Risk factors for secondary substance use disorders in people with childhood and adolescent-onset bipolar disorder: Opportunities for prevention

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Comprehensive Psychiatry 54 (2013) 439 – 446 www.elsevier.com/locate/comppsych

Risk factors for secondary substance use disorders in people with childhood and adolescent-onset bipolar disorder: Opportunities for prevention Aileen Kenneson a,⁎, Jennifer S. Funderburk a , Stephen A. Maisto a, b a

Center for Integrated Healthcare, Syracuse Veteran's Affairs Medical Center, Syracuse, NY, USA b Department of Psychology, Syracuse University, Syracuse, NY, USA

Abstract Background: Compared to other mental illnesses, bipolar disorder is associated with a disproportionately high rate of substance use disorders (SUDs), and the co-occurrence is associated with significant morbidity and mortality. Early diagnosis of primary bipolar disorder may provide opportunities for SUD prevention, but little is known about the risk factors for secondary SUD among individuals with bipolar disorder. The purposes of this study were to describe the population of people with childhood and adolescent-onset primary bipolar disorder, and to identify risk factors for secondary SUD in this population. Methods: Using data collected from the National Comorbidity Survey Replication study, we identified 158 individuals with childhood-onset (b13 years) or adolescent-onset (13–18 years) primary bipolar disorder (I, II or subthreshold). Survival analysis was used to identify risk factors for SUD. Results: Compared to adolescent-onset, people with childhood-onset bipolar disorder had increased likelihoods of attention deficit hyperactivity disorder (ADHD) (adjusted odds ratio = 2.81) and suicide attempt (aOR = 3.61). Males were more likely than females to develop SUD, and did so at a faster rate. Hazard ratios of risk factors for SUD were: lifetime oppositional defiant disorder (2.048), any lifetime anxiety disorder (3.077), adolescent-onset bipolar disorder (1.653), and suicide attempt (15.424). SUD was not predicted by bipolar disorder type, family history of bipolar disorder, hospitalization for a mood episode, ADHD or conduct disorder. Conclusions: As clinicians struggle to help individuals with bipolar disorder, this study provides information that might be useful in identifying individuals at higher risk for SUD. Future research can examine whether targeting these risk factors may help prevent secondary SUD. Published by Elsevier Inc.

1. Introduction A large epidemiologic study in the US indicated that the lifetime prevalence of substance use disorders (SUD) among people with bipolar disorder is 60.3%, 40.4% and 35.5% for types I, II and subthreshold, respectively [1]. Many studies have indicated that bipolar I disorder and bipolar II disorder do not have significantly different risks for SUD [2–9], but studies of the risk associated with subthreshold bipolar disorder have produced conflicting results [1,10,11]. Com-

⁎ Corresponding author. Center for Integrated Healthcare, Mailstop 116C, Veterans Affairs Medical Center, 800 Irving Avenue, Syracuse, NY 13210, USA. Fax: +1 315-425-4871. E-mail address: [email protected] (A. Kenneson). 0010-440X/$ – see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.comppsych.2012.12.008

pared to people with bipolar disorder alone, those who have bipolar disorder with comorbid SUD have an increased prevalence of suicide attempts [9,12–15], and a more severe bipolar disorder clinical course, including delayed recovery from mood episodes, lower remission rates, and faster relapses [16–18]. Commonly, researchers define primary SUD as one that precedes the onset of bipolar disorder, and secondary SUD as one that begins after the onset of bipolar disorder. The frequency of these SUD categories among people with the dual-diagnosis of bipolar disorder in a treatment setting is about 30%–53% for primary SUD and 47%–70% for secondary SUD, respectively [19–21]. Recent models suggest that bipolar disorder with primary and secondary SUD have different etiologies. Primary SUD may lead to the onset of bipolar disorder in people who have an underlying

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susceptibility to bipolar disorder, while secondary SUD may represent an attempt to self-medicate symptoms of bipolar disorder or be a result of increased impulsivity during hypomanic, manic or mixed-mood states [22]. Differential etiologies would suggest that optimal prevention and treatment of SUD differ for people with bipolar disorder and primary versus secondary SUD. Prevention of SUD among people with bipolar disorder could theoretically lead to reduction of morbidity and improved quality of life. Identification of risk factors for secondary SUD among people with bipolar disorder would be beneficial in the development of effective SUD prevention strategies in this population. The results of two studies indicated that secondary SUD was more likely to develop in males and in individuals with a younger age at bipolar disorder onset [21,23]. Otherwise, little is known about factors that might predict secondary SUD. Some studies have compared people with bipolar disorder who have primary or secondary SUD, and have identified the following as factors that distinguish primary and secondary bipolar disorder: talking to a professional about mood problems [24], hospitalization for a mood episode [5,24], and family history of SUD [25]. Most other studies focus on the diagnosis of lifetime SUD, and do not distinguish between primary or secondary SUD in people with bipolar disorder. However, factors associated with lifetime SUD among people with bipolar disorder could also be potential risk factors for secondary SUD. Such factors include the following: sex [26], attention deficit hyperactivity disorder (ADHD) [27], anxiety disorders [28], conduct disorder (CD) [29,30], and suicide attempts [9,12–15]. Oppositional defiant disorder (ODD) has also been examined within a limited number of studies, but it has not been found to be associated with SUD [29]. Among those with early-onset bipolar disorder, adolescentonset (bipolar disorder) (approximately age 13–18 years) conveys an increased risk of lifetime SUD compared to childhood-onset bipolar disorder (b13 years) [30–32]. The studies described above did not look at risk factors for secondary SUD specifically compared to individuals with bipolar disorder who do not develop SUD. Identification of risk factors for secondary SUD among people with bipolar disorder is a critical next step in the development of SUD prevention strategies for this population. Targeting earlyonset bipolar disorder offers the most opportunities for prevention of secondary SUD; therefore, this study focuses on individuals with early-onset bipolar disorder. The first goal of this study was to determine the prevalence of potential risk factors for secondary SUD in people with childhood or adolescent-onset primary bipolar disorder. We used the existing research described above to guide the identification of potential risk factors to be considered in this analysis. The second goal was to identify the factors that increase the chances of developing a secondary SUD among people in this population. We used data from the population-based National Comorbidity

Survey Replication (NCS-R) study; a major advantage of this data set is that risk factors can be placed in temporal order relative to the onset of SUD. As temporal data are lost in the more commonly used analytic techniques such as logistic regression, survival analysis is an ideal method to retain this information and therefore to identify risk factors that are present before the onset of secondary SUD. 2. Materials and methods 2.1. Sample The National Comorbidity Survey Replication (NCS-R) study collected data on symptoms of mental disorders from a nationally representative population in the United States (US) in 2001 through 2003. Data were collected on 9282 individuals aged 18 years and older. Study procedures have been published elsewhere [33]. 2.2. Assessment The NCS-R diagnoses and ages of onset were based on Version 3.0 of the World Health Organization's (WHO) Composite International Diagnostic Interview (CIDI), a fully-structured lay-administered interview [34]. Diagnoses of bipolar disorder, conduct disorder (CD), oppositional defiant disorder (ODD), attention deficit hyperactivity disorder (ADHD), substance use disorder (SUD), and any anxiety disorder (social phobia, specific phobia, agoraphobia, panic disorder, post-traumatic stress disorder, or general anxiety disorder) were made according to Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria. The age at onset of bipolar disorder was defined as the age at first mood episode, regardless of whether it was mania, hypomania, subthreshold hypomania, or a major depressive episode. 2.3. Variables 2.3.1. Dependent variables SUD was defined as alcohol abuse or dependence, or drug (cocaine, cannabis, prescription, or other) abuse or dependence. Among individuals with more than one of the above four lifetime SUD diagnoses, the one that occurred first was used to determine the age at onset of SUD in the individual. We defined primary bipolar disorder as that which occurs without SUD at the time of or concurrent with (within the same year) the onset of bipolar disorder. 2.3.2. Time-independent covariates We considered three time-independent variables. The first was sex (male vs. female). The second was type of bipolar disorder (I, II, subthreshold). Bipolar I disorder was defined as ever having had a manic episode. Bipolar II disorder was defined as ever having had a hypomanic episode, ever having had an episode of MDE, and never having had a manic episode. Subthreshold bipolar disorder was defined as (a) recurrent subthreshold hypomania and intercurrent MDE,

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or (b) recurrent hypomania without recurrent MDE, or (c) recurrent subthreshold hypomania without intercurrent MDE. Subthreshold hypomania was defined as meeting two or more criterion B symptoms and all other criteria for hypomania. Cases with plausible organic causes were excluded. Additional details regarding the categorization of bipolar disorder in the NCS-R study have been previously published [1]. Third, age of bipolar disorder onset was categorized as childhood vs. adolescent. We defined childhood-onset as the onset of a manic/hypomanic or major depressive episode before the age of 13 years, and adolescent-onset as 13 through 18 years [30,32,35]. Fourth, we considered family history of SUD. Because only a subset of participants was asked about family history, almost half (49.4%) of the observations in the data set were missing data for family history of SUD. Therefore, we instead used the variables of having grown up with an adult male or female with SUD to indicate a possible family history of SUD. 2.3.3. Time-dependent covariates The time-dependent covariates were the ages at which the individual reported his/her first suicide attempt; first hospitalization for a mood episode; first experience talking to a professional about mood problems; first diagnosis of CD, ODD, ADHD, and any anxiety disorder prior to the report of the diagnosis of the secondary SUD. Due to the complex assessment and diagnosis of obsessive compulsive disorder (OCD), diagnostic data on OCD were collected on only 30% of the participants [36]; therefore, OCD was not included in the definition of any anxiety disorder for the purposes of this analysis. Among individuals with more than one lifetime anxiety disorder, the disorder with the earliest onset was used to determine the age at onset of anxiety disorder in the individual. In addition, we included whether the individual's age of the first drink of alcohol occurred during childhood (b14 years) or adolescence (14–18 years) due to existing research demonstrating that individuals in the general population who had their first drink of alcohol before the age of 15 years have a higher rate of lifetime alcohol abuse compared to those whose first drink was at age 15 years or greater [37,38]. The risk of lifetime alcohol dependence is lower among those who had their first drink after the age of 18 years than those who drank at an earlier age [39]. 2.4. Statistical analysis All statistical analyses were conducted using Statistical Analysis Software (SAS) version 9.2. To account for the complex design structure and weighting of NCS-R, we used the survey applications, which utilize the Taylor series linearization method [40]. Logistic regression, controlling for current age, was used to compare the prevalence and age at onset of demographic and clinical covariates. Reported pvalues are not corrected for multiple comparisons.

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Both time-dependent and time-independent covariates were used in an extended Cox proportional hazards survival analysis. The assumption of proportionate hazards (PH) for each covariate was assessed by testing its interaction with time. Sex did not meet the PH assumption; therefore, we stratified the multivariate models by sex. The cosandwich function was used to account for multicollinearity. We began with a model that included the main effects of all variables, and removed the covariate with the highest p-value in each subsequent model until all of the remaining covariates had a p-value less than 0.05. The PH assumption was again tested for each of the remaining variables within the context of the final model. Finally, we assessed two-way interactions between the categorical variable age at bipolar disorder onset (childhood versus adolescent) and each of the other covariates in the final model. 2.5. Approval The study procedures were approved by the institutional review board of the Syracuse Veterans Administration Medical Center. 3. Results Within the NCS-R sample population, there were 192 people with early-onset (b18 years) bipolar disorder (I, II or subthreshold). Of these, 60 had childhood-onset (b13 years) and 132 had adolescent-onset (13–18 years) bipolar disorder. SUD was not present at the time of bipolar disorder onset in 98.3% and 75.0% of people with childhood and adolescent-onset bipolar disorder, respectively (Table 1); these are the individuals that comprise our study group. The demographic, history and comorbidity variables of the study groups are presented in Table 2. People with childhood-onset bipolar disorder had a higher frequency of ADHD and suicide attempts than did those with adolescentonset bipolar disorder. Adjusting for age at the time of the survey, people with childhood-onset bipolar disorder had higher odds of lifetime ADHD (aOR = 2.81, 95% CI: 1.46–5.40, p = 0.0020) and suicide attempts (aOR = 3.61, 95% CI: 1.48–9.01, p = 0.0059) compared to those with adolescent-onset bipolar disorder. Childhood-onset bipolar disorder also was associated with an earlier age at onset of CD, younger age at time of first drink, and younger age at which the individual first talked to a professional about mood problems. Otherwise, there were no significant differences between people with childhood and adolescent-onset bipolar disorder in demographics, prevalence of comorbidities, or age at onset of comorbidities. The average time between onset of bipolar disorder and first talking to a professional about mood was approximately 8 years (Table 1), and did not differ between those with childhood versus adolescent onset bipolar disorder. Eightyone individuals first talked to someone the same year as or

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Table 1 Prevalence of SUD among childhood and adolescent-onset bipolar and estimates of population prevalence. Unadjusted

BPD without SUD BPD with secondary SUD BPD with concurrent SUD (within same year) BPD with primary SUD

Adjusted for sampling method

Childhood-Onset (b13) N = 60

Adolescent-Onset (13–18) N = 132

Childhood-Onset

Adolescent-Onset

30 (50.0%) 29 (48.3%) 1 (1.7%) 0

64 (48.5%) 35 (26.5%) 18 (13.6%) 15 (11.4%)

48.9% 50.2% 0.8% 0

45.7% 28.8% 13.7% 11.8%

after the onset of bipolar disorder, with a mean lag time of 9.9 years (sd = 10.3). Fourteen individuals reported that they talked to someone about mood an average of 2.5 years (sd = 2.1) before the onset of bipolar disorder. The prevalence of secondary SUD among people with early-onset primary bipolar disorder was 43.1% and did not differ between those with childhood and adolescent-onset bipolar disorder in a univariate analysis. Survival analysis was used to identify risk factors for the development of a

secondary SUD among people early-onset bipolar disorder. Males with bipolar disorder were more likely than females to develop secondary SUD, and did so at a faster rate (Fig. 1). Because the effect of sex on development of SUD did not meet the PH assumption, we developed a PH model that was stratified by sex. The final Cox proportional hazards model, stratified by sex, is shown in Table 3. Onset of bipolar disorder during adolescence, ODD, any anxiety disorder, and suicide

Table 2 Characteristics of childhood and adolescent onset bipolar in the NCS-R.

DEMOGRAPHICS Current age, mean (SD) Male (%) Race/Ethnicity (%) White, Non-Hispanic Black or African–American Other BP Subtype (%) BP type 1 BP type 2 Subthreshold BP HISTORY Grew up with an adult female who had a drug/alcohol problem (%) Grew up with an adult male who had a drug/alcohol problem (%) Ever talk to someone about mood, lifetime Age first talked to someone about mood, mean (SD) a Duration from bipolar onset to time first talked to someone about mood b Age at first drink, mean (SD) a Duration from first drink to onset of SUD, mean (SD) CO-MORBIDITIES ADD, lifetime (%) Age of onset of ADD, mean (SD) a CD, lifetime (%) Age of onset of CD, (SD) a Any anxiety disorder, lifetime (%) Age of onset of any anxiety disorder, mean (SD) a ODD, lifetime (%) Age of onset of ODD, mean (SD) a Suicide attempt, lifetime (%) Age at first suicide attempt, mean (SD) a Secondary SUD, lifetime (%) Age of onset of SUD, mean (SD) a a b

Childhood-Onset (b13 years) N = 59

Adolescent-Onset (13–18 years) N = 99

p-value controlling for current age

31.4 years (1.51) 51.2%

34.2 years (1.17) 48.5%

0.3510 0.8209

72.7% 13.6% 13.7%

72.2% 10.9% 16.9%

0.8314 0.5763 0.5237

17.7% 15.3% 67.0%

23.3% 25.0% 51.7%

0.3990 0.1975 0.1241

17.4% 38.7% 75.9% 17.2 years (0.37) 8.2 years (10.1)

10.5% 28.0% 80.9% 23.0 years (0.52) 8.0 years (1.9)

0.1419 0.0828 0.5976 0.0460 0.9439

12.5 years (0.49) 6.1 years (0.61)

13.9 years (0.27) 6.2 years (0.16)

0.0134 0.7256

40.6% 6.5 years (0.07) 27.4% 10.6 years (0.07) 80.1% 10.4 years (0.64) 35.2% 9.2 years (0.04) 16.0% 15.0 years (0.81) 50.6% 16.7 years (0.46)

19.5% 7.4 years (0.03) 25.7% 12.3 years (0.49) 83.3% 11.9 years (0.58) 24.3% 10.2 years (0.10) 5.3% 23.5 years (3.9) 38.6% 19.4 years (0.20)

0.0020 0.1056 0.9657 0.0457 0.8690 0.3154 0.2584 0.1790 0.0059 0.3890 0.1253 0.2267

Bottom coded at 4 years. 14 individuals talked to someone about mood before onset of bipolar disorder.

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Fig. 1. Sex-Specific Survival Curves for Time to Secondary SUD for People with Early-Onset bipolar disorder (N = 158).

attempts were significant predictors of time to secondary SUD in people with early-onset bipolar disorder. There were no significant two-way interactions between the categorical variable age at onset (childhood versus adolescent) and any of the other variables. The following variables were not significant predictors of secondary SUD in this model: bipolar disorder type (I, II or sub-threshold), age of first drink (childhood or adolescence), family history of bipolar disorder, growing up in a family with an adult with SUD, talking to a care provider about mood problems, hospitalization for a mood episode, ADHD and CD. Sixteen individuals in the study population had one or more suicide attempts. Of these, seven had SUD with onset before the attempt, and 3 developed SUD after the attempt. Thus, three out of six individuals who did not have SUD at the time of the attempt went on to develop SUD (50%, 95% CI: 18.8%–81.2%). Among males, 80.1% had two or more risk factors in addition to sex, and 75.5% of females had two or more risk factors (Table 4). In the study groups, there were five males and one female who did not have any of the other risk factors; none of these individuals developed SUD during the study period. There were 20 males and ten females that had all four additional risk factors; all 30 of these individuals developed secondary SUD.

4. Discussion Our main finding was that there are several risk factors associated with increased risk of SUD and faster progression to SUD in people with early-onset primary bipolar disorder, such as being male; having a history of any anxiety disorder, ODD, suicide attempts; and the onset of bipolar disorder during adolescence. The risk factors for secondary SUD that were identified in our study are largely consistent with risk factors for lifetime SUD among people with early-onset bipolar disorder. For example, being male and having adolescent-onset bipolar disorder have been consistently identified as risk factors for SUD [31,32]. Based on our results,

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we hypothesize that the effect of sex is at least partially due to the higher rate of multiple risk factors among males than females, although future research would need to confirm this hypothesis. Regarding bipolar I disorder versus bipolar II disorder, our results were consistent with the many published studies showing that the two types do not differ in lifetime SUD rate [2,5,41,42]. Previous research using the same NCS-R data set reported a difference in prevalence rates, such that lifetime SUD was more prevalent among individuals with bipolar I than bipolar II or subthreshold bipolar [1]. However, their analyses were not adjusted for sex or any of the other risk factors as reported here. The inclusion of subthreshold bipolar disorder in this study shows that the people with subthreshold bipolar disorder do not differ in risk for secondary SUD from those with bipolar I disorder or bipolar II disorder. Thus, clinicians should monitor patients with any of the bipolar spectrum disorder for SUD risk factors and early signs of SUD. The largest risk factor for SUD in our study population was a history of one or more suicide attempts. About twothirds of individuals with bipolar disorder and a history of a suicide attempt had comorbid lifetime SUD in our study population. This estimate is higher than a previous report in which 12% of individuals with bipolar disorder who have attempted suicide had alcohol abuse, compared to 8% in those without a history of suicide attempts [13]. Our higher estimate is at least partially due to our inclusion of alcohol dependence and other substance abuse/dependence as the outcome variable. Our results are also consistent with reports that individuals with bipolar disorder and comorbid AUD are more likely to have a history of suicide attempts than are those without AUD [9,14,15]. We were also able to estimate the frequency of individuals who did not have SUD at the time of their suicide attempts who went on to develop SUD. Notably, 50% of those with a suicide attempt subsequently developed SUD. Although the number of individuals with a suicide attempt in this sample was small, the results highlight suicide attempts as a major risk factor in the development of a subsequent SUD. The survival analysis results indicate that this strong association between suicide attempts and SUD is significant even when accounting for the other risk factors identified here. Table 3 Predictors of time to onset of secondary SUD in individuals with early-onset BPD (Cox proportional hazards model stratified by sex). Hazard ratio Adolescent-onset bipolar Oppositional defiant disorder Any anxiety disorder Suicide attempt

95% confidence interval

p-value

1.653 2.048

1.023–2.668 1.153–3.639

0.0399 0.0145

3.077 15.424

1.249–7.583 6.949–34.235

b.0001 0.0146

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Table 4 Number of SUD risk factors: prevalence among people with early-onset primary BPD and frequency of secondary SUD. Number of Risk Factors 0 1 2 3 4

Males

Females

Prevalence (SE)

Frequency of secondary SUD (95% CI)

Prevalence (SE)

Frequency of secondary SUD (95% CI)

9.3% (4.08) 10.6% (2.26) 23.7% (5.37) 28.9% (4.49) 27.5% (3.77)

0% (0–43.4) 0% (0–35.4) 36.8% (19.2–59.0) 73.7% (51.2–88.2) 100% (83.9–100)

1.9% (1.80) 22.6% (4.51) 44.8% (5.26) 20.4% (4.24) 10.3% (3.27)

0% (0–65.8) 10% (2.8–30.1) 2.5% (0.4–12.9) 62.5% (38.6–81.5) 100% (72.2–100%)

In contrast to previous reports, we found that ODD was a significant risk factor for secondary SUD; whereas, other studies reported that ODD was not a predictor of lifetime SUD [30,34]. In addition, several studies found CD to be predictive of SUD [35,43,44], but we did not. We also found the age of onset of any anxiety disorder was a risk factor for secondary SUD. Other studies have failed to detect that association between anxiety disorders and secondary SUD [7,29,43], although some did find that anxiety disorders were significantly positively correlated with SUD [28,42]. The comparison of our results to those of other reports is complicated by the unique nature of our study and control groups. Our model differs from other studies in three ways. First, our study population had a higher current age (mean = 34.2 years, SD = 12.9 years), allowing more time for development of comorbidities. Second, we excluded individuals with concurrent or primary SUD. Third, we used proportional hazards survival analysis, which allows for the temporal order of onset of secondary SUD and other comorbidities. This approach allowed us to focus exclusively on risk factors for secondary SUD. Of note, the rate of anxiety disorders was higher among our study group (80%–83%), than in other reports of people with early-onset bipolar disorder (30%–70%) [32,35,45]. This might be due to the distinctive nature of our study group, because anxiety disorders are more common among individuals with secondary than primary SUD [46], and people with primary SUD were excluded from our study. The frequencies of other comorbid conditions, including lifetime ADD, ODD and suicide attempts, were similar to those reported elsewhere [5,31,32]. Because many of the subgroups had small sample sizes, interpretation of these results need to be tempered accordingly. The other limitations of this analysis are related to the survey methodology. The data are cross-sectional and retrospective, and the results need to be verified in a prospective longitudinal study. The CIDI protocol collects data based on recall and calculates age at onset retrospectively. Although this approach is limited by recall bias, test– retest reliability of age at onset in the CIDI was high (ICC between 0.70 and 0.80) for depressive episodes, dysthymia, generalized anxiety disorder, agoraphobia and panic disorder [47]. Chengappa et al. [48] cross-checked responses to different questions about age of first mood episode in two

separate parts of SCID-based interview and reported that recall bias in bipolar disorder is limited to three to six months, well within the one-year time frame that we used to temporally order events in our analysis. The CIDI data in the NCS-R study do not include diagnostic data on OCD for the majority of participants. Therefore, OCD was not included in our analysis. However, the rate of comorbid OCD is low in people with bipolar disorder [1,7,48] and the co-occurrence of both OCD and other anxiety disorders is high [36], so exclusion of OCD from our analysis probably had very little, if any, impact on our results. On the other hand, given the high rate of anxiety disorders in our study group, it is possible that the CIDI over-diagnosed anxiety disorders. More research is needed to determine if the high rate of anxiety disorders in our study was due to the nature of our sample (primary SUD was excluded) or due to bias introduced by the CIDI. Our findings highlight the importance of early diagnosis of bipolar disorder, as well as comorbid ODD and anxiety disorders, in order to maximize SUD prevention opportunities. Hospitalization for a mood episode did not predict secondary SUD in our survival analysis. Likewise, subthreshold bipolar disorder carried the same risk of SUD as did bipolar I disorder and bipolar II disorder. Therefore, diagnosis of early-onset bipolar disorder is critical, even in the early course of the disorder when the individual may not meet the full diagnostic criteria for bipolar I disorder or bipolar II disorder. Further research is needed to explore the differential risk of SUD based on age at onset. The lower SUD risk associated with childhood-onset (versus adolescent-onset) bipolar disorder could be due to differences in clinical course in that people with childhood-onset bipolar disorder had higher frequencies of ADD, ODD and suicide attempts than those with adolescent-onset bipolar disorder. Alternatively, or in addition, early treatment of people with childhoodonset bipolar disorder may help protect against development of secondary SUD [41]. An understanding of the cause of this difference would also help inform the development of SUD prevention strategies. In addition, interventions that target modifiable health behaviors that have an impact on mood, as well as strategies for coping with mood-related problems, may be more

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effective than traditional treatment strategies [49,50] since our data found that those who had talked to a professional about their mood were not protected. Further research could also assess the effectiveness of tailoring prevention strategies for individual patients based on their presentation, particularly ODD, suicide attempts, anxiety disorders, and early alcohol use. The lack of impact of talking to a professional about mood could also be due to the large time period between the onset of bipolar disorder and first talking to someone about mood problems (about eight years). Onset of secondary SUD during this gap may be related to use of alcohol or other drugs for self-medication of mood symptoms. Given that the mean amount of time between having a first alcoholic beverage and developing secondary SUD was only about six years, this highlights the importance of early identification and treatment of bipolar disorder in the prevention of SUD. To our knowledge, our study is the first to extensively assess the risk factors for secondary SUD among individuals with primary bipolar disorder. There are two major strengths of this analysis. First, the study is based on individuals with bipolar disorder who were identified via a nationally-representative general population study group. Whereas most studies ascertain participants via clinics or hospitals, our study group includes individuals with bipolar disorder who have not been formally diagnosed. We also included individuals with subthreshold bipolar disorder. Thus, the results of our study may be uniquely applicable to individuals who are identified early in the course of bipolar disorder. Second, the proportional hazards survival analysis used here retains the information about temporal presentation of bipolar disorder, comorbidities, and health behaviors such as drinking and treatment for mood problems. Therefore, we were able to assess the hazard ratios for the development of SUD based on the comorbidities of individuals with bipolar disorder at the time of presentation. In conclusion, when assessing a patient with earlyonset bipolar disorder who does not have an SUD, anyone with one or more of these factors should be considered to be at an increased risk of development of secondary SUD: any anxiety disorder, ODD, adolescentonset bipolar, being male, and history suicide attempts. Many patients have multiple risk factors for secondary SUD and are therefore at very high risk of developing SUD, and the risk of SUD appears to increase with the number of risk factors. People with subthreshold bipolar disorder, bipolar I disorder or bipolar II disorder do not appear to differ in the risk of SUD. This would simplify clinical interventions, as it may not be necessary to develop different prevention protocols for people who fall within different parts of the bipolar disorder spectrum. Early identification of bipolar disorder, along with treatment and prevention strategies tailored toward the patient's risk factors may prevent the development of

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SUD, and thereby decrease the morbidity and mortality of people with bipolar disorder.

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