Comorbid Anxiety in Children and Adolescents With Bipolar Spectrum Disorders: Prevalence and Clinical Correlates
Objective: Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder. We aimed to examine the prevalence and correlates of comorbid anxiety disorders among youth with bipolar disorder.
Method: As part of the Course and Outcome of Bipolar Youth study, 446 youth, ages 7 to 17 years, who met DSM-IV criteria for bipolar I disorder (n = 260) or bipolar II disorder (n = 32) or met operationalized criteria for bipolar disorder not otherwise specified (n = 154) were included. Subjects were evaluated for current and lifetime Axis I psychiatric disorders at intake using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children–Present and Lifetime version, and standardized instruments were used to assess functioning and family history.
Results: Forty-four percent (n = 194) of the sample met DSM-IV criteria for at least 1 lifetime anxiety disorder, most commonly separation anxiety (24%) and generalized anxiety disorders (16%). Nearly 20% met criteria for 2 or more anxiety disorders. Overall, anxiety disorders predated the onset of bipolar disorder. Subjects with bipolar II disorder were more likely than subjects with bipolar I disorder or bipolar disorder not otherwise specified to have a comorbid anxiety disorder. After adjusting for confounding factors, youth with bipolar disorder with anxiety were more likely to have bipolar II disorder; longer duration of mood symptoms; more severe ratings of depression; and family history of depression, hopelessness, and somatic complaints during their worst lifetime depressive episode than those without anxiety.
Conclusions: Comorbid anxiety disorders are common in youth with bipolar disorder, and they most often predate bipolar disorder onset. Bipolar II disorder, a family history of depression, and more severe lifetime depressive episodes distinguish youth with bipolar disorder with comorbid anxiety disorders from those without. Careful consideration should be given to the assessment of comorbid anxiety in youth with bipolar disorder.
J Clin Psychiatry 2010;71(10):1344–1350
© Copyright 2010 Physicians Postgraduate Press, Inc.
Submitted: November 20, 2009; accepted April 13, 2010.
Online ahead of print: September 7, 2010 (doi:10.4088/JCP.09m05845gre).
Corresponding author: Regina Sala, MD, University of Pittsburgh, Western Psychiatric Institute and Clinic, 100 N Bellefield Ave, No. 542, Pittsburgh, PA 15213 (email@example.com).
Onset of bipolar disorder during childhood significantly affects an individual’s psychosocial development. Moreover, youth with bipolar disorder are at high risk for suicidal behaviors and completed suicide, substance abuse, and legal problems, and they have particularly high rates of health services utilization.1–3
Some of the most common comorbid disorders among youth with bipolar disorder are the anxiety disorders.4 Since anxiety disorders are also accompanied by significant impairment in the psychosocial functioning of the child,5 it is important to evaluate the prevalence and clinical correlates of the association between bipolar disorder and anxiety in youth. The few studies that have addressed this issue in small samples of youth with bipolar disorder have shown lifetime prevalence of comorbid anxiety disorders between 14% and 56%, with a weighted average of 27%.3,6–10 Moreover, family studies have consistently shown high rates of anxiety disorders in offspring of parents with bipolar disorder.11–15
The above-noted findings are consistent with the adult epidemiologic16–18 and clinical literature.19,20 In fact, retrospective data from studies of adults with bipolar disorder indicate higher rates of comorbid lifetime anxiety disorders among those with earlier age at bipolar disorder onset. Specifically, in 1 study by Perlis and colleagues,21 adults who reported bipolar disorder onset before age 13 years demonstrated a 70% rate of comorbid lifetime anxiety disorder as compared with 54% of those with bipolar disorder onset between 13 and 18 years and 38% of those with bipolar disorder onset after age 18 years.
Prior research indicates that the presence of comorbid anxiety disorders negatively affects course, outcome, and treatment response in bipolar disorder. In a study by Masi and colleagues,22 youth with bipolar disorder with panic disorder, as compared to those without panic, demonstrated less bipolar disorder severity at baseline but had poorer response to treatment. Furthermore, DelBello and colleagues7 found that adolescents with bipolar disorder and comorbid anxiety had more severe mood symptoms and lower rates of recovery 1 year after index hospitalization than adolescents without comorbid anxiety. Similarly, studies among adults with bipolar disorder consistently find that the presence of comorbid anxiety is associated with worse course and outcomes, including higher rates of rapid cycling, more severe depression, substance abuse, and suicide attempts, as well as lower rates of treatment response and recovery. Furthermore, adult patients with bipolar disorder and comorbid anxiety report poorer psychosocial functioning and lower overall quality of life.19,20
The association between bipolar disorder and comorbid anxiety disorders is of particular clinical significance, since the pharmacologic treatment for anxiety disorders with the most evidence of efficacy in both children and adults is the use of selective serotonin reuptake inhibitors (SSRIs).23–25 Unfortunately, these medications have been shown to destabilize the symptoms of bipolar disorder.26,27
Given the clinical relevance of comorbid anxiety and bipolar disorder and the existence of few studies with small samples, we aimed to investigate the prevalence, correlates, and familial risk associated with comorbid anxiety disorder in a large sample of children and adolescents with bipolar disorder spectrum disorders. We hypothesized that, as compared with youth with bipolar disorder and no comorbid anxiety (BP/no anxiety), those with bipolar disorder and a comorbid anxiety disorder (BP/anxiety) would have (1) earlier bipolar disorder onset and more severe lifetime bipolar disorder symptoms, (2) higher rates of suicidal behavior and substance use disorders, (3) poorer overall functioning, and (4) higher rates of familial mood and anxiety disorders.
Subjects and Procedures
The methods for the Course and Outcome of Bipolar Youth (COBY) study have been described in detail elsewhere.3,28 Briefly, 446 youth, ages 7 to 17 years 11 months (mean = 12.7 years, SD = 3.2 years), who met criteria for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)29 bipolar I disorder (n = 260), bipolar II disorder (n = 32), and operationally defined bipolar disorder not otherwise specified (NOS; n = 154)3,28,30 were recruited primarily though clinical referrals from 3 academic medical centers (University of Pittsburgh [Pittsburgh, Pennsylvania], Brown University [Providence, Rhode Island], and University of California at Los Angeles [Los Angeles, California]). Institutional review board approval was obtained at each site prior to subject enrollment.
Because the DSM-IV criteria for bipolar disorder NOS are vague, the COBY study investigators set the minimum inclusion threshold for the bipolar disorder NOS group as subjects who did not meet the DSM-IV criteria for bipolar I disorder or bipolar II disorder but had a distinct period of abnormally elevated, expansive, or irritable mood plus the following: (1) 2 DSM-IV manic symptoms (3 if the mood is irritability only) that were clearly associated with the onset of abnormal mood; (2) a clear change in functioning; (3) mood and symptom duration of a minimum of 4 hours within a 24-hour period for a day to be considered meeting the diagnostic threshold; and (4) a minimum of 4 days (not necessarily consecutive) meeting the mood, symptom, duration, and functional change criteria over the subject’s lifetime, which could be two 2-day episodes, four 1-day episodes, or another variation.
Children and parents were directly interviewed for the presence of current and lifetime psychiatric disorders using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children–Present and Lifetime version (K-SADS-PL),30 the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children Mania Rating Scale (K-SADS-MRS),31 and the depression section of the K-SADS-P (from which the Dep-12 depression rating scale was extracted). The K-SADS-PL utilized in COBY did not include the new pervasive developmental disorder (PDD) module. For PDD, we used a DSM-IV checklist.
Parents were interviewed at intake about their personal psychiatric history using the Structured Clinical Interview for DSM-IV (SCID),32 and about their first- and second-degree psychiatric family history using the Family History Screen (FHS).33 The Petersen Pubertal Developmental Scale (PDS)34 was used to evaluate and categorize pubertal stages. Socioeconomic status was measured using the Hollingshead 4-factor scale (Hollingshead AB, 1975, unpublished), and functional impairment was assessed using the Children’s Global Assessment Scale (CGAS).35
Research interviewers were trained to high reliability in administration of the K-SADS, the SCID, and the FHS before interviewing any subjects or parents. The results of each interview were reviewed by a child psychiatrist or psychologist. Diagnostic reliability was measured by having research interviewers from all sites rate 13 audiotapes of actual COBY study interviews. There was high reliability for differentiating subjects with bipolar disorder from non–bipolar disorder subjects (κ = 0.90) and for the bipolar disorder diagnostic subtypes (κ = 0.79). For the non–mood disorders, κ values were 0.80 or higher. The intraclass correlation coefficient was 0.96 for the K-SADS-MRS and 0.98 for the K-SADS depression scale.
We considered subjects positive for the presence of any lifetime anxiety disorder if they met full threshold criteria for at least 1 of the following disorders: separation anxiety disorder, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), social phobia, panic disorder, anxiety disorder NOS, or agoraphobia. Obsessive-compulsive disorder and PTSD have often been classified as distinct from other anxiety disorders for the complexity of the clinical description and diagnosis. Obsessive-compulsive disorder is characterized by the presence of either obsessions or compulsions, and PTSD refers to a characteristic set of psychological and physiologic symptoms following exposure to a stressor event. The majority of subjects with OCD or PTSD also met criteria for a different anxiety disorder (11.9%), and that is the reason that we decided to include them in the BP/anxiety group—because both cause marked distress and significant impairment similar to the other anxiety disorders. Twenty-nine youth with only specific phobia (eg, fear of spider, dark, or insects) were excluded from the BP/anxiety group because simple phobias are ubiquitous. In addition, they are one of the least reliable anxiety diagnoses in children, perhaps due, in part, to imprecision in standards for distress and impairment, since the threshold between a fear and a phobia is not always straightforward.36
Youth with autism were not included because it is very difficult to obtain information about their mood status, and about 70% have low IQ. Subjects with IQ less than 70 were excluded from the grant. In contrast, youth with Asperger’s disorder or PDD NOS were recruited. In COBY, only 2% of the subjects fulfilled criteria for these disorders.
Between-group comparisons in demographic factors were carried out using standard parametric and nonparametric univariate tests. Results were adjusted for bipolar disorder subtype and any other significant between-group demographic differences. Those variables with P values ≤ .25 were then entered into a multivariate logistic regression. Exploratory analyses were carried out examining the presence or absence of mood symptoms during the most severe lifetime episodes using the items from the K-SADS-MRS and the Dep-12 plus the hopelessness and aches and pains questions from the K-SADS-P depression section, because these symptoms have been associated with more severe anxiety.37,38 All P values were based on 2-sided tests, and, when appropriate, we used Bonferroni corrections to keep the family-wise error rate at α = .05, at most. Odds ratios (ORs) and confidence intervals (CIs) were computed.
Prevalence and Demographics
Forty-four percent (194/446) of subjects met lifetime criteria for at least 1 comorbid anxiety disorder. The most common comorbid anxiety disorders included separation anxiety disorder (n = 108, 24%) and GAD (n = 71, 16%), followed by OCD (n = 29, 7%), PTSD (n = 27, 6%), social phobia (n = 26, 6%), panic disorder (n = 25, 6%), anxiety disorder NOS (n = 11, 3%), and agoraphobia (n = 10, 2%). Eighteen percent of subjects had more than 1 lifetime anxiety disorder, and 5% met criteria for 3 or more anxiety disorders. The proportion of subjects whose age at onset of anxiety was less than age at onset of bipolar disorder was 78.7% (151 out of 192 subjects, as 2 subjects were missing information on age at onset of anxiety). The means and standard deviations of age at onset of anxiety and bipolar disorder for these 192 subjects were 6.3 ± 3.3 years and 9.0 ± 3.7 years, respectively.
As shown in Table 1, compared to the BP/no anxiety group, those with BP/anxiety had significantly lower socioeconomic status, although the actual difference is minimal (3.3 vs 3.5), and a trend to be less likely to live with both natural parents. There were no other between-group demographic differences.
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Clinical Characteristics of Bipolar Illness and Comorbidity
As shown in Table 2, the overall χ2 comparing bipolar disorder subtypes and presence of any lifetime anxiety disorder was significant (χ22 = 8.94, P value = .01). However, the differences were only accounted by the bipolar II disorder subtype.
After adjusting for bipolar disorder subtype, socioeconomic status, and living with both natural parents, the BP/anxiety group had significantly longer duration of mood symptoms and higher depression scores for both current and most severe lifetime episodes compared with the BP/no anxiety group. In addition, the BP/anxiety group was more likely to report that their most recent DSM mood episode was of the depressive subtype and less likely to indicate that their index episode was of the manic subtype (all P values ≤ .05). Lifetime history of suicidal ideation or attempts was not significantly different between groups. There were no other significant differences in comorbidity or functioning between groups (Table 3).
In comparison with the BP/no anxiety group, those with BP/anxiety were more likely to endorse a positive first- or second-degree family history of depression and anxiety disorders (all P values ≤ .001), and a trend of positive first- or second-degree family history of mania or hypomania (P value = .06) (Table 3).
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Multivariate Logistic Regression
The BP/anxiety group remained significantly associated with bipolar II disorder (OR = 2.34; 95% CI, 1.02–5.35), longer duration of mood symptoms (OR = 1.11; 95% CI, 1.03–1.19), higher current depression scores in Dep-12 (OR = 1.04; 95% CI, 1.02–1.07), fewer manic episodes (OR = 0.38; 95% CI, 0.2–0.73), and higher rates of depression among first- or second-degree relatives (OR = 3.58; 95% CI, 1.62–7.93) (Table 4).
Severity of Manic and Depressive Symptoms
We examined whether there were differences between the BP/anxiety and BP/no anxiety groups in the severity of manic and depressive symptoms. Exploratory analyses, adjusted for multiple comparisons, were conducted using ratings from the most severe lifetime manic or hypomanic (K-SADS-MRS) and depressive episodes (Dep-12). Only symptoms rated at mild or higher (≥ 3) were analyzed. There were no between-group differences in manic or hypomanic symptoms. In contrast, youth with BP/anxiety depressive episodes had significantly more depressed mood, hopelessness, aches and pains, anhedonia, and fatigue after controlling for multiple comparisons using Bonferroni correction. Suicidal ideation was also significantly higher in the BP/anxiety group but did not survive Bonferroni correction (Table 5).
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In the multivariate analysis of Dep-12, hopelessness (OR = 2.1; 95% CI, 1.28–3.28) and aches and pains (OR = 2.5; 95% CI, 1.56–3.95) were the only 2 items that were significant in the BP/anxiety group during their worst lifetime depressive episode.
To our knowledge, this is the largest study to date examining prevalence and demographic and clinical correlates of comorbid anxiety disorder among children and adolescents with bipolar disorder.
Forty-four percent of youth with bipolar disorder in our sample met criteria for at least 1 lifetime anxiety disorder, most commonly separation anxiety disorder and GAD; 18% had 2 or more lifetime anxiety disorders. On average, the onset of anxiety predated the onset of bipolar disorder. After adjusting for significant demographic factors and bipolar disorder subtypes, youth with BP/anxiety, as compared with BP/no anxiety, showed significantly higher rates of bipolar II disorder, longer duration of mood symptoms, higher current depression scores, lower likelihood of reporting an index episode of the manic subtype, and higher rates of familial depression, and they had a worst lifetime depressive episode characterized by greater severity of hopelessness and aches and pains.
Our findings are consistent with those of previous studies in which anxiety disorders, particularly separation anxiety disorder and GAD, have been reported at high rates among youth and adults with bipolar disorder.6,8–10,18,39–45 Also similar to other studies in the child and adult literature, we found that subjects with bipolar disorder with comorbid anxiety disorders were more likely to have a diagnosis of bipolar II disorder,22,42,44,46–48 longer duration of mood symptoms, and greater severity of depressive episodes.49–53 This association may be related to the fact that bipolar II disorder has a more chronic course and outcome, longer length of illness, shorter cycles, greater number of episodes, more major and minor depressive episodes, shorter well intervals between episodes, and lower rates of recovery.54,55 Moreover, we found, similar to the bipolar disorder9,56 and unipolar depression57,58 literature, that, on average, the anxiety disorders preceded the onset of the mood disorder. Contrary to our initial hypothesis,10,40,59–60 age at onset of bipolar disorder episode did not differ between the 2 groups.
These findings are clinically relevant because, currently, the first-line pharmacologic treatments for anxiety disorders in youth are the SSRIs.24,25 Selective serotonin reuptake inhibitors have been shown to trigger or destabilize bipolar disorder symptoms.26 Thus, it is critically important to evaluate a child presenting with anxiety for the presence of manic or hypomanic symptoms, especially if depressive symptoms and a positive family history of mood disorders are also present. Although hypomanic symptoms can be difficult to ascertain in youth due to the unique developmental presentation61 as well as symptom overlap with other conditions including depression and anxiety, recent studies clearly demonstrate that mania or hypomania in youth can be reliably diagnosed.3 Additionally, anxious children treated with antidepressants should be carefully monitored for the presence of manic or hypomanic symptoms.40
Little is known about the most efficacious treatments for the treatment of comorbid anxiety in youth with bipolar disorder. Future studies may evaluate the efficacy of psychotherapy approaches with empirical support for the treatment of anxious youth, such as cognitive-behavioral therapy.23 The risk/benefit ratio of the use of SSRIs in youth with bipolar disorder who are taking concurrent mood stabilizers may also be explored.
Interestingly, we found that youth with BP/anxiety showed significantly more family history of depression. This finding is consistent with Wozniak et al,62 who reported elevated risk for both bipolar disorder and anxiety among relatives of BP/anxiety probands. As such, this group suggested that comorbid anxiety and bipolar disorder may represent a genetic subtype of bipolar disorder. Furthermore, a recent study by Birmaher and colleagues11 found that offspring of parents with bipolar disorder had higher rates of anxiety disorders than offspring of control parents, suggesting that anxiety may be a precursor of bipolar disorder among bipolar disorder offspring. Thus, systematic evaluation of youth with anxiety disorder and family history of mood disorders is warranted because these youth may be at high risk to develop bipolar disorder.
Contrary to our initial hypothesis,4,20,49,59,63–66 we did not find significantly more suicidal behaviors9 or substance use disorders in the bipolar disorder with comorbid anxiety group as compared to those without. These discrepancies may be explained by the fact that most subjects in this study have not yet reached the age of highest risk for these conditions. Nonetheless, youth with bipolar disorder and anxiety had significantly more suicidal ideation as well as hopelessness during the most severe lifetime depressive episode than subjects without comorbid anxiety. Since hopelessness is highly associated with suicide attempts and suicide,67–69 careful evaluation and monitoring of suicide risk in youth with BP/anxiety are clearly indicated. Also contrary to our initial hypothesis,4,20 we did not find poorer functioning in the bipolar disorder group with comorbid anxiety as compared with those without. It is possible that the impact of bipolar disorder on global functioning during childhood and adolescence is significantly profound, such that any additional impairment associated with comorbid anxiety is relatively negligible.
Finally, after adjusting for multiple comparisons, youth with bipolar disorder and comorbid anxiety reported more aches and pains than those without anxiety, as is the case in adult studies.70 It has been well documented that anxious youth experience somatic complaints and tend to consult primary care physicians or pediatricians before mental health clinicians.71 Thus, it is important to educate such front-line providers about the possibility that anxious youth with a positive family history of mood disorder may also have bipolar disorder.
It is important to note the limitations of this study. First, as most subjects were white and were recruited primarily from outpatient clinical settings, the generalizability of the findings remains uncertain. However, a community-based study of nonreferred adolescents with bipolar disorder reported similarly high rates of comorbid anxiety disorders.72 Second, subjects were ascertained for bipolarity. Thus, results may not apply to subjects whose primary diagnosis is anxiety and then develop bipolar disorder. Third, this study is cross-sectional, and data were ascertained retrospectively. We are currently following these subjects longitudinally, and we will thus be able to further examine the associations over follow-up. Finally, no psychiatric control group was included. Thus, using the current sample, we cannot conclude that lifetime anxiety disorders are more common in youth with bipolar disorder than in youth with other childhood psychiatric disorders (eg, major depressive disorder).
In summary, anxiety disorders usually predate the onset of bipolar disorder and are very common in youth with bipolar disorder, especially those with bipolar II disorder, longer duration of mood symptoms, more severe depressions, and family history of depression. Given the clinical and treatment implications of these findings, early identification and accurate diagnosis for these youth is very important. Randomized trials to evaluate treatments for anxiety in youth with bipolar disorder are needed. Finally, longitudinal studies to determine the impact of comorbid anxiety disorder on the course and outcome of pediatric bipolar disorder spectrum disorders are warranted.
Author affiliations: Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pennsylvania (Drs Sala, Axelson, T. Goldstein, Ha, B. Goldstein, Ryan, and Birmaher and Mss Liao and Gill); Department of Child and Adolescent Psychiatry and Psychology, IDIBAPS, CIBERSAM, Neurosciences Institute, Hospital Clinic de Barcelona, Universitat de Barcelona, Spain (Dr Castro-Fornieles); Department of Statistics, University of Pittsburgh, Pennsylvania (Dr Iyengar); Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, California (Dr Strober); Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada (Dr B. Goldstein); and Department of Psychiatry and Butler Hospital, Brown University School of Medicine, Providence, Rhode Island (Drs Yen, Hunt, Dickstein, and Keller and Ms Hower).
Potential conflicts of interest: Dr Sala was supported by a grant from the Alicia Koplowitz Foundation. Dr Hunt has received financial or material support from Wiley Publishing. Dr Keller has been a consultant for or received honoraria from Abbott, CENERX, Cephalon, Cypress Bioscience, Cyberonics, Forest, Janssen, JDS, Medtronic, Organon, Novartis, Pfizer, Roche, Solvay, and Wyeth; has received grant/research support from Pfizer; and has been a member of the advisory boards for Abbott, Bristol-Myers Squibb, CENERX, Cyberonics, Cypress Bioscience, Forest, Janssen, Neuronetics, Novartis, Organon, and Pfizer. Dr Birmaher receives research support from the National Institute of Mental Health (NIMH); is a consultant for Schering-Plough; participated in a forum sponsored by Forest; has or will receive royalties for publications from Random House, Inc, and Lippincott Williams and Wilkins; and is currently employed by the University of Pittsburgh and the University of Pittsburgh Medical Center/Western Psychiatric Institute and Clinic. Drs Axelson, Castro-Fornieles, T. Goldstein, Ha, Iyengar, Strober, B. Goldstein, Yen, Ryan, and Dickstein and Mss Liao, Gill, and Hower have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article.
Funding/support: Funding for this study was provided by the NIMH grants MH59929 (Dr Birmaher), MH59977 (Dr Strober), and MH59691 (Dr Keller). The NIMH had no further role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Previous presentation: Preliminary findings were presented in poster form at the 56th Annual Meeting of the American Academy of Child and Adolescent Psychiatry; October 2009; Honolulu, Hawaii.
1. Sala R, Axelson D, Birmaher B. Phenomenology, longitudinal course, and outcome of children and adolescents with bipolar spectrum disorders. Child Adolesc Psychiatr Clin N Am. 2009;18(2):273–289, vii. doi:10.1016/j.chc.2008.11.002 PubMed
2. Pavuluri MN, Birmaher B, Naylor MW. Pediatric bipolar disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry. 2005;44(9):846–871. PubMed doi:10.1097/01.chi.0000170554.23422.c1
3. Axelson D, Birmaher B, Strober M, et al. Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry. 2006;63(10):1139–1148. PubMed doi:10.1001/archpsyc.63.10.1139
4. Joshi G, Wilens T. Comorbidity in pediatric bipolar disorder. Child Adolesc Psychiatr Clin North Am. 2009;18(2):291–319, vii–viii. PubMed doi:10.1016/j.chc.2008.12.005
5. Beesdo K, Knappe S, Pine DS. Anxiety and anxiety disorders in children and adolescents: developmental issues and implications for DSM-V. Psychiatr Clin North Am. 2009;32(3):483–524. PubMed doi:10.1016/j.psc.2009.06.002
6. Kowatch RA, Youngstrom EA, Danielyan A, et al. Review and meta-analysis of the phenomenology and clinical characteristics of mania in children and adolescents. Bipolar Disord. 2005;7(6):483–496. PubMed doi:10.1111/j.1399-5618.2005.00261.x
7. DelBello MP, Hanseman D, Adler CM, et al. Twelve-month outcome of adolescents with bipolar disorder following first hospitalization for a manic or mixed episode. Am J Psychiatry. 2007;164(4):582–590. PubMed doi:10.1176/appi.ajp.164.4.582
8. Biederman J, Faraone SV, Marrs A, et al. Panic disorder and agoraphobia in consecutively referred children and adolescents. J Am Acad Child Adolesc Psychiatry. 1997;36(2):214–223. PubMed doi:10.1097/00004583-199702000-00012
9. Dickstein DP, Rich BA, Binstock AB, et al. Comorbid anxiety in phenotypes of pediatric bipolar disorder. J Child Adolesc Psychopharmacol. 2005;15(4):534–548. PubMed doi:10.1089/cap.2005.15.534
10. Tillman R, Geller B, Bolhofner K, et al. Ages of onset and rates of syndromal and subsyndromal comorbid DSM-IV diagnoses in a prepubertal and early adolescent bipolar disorder phenotype. J Am Acad Child Adolesc Psychiatry. 2003;42(12):1486–1493. PubMed doi:10.1097/00004583-200312000-00016
11. Birmaher B, Axelson D, Monk K, et al. Lifetime psychiatric disorders in school-aged offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring study. Arch Gen Psychiatry. 2009;66(3):287–296. PubMed doi:10.1001/archgenpsychiatry.2008.546
12. Simeonova DI, Jackson V, Attalla A, et al. Subcortical volumetric correlates of anxiety in familial pediatric bipolar disorder: a preliminary investigation. Psychiatry Res. 2009;173(2):113–120. PubMed doi:10.1016/j.pscychresns.2009.01.004
13. Henin A, Biederman J, Mick E, et al. Psychopathology in the offspring of parents with bipolar disorder: a controlled study. Biol Psychiatry. 2005;58(7):554–561. PubMed doi:10.1016/j.biopsych.2005.06.010
14. Grigoroiu-Serbănescu M, Christodorescu D, Jipescu I, et al. Psychopathology in children aged 10–17 of bipolar parents: psychopathology rate and correlates of the severity of the psychopathology. J Affect Disord. 1989;16(2–3):167–179. PubMed doi:10.1016/0165-0327(89)90071-2
15. Hammen C, Burge D, Burney E, et al. Longitudinal study of diagnoses in children of women with unipolar and bipolar affective disorder. Arch Gen Psychiatry. 1990;47(12):1112–1117. PubMed
16. Chen YW, Dilsaver SC. Comorbidity of panic disorder in bipolar illness: evidence from the Epidemiologic Catchment Area Survey. Am J Psychiatry. 1995;152(2):280–282. PubMed
17. Chen YW, Dilsaver SC. Comorbidity for obsessive-compulsive disorder in bipolar and unipolar disorders. Psychiatry Res. 1995;59(1–2):57–64. PubMed doi:10.1016/0165-1781(95)02752-1
18. Kessler RC, Rubinow DR, Holmes C, et al. The epidemiology of DSM-III-R bipolar I disorder in a general population survey. Psychol Med. 1997;27(5):1079–1089. PubMed doi:10.1017/S0033291797005333
19. Keller MB. Prevalence and impact of comorbid anxiety and bipolar disorder. J Clin Psychiatry. 2006;67(suppl 1):5–7. PubMed
20. Freeman MP, Freeman SA, McElroy SL. The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues. J Affect Disord. 2002;68(1):1–23. PubMed doi:10.1016/S0165-0327(00)00299-8
21. Perlis RH, Miyahara S, Marangell LB, et al. STEP-BD Investigators. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry. 2004;55(9):875–881. PubMed doi:10.1016/j.biopsych.2004.01.022
22. Masi G, Perugi G, Millepiedi S, et al. Clinical and research implications of panic-bipolar comorbidity in children and adolescents. Psychiatry Res. 2007;153(1):47–54. PubMed doi:10.1016/j.psychres.2006.10.010
23. Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359(26):2753–2766. PubMed doi:10.1056/NEJMoa0804633
24. Birmaher B, Axelson DA, Monk K, et al. Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2003;42(4):415–423. PubMed
25. Allgulander C, Dahl AA, Austin C, et al. Efficacy of sertraline in a 12-week trial for generalized anxiety disorder. Am J Psychiatry. 2004;161(9):1642–1649. PubMed doi:10.1176/appi.ajp.161.9.1642
26. Ghaemi SN, Hsu DJ, Soldani F, et al. Antidepressants in bipolar disorder: the case for caution. Bipolar Disord. 2003;5(6):421–433. PubMed doi:10.1046/j.1399-5618.2003.00074.x
27. Goldberg JF, Nassir Ghaemi S. Benefits and limitations of antidepressants and traditional mood stabilizers for treatment of bipolar depression. Bipolar Disord. 2005;7(suppl 5):3–12. PubMed doi:10.1111/j.1399-5618.2005.00251.x
28. Birmaher B, Axelson D, Strober M, et al. Clinical course of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry. 2006;63(2):175–183. PubMed doi:10.1001/archpsyc.63.2.175
29. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.
30. Kaufman J, Birmaher B, Brent D, et al. Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36(7):980–988. PubMed doi:10.1097/00004583-199707000-00021
31. Axelson D, Birmaher BJ, Brent D, et al. A preliminary study of the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Mania Rating Scale for children and adolescents. J Child Adolesc Psychopharmacol. 2003;13(4):463–470. PubMed doi:10.1089/104454603322724850
32. First MB Sr, Williams JBW, Gibbon M. Structured Clinical Interview for DSM-IV (SCID). Washington, DC: American Psychiatric Association; 1995.
33. Weissman MM, Wickramaratne P, Adams P, et al. Brief screening for family psychiatric history: the Family History Screen. Arch Gen Psychiatry. 2000;57(7):675–682. PubMed doi:10.1001/archpsyc.57.7.675
34. Petersen AC, Crockett L, Richards M, et al. A self-report measure of pubertal status: reliability, validity, and initial norms. J Youth Adolesc. 1988;17(2):117–133. doi:10.1007/BF01537962
35. Shaffer D, Gould MS, Brasic J, et al. A Children’s Global Assessment Scale (CGAS). Arch Gen Psychiatry. 1983;40(11):1228–1231. PubMed
36. Klein RG. Anxiety disorders. J Child Psychol Psychiatry. 2009;50(1–2):153–162. PubMed doi:10.1111/j.1469-7610.2008.02061.x
37. Valtonen HM, Suominen K, Haukka J, et al. Hopelessness across phases of bipolar I or II disorder: a prospective study. J Affect Disord. 2009;115(1–2):11–17. PubMed doi:10.1016/j.jad.2008.06.013
38. Carleton RN, Abrams MP, Asmundson GJ, et al. Pain-related anxiety and anxiety sensitivity across anxiety and depressive disorders. J Anxiety Disord. 2009;23(6):791–798. PubMed doi:10.1016/j.janxdis.2009.03.003
39. Harpold TL, Wozniak J, Kwon A, et al. Examining the association between pediatric bipolar disorder and anxiety disorders in psychiatrically referred children and adolescents. J Affect Disord. 2005;88(1):19–26. PubMed doi:10.1016/j.jad.2005.05.016
40. Masi G, Toni C, Perugi G, et al. Anxiety disorders in children and adolescents with bipolar disorder: a neglected comorbidity. Can J Psychiatry. 2001;46(9):797–802. PubMed
41. McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry. 2001;158(3):420–426. PubMed doi:10.1176/appi.ajp.158.3.420
42. Pini S, Cassano GB, Simonini E, et al. Prevalence of anxiety disorders comorbidity in bipolar depression, unipolar depression and dysthymia. J Affect Disord. 1997;42(2–3):145–153. PubMed doi:10.1016/S0165-0327(96)01405-X
43. Boylan KR, Bieling PJ, Marriott M, et al. Impact of comorbid anxiety disorders on outcome in a cohort of patients with bipolar disorder. J Clin Psychiatry. 2004;65(8):1106–1113. PubMed doi:10.4088/JCP.v65n0813
44. Henry C, Van den Bulke D, Bellivier F, et al. Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer. J Clin Psychiatry. 2003;64(3):331–335. PubMed
45. Lewinsohn PM, Klein DN, Seeley JR. Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry. 1995;34(4):454–463. PubMed
46. Perugi G, Akiskal HS, Ramacciotti S, et al. Depressive comorbidity of panic, social phobic, and obsessive-compulsive disorders re-examined: is there a bipolar II connection? J Psychiatr Res. 1999;33(1):53–61. PubMed doi:10.1016/S0022-3956(98)00044-2
47. Cassano GB, Pini S, Saettoni M, et al. Multiple anxiety disorder comorbidity in patients with mood spectrum disorders with psychotic features. Am J Psychiatry. 1999;156(3):474–476. PubMed
48. Doughty CJ, Wells JE, Joyce PR, et al. Bipolar-panic disorder comorbidity within bipolar disorder families: a study of siblings. Bipolar Disord. 2004;6(3):245–252. PubMed doi:10.1111/j.1399-5618.2004.00120.x
49. Lee JH, Dunner DL. The effect of anxiety disorder comorbidity on treatment resistant bipolar disorders. Depress Anxiety. 2008;25(2):91–97. PubMed doi:10.1002/da.20279
50. Bauer MS, Altshuler L, Evans DR, et al. VA Cooperative Study No 430 Team. Prevalence and distinct correlates of anxiety, substance, and combined comorbidity in a multi-site public sector sample with bipolar disorder. J Affect Disord. 2005;85(3):301–315. PubMed doi:10.1016/j.jad.2004.11.009
51. Feske U, Frank E, Mallinger AG, et al. Anxiety as a correlate of response to the acute treatment of bipolar I disorder. Am J Psychiatry. 2000;157(6):956–962. PubMed doi:10.1176/appi.ajp.157.6.956
52. Frank E, Cyranowski JM, Rucci P, et al. Clinical significance of lifetime panic spectrum symptoms in the treatment of patients with bipolar I disorder. Arch Gen Psychiatry. 2002;59(10):905–911. PubMed doi:10.1001/archpsyc.59.10.905
53. Gaudiano BA, Miller IW. Anxiety disorder comorbidity in bipolar I disorder: relationship to depression severity and treatment outcome. Depress Anxiety. 2005;21(2):71–77. PubMed doi:10.1002/da.20053
54. Judd LL, Akiskal HS, Schettler PJ, et al. Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study. Arch Gen Psychiatry. 2005;62(12):1322–1330. PubMed doi:10.1001/archpsyc.62.12.1322
55. Angst J. The course of affective disorders. Psychopathology. 1986;19(suppl 2):47–52. PubMed doi:10.1159/000285131
56. Henin A, Biederman J, Mick E, et al. Childhood antecedent disorders to bipolar disorder in adults: a controlled study. J Affect Disord. 2007;99(1–3):51–57. PubMed doi:10.1016/j.jad.2006.09.001
57. Pine DS, Cohen P, Gurley D, et al. The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch Gen Psychiatry. 1998;55(1):56–64. PubMed doi:10.1001/archpsyc.55.1.56
58. Merikangas KR, Zhang H, Avenevoli S, et al. Zurich Cohort Study. Longitudinal trajectories of depression and anxiety in a prospective community study: the Zurich Cohort Study. Arch Gen Psychiatry. 2003;60(10):993–1000. PubMed doi:10.1001/archpsyc.60.9.993
59. Simon NM, Otto MW, Wisniewski SR, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2004;161(12):2222–2229. PubMed doi:10.1176/appi.ajp.161.12.2222
60. Johnson JG, Cohen P, Brook JS. Associations between bipolar disorder and other psychiatric disorders during adolescence and early adulthood: a community-based longitudinal investigation. Am J Psychiatry. 2000;157(10):1679–1681. PubMed doi:10.1176/appi.ajp.157.10.1679
61. Birmaher BAD, Pavuluri MN. In; Martin A, Volkmar FR, eds. Pediatric Bipolar Disorder, in Lewis’ Child and Adolescent Psychiatric. A Comprehensive Textbook, 4th ed. Baltimore, MD: Lippincott Williams and Wilkins; 2007.
62. Wozniak J, Biederman J, Monuteaux MC, et al. Parsing the comorbidity between bipolar disorder and anxiety disorders: a familial risk analysis. J Child Adolesc Psychopharmacol. 2002;12(2):101–111. PubMed doi:10.1089/104454602760219144
63. Goldstein TR, Birmaher B, Axelson D, et al. History of suicide attempts in pediatric bipolar disorder: factors associated with increased risk. Bipolar Disord. 2005;7(6):525–535. PubMed doi:10.1111/j.1399-5618.2005.00263.x
64. Goldstein BI, Strober MA, Birmaher B, et al. Substance use disorders among adolescents with bipolar spectrum disorders. Bipolar Disord. 2008;10(4):469–478. PubMed doi:10.1111/j.1399-5618.2008.00584.x
65. Steinbuchel PH, Wilens TE, Adamson JJ, et al. Posttraumatic stress disorder and substance use disorder in adolescent bipolar disorder. Bipolar Disord. 2009;11(2):198–204. PubMed doi:10.1111/j.1399-5618.2008.00652.x
66. Goldstein BI, Levitt AJ. The specific burden of comorbid anxiety disorders and of substance use disorders in bipolar I disorder. Bipolar Disord. 2008;10(1):67–78. PubMed
67. Beck AT, Brown GK, Steer RA, et al. Suicide ideation at its worst point: a predictor of eventual suicide in psychiatric outpatients. Suicide Life Threat Behav. 1999;29(1):1–9. PubMed
68. Brown GK, Beck AT, Steer RA, et al. Risk factors for suicide in psychiatric outpatients: a 20-year prospective study. J Consult Clin Psychol. 2000;68(3):371–377. PubMed doi:10.1037/0022-006X.68.3.371
69. Fawcett J, Scheftner WA, Fogg L, et al. Time-related predictors of suicide in major affective disorder. Am J Psychiatry. 1990;147(9):1189–1194. PubMed
70. Goldstein BI, Houck PR, Karp JF. Factors associated with pain interference in an epidemiologic sample of adults with bipolar I disorder. J Affect Disord. 2009;117(3):151–156. PubMed doi:10.1016/j.jad.2009.01.011
71. Bell-Dolan DB. Separation anxiety disorder, overanxious disorder, and school refusal. Child Adolesc Psychiatr Clin N Am. 1993;2:563–580.
72. Lewinsohn PM, Klein DN, Seeley JR. Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar Disord. 2000;2(3 pt 2):281–293. PubMed doi:10.1034/j.1399-5618.2000.20309.x