have used the DIS Version III (using the DSM III criteria) found the lifetime rates of bipolar disorder to range between 0.3% and 1.5% (only respondents with a full manic episode were included) (Weissman et al., 1996). In the United States, the Epidemiological Catchment Area (ECA) study conducted between the years 1980–1985, also using the DISIII, reported the lifetime prevalence rate of bipolar disorder to be 1.3% and 6.4% if “sub-threshold sub-syndromal manic subjects” were included (Judd and Akiskal, 2003). The first wave of the National Comorbidity Survey (NCS), conducted in the USA between 1992 and 1994 (based on the UM-CIDI version which adopts the DSMIIIR criteria) estimated the lifetime prevalence of bipolar disorder to be 1.6% (Kessler et al., 1994). Conducted between 2002 and 2003, the National Comorbidity Survey Replication (NCS-R), using the CIDI Version 3.0 (based on DSM IV criteria), reported the lifetime prevalence of bipolar disorder to be 2.1% and when including sub-threshold cases 4.4% (Merikangas et al., 2007). A crossnational study pooling the data of 11 population-based studies using the same CIDI version 3 and the same methodology as that used in the NCS-R in the context of the World Mental Health Surveys estimated the lifetime prevalence of bipolar disorder to be 1% (ranging from 0% in India to 2.1% in the US) and to be 2.4% if sub-threshold cases were included (Merikangas et al., 2011). Other nationally representative studies in the United States report a range of 3.3% for lifetime bipolar I disorder only (Grant et al., 2005), to 1.6% for any lifetime bipolar disorder (Jonas et al., 2003). Recently several clinical studies in the literature argue that the diagnostic criteria for bipolar disorder in the DSM and ICD systems are too narrow (Angst et al., 2002, 2011; Akiskal and Benazzi, 2005; Akiskal et al., 2003a,b; Hantouche et al., 2003, 2006) and propose changes in these criteria. These studies additionally suggest that bipolar disorder is likely to be under-diagnosed even according to the criteria used in making the diagnoses due to difficulties inherent in assessing core criteria. Retrospective recall failure is one of the issues considered in these discussions and it has been suggested in this regard that recall could be improved by focusing interview questions on “overactive” changes rather than on mood changes (Benazzi and Akiskal, 2009). The efforts to address the problem of under-reporting bipolar disorder in epidemiologic and clinical studies up to now have been largely to include subthreshold cases in the assessment within the larger framework of bipolar spectrum disorders. An additional potential problem is the existence of methodological confounds specific to wording in epidemiologic survey studies (Waraich et al., 2004). To investigate the issue of under-reporting bipolar disorder in epidemiologic surveys, we studied the structure and wording of questions used to diagnose bipolar I and II

disorders in the most recent version of the CIDI, the most commonly used instrument in community epidemiological surveys around the world. The objective of this study was not to examine the DSM criteria for bipolar disorder, but rather to analyze how the questions within the CIDI could have contributed to the possible underestimation of the prevalence of bipolar disorder. We pooled data from eight population surveys from the World Mental Health (WMH) surveys (Kessler and Ustun, 2004) with a combined sample size of 47,552 subjects. Our strategy consisted of identifying problematic questions and looking at their effect on a variety of parameters known to be associated with bipolar disorders. The most obvious were the occurrence and characteristics of Major depression in the false negative bipolar cases. Another was the widely-reported comorbidity of bipolar disorder with other non-mood disorders (Merikangas et al., 2011; Keller, 2006; Strakowski and DelBello, 2000). As subjects with bipolar disorder are also at a higher risk of suicide (Hawton et al., 2005), we also examined CIDI reports of suicidality. The CIDI, as many epidemiologic tools, uses a screening out approach whereby subjects who do not answer positively to a question or set of questions skip the remainder of the specific section they have reached during the interview. We consequently analyzed the seven skip-out/gate questions in the bipolarity section and identified five questions the wording of which includes problems that could lead to the potential inappropriate exclusion of respondents from the diagnosis of bipolarity (false negatives). The inappropriate exclusions vary from including too many symptoms in a single question to negative connotations that are not included in the DSM criteria (Appendix A). The WMH survey samples were thus divided into three mutually exclusive groups based on this evaluation of the skip out/gate questions of the CIDI: 1. The “Reference” (REF) group: it consists of respondents who responded with “No” to all diagnostic stem questions and is most likely free of bipolar disorder. 2. The “Screened Out Inappropriately” (SCI) group: it consists of all respondents who were skipped out by the problematic skip out/gate questions. 3. The “Continued” (CONT) group: it consists of respondents who were not skipped out of the mania/hypomania section, and thus completed the whole section. The algorithms designed to diagnose bipolar I or II in the CIDI draw only on the CONT group. We then compared the problematic group (SCI) to the REF (and CONT) groups based on outcome measures known to be associated with bipolar disorder. We looked at the co-occurrence and profile of Major Depression (occurrence, age of onset, recurrence, symptoms including suicidality) as well as anxiety, substance and disruptive behavior disorders. Our hypothesis is that the SCI subjects, when compared against these parameters, are different from the REF groups and that those differences are in the direction of those that continued the mania section (CONT).

2. Methods 2.1. Samples The eight population-based surveys considered here were carried out in the Americas (Brazil, Mexico, and the United States), Asia (Japan), Europe (Bulgaria and Romania), the Middle East (Lebanon), and the Pacific (New Zealand). A total of 47,552 adult respondents were interviewed, with within-country sample sizes ranging from 2357 (Romania) to 12,790 (New Zealand). The respondents were household residents 18 years or older (16 þ in

E.G. Karam et al. / Journal of Affective Disorders 159 (2014) 147–154

New Zealand and 20 þ in Japan). The response rates ranged from 55.1% (Japan) to 81.3% (Brazil) (Table 1). All the samples were stratified multistage clustered probability samples, with the exception of Japan (unclustered two-stage probability sample). All interviews were conducted face-to-face by trained lay interviewers that received the same standardized WMH training. 2.2. Training and field procedures For each country, the WMH staff trained survey supervisors who were fluent in English and their local language according to a standardized World Health Organization (WHO) CIDI training protocol. The CIDI instrument and the interviewer training material were translated into the official language of each country according to the standard WHO translation, back-translation, and harmonization protocol (Kessler and Ustun, 2008; Harkness et al., 2008). Persons who could not speak this language were excluded. Quality control protocols, described in a more detailed manner elsewhere (Merikangas et al., 2011), were implemented to check on interviewers’ accuracy and to specify data cleaning and coding procedures. In each country, the institutional review board of the organization that coordinated the survey approved and monitored compliance with procedures for obtaining informed consent and protecting human subjects. 2.3. Measures All surveys used CIDI Version 3.0, a fully-structured diagnostic interview. Disorders were evaluated according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV). Part I of the CIDI assesses core disorders, whereas Part 2 includes information about correlates and other disorders. All respondents in all surveys completed Part 1, and all the results reported are from the Part I samples, unless otherwise noted. Respondents meeting the criteria for any core disorder as well as an approximate 25% of other respondents were then administered in Part 2.

149

The Part 2 sample included a total of 25,611 respondents. Noncertainty selections in Part 2 were weighted by the reciprocal of their probability of selection to adjust for their under-sampling. The Part 2 sample was also weighed to adjust for the probability of selection and differential nonresponse and post-stratified to approximate the general population distribution of the country on a range of demographic and geographic variables. The disorders considered here include anxiety disorders (panic disorder, social phobia, post-traumatic stress disorder, generalized anxiety disorder, specific phobia, agoraphobia, separation anxiety disorder, and adult separation anxiety disorder), disruptive behavior disorders (intermittent explosive disorder, conduct disorder, and attentiondeficit/hyperactivity disorder), substance dependence (alcohol dependence, and drug dependence), substance abuse (alcohol abuse, and drug abuse), and major depressive episode (MDE). Age of onset, recurrence, and symptoms of MDE including suicidality (ideation, plans and attempts) were also assessed. 2.4. Creation of “Groups of Comparison” The CIDI assessment of mania/hypomania starts with screener questions administered in a special screening section (SC) of the interview. Respondents who endorse one or more of the two diagnostic stem questions in the SC section are then assessed for symptoms of mania/hypomania in a later section of the interview. Additional gating questions in the mania/hypomania section also skip respondents out of subsequent questions in the section. A respondent who is screened out at any point in the section will not complete the diagnostic assessment for mania/hypomania and thus will not be considered by the diagnostic algorithms as meeting criteria for mania/hypomania or bipolar disorder. The gate/skip-out questions are presented in their entirety in Appendix A. The problems detected in these questions include citing symptoms other than “mood”, requiring symptoms that last “several days or longer”, including too many symptoms, stating examples not found in the DSM criteria, and using negative

Table 1 WMH sample characteristics. Country

Surveya

Brazil – São Paulo Bulgaria Japan Lebanon Mexico

São PauloMegacity NSHS WMHJ2002–2006 L.E.B.A.N.O.N M-NCS

New Zealande Romania The United States

NZMHS RMHS NCS-R

IV. Total a

Sample characteristicsb

São Paulo metropolitan area Nationally representative Eleven metropolitan areas Nationally representative All urban areas of the country (approximately 75% of the total national population) Nationally representative Nationally representative Nationally representative

Field dates

Age range

Response rated

Sample size Part 1

Part 2

Part 2 and age r 44c

2005–7 2003–7 2002–6 2002–3 2001–2

18–93 18–98 20–98 18–94 18–65

5037 5318 4129 2857 5782

2942 2233 1682 1031 2362

– 741 – 602 1736

81.3 72.0 55.1 70.0 76.6

2003–4 2005–6 2002–3

18–98 18–96 18–99

12,790 2357 9282

7312 2357 5692

– – 3197

73.3 70.9 70.9

47,552

25,611

6276

71.4

NSHS (Bulgaria National Survey of Health and Stress); WMHJ2002–2006 (World Mental Health Japan Survey); L.E.B.A.N.O.N (Lebanese Evaluation of the Burden of Ailments and Needs of the Nation); M-NCS (The Mexico National Comorbidity Survey); NZMHS (New Zealand Mental Health Survey); RMHS (Romania Mental Health Survey); NCS-R (The US National Comorbidity Survey Replication). b Most WMH surveys are based on stratified multistage clustered area probability household samples in which samples of areas equivalent to counties or municipalities in the US were selected in the first stage followed by one or more subsequent stages of geographic sampling (e.g., towns within counties, blocks within towns, households within blocks) to arrive at a sample of households, in each of which a listing of household members was created and one or two people were selected from this listing to be interviewed. No substitution was allowed when the originally sampled household resident could not be interviewed. The Japanese sample is the only totally un-clustered sample, with households randomly selected in each of the 11 metropolitan areas and one random respondent selected in each sample household. 5 of the 8 surveys are based on nationally representative household samples. c Brazil, Japan, New Zealand, and Romania did not have an age restricted Part 2 sample. All other countries were age restricted to r44. d The response rate is calculated as the ratio of the number of households in which an interview was completed to the number of households originally sampled, excluding from the denominator households known not to be eligible either because of being vacant at the time of initial contact or because the residents were unable to speak the designated languages of the survey. The weighted average response rate is 71.4%. e For the purposes of cross-national comparisons, we limit the sample to those 18 þ.

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wording such as “inappropriate” and “interference,” which are not part of the bipolar II definition. Based on our assessment of these problems, the following comparison groups were created for both euphoric and irritable mania (Appendix B1 and B2). 1. The “Reference” (REF) group consists of subjects who answered “No” to both CIDI screening questions about euphoria and irritability. 2. The “Screened Out Inappropriately” (SCI) group consists of respondents who have been screened out by the problematic gate/skip-out questions. 3. The “Continued” (CONT) group consists of respondents administered the entire mania/hypomania section. As noted above, it was only among the respondents in this group that the CIDI diagnostic algorithms can classify respondents as being bipolar or not. Approximately 35% of the CONT group was classified as meeting lifetime criteria for bipolar I or II disorder.

2.5. Analysis methods The SCI group was compared to the REF and the CONT according to the following outcomes: lifetime prevalence of MDE and other features of MDE usually associated with bipolarity (types of symptoms, age of onset, recurrence, suicide attempts), and comorbidity with anxiety, disruptive behavior, and substance use disorders. Analyses were conducted using SAS version 9.3 and SUDAAN 10.0.1 statistical software. The χ2 test was used for categorical variables (presence of disorders and MDE symptoms), whereas the t-test was used for continuous variables (mean age of onset of MDE and mean number of episodes). The REF group was compared to both the SCI and CONT groups, then the SCI group was compared to the CONT group. Statistical significance was consistently evaluated using 0.05-level two-sided tests.

3. Results 3.1. Characteristics of the “Groups of Comparison” 3.1.1. Total prevalence In the pooled data, the REF group represents 69.5% of the total sample (range: 61.4% in the US to 88.4% in Bulgaria), the SCI groups comprised 25.6% of the total sample (range: 10.9% in Bulgaria to 33.6% in Brazil). The subgroups of the SCI were as follows: 6.8% for euphoric SCI (range: 0.9% in Japan to 10.2% in both New Zealand and US) and 18.9% for irritable SCI (range: 9.6% in Bulgaria to 32.5% in Brazil). The total CONT comprised 3.6% of the sample (range: 0.4% in Bulgaria to 5.8% in the US). The subgroups of the CONT were as follows: 2.6% of the sample for euphoric CONT (range: 0.3% in Bulgaria to 4.5% in US) and 1.0% for irritable CONT (range: 0.2% in Bulgaria to 2.3% in Brazil) (Table 2).

3.1.2. Gender Males represent 47.8% of the total pooled sample (range: 47.0% in Brazil to 49.5% in Lebanon), 48.9% of the REF group (range: 47.9% in New Zealand to 51.5% in Brazil), 44.5% of the total SCI group (range: 39.5% in Brazil to 47.0% in New Zealand) and more specifically 52.2% of the euphoric SCI (range: 35.0% in Japan to 55.0% in Romania), and 41.8% of the irritable SCI (range: 36.5% in Mexico to 45.1% in New Zealand). Males comprised 49.9% of the total CONT (range: 38.8% in Japan to 56.4% in Lebanon) and more specifically 51.6% of the euphoric CONT (range: 42.8% in Japan to 65.1% in Mexico) and 45.7% of the irritable CONT (range: 30.6% in Mexico to 53.0% in New Zealand) (Table 2). 3.1.3. Age The mean age of the total pooled sample is 43.6 years. For the euphoric mania stem questions group, the mean age was highest for the REF group (45.3 y, range: 35.9 y in Mexico to 52.5 y in the Japan), then the SCI (37.4 y, range: 30.7 y in Mexico to 49.5 y in Japan) followed by the CONT (35.6 y, range: 27.9 y in Lebanon to 42.3 y in Japan). For the irritable mania stem questions group, the mean age is also highest for the REF group, followed by the SCI (41.1 y, range: 35.0 in Mexico to 49.0 in Bulgaria) and the CONT(36.0 y, range: 28.4 y in Mexico to 49.0 y in Romania). The mean age of the total SCI group is 40.1 y (range: 33.6 y in Mexico to 48.0 y in Bulgaria) and for the total CONT group is 35.8 y (range: 28.6 y in Lebanon to 41.7 y in Romania). Country specific data are available upon request (Table 2). 3.2. MDE and its characteristics 3.2.1. Prevalence of major depression In the pooled data, the SCI groups have significantly higher rates of MDE (euphoric: 29.1% and irritable: 26.0%) than the REF (6.4%, p o0.001). This is the same for all the countries. In turn, the SCI groups have significantly lower rates of MDE than the CONT (euphoric: 48.6%, irritable: 51.3%) (p o0.001). The ratio of the prevalence of MDE in the SCI vs. REF groups is 4.5 (range: 2.3–8.7) for euphoric, and 4.1 (range: 2.9–6.7) for irritable. By contrast, the ratio of MDE in CONT vs. SCI groups is 1.7 (range: 1.4–3.0) for euphoric, and 2.0 (range: 0.9–2.7) for irritable (Table 3). 3.2.2. Age of onset In the pooled data, the subset of respondents in the SCI groups who have a lifetime history of DSM-IV/CIDI MDE have a significantly lower mean age of onset (AOO) of MDE (euphoric: 24.3 y and irritable: 27.5 y) than the REF (32.4 y, po0.001). In turn, the SCI groups have a significantly higher mean AOO of MDE than the CONT (euphoric: 21.5 y, irritable: 22.9 y, po0.001). Individual countries had varying results (data available upon request)(Table 3). 3.2.3. Recurrence In the pooled data, the subset of respondents in the SCI groups who have a lifetime history of DSM-IV/CIDI MDE have a significantly higher mean number of MDE episodes (euphoric: 4.2 and irritable: 3.7) than the REF (2.7, p o0.001). In turn, the SCI groups have a lower mean number of episodes of MDE than the CONT

Table 2 Percentage of the subgroups (Reference, Screened Out Inappropriately and Continued) from the total sample, their gender composition, and mean age (n ¼47,552). Total sample

% of total sample (n) % Males (se) Mean age (se)

100.0 (47,552) 47.8 (0.3) 43.6 (0.1)

REF

69.5 (32,980) 48.9 (0.3) 45.3 (0.1)

Euphoric

Irritable

SCI

CONT

SCI

CONT

6.8 (3284) 52.2 (1.0) 37.4 (0.4)

2.6 (1291) 51.6 (1.7) 35.6 (0.5)

18.9 (8914) 41.8 (0.7) 41.1 (0.2)

1.0 (532) 45.7 (2.7) 36.0 (0.7)

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Table 3 Comparison of groups based on MDE and its characteristics (total n with lifetime MDE ¼6690). MDE and characteristics

REF Mean (se)

Euphoric

Irritable

SCI Mean (se)

CONT Mean (se)

SCI Mean (se)

CONT Mean (se)

Age of onset Mean number of lifetime episodesa

32.4 (0.4) 2.7 (0.1)

24.3 (0.5)n 4.2 (0.2)n

21.5 (0.5)n,nn 6.7 (0.4)n,nn

27.5 (0.4)n 3.7 (0.2)n

22.9 (0.9)n,nn 4.6 (0.4)n,nn

% with Major Depressive Episodeb Suicide attempt Feeling irritable, grouchy, or in bad mood Feeling restless or jittery

% (se) 6.4 (0.2) 5.9 (0.6) 36.6 (1.3) 14.3 (1.0)

% (se) 29.1 (0.9) n 13.3 (1.4)n 69.2 (2.0)n 17.7 (1.5)n

% (se) 48.6 (1.7)n,nn 24.8 (2.2)n,nn 78.0 (2.1)n,nn 21.7 (1.9)n†

% (se) 26.0 (0.6)n 8.8 (0.8)n 71.4 (1.1)n 14.9 (0.8)

% (se) 51.3 (3.2)n,nn 22.7 (2.9)n,nn 89.0 (2.1)n,nn 22.4 (3.2)n,nn

n

Significantly different from REF (po 0.05). Significantly different from SCI (p o 0.05). † Borderline significantly different from the SCI group (p ¼ 0.06). a Excluding outliers ( Z 50 episodes). b While all other rows in this table are among the subset of those with lifetime MDE, this row is among the total population (n¼ 47,552). nn

Table 4 Comparison of groups based on disorders (anxiety, disruptive behavior, substance use and dependence). Disorder

REF % (se)

Euphoric SCI % (se)

Panic Disorder Social Phobia Post-traumatic Stress Disordera Generalized Anxiety Disorder Any Anxiety Disorder‡,a Intermittent Explosive Disorderb Conduct Disorderc Attention Deficit Disorderd

Irritable CONT % (se)

SCI % (se)

CONT % (se)

1.0 3.1 2.1 2.1

(0.1) (0.1) (0.1) (0.1)

5.4 14.4 8.4 11.4

(0.4)n (0.7)n (0.7)n (0.7)n

12.7 29.6 19.1 21.9

(1.2)n,nn (1.2)n,nn (1.4)n,nn (1.4)n,nn

3.6 10.4 6.9 9.7

(0.2)n (0.2)n (0.4)n (0.3)n

8.0 23.1 20.6 20.5

(1.2)n,nn (2.6)n,nn (2.2)n,nn (2.3)n,nn

12.8 1.6 1.5 1.2

(0.4) (0.1) (0.2) (0.2)

38.8 11.7 7.6 7.3

(1.4)n (0.8)n (0.9)n (0.7)n

60.1 23.6 18.9 24.4

(1.8)n,nn (2.1)n,nn (2.0)n,nn (2.4)n,nn

36.0 8.2 3.8 4.0

(0.8)n (0.5)n (0.4)n (0.4)n

65.3 23.5 14.4 12.2

(2.7)n,nn (3.4)n,nn (2.6)n,nn (2.7)n,nn

Any Disruptive BehaviorDisordere Alcohol dependencef Drug dependenceg

3.1 (0.2) 1.5 (0.1) 0.5 (0.1)

19.1 (1.3)n 7.7 (0.6)n 4.4 (0.6)n

Any Substance Dependenceg Alcohol abusef Drug abuseg Any Substance Abuseg

2.0 5.4 1.8 6.4

10.0 18.0 9.3 20.6

(0.1) (0.2) (0.1) (0.2)

(0.8)n (0.9)n (0.7)n (0.9)n

41.5 (2.7)n,nn 18.9 (1.3)n,nn 13.1 (1.3)n,nn 22.8 35.2 21.2 38.4

(1.5)n,nn (1.8)n,nn (1.6)n,nn (1.9)n,nn

12.8 (0.7)n 4.0 (0.3)n 1.8 (0.2)n 5.2 11.0 4.9 13.0

(0.4)n (0.5)n (0.3)n (0.6)n

35.4 (4.5)n,nn 15.3 (2.2)n,nn 9.0 (1.8)n,nn 19.9 31.5 14.9 34.3

(2.4)n,nn (2.5)n,nn (2.1)n,nn (2.6)n,nn

n

Significantly different from REF (po 0.05). Significantly different from SCI (p o 0.05). Includes panic disorder, social phobia, post-traumatic stress disorder, generalized anxiety disorder, specific phobia, agoraphobia, separation anxiety disorder, and adult separation anxiety. a Except for Romania which used Part 1, Part 2 was used for others. b Excluded Mexico and New Zealand since disorder was not assessed. c Excluded Japan and New Zealand since disorder was not assessed. Except for Brazil and Romania, which used Part 1, others were restricted to those who are less than 44 years old in Part 2. d Excluded Bulgaria, Japan and New Zealand since disorder was not assessed. Except for Brazil and Romania, which used Part 1, others were restricted to those who are less than 44 years old in Part 2. e Excluded New Zealand since disorder was not assessed. Except for Brazil, Romania and Japan which used Part 1, others were restricted to those r 44. f Except for Japan and the United States which used Part 2, Part 1 was used for others. g Except for Bulgaria, Lebanon, Japan and the United States which used Part 2, Part 1 was used for others. nn

‡

(euphoric: 6.7, irritable: 4.6) (p o0.001 for euphoric, and p ¼0.045 for irritable). Individual countries had varying results (data available upon request) (Table 3).

3.2.4. Suicide attempt In the pooled data of respondents with a lifetime history of DSM-IV/CIDI MDE, the SCI groups have significantly higher rates of suicide attempt (euphoric: 13.3% and irritable: 8.8%) than the REF (5.9%) – (p o0.001 for euphoric, p¼ 0.009 for irritable). In turn, the SCI groups with lifetime MDE have significantly lower rates of suicide attempt than the CONT (euphoric: 24.8%, irritable: 22.7%) (p o0.001) (Table 3).

3.2.5. MDE symptoms In the pooled data with a lifetime history of DSM-IV/CIDI MDE, the SCI group had significantly higher rates than the REF for “feeling irritable/grouchy/in a bad mood”, and “feeling restless and jittery” (for euphoric only). Low energy too was different in the irritable (REF¼82.9%, SCI ¼87.3%). Individual countries, however also had significantly more of the following symptoms in the euphoric SCI group than the REF: “having more energy than usual” in 2 countries (Bulgaria and New Zealand), “thoughts jumping or racing through the head” in 2 countries (Brazil and Japan), “sleeping more than usual” in 3 countries (Japan, Lebanon and Mexico) and “sleeping less than usual” in 1 country (New Zealand). For the irritable type, the following symptoms were higher in the

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SCI group than in the REF: “having more energy than usual” in 2 countries (Bulgaria and Mexico), “sleeping more than usual” in 2 countries (Lebanon and Romania) and “sleeping less than usual” in 1 country (the US) (Table 3). 3.3. Co-morbid disorders 3.3.1. Anxiety disorders As a class, anxiety disorders were significantly more prevalent in the SCI (euphoric 38.8%, range: 12.3% in Romania to 51.2% in Brazil; and irritable 36.0%, range: 18.5% in Romania to 45.4% in the US) than the REF groups (12.8%, range: 3.0% in Romania to 19.1% in the US) – (p o0.001). On the other hand, the prevalence of any anxiety disorder in the SCI groups was significantly lower than that in the CONT (euphoric: 60.1%, range: 31.3% in Bulgaria to 73.5% in the US; and irritable: 65.3%, range: 34.4% in Romania to 77.4% in the US). The same trends described above exist for all anxiety disorders studied including: panic disorder (REF: 1.0%; euphoric SCI: 5.4%; euphoric CONT: 12.7%; irritable SCI: 3.6%; irritable CONT: 8.0%), social phobia (REF: 3.1%; euphoric SCI: 14.4%; euphoric CONT: 29.6%; irritable SCI: 10.4%; irritable CONT: 23.1%), PTSD (REF: 2.1%; euphoric SCI: 8.4%; euphoric CONT: 19.1%; irritable SCI: 6.9%; irritable CONT: 20.6%), and GAD (REF: 2.1%; euphoric SCI: 11.4%; euphoric CONT: 21.9%; irritable SCI: 9.7%; irritable CONT: 20.5%) (Table 4). This was true for most individual countries across most anxiety disorders, with some variations (data available upon request).

3.3.2. Disruptive behavior disorders Disruptive behavior disorders were significantly more prevalent in the SCI (euphoric 19.1%, range: 2.2% in Japan to 32.0% in the US; and irritable 12.8%, range: 1.7% in Bulgaria to 27.2% in the US) than the REF groups (3.1%, range: 0.7% in Romania to 11.6% in the US) – (p o0.001). On the other hand, the prevalence of any disruptive behavior disorder was significantly lower than in the CONT (euphoric: 41.5%, range: 6.1% in Japan to 58.8% in the US; and irritable: 35.4%, range: 0.0% in Bulgaria to 55.9% in the US). The same trends described above exist for all disruptive behavior disorders studied including: intermittent explosive disorder (REF: 1.6%; euphoric SCI: 11.7%; euphoric CONT: 23.6%; irritable SCI: 8.2%; irritable CONT: 23.5%), conduct disorder (REF: 1.5%; euphoric SCI: 7.6%; euphoric CONT: 18.9%; irritable SCI: 3.8%; irritable CONT: 14.4%), and attention deficit disorder (REF: 1.2%; euphoric SCI: 7.3%; euphoric CONT: 24.4%; irritable SCI: 4.0%; irritable CONT: 12.2%) (Table 4). This was true for most individual countries across most disruptive behavior disorders, with some variations (data available upon request).

3.3.3. Substance disorders “Any substance dependence” was significantly more prevalent in the SCI (euphoric 10.0%, range: 0.9% in Bulgaria to 21.4% in Brazil; and irritable 5.2%, range: 0.5% in Lebanon to 7.5% in the US) than the REF groups (2.0%, range: 0.1% in Lebanon to 3.0% in the US) – (po0.001). On the other hand, the prevalence of “any substance dependence” was significantly lower in the SCI than that in the CONT (euphoric:22.8%, range: 0.0% in Japan to 30.4% in Brazil; and irritable: 19.9%, range: 0.0% in Bulgaria/Lebanon/ Romania to 26.3% in the US). The same trends described above exist for: alcohol dependence (REF: 1.5%; euphoric SCI: 7.7%; euphoric CONT: 18.9%; irritable SCI: 4.0%; irritable CONT: 15.3%), and drug dependence (REF: 0.5%; euphoric SCI: 4.4%; euphoric CONT: 13.1%; irritable SCI: 1.8%; irritable CONT: 9.0%) (Table 4). This was true for most individual countries, with some variations (data available upon request).

“Any substance abuse” was significantly more prevalent in the SCI (euphoric 20.6%, range: 6.1% in Lebanon to 39.4% in Brazil; and irritable 13.0%, range: 0.5% in Lebanon to 17.5% in the US) than the REF groups (6.4%, range: 1.8% in Lebanon to 8.6% in the US) – (p o0.001). The prevalence of “any substance abuse” was significantly lower than the SCI in the CONT (euphoric: 38.4%, range: 7.5% in Romania to 54.5% in Brazil; and irritable: 34.3%, range: 0.0% in Bulgaria/Lebanon to 43.1% in the US). The same trends described above exist for: alcohol abuse (REF: 5.4%; euphoric SCI: 18.0%; euphoric CONT: 35.2%; irritable SCI: 11.0%; irritable CONT: 31.5%), and drug abuse (REF: 1.8%; euphoric SCI: 9.3%; euphoric CONT: 21.2%; irritable SCI: 4.9%; irritable CONT: 14.9%) (Table 4). This was true for most individual countries, with some variations (data available upon request).

4. Discussion The results of this study should be interpreted in view of some limitations. First, the present surveys vary across countries in response rates, and sample frames. Second, inspite of the rigorous training of lay interviewers that enhances reliability and the intensive supervision of field work, we cannot rule out variability in eliciting information across countries. Third, the reporting of the onset and the occurrence of past symptoms could be subject to recall bias not only for bipolar disorder but also for MDE, anxiety, and other mental disorders. Fourth, symptoms of mental disorders specifically related to mania/hypomania and suicide might have been under-reported to lay interviewers, and this might in turn vary across countries. Fifth, institutionalized respondents were not included in the studies. Notwithstanding these limitations, the World Mental Health Surveys offer the field of epidemiology a valuable source for the assessment of bipolar disorder around the world, by using the same instrument, the CIDI, on a uniquely large number of subjects (47,552) with uniform training and supervision procedures (Demyttenaere et al., 2004). Many studies strongly suggest that bipolar disorder is underdiagnosed (Angst et al., 2002, 2011; Akiskal and Benazzi, 2005). Two reasons for this purported under-diagnosis are cited in these studies: the first is the set of criteria used for the diagnosis of bipolarity, the second is the method used to establish such a diagnosis. We address, in this study, the second possibility. All experienced clinicians would agree that the diagnosis of bipolar disorder, especially hypomania, is not always easy to elicit and might need careful and repeated interviewing as well as calling on other informants (spouse and relatives) (Carta and Angst, 2005). These difficulties are a challenge in the field of epidemiology where lay interviewers collect data through questionnaires, from one source, in one session and have to follow the letter of the questions, to ensure uniformity and reliability. We have reviewed here the data collected through the CIDI in the World Mental Health (WMH) surveys. The lifetime diagnosis of bipolarity (I and II) varied across the 8 countries used for this analysis from 0 to 2.1%. A more obvious and direct way of assessing the limitations of a fully-structured interview like the CIDI than the method used in this report would be to compare concordance of diagnoses with those obtained in blinded clinical reappraisal interviews. Tests of this sort have shown that the CIDI assessment of DSM-IV bipolar disorder has excellent concordance with diagnoses based on blinded clinical reappraisal interviews with the SCID (Haro et al., 2006). However, the SCID, like the CIDI, is an interview, albeit one delivered by more experienced clinicians rather than the lay interviewers used to administer the CIDI. Questions can be raised about the appropriateness of the questions used in the SCID to assess bipolar disorder. We initiated suggestions to the authors of the SCID, who were themselves eager to take those into

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consideration and in fact brought changes to the SCID bipolar section; link: http://www.scid4.org/revisions/nov11.html. The changes we suggested did not address the criteria but the wording of the questions, which had focused on the negative aspects of hypomania, and thus clearly would under-diagnose bipolar II disorders. Additional suggestions had been made by one of us (H.S.A) to focus stem questions on changes in energy (overactivity) rather than mood when evaluating hypomania. As a result of the problems in the SCID prior to these changes, the fact that prevalence estimates based on the CIDI and SCID in clinical reappraisal samples were equivalent could still mean that the CIDI under-diagnoses true DMS-IV bipolar disorder. The results presented in the current report address this possibility of under-reporting indirectly by comparing characteristics of WMH respondents who endorsed CIDI diagnostic one or more of stem questions for bipolar disorder but were subsequently skipped out vs. those who failed to endorse stem questions or endorsed these questions and went through the entire diagnostic section without a skip out. We found that most of the characteristics studied – including lifetime prevalence of major depressive episodes, several characteristics of those episodes among people with lifetime MDE, and lifetime comorbidities with other DSM-IV/CIDI disorders – were intermediate in the skip-out group compared to the groups that either failed to endorse mania/hypomania stem questions or continued the mania/ hypomania section. This intermediate status could indicate that at least some of the individuals in the middle group were, in fact, inappropriately skipped out and that a more thorough diagnostic assessment would find them to meet DSM-IV criteria for bipolar disorder. There are, of course, other possible explanations, the most obvious being that their endorsement of the CIDI diagnostic stem questions on bipolarity were markers or more general aspects of such psychopathology even though they did not meet full criteria for bipolar disorder. Although there is no definitive way to adjudicate between these different possibilities with the data reported here, the elevation in the intermediate group in relation to the reference group is striking. The prevalence of MDE in the intermediate group, for example, is more than fourfold that of the reference group whether the intermediate group consisted of subjects screened out from the euphoric or from the irritable mania sections. This pattern is present with regular uniformity through many other diagnoses: panic, GAD, social phobia, PTSD, substance use and dependence disorders and reaches six-fold in disruptive behavior disorders. Furthermore, the age of onset of major depressive episodes, when present, was lower in the screened out group than in the reference group and close to those who were allowed to continue the mania section (CONT). Similarly, the recurrence rate of major depression, and quite importantly suicidality as a symptom of major depression was significantly higher in the SCI group than the reference group. How many of the inappropriately screened out subjects would have been classified as bipolar if the CIDI questions were more in line with our comments (Appendix A)? This is difficult to judge. It could be argued that the respondents in this intermediate group represent non-bipolar subjects that simply have a high rate of depression, suicidality, comorbidity with other disorders (anxiety, substance, and disruptive behavior), or more irritability during their depressive episodes and, quite importantly, have an earlier age of onset of their depressive disorders and a higher recurrence. If this interpretation is maintained, though, it would have to be recalled that all these subjects also endorsed diagnostic stem questions that target bipolarity directly. For the euphoric stem question, this wording was as follows: “Some people have a period lasting several days or longer when they feel much more excited and full of energy than usual. Their minds go too fast. They talk a lot. They are very restless or unable to sit still and they sometimes do things that are unusual for them, such as driving too fast or

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spending too much money”. The irritability stem question, in comparison, spoke of having periods “lasting several days or longer when most of the time you were so irritable that you either started arguments, shouted at people, or hit people”. Such individuals do not constitute, to be sure, a category of subthreshold disorder as defined by the algorithms devised by the WMH team in that sub-threshold diagnoses were imputed after correction (against the SCID before its recent changes) from the original bipolar I and II exclusively (Kessler et al., 2006) and who all belong by definition to the group that continued the mania section (CONT). It is possible that had these subjects crossed the hurdles and were allowed to continue the mania section, some meaningful proportion of them would have reached the full-blown bipolar diagnosis and would have eventually been classified as meeting criteria for BPI or BPII disorder. This was predicted by a previous publication assessing the validity of diagnosis of bipolar disorder, which states that “ tentatively the SCID and CIDI prevalence estimates of DSM-IV BPD should be interpreted as “conservative”” (Kessler et al., 2006). It is important to note that the possibility of under-diagnosis of bipolar disorder in epidemiological studies is not restricted to the CIDI. As an example, we reviewed the DIS version III (which is based on DSM III) and found that it has similar problems. The DIS stem question which precedes the probing into individual symptoms of mania/ hypomania asks the respondents if the “doctor ever described the subject as manic”. This would obviously scare off many subjects from continuing. Additionally, the individual symptom questions stress the negative aspects of hypomania/mania that are also not mentioned in the DSM. It translates the DSM symptom “more talkative than usual or pressure to keep on talking” into negatively asking respondents if they “talked too fast that people could not understand them”. It also converts the DSM criteria “flight of ideas or subjective experience that thoughts are racing” into asking respondents if they had “thoughts that they could not keep track of” as well as the DSM symptom “decreased need for sleep” into the negative “hardly sleeping at all”. Moreover, the DIS assesses “excessive involvement in pleasurable activities that have high potential for painful consequences” by asking respondents if they “spent so much money that it caused them or their family financial trouble” – an unnecessary exaggeration. Lastly, the DIS asks if respondents' “friends or family were concerned about them being more active than usual” whereas the DSM only requires an “increase in activity or physical restlessness”. The CIDI, the DIS and the SCID, have been extensively used to assess the prevalence of bipolarity in epidemiologic studies and it is clear from the above that all these instruments have had problems in the wording of the bipolarity section which might have led to under-diagnosis. Most of the problems we identified reflect a tendency to equate bipolarity with its more disruptive type (bipolar I) and neglect relatively bipolar II disorder as defined by the DSM system of classification. In conclusion, a revision of these instruments will undoubtedly prove correct what many clinical studies have been showing lately, namely that bipolar disorder is more common than results from what most epidemiologic studies have shown so far.

Role of funding source None.

Conflict of interest None.

Acknowledgments The World Health Organization (WHO) World Mental Health (WMH) Survey Initiative is supported by the National Institute of Mental Health (NIMH; R01 MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the US Public Health Service (R13-MH066849, R01-MH069864, and

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R01 DA016558), the Fogarty International Center (FIRCA R03-TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical, GlaxoSmithKline, and Bristol-Myers Squibb. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centers for assistance with instrumentation, fieldwork, and consultation on data analysis. None of the funders had any role in the design, analysis, interpretation of results, or preparation of this paper. A complete list of all within country and cross-national WMH publications can be found at http://www.hcp.med.harvard.edu/wmh/. The São Paulo Megacity Mental Health Survey is supported by the State of São Paulo Research Foundation (FAPESP) Thematic Project Grant 03/00204-3. The Bulgarian Epidemiological Study of common mental disorders EPIBUL is supported by the Ministry of Health and the National Center for Public Health Protection. The World Mental Health Japan (WMHJ) Survey is supported by the Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H13-SHOGAI-023, H14-TOKUBETSU-026, and H16-KOKORO-013) from the Japan Ministry of Health, Labor and Welfare. The Lebanese National Mental Health Survey (L.E.B.A.N.O.N.) is supported by the Lebanese Ministry of Public Health, the WHO (Lebanon), National Institute of Health/Fogarty International Center (R03 TW006481-01), Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences, anonymous private donations to IDRAAC, Lebanon, and grants from AstraZeneca, Eli Lilly, GalaxoSmithKline, Lundbeck, Novartis, and Servier. The Mexican National Comorbidity Survey (MNCS) is supported by The National Institute of Psychiatry Ramon de la Fuente (INPRFMDIES 4280) and by the National Council on Science and Technology (CONACyT-G30544-H), with supplemental support from the PanAmerican Health Organization (PAHO). Te Rau Hinengaro: The New Zealand Mental Health Survey (NZMHS) is supported by the New Zealand Ministry of Health, Alcohol Advisory Council, and the Health Research Council. The Romania WMH study projects “Policies in Mental Health Area” and “National Study regarding Mental Health and Services Use” were carried out by National School of Public Health & Health Services Management (former National Institute for Research & Development in Health, present National School of Public Health Management & Professional Development, Bucharest), with technical support of Metro Media Transylvania, the National Institute of Statistics – National Centre for Training in Statistics, SC. Cheyenne Services SRL, Statistics Netherlands and were funded by Ministry of Public Health (former Ministry of Health) with supplemental support of Eli Lilly Romania SRL. The US National Comorbidity Survey Replication (NCS-R) is supported by the National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the National Institute of Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044708), and the John W. Alden Trust.

Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.jad.2014.01.011.

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