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Predictors of later bipolar disorder in patients with subthreshold symptoms
Journal of Affective Disorders 144 (2013) 129–133
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Predictors of later bipolar disorder in patients with subthreshold symptoms Gregory G. Homish a,b, Dori Marshall b,c, Steven L. Dubovsky b,c,n, Kenneth Leonard b,c,d a
Department of Community Health and Health Behavior University at Buffalo, 462 Grider St, Room 1182, Buffalo, NY 14215, USA c Department of Psychiatry, University at Buffalo, 462 Grider St, Room 1182, Buffalo, NY 14215, USA d Research Institute on Addictions b
a r t i c l e i n f o
abstract
Article history: Received 24 March 2012 Accepted 13 June 2012 Available online 28 July 2012
Introduction: The clinical significance of subthreshold bipolar disorder (SBD), which is characterized by an insufficient number or severity of hypomanic symptoms to qualify for a formal bipolar disorder diagnosis, remains to be determined. Methods: We examined the outcomes three years later (2004–2005; Wave 2) of 40,512 civilian, noninstitutionalized subjects who endorsed elation and/or irritability but did not meet full criteria for lifetime mania or hypomania in 2001–2002 (Wave 1). Results: The likelihood of developing a clear episode of mania or hypomania by Wave 2 was significantly increased in subjects with elation or only irritability at Wave 1 compared with subjects who did not endorse either (OR 2.8, po 0.01 for each). Endorsement of both symptoms at Wave 1 increased the likelihood of a new episode of mania or hypomania 4.6 times, which was significantly higher than for those with only elation or irritability (p o .05 for each). Limitations: SBD was not limited to depression, reducing comparability to previous studies. Despite the large sample size, there were not enough subjects to determine the impact of different numbers and types of additional symptoms on bipolar outcome. Although the majority of subjects were followed between the two Waves, the total duration of follow-up was probably too short to determine the longterm conversion rate to mania or hypomania. Conclusions: Elation and/or irritability, especially if accompanied by trouble concentrating, racing thoughts or hyperactivity, may represent a prodrome of formal bipolar disorder that indicate close follow-up and cautious use of antidepressants. & 2012 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder Epidemiology Subthreshold Prodromal
1. Introduction Bipolar disorder causes more disability than cancer, epilepsy and Alzheimer’s disease (Kleinman et al., 2003; Merikangas et al., 2011). People with bipolar disorder have high rates of suicide, substance use, obesity, heart disease, smoking, and sedentary lifestyle, with consequent increased morbidity and mortality (Jansen et al., 2011). In 2009 the direct and indirect costs, respectively, of bipolar I and bipolar II disorder were $30.7 and $120.3 billion, respectively (Dilsaver, 2011). Unrecognized bipolar disorder is an important clinical problem. Around 20–28% of depressed patients taking antidepressants in primary care practices have been found to have clear cut bipolar disorder, and in these cases the diagnosis is rarely made by the primary care physician (Das et al., 2005; Dubovsky et al.,
n Corresponding author at: University at Buffalo, Psychiatry, 462 Grider St, Room 1182, Buffalo, NY 14215, US. Tel.: þ 1 716 898 5940; fax: þ 1 716 898 4538. E-mail address: [email protected] (S.L. Dubovsky).
0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.06.020
2011; Hirschfeld et al., 2005; Olfson et al., 2005; Shi et al., 2004). In one study, patients with unrecognized bipolar depression were almost four times more likely to attempt suicide and 50% more likely to be hospitalized as unipolar depressed patients (Shi et al., 2004). Most of these patients are treated with antidepressants, which have not been found to be more effective than placebo for bipolar depression (Ghaemi et al., 2003; Sachs et al., 2007) and which have the potential to destabilize bipolar disorder, especially if any residual hypomanic symptoms are present (Ghaemi et al., 2003; Schneck et al., 2008; Shi et al., 2004). The combined prevalence of bipolar I and II disorders has generally been estimated to range roughly between 0.5% and 2% (Bauer and Pfennig, 2005; Dunner, 2003; Grant et al., 2005; Judd and Akiskal, 2003; Pini et al., 2005; Weissman et al., 1996), although a single study reported a lifetime prevalence of mania and hypomania of 7.5% and 5.3%, respectively (Jansen et al., 2011). A number of investigators have suggested that bipolar disorder comprises a larger spectrum of conditions causing clinically significant morbidity (Akiskal, 1996; Angst et al., 2011). One proposed subtype has been called subthreshold bipolar disorder
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(SBD), in which features of bipolar I or II disorder are present, but without sufficient duration or a sufficient number of symptoms to qualify for a formal bipolar diagnosis (Akiskal et al., 2000; Angst et al., 2003). Compared with unipolar depression, SBD has been thought to be associated with more suicide attempts, greater familial loading for bipolar disorder, more comorbidity with anxiety, impulse control and substance use disorders, and a higher rate of conversion to frank bipolar disorder (Angst et al., 2010), as well as similar degrees of role impairment to bipolar I and II disorder (Merikangas et al., 2007). The National Comorbidity Survey Replication (NCS-R), utilizing the WHO Composite International Diagnostic Interview (CIDI), defined SBD as major depression with subthreshold hypomania (hypomania without impairment, or the presence over at least several days of persistent elation or irritability with three or more manic symptoms but an insufficient number of symptoms to meet full criteria for hypomania (Angst et al., 2010). In the overall household population, lifetime and 12-month prevalences of bipolar I, bipolar II, SBD and major depressive disorder (MDD) were 0.7% and 0.3%, 1.6% and 0.8%, 6.7% and 2.2%, and 10.2% and 5.4%, respectively (Angst et al., 2010). The NCS-R also found either recurrent subthreshold or frank hypomania without depression in 2.4% of respondents (Merikangas et al., 2007). SBD was associated with more comorbidity with anxiety and substance use disorders and more ‘‘behavioral problems’’ than MDD, but less than bipolar II disorder. Although severity and family history of depression were similar in SBD and MDD, SBD was associated with significantly more lifetime depressive episodes, and a younger age of onset of depression (Angst et al., 2010); 41% of subjects with SBD had made suicide attempts (Angst et al., 2010). The CIDI equivalent of DSM-IV rapid cycling occurred in 1/3 of subjects with lifetime bipolar disorder and half of those with any 12-month bipolar disorder, including SBD (Nierenberg et al., 2010). In the Epidemiologic Catchment Area (ECA) study, the prevalence of the ‘‘bipolar spectrum’’ (bipolar I, bipolar II and subthreshold bipolar disorder) was 6.4% of the general population (Judd and Akiskal, 2003). In an international study, 61,392 adults underwent structured diagnostic interviews in their homes in the United States, Mexico, South America, Eastern Europe, Asia, Lebanon and New Zealand to determine the lifetime and 12month prevalence of the bipolar spectrum (Merikangas et al., 2011). In the pooled sample, lifetime and one-year prevalence was 0.6 and 0.4% for bipolar I disorder, 0.4 and 0.3% for bipolar II disorder, and 1.4 and 0.8% for SBD. Lifetime and 12-month rates of all bipolar spectrum disorders were highest in the United States (4.4% and 2.8%, respectively). Within the bipolar spectrum, 3/4 of patients also met criteria for another lifetime disorder, and more than half of these had three or more comorbid disorders, especially panic attacks, behavior disorders, and substance use disorders. Although symptom severity and suicidality increased from SBD to bipolar II to bipolar I disorder, the risk of significant role impairment was statistically similar in all subtypes (29–57%). Among subjects with subthreshold bipolar disorder, 36% reported suicidal ideation in the past 12 months, 15% had a plan, and 9.5% had made a suicide attempt. As is true of bipolar disorder in general, the prevalence of SBD would be expected to be higher in depressed patients. In the NCS-R, subthreshold hypomania was present in 39% of patients with a diagnosis of MDD (Angst et al., 2010). Similarly, 31% of a clinical sample of depressed patients in two primary care practices being treated with antidepressants met NCS-R criteria for SBD (Dubovsky et al., 2011). A multicenter study conducted in Asia, Europe and Africa of 5635 adults with a current major depressive episode examined by practicing psychiatrists found that 16% met formal criteria for bipolar disorder (12.2% bipolar I and 3.9% bipolar II), while another 31% met ‘‘bipolarity specifier’’ criteria, which were
defined as depression with a history of an episode of elevated mood, irritable mood, or increased activity with at least 3 DSM-IV-TR Criterion B symptoms and producing uncharacteristic change in or impairment of functioning or requiring treatment (Angst et al., 2011). Features associated with a DSM bipolar or a bipolarity specifier diagnosis included more than two prior mood episodes, mood lability, mania or hypomania on an antidepressant, earlier age of onset, and current mixed state; psychotic features also discriminated DSM-IV-TR bipolar but not bipolarity specifier patients. A total of 79% of patients meeting DSM bipolar criteria and 85% of those meeting bipolarity specifier criteria were taking antidepressants, while 69% and 61%, respectively, were taking mood stabilizers. These kinds of results suggest that SBD, which predominantly but not universally has been reported to include depressive episodes, is a clinically important subtype that is not captured by current bipolar disorder criteria and that is often mistaken for MDD (Angst et al., 2010). To address the question of whether SBD is a distinct and stable subtype or a precursor of other forms of bipolar disorder, we utilized a prospective household survey that obtained data about SBD and DSM-IV bipolar disorder on two occasions, three to four years apart.
2. Methods 2.1. Study sample The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) has been previously described in detail (Grant and Kaplan, 2005; Grant et al., 2003b, 2004). Briefly, two waves of data, in 2001–2002 (Wave 1), and 2004–2005 (Wave 2; 81% of the original sample), were obtained from 43,093 civilian, non-institutionalized adults in the United States. Based on the 2000 Decennial Census, sample selection was adjusted according to socio-demographic variables to ensure a representative sample of the United States population. For both waves, surveys were administered face-to-face, using computer-assisted interviews described below. African Americans, Hispanics, and young adults were oversampled, and the data were weighted to adjust for nonresponse at the household and individual levels. The present report excludes the 2581 subjects who met full criteria for lifetime mania or hypomania, leaving an initial sample size of 40,512. All data were de-identified and the study was determined to be exempt.
2.2. Measures/analyses The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) was administered to generate DSM-IV diagnoses for lifetime alcohol abuse and dependence, generalized anxiety disorder, major depressive disorder, mania, and hypomania (Grant et al., 2003a, 1995). In the present study, we included all subjects who endorsed the screening symptoms for bipolar disorder (elation and/or irritability) at Wave 1 but did not meet full criteria for mania or hypomania. The outcome variable was a first episode of DSM-IV mania or hypomania that occurred after Wave 1 and was identified at Wave 2. Logistic regression was used to examine the relation between Wave 1 predictors of identification of a new episode of mania or hypomania at Wave 2. All analyses accounted for the complex sampling design of the NESARC survey and were adjusted for age, gender, and race/ ethnicity.
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3. Results
Table 2 Predictors of new onset episode of mania or hypomania at Wave 2.
3.1. Screening symptoms Overall, 6.8% of the sample acknowledged at least one of the screening symptoms at Wave 1. Specifically, 1.8% reported elation only, 4.4% reported irritability only, and 0.6% reported both elation and irritability. Uncorrected incidence rates of a new manic or hypomanic episode identified at Wave 2 were significantly different for those who did and did not endorse elation or irritability at Wave 1. The incidence rate of a first episode at Wave 2 for those who had no screening symptoms at Wave 1 was 2.6%. For those with only elation or only irritability, the incidence rate was 8%, while for those with both elation and irritability, the incidence rate of a first episode at Wave 2 was 13%. Because participants with a first episode of mania or hypomania between Wave 1 and Wave 2 were significantly younger, more likely to be female, and less likely to be Caucasian (Table 1), age, gender, and ethnicity were controlled in subsequent analyses.
3.2. Controlling for age, gender, ethnicity and comorbidity We then conducted two analyses of the incidence of a new mania or hypomania diagnosis between Wave 1 and Wave 2 as a function of the screening symptom(s) endorsed. In the first analysis (Table 2, Model 1), we controlled for age, gender, and ethnicity, and examined the incidence rates for participants who endorsed elation only, irritability only, both elation and irritability, or neither; individuals who endorsed the entry criteria may have also endorsed additional symptoms. Both elation and irritability significantly increased the likelihood of developing a manic or hypomanic episode threefold (po0.01). Endorsement of both elation and irritability substantially increased the likelihood of a new episode of mania or hypomania, with an odds ratio of 4.6, which was significantly higher than the odds of an incident diagnosis for those with only elation (po.05) or only irritability (po.05). In a second analysis (Table 2, Model 2), we examined whether other lifetime diagnoses at Wave 1 predicted the development of a new episode of mania or hypomania, and whether the inclusion of another Axis 1 diagnosis weakened the value of the entry level criteria. In this model, alcohol abuse/dependence, major depression, and generalized anxiety disorder at Wave I were each individually predictive of a new diagnosis of mania or hypomania by Wave 2 after controlling for age, gender, ethnicity and the other disorders. The screening symptoms continued to predict a new manic or hypomanic episode, although the odds ratio for
Table 1 Descriptive statistics. Factor
No new episode
New episode
Age Race White, not Hispanic or Latino Black, not Hispanic or Latino American Indian/native Hawaiian/Pacific Islander, not Hispanic or Latino Hispanic/Latino Sex Female Male
45.7 (SE ¼0.06)
37.0 (SE ¼0.25)
73.0% 10.5% 4.0%
65.2% 17.7% 2.9%
10.5%
11.3%
52.7% 47.3%
56.0%nnn 43.9%
nnn
nnn
p o.001.
Model number
Predictors
Odds ratio
95% CI
1
Elation only (vs. no screening symptom) Irritable only (vs. no screening symptom) Both elation and irritable (vs. no screening symptom)
2.8nnn 2.8nnn 4.6nnn
2.4, 3.1 2.4, 3.2 3.7, 5.8
2
Elation only (vs. no screening symptom) Irritable only (vs. no screening symptom) Elation and irritable (vs. no screening symptom) Alcohol abuse/dependence Major depression Generalized anxiety disorder
2.4nnn 1.9nnn 3.0nnn
2.1, 2.7 1.6, 2.3 2.4, 3.8
1.2n 2.2nnn 2.1nnn
1.1, 1.3 2.1, 2.4 1.8, 2.4
NOTE: All models exclude individuals who met lifetime bipolar or hypomania diagnoses at Wave 1 and all models control for age, race/ethnicity and gender. p o .001. p o .05.
nnn n
each of these was slightly decreased by accounting for all other factors (Table 2, Model 2). Although 6.45% of 5238 subjects with a lifetime diagnosis of major depression had a new episode of mania or hypomania compared with 2.38% of 26,609 without this diagnosis, the screening symptoms remained significantly predictive of later mania or hypomania independent of the presence of major depression, and odds ratios of the bipolar screening items were not different in those with and without a lifetime diagnosis of major depression. 3.3. Additional subthreshold symptoms In examining whether the endorsement of any symptoms beyond elation and irritability predicted a new bipolar disorder among those who endorsed either elation or irritability at Wave 1 without meeting criteria for lifetime bipolar disorder at that point, neither the dichotomous variable of any additional symptom nor the number of additional symptoms were predictive of a new bipolar disorder diagnosis in this group by Wave 2. However, analyses of specific additional symptoms demonstrated that those who endorsed trouble concentrating (OR¼1.3, po.05), racing thoughts (OR¼1.3, po.05), and increased activity (active/restless/sexually more active) (OR¼1.4, po.05) along with a screening symptom at Wave 1 were more likely to receive a Wave 2 diagnosis of mania or hypomania than subjects without these symptoms. Decreased sleep, pressured speech, getting into trouble, and grandiosity did not have an independent association with a new bipolar disorder diagnosis. When other concomitant disorders were controlled, only racing thoughts (OR¼1.2, po.05) and increased activity (OR¼1.2, po.05) remained significant for predicting a new diagnosis of bipolar disorder when accompanying one of the screening symptoms. Because the AUDADIS-IV only assessed specific bipolar symptoms among those who first endorsed elation or irritability, we were unable to determine whether any of these symptoms in the absence of a screening symptom alone or in combination predicted the later development of mania or hypomania.
4. Discussion
Note: table excludes all individuals who met lifetime mania or hypomania diagnoses at Wave 1; nnn
131
In this representative sample of the U.S. population, endorsement of elation or irritability at baseline significantly increased the likelihood of a new diagnosis of mania or hypomania three to four years later; the initial presence of both elation and irritability increased the likelihood of a bipolar outcome more than either one alone. Trouble concentrating (OR¼1.3, po.05), racing thoughts (OR¼1.3,
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po.05), and increased activity (active/restless/sexually more active) (OR¼1.4, po.05) along with elation and/or irritability, made the later development of mania or hypomania more likely, but other features of mania or hypomania did not. Comparing these results to studies of SBD (Angst et al., 2010) is complicated because our independent variables were elation and/or irritability, rather than one of these symptoms along with three or more DSM-IV hypomanic symptoms in the presence of depression. However, the observation that certain additional hypomanic symptoms increased the likelihood of a bipolar disorder diagnosis in just three years suggests that SBD, even if it consists of elation and/or irritability with a smaller number of additional symptoms than have previously been considered, may have a propensity to evolve into more consensually defined bipolar disorder. Longer prospective studies of patients with different degrees of SBD could clarify whether SBD is a prodromal stage of bipolar disorder, a stable bipolar subtype with a different outcome than bipolar I or bipolar II disorder that deserves its own diagnostic category, or a spectrum of its own (Merikangas et al., 2011; Zimmerman et al., 2009). Although a past history of major depression along with one or more screening symptoms predicted the development of mania or hypomania three years later, the observation that the likelihood of a formal bipolar diagnosis was not greater in depressed subjects than in those with other diagnoses examined may seem out of keeping with studies cited earlier demonstrating a high rate of bipolar disorder in depressed patients. However, previous research on this subject has been with depressed patients who have a current bipolar spectrum diagnosis and has not investigated the ability of lifetime major depression to predict later bipolar disorder more readily than the other lifetime diagnoses we considered, which also have high rates of comorbidity with bipolar disorder. We were able to follow the majority of a large sample of subjects using a validated instrument to determine the likelihood the likelihood that a form of subthreshold bipolar disorder with fewer symptoms than have previously been described will predict the later development of a formal bipolar diagnosis. Interpretation of the results is limited by the use of a household sample rather than a clinical population and our not having enough subjects meeting previously defined criteria for SBD without a formal bipolar diagnosis to permit direct comparisons with previous research. The majority of subjects could be followed between Wave 1 and Wave 2, but the duration of follow-up was probably too short to determine the long-term conversion rate to mania or hypomania. Although our findings are consistent with research demonstrating that SBD is related to formal bipolar disorder, more research is needed to define the most clinically relevant features of SBD (Merikangas et al., 2011; Zimmerman et al., 2009), especially how many symptoms must be present to be clinically significant, what the duration of these symptoms should be, and how symptoms such as irritability and anger fit into the bipolar spectrum (Perlis et al., 2011). It is not yet clear whether subthreshold bipolar disorder should be treated similarly to other forms of bipolar disorder (Westermeyer, 2010). However, similar precautions might be observed in treating comorbid target symptoms such as anxiety or depression (Ghaemi et al., 2004; Leverich et al., 2006). Patients with elation and/or irritability, particularly if accompanied by trouble concentrating, racing thoughts or hyperactivity, should be observed closely over time for evidence of additional diagnostic criteria for bipolar disorder.
Role of funding source This study was funded by the Department of Psychiatry at the University at Buffalo, which had no role in the analysis of data or the preparation of the manuscript.
Conflict of interest Dr. Dubovsky has received research support from Pfizer, Lilly, Jansen, Otsuka, Sumitomo and Biogen. Dr. Leonard has received research support from NIMH. The other authors declare that they have no conflict of interest.
Acknowledgment The authors are grateful to the National Epidemiologic Survey on Alcohol and Related Conditions for making data available for analysis.
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Contents lists available at SciVerse ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Predictors of later bipolar disorder in patients with subthreshold symptoms Gregory G. Homish a,b, Dori Marshall b,c, Steven L. Dubovsky b,c,n, Kenneth Leonard b,c,d a
Department of Community Health and Health Behavior University at Buffalo, 462 Grider St, Room 1182, Buffalo, NY 14215, USA c Department of Psychiatry, University at Buffalo, 462 Grider St, Room 1182, Buffalo, NY 14215, USA d Research Institute on Addictions b
a r t i c l e i n f o
abstract
Article history: Received 24 March 2012 Accepted 13 June 2012 Available online 28 July 2012
Introduction: The clinical significance of subthreshold bipolar disorder (SBD), which is characterized by an insufficient number or severity of hypomanic symptoms to qualify for a formal bipolar disorder diagnosis, remains to be determined. Methods: We examined the outcomes three years later (2004–2005; Wave 2) of 40,512 civilian, noninstitutionalized subjects who endorsed elation and/or irritability but did not meet full criteria for lifetime mania or hypomania in 2001–2002 (Wave 1). Results: The likelihood of developing a clear episode of mania or hypomania by Wave 2 was significantly increased in subjects with elation or only irritability at Wave 1 compared with subjects who did not endorse either (OR 2.8, po 0.01 for each). Endorsement of both symptoms at Wave 1 increased the likelihood of a new episode of mania or hypomania 4.6 times, which was significantly higher than for those with only elation or irritability (p o .05 for each). Limitations: SBD was not limited to depression, reducing comparability to previous studies. Despite the large sample size, there were not enough subjects to determine the impact of different numbers and types of additional symptoms on bipolar outcome. Although the majority of subjects were followed between the two Waves, the total duration of follow-up was probably too short to determine the longterm conversion rate to mania or hypomania. Conclusions: Elation and/or irritability, especially if accompanied by trouble concentrating, racing thoughts or hyperactivity, may represent a prodrome of formal bipolar disorder that indicate close follow-up and cautious use of antidepressants. & 2012 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder Epidemiology Subthreshold Prodromal
1. Introduction Bipolar disorder causes more disability than cancer, epilepsy and Alzheimer’s disease (Kleinman et al., 2003; Merikangas et al., 2011). People with bipolar disorder have high rates of suicide, substance use, obesity, heart disease, smoking, and sedentary lifestyle, with consequent increased morbidity and mortality (Jansen et al., 2011). In 2009 the direct and indirect costs, respectively, of bipolar I and bipolar II disorder were $30.7 and $120.3 billion, respectively (Dilsaver, 2011). Unrecognized bipolar disorder is an important clinical problem. Around 20–28% of depressed patients taking antidepressants in primary care practices have been found to have clear cut bipolar disorder, and in these cases the diagnosis is rarely made by the primary care physician (Das et al., 2005; Dubovsky et al.,
n Corresponding author at: University at Buffalo, Psychiatry, 462 Grider St, Room 1182, Buffalo, NY 14215, US. Tel.: þ 1 716 898 5940; fax: þ 1 716 898 4538. E-mail address: [email protected] (S.L. Dubovsky).
0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.06.020
2011; Hirschfeld et al., 2005; Olfson et al., 2005; Shi et al., 2004). In one study, patients with unrecognized bipolar depression were almost four times more likely to attempt suicide and 50% more likely to be hospitalized as unipolar depressed patients (Shi et al., 2004). Most of these patients are treated with antidepressants, which have not been found to be more effective than placebo for bipolar depression (Ghaemi et al., 2003; Sachs et al., 2007) and which have the potential to destabilize bipolar disorder, especially if any residual hypomanic symptoms are present (Ghaemi et al., 2003; Schneck et al., 2008; Shi et al., 2004). The combined prevalence of bipolar I and II disorders has generally been estimated to range roughly between 0.5% and 2% (Bauer and Pfennig, 2005; Dunner, 2003; Grant et al., 2005; Judd and Akiskal, 2003; Pini et al., 2005; Weissman et al., 1996), although a single study reported a lifetime prevalence of mania and hypomania of 7.5% and 5.3%, respectively (Jansen et al., 2011). A number of investigators have suggested that bipolar disorder comprises a larger spectrum of conditions causing clinically significant morbidity (Akiskal, 1996; Angst et al., 2011). One proposed subtype has been called subthreshold bipolar disorder
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(SBD), in which features of bipolar I or II disorder are present, but without sufficient duration or a sufficient number of symptoms to qualify for a formal bipolar diagnosis (Akiskal et al., 2000; Angst et al., 2003). Compared with unipolar depression, SBD has been thought to be associated with more suicide attempts, greater familial loading for bipolar disorder, more comorbidity with anxiety, impulse control and substance use disorders, and a higher rate of conversion to frank bipolar disorder (Angst et al., 2010), as well as similar degrees of role impairment to bipolar I and II disorder (Merikangas et al., 2007). The National Comorbidity Survey Replication (NCS-R), utilizing the WHO Composite International Diagnostic Interview (CIDI), defined SBD as major depression with subthreshold hypomania (hypomania without impairment, or the presence over at least several days of persistent elation or irritability with three or more manic symptoms but an insufficient number of symptoms to meet full criteria for hypomania (Angst et al., 2010). In the overall household population, lifetime and 12-month prevalences of bipolar I, bipolar II, SBD and major depressive disorder (MDD) were 0.7% and 0.3%, 1.6% and 0.8%, 6.7% and 2.2%, and 10.2% and 5.4%, respectively (Angst et al., 2010). The NCS-R also found either recurrent subthreshold or frank hypomania without depression in 2.4% of respondents (Merikangas et al., 2007). SBD was associated with more comorbidity with anxiety and substance use disorders and more ‘‘behavioral problems’’ than MDD, but less than bipolar II disorder. Although severity and family history of depression were similar in SBD and MDD, SBD was associated with significantly more lifetime depressive episodes, and a younger age of onset of depression (Angst et al., 2010); 41% of subjects with SBD had made suicide attempts (Angst et al., 2010). The CIDI equivalent of DSM-IV rapid cycling occurred in 1/3 of subjects with lifetime bipolar disorder and half of those with any 12-month bipolar disorder, including SBD (Nierenberg et al., 2010). In the Epidemiologic Catchment Area (ECA) study, the prevalence of the ‘‘bipolar spectrum’’ (bipolar I, bipolar II and subthreshold bipolar disorder) was 6.4% of the general population (Judd and Akiskal, 2003). In an international study, 61,392 adults underwent structured diagnostic interviews in their homes in the United States, Mexico, South America, Eastern Europe, Asia, Lebanon and New Zealand to determine the lifetime and 12month prevalence of the bipolar spectrum (Merikangas et al., 2011). In the pooled sample, lifetime and one-year prevalence was 0.6 and 0.4% for bipolar I disorder, 0.4 and 0.3% for bipolar II disorder, and 1.4 and 0.8% for SBD. Lifetime and 12-month rates of all bipolar spectrum disorders were highest in the United States (4.4% and 2.8%, respectively). Within the bipolar spectrum, 3/4 of patients also met criteria for another lifetime disorder, and more than half of these had three or more comorbid disorders, especially panic attacks, behavior disorders, and substance use disorders. Although symptom severity and suicidality increased from SBD to bipolar II to bipolar I disorder, the risk of significant role impairment was statistically similar in all subtypes (29–57%). Among subjects with subthreshold bipolar disorder, 36% reported suicidal ideation in the past 12 months, 15% had a plan, and 9.5% had made a suicide attempt. As is true of bipolar disorder in general, the prevalence of SBD would be expected to be higher in depressed patients. In the NCS-R, subthreshold hypomania was present in 39% of patients with a diagnosis of MDD (Angst et al., 2010). Similarly, 31% of a clinical sample of depressed patients in two primary care practices being treated with antidepressants met NCS-R criteria for SBD (Dubovsky et al., 2011). A multicenter study conducted in Asia, Europe and Africa of 5635 adults with a current major depressive episode examined by practicing psychiatrists found that 16% met formal criteria for bipolar disorder (12.2% bipolar I and 3.9% bipolar II), while another 31% met ‘‘bipolarity specifier’’ criteria, which were
defined as depression with a history of an episode of elevated mood, irritable mood, or increased activity with at least 3 DSM-IV-TR Criterion B symptoms and producing uncharacteristic change in or impairment of functioning or requiring treatment (Angst et al., 2011). Features associated with a DSM bipolar or a bipolarity specifier diagnosis included more than two prior mood episodes, mood lability, mania or hypomania on an antidepressant, earlier age of onset, and current mixed state; psychotic features also discriminated DSM-IV-TR bipolar but not bipolarity specifier patients. A total of 79% of patients meeting DSM bipolar criteria and 85% of those meeting bipolarity specifier criteria were taking antidepressants, while 69% and 61%, respectively, were taking mood stabilizers. These kinds of results suggest that SBD, which predominantly but not universally has been reported to include depressive episodes, is a clinically important subtype that is not captured by current bipolar disorder criteria and that is often mistaken for MDD (Angst et al., 2010). To address the question of whether SBD is a distinct and stable subtype or a precursor of other forms of bipolar disorder, we utilized a prospective household survey that obtained data about SBD and DSM-IV bipolar disorder on two occasions, three to four years apart.
2. Methods 2.1. Study sample The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) has been previously described in detail (Grant and Kaplan, 2005; Grant et al., 2003b, 2004). Briefly, two waves of data, in 2001–2002 (Wave 1), and 2004–2005 (Wave 2; 81% of the original sample), were obtained from 43,093 civilian, non-institutionalized adults in the United States. Based on the 2000 Decennial Census, sample selection was adjusted according to socio-demographic variables to ensure a representative sample of the United States population. For both waves, surveys were administered face-to-face, using computer-assisted interviews described below. African Americans, Hispanics, and young adults were oversampled, and the data were weighted to adjust for nonresponse at the household and individual levels. The present report excludes the 2581 subjects who met full criteria for lifetime mania or hypomania, leaving an initial sample size of 40,512. All data were de-identified and the study was determined to be exempt.
2.2. Measures/analyses The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) was administered to generate DSM-IV diagnoses for lifetime alcohol abuse and dependence, generalized anxiety disorder, major depressive disorder, mania, and hypomania (Grant et al., 2003a, 1995). In the present study, we included all subjects who endorsed the screening symptoms for bipolar disorder (elation and/or irritability) at Wave 1 but did not meet full criteria for mania or hypomania. The outcome variable was a first episode of DSM-IV mania or hypomania that occurred after Wave 1 and was identified at Wave 2. Logistic regression was used to examine the relation between Wave 1 predictors of identification of a new episode of mania or hypomania at Wave 2. All analyses accounted for the complex sampling design of the NESARC survey and were adjusted for age, gender, and race/ ethnicity.
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3. Results
Table 2 Predictors of new onset episode of mania or hypomania at Wave 2.
3.1. Screening symptoms Overall, 6.8% of the sample acknowledged at least one of the screening symptoms at Wave 1. Specifically, 1.8% reported elation only, 4.4% reported irritability only, and 0.6% reported both elation and irritability. Uncorrected incidence rates of a new manic or hypomanic episode identified at Wave 2 were significantly different for those who did and did not endorse elation or irritability at Wave 1. The incidence rate of a first episode at Wave 2 for those who had no screening symptoms at Wave 1 was 2.6%. For those with only elation or only irritability, the incidence rate was 8%, while for those with both elation and irritability, the incidence rate of a first episode at Wave 2 was 13%. Because participants with a first episode of mania or hypomania between Wave 1 and Wave 2 were significantly younger, more likely to be female, and less likely to be Caucasian (Table 1), age, gender, and ethnicity were controlled in subsequent analyses.
3.2. Controlling for age, gender, ethnicity and comorbidity We then conducted two analyses of the incidence of a new mania or hypomania diagnosis between Wave 1 and Wave 2 as a function of the screening symptom(s) endorsed. In the first analysis (Table 2, Model 1), we controlled for age, gender, and ethnicity, and examined the incidence rates for participants who endorsed elation only, irritability only, both elation and irritability, or neither; individuals who endorsed the entry criteria may have also endorsed additional symptoms. Both elation and irritability significantly increased the likelihood of developing a manic or hypomanic episode threefold (po0.01). Endorsement of both elation and irritability substantially increased the likelihood of a new episode of mania or hypomania, with an odds ratio of 4.6, which was significantly higher than the odds of an incident diagnosis for those with only elation (po.05) or only irritability (po.05). In a second analysis (Table 2, Model 2), we examined whether other lifetime diagnoses at Wave 1 predicted the development of a new episode of mania or hypomania, and whether the inclusion of another Axis 1 diagnosis weakened the value of the entry level criteria. In this model, alcohol abuse/dependence, major depression, and generalized anxiety disorder at Wave I were each individually predictive of a new diagnosis of mania or hypomania by Wave 2 after controlling for age, gender, ethnicity and the other disorders. The screening symptoms continued to predict a new manic or hypomanic episode, although the odds ratio for
Table 1 Descriptive statistics. Factor
No new episode
New episode
Age Race White, not Hispanic or Latino Black, not Hispanic or Latino American Indian/native Hawaiian/Pacific Islander, not Hispanic or Latino Hispanic/Latino Sex Female Male
45.7 (SE ¼0.06)
37.0 (SE ¼0.25)
73.0% 10.5% 4.0%
65.2% 17.7% 2.9%
10.5%
11.3%
52.7% 47.3%
56.0%nnn 43.9%
nnn
nnn
p o.001.
Model number
Predictors
Odds ratio
95% CI
1
Elation only (vs. no screening symptom) Irritable only (vs. no screening symptom) Both elation and irritable (vs. no screening symptom)
2.8nnn 2.8nnn 4.6nnn
2.4, 3.1 2.4, 3.2 3.7, 5.8
2
Elation only (vs. no screening symptom) Irritable only (vs. no screening symptom) Elation and irritable (vs. no screening symptom) Alcohol abuse/dependence Major depression Generalized anxiety disorder
2.4nnn 1.9nnn 3.0nnn
2.1, 2.7 1.6, 2.3 2.4, 3.8
1.2n 2.2nnn 2.1nnn
1.1, 1.3 2.1, 2.4 1.8, 2.4
NOTE: All models exclude individuals who met lifetime bipolar or hypomania diagnoses at Wave 1 and all models control for age, race/ethnicity and gender. p o .001. p o .05.
nnn n
each of these was slightly decreased by accounting for all other factors (Table 2, Model 2). Although 6.45% of 5238 subjects with a lifetime diagnosis of major depression had a new episode of mania or hypomania compared with 2.38% of 26,609 without this diagnosis, the screening symptoms remained significantly predictive of later mania or hypomania independent of the presence of major depression, and odds ratios of the bipolar screening items were not different in those with and without a lifetime diagnosis of major depression. 3.3. Additional subthreshold symptoms In examining whether the endorsement of any symptoms beyond elation and irritability predicted a new bipolar disorder among those who endorsed either elation or irritability at Wave 1 without meeting criteria for lifetime bipolar disorder at that point, neither the dichotomous variable of any additional symptom nor the number of additional symptoms were predictive of a new bipolar disorder diagnosis in this group by Wave 2. However, analyses of specific additional symptoms demonstrated that those who endorsed trouble concentrating (OR¼1.3, po.05), racing thoughts (OR¼1.3, po.05), and increased activity (active/restless/sexually more active) (OR¼1.4, po.05) along with a screening symptom at Wave 1 were more likely to receive a Wave 2 diagnosis of mania or hypomania than subjects without these symptoms. Decreased sleep, pressured speech, getting into trouble, and grandiosity did not have an independent association with a new bipolar disorder diagnosis. When other concomitant disorders were controlled, only racing thoughts (OR¼1.2, po.05) and increased activity (OR¼1.2, po.05) remained significant for predicting a new diagnosis of bipolar disorder when accompanying one of the screening symptoms. Because the AUDADIS-IV only assessed specific bipolar symptoms among those who first endorsed elation or irritability, we were unable to determine whether any of these symptoms in the absence of a screening symptom alone or in combination predicted the later development of mania or hypomania.
4. Discussion
Note: table excludes all individuals who met lifetime mania or hypomania diagnoses at Wave 1; nnn
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In this representative sample of the U.S. population, endorsement of elation or irritability at baseline significantly increased the likelihood of a new diagnosis of mania or hypomania three to four years later; the initial presence of both elation and irritability increased the likelihood of a bipolar outcome more than either one alone. Trouble concentrating (OR¼1.3, po.05), racing thoughts (OR¼1.3,
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po.05), and increased activity (active/restless/sexually more active) (OR¼1.4, po.05) along with elation and/or irritability, made the later development of mania or hypomania more likely, but other features of mania or hypomania did not. Comparing these results to studies of SBD (Angst et al., 2010) is complicated because our independent variables were elation and/or irritability, rather than one of these symptoms along with three or more DSM-IV hypomanic symptoms in the presence of depression. However, the observation that certain additional hypomanic symptoms increased the likelihood of a bipolar disorder diagnosis in just three years suggests that SBD, even if it consists of elation and/or irritability with a smaller number of additional symptoms than have previously been considered, may have a propensity to evolve into more consensually defined bipolar disorder. Longer prospective studies of patients with different degrees of SBD could clarify whether SBD is a prodromal stage of bipolar disorder, a stable bipolar subtype with a different outcome than bipolar I or bipolar II disorder that deserves its own diagnostic category, or a spectrum of its own (Merikangas et al., 2011; Zimmerman et al., 2009). Although a past history of major depression along with one or more screening symptoms predicted the development of mania or hypomania three years later, the observation that the likelihood of a formal bipolar diagnosis was not greater in depressed subjects than in those with other diagnoses examined may seem out of keeping with studies cited earlier demonstrating a high rate of bipolar disorder in depressed patients. However, previous research on this subject has been with depressed patients who have a current bipolar spectrum diagnosis and has not investigated the ability of lifetime major depression to predict later bipolar disorder more readily than the other lifetime diagnoses we considered, which also have high rates of comorbidity with bipolar disorder. We were able to follow the majority of a large sample of subjects using a validated instrument to determine the likelihood the likelihood that a form of subthreshold bipolar disorder with fewer symptoms than have previously been described will predict the later development of a formal bipolar diagnosis. Interpretation of the results is limited by the use of a household sample rather than a clinical population and our not having enough subjects meeting previously defined criteria for SBD without a formal bipolar diagnosis to permit direct comparisons with previous research. The majority of subjects could be followed between Wave 1 and Wave 2, but the duration of follow-up was probably too short to determine the long-term conversion rate to mania or hypomania. Although our findings are consistent with research demonstrating that SBD is related to formal bipolar disorder, more research is needed to define the most clinically relevant features of SBD (Merikangas et al., 2011; Zimmerman et al., 2009), especially how many symptoms must be present to be clinically significant, what the duration of these symptoms should be, and how symptoms such as irritability and anger fit into the bipolar spectrum (Perlis et al., 2011). It is not yet clear whether subthreshold bipolar disorder should be treated similarly to other forms of bipolar disorder (Westermeyer, 2010). However, similar precautions might be observed in treating comorbid target symptoms such as anxiety or depression (Ghaemi et al., 2004; Leverich et al., 2006). Patients with elation and/or irritability, particularly if accompanied by trouble concentrating, racing thoughts or hyperactivity, should be observed closely over time for evidence of additional diagnostic criteria for bipolar disorder.
Role of funding source This study was funded by the Department of Psychiatry at the University at Buffalo, which had no role in the analysis of data or the preparation of the manuscript.
Conflict of interest Dr. Dubovsky has received research support from Pfizer, Lilly, Jansen, Otsuka, Sumitomo and Biogen. Dr. Leonard has received research support from NIMH. The other authors declare that they have no conflict of interest.
Acknowledgment The authors are grateful to the National Epidemiologic Survey on Alcohol and Related Conditions for making data available for analysis.
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