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J Clin Psychiatry. Author manuscript; available in PMC Oct 1, 2011.
Published in final edited form as:
PMCID: PMC2978760
NIHMSID: NIHMS209455
COMORBID ANXIETY IN CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERS: PREVALENCE AND CLINICAL CORRELATES
Regina Sala, M.D,a David A. Axelson, M.D,a Josefina Castro-Fornieles, M.D, Ph.D,b Tina R. Goldstein, Ph.D,a Wonho Ha, Ph.D,a Fangzi Liao, M.S,a Mary Kay Gill, M.S.N,a Satish Iyengar, Ph.D,c Michael A Strober, Ph.D,d Benjamin I. Goldstein, M.D, PhD,ae Shirley Yen, Ph.D,f Heather Hower, M.S.W,f Jeffrey Hunt, M.D,f Neal D. Ryan, M.D,a Daniel Dickstein, M.D,f Martin B. Keller, M.D,f and Boris Birmaher, M.Da
a Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
b Department of Child and Adolescent Psychiatry and Psychology, IDIBAPS, CIBERSAM, Neurosciences Institute, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain
c Department of Statistics, University of Pittsburgh, Pittsburgh, PA, USA
d Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
e Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
f Department of Psychiatry and Butler Hospital, Brown University School of Medicine, Providence, RI, USA
Corresponding author: Regina Sala, MD, University of Pittsburgh, Western Psychiatric Institute and Clinic, 100 North Bellefield Avenue, #542, Pittsburgh, PA 15213, USA. Telephone: 412 246 6569. Fax: 412 246 5230., salar/at/upmc.edu
Objective
Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder (BP). We aimed to examine the prevalence and correlates of comorbid anxiety disorders among youth with BP.
Methods
As part of the Course and Outcome of Bipolar Youth study (COBY), 446 youth ages 7 to 17, who met DSM-IV criteria for BP-I (n=260), BP-II (n=32) or operationalized criteria for BP not otherwise specified (BP-NOS; n=154) were included. Subjects were evaluated for current and lifetime Axis-I psychiatric disorders at intake using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children–Present and Lifetime version (K-SADS-PL), and standardized instruments to assess functioning and family history.
Results
Forty-four percent (n=194) of the sample met DSM-IV criteria for at least one lifetime anxiety disorder, most commonly Separation Anxiety (24%) and Generalized Anxiety Disorders (16%). Nearly 20% met criteria for two or more anxiety disorders. Overall, anxiety disorders predated the onset of BP. BP-II subjects were more likely than BP-I or BP-NOS subjects to have a comorbid anxiety disorder. After adjusting for confounding factors, BP youth with anxiety were more likely to have BP-II, 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 BP, and most often predate BP onset. BP-II, a family history of depression, and more severe lifetime depressive episodes distinguish BP youth with comorbid anxiety disorders from those without. Careful consideration should be given to the assessment of comorbid anxiety in BP youth.
Keywords: Youth, anxiety, bipolar disorder, prevalence, clinical correlates
Onset of bipolar disorder (BP) during childhood significantly affects an individual’s psychosocial development. Moreover, youth with BP are at high risk for suicidal behaviors and completed suicide, substance abuse, and legal problems, and have particularly high rates of health services utilization13.
Some of the most common comorbid disorders among youth with BP 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 BP and anxiety in youth. The few studies that have addressed this issue in small samples of youth with BP, have shown lifetime prevalence of comorbid anxiety disorders between 14% and 56%, with a weighted average of 27% 3, 610. Moreover, family studies have consistently shown high rates of anxiety disorders in offspring of parents with BP 1115.
The above-noted findings are consistent with the adult epidemiological 1618 and clinical literature 2023. In fact, retrospective data from studies of adults with BP indicate higher rates of comorbid lifetime anxiety disorders among those with earlier age of BP onset. Specifically, in one study by Perlis and colleagues (2004), adults who reported BP onset before age 13 demonstrated a 70% rate of comorbid lifetime anxiety disorder, as compared with 54% of those with BP onset between 13 and 18 years, and 38% of those with BP onset after age 18 24.
Prior research indicates that the presence of comorbid anxiety disorders negatively affects course, outcome, and treatment response in BP. In a study by Masi and colleagues (2007), BP youth with panic disorder, as compared to those without panic, demonstrated less BP severity at baseline, but had poorer response to treatment 19. Furthermore, DelBello and colleagues (2007) found that adolescents with BP and comorbid anxiety had more severe mood symptoms and lower rates of recovery one year after index hospitalization than adolescents without comorbid anxiety 7. Similarly, studies among adults with BP consistently find 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 BP and comorbid anxiety report poorer psychosocial functioning and lower overall quality of life 20, 21.
The association between BP and comorbid anxiety disorders is of particular clinical significance since the pharmacological treatment for anxiety disorders with the most evidence of efficacy in both children and adults is the serotonin reuptake inhibitors (SSRIs) 2224. Unfortunately, these medications have been shown to destabilize the symptoms of BP 25, 26.
Given the clinical relevance of comorbid anxiety and BP 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 BP spectrum disorders. We hypothesized that as compared with youth with BP and no comorbid anxiety (BP/no-anxiety), those with BP and a comorbid anxiety disorder (BP/anxiety) would have: (1) earlier BP onset and more severe lifetime BP 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, 27. Briefly, 446 youth, ages 7 to 17 years 11 months (mean = 12.7, SD = 3.2) who met criteria for Diagnostic and Statistical Manual IV (DSM-IV) 28 BP-I (n=260), BP-II (n=32), and operationally defined BP-NOS (n=154) 3, 27, 29 were recruited primarily though clinical referrals from three academic medical centers (University of Pittsburgh, Brown University, and University of California at Los Angeles). Institutional Review Board approval was obtained at each site prior to subject enrollment.
Because the DSM-IV criteriafor BP-NOS are vague, the COBY study investigators set the minimuminclusion threshold for the BP-NOS group as subjects who did not meet the DSM-IV criteria for BP-I or BP-II but had a distinctperiod 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 Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime Version (K-SADS-PL) 29, the Kiddie Mania Rating Scale (K-MRS) 30, and the depression section of the KSADS-P (from which the Dep-12 depression rating scale was extracted). The KSADS-PL utilized in COBY did not include the new 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 (SCID) 31 for DSM-IV, and about their first- and second-degree psychiatric family history using the Family History Screen (FHS) 32. The Petersen Pubertal Developmental Scale (PDS) 33 was used to evaluate and categorize pubertal stages. Socioeconomic status was measured using the Hollingshead four-factor scale 34, and functional impairment was assessed using the Child Global Assessment Scale (CGAS) 35.
Research interviewers were trained to high reliability in administration of the KSADS, the Structured Clinical Interview for DSM-IV, and the Family History Screen 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 BP from non-BP subjects (κ= 0.90)and for the BP diagnostic subtypes κ= 0.79). For the non mood disorders, κvalues were 0.80 or higher. The intraclass correlation coefficient was 0.96 for the KSADS MRS and 0.98 for the KSADS Depression Scale.
We considered a subject positive for the presence of any lifetime anxiety disorder if they met full threshold criteria for at least one of the following disorders: Separation Anxiety Disorder (SAD), Generalized Anxiety Disorder (GAD), Obsessive Compulsive Disorder (OCD), Post-traumatic Stress Disorder (PTSD), Social Phobia, Panic Disorder, Anxiety Disorder Not Otherwise Specified (Anxiety NOS), or Agoraphobia. OCD and PTSD have been often classified as distinct from other anxiety disorders for the complexity of the clinical description and diagnosis. OCD 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%) 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 others anxiety disorders. Twenty-nine youth with only specific phobia (i.e. fear to spider, dark, and 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 or PDD-NOS were recruited. In COBY only 2% of the subjects fulfilled criteria for these disorders.
Statistical analyses
Between-group comparisons in demographic factors were carried out using standard parametric and nonparametric univariate tests. Results were adjusted for BP subtype and any other significant between group demographic differences. Those variables with p-values ≤0.25 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-MRS, and the Dep-12 plus the Hopelessness and Aches and Pains questions from the KSADS-P depression section, because these symptoms have been associated with more severe anxiety 37, 38. All p-values are based on two-sided tests; when appropriate, we use Bonferroni corrections to keep the family-wise error rate at most alpha=0.05. Odds ratios (OR) and confidence intervals (CI) were computed.
Prevalence and demographics
Forty-four percent (194/446) of subjects met lifetime criteria for at least one comorbid anxiety disorder. The most common comorbid anxiety disorders included SAD (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 one lifetime anxiety disorder, and 5% met criteria for three or more anxiety disorders. The proportion of subjects whose age onset of anxiety is less than age onset of BP was 78.7% (151 out of 192 subjects as two subjects were missing information of age onset of anxiety). The mean and standard deviation of age onset of anxiety and BP for these 192 subjects were 6.3 ± 3.3 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.
Table 1
Table 1
Demographic factors associated with BP/anxiety vs. BP/non-anxiety in children and adolescent with bipolar disorder spectrum
Clinical characteristics of bipolar illness and comorbidity
As shown in Table 2, the overall chi square comparing BP subtypes and presence of any lifetime anxiety disorder was significant (χ2= 8.94, p-value = 0.01). However the differences were only accounted by the BP-II subtype.
Table 2
Table 2
Frequencies of BP subtype vs. presence of any lifetime anxiety disorder
After adjusting for BP subtype, SES, 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/non-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 ≤ 0.05). 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).
Table 3
Table 3
Factors associated with BP/anxiety vs. BP/non-anxiety in children and adolescent with bipolar disorder spectrum
Family history
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, anxiety disorders (all p-values ≤ 0.001), and a trend of positive first-or-second degree family history of mania/hypomania (p-value =0.06) (Table 3).
Multivariate logistic regression
The BP/anxiety group remained significantly associated with BP-II (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).
Table 4
Table 4
Logistic regression of the variables associated with BP/anxiety vs. BP/no-anxiety in children and adolescents with bipolar disorder spectrum
Severity of manic and depressive symptoms
We examined whether there were differences between the BP/anxiety versus 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/hypomanic (K-MRS) and depressive episodes (Dep-12). Only symptoms rated at mild or higher (≥3) were analyzed. There were no between-group differences in manic/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).
Table 5
Table 5
Depressive symptoms* during the most severe lifetime in BP/anxiety vs. BP/non-anxiety in children and adolescent with bipolar disorder spectrum
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 two 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, demographic and clinical correlates of comorbid anxiety disorder among children and adolescents with BP.
Forty-four percent of BP youth in our sample met criteria for at least one lifetime anxiety disorder, most commonly SAD and GAD; 18% had two or more lifetime anxiety disorders. On average, the onset of anxiety predated the onset of BP. After adjusting for significant demographic factors and BP subtypes, youth with BP/anxiety, as compared with BP/no-anxiety, showed significantly higher rates of BP-II, longer duration of mood symptoms, higher current depression scores, lower likelihood of reporting an index episode of the manic subtype, higher rates of familial depression, and 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 SAD and GAD, have been reported at high rates among youth and adults with BP 6, 810, 18, 3945. Also similar to other studies in the child and adult literature, we found that BP subjects with comorbid anxiety disorders were more likely to have a diagnosis of BP-II 19, 42, 44, 4648, longer duration of mood symptoms, and greater severity of depressive episodes 4953. This association may be related to the fact that BP-II has a more chronic course and outcome, longer length of illness, shorter cycles, and greater number of episodes, more major and minor depressive episodes, shorter well intervals between episodes, and lower rates of recovery 54, 55.
Moreover, similar to the BP 9, 56 and unipolar depression 57, 58 literature we found that, on average, the anxiety disorders preceded the onset of the mood disorder. Contrary to our initial hypothesis 10, 40, 5961, age onset of BP episode did not differ between the two groups.
These findings are clinically relevant because currently the first line pharmacological treatments for anxiety disorders in youth are the selective serotonin reuptake inhibitors (SSRIs) 23, 24. SSRIs have been shown to trigger or destabilize BP symptoms 25. 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 presentation 62 as well as symptom overlap with other conditions including depression and anxiety, recent studies clearly demonstrate that mania/hypomania in youth can be reliably diagnosed 3. Additionally, anxious children treated with antidepressants should be carefully monitored for the presence of manic/hypomanic symptoms 40.
Little is known about the most efficacious treatments for the treatment of comorbid anxiety in youth with BP. Future studies may evaluate the efficacy of psychotherapy approaches with empirical support for the treatment of anxious youth, such as cognitive-behavioral therapy 22. The risk/benefit ratio of the use of SSRIs in youth with BP who are on concurrent mood stabilizers also may 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. (2002) 63, who reported elevated risk for both BP and anxiety among relatives of BP/anxiety probands. As such, this group suggested that comorbid anxiety and BP may represent a genetic subtype of BP. Furthermore, a recent study by Birmaher and colleagues (2009) 11 found that offspring of parents with BP had higher rates of anxiety disorders than offspring of control parents suggesting that anxiety may be a precursor of BP among BP 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 BP.
Contrary to our initial hypothesis 4, 21, 49, 59, 6467, we did not find significantly more suicidal behaviors 9, or substance use disorders in the BP 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 BP 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 6870, careful evaluation and monitoring of suicide risk in youth with BP/anxiety is clearly indicated. Also contrary to our initial hypothesis 4, 21, we did not find poorer functioning in the BP group with comorbid anxiety as compared with those without. It is possible that the impact of BP 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 BP and comorbid anxiety reported more aches and pains than those without anxiety, as is the case in adults studies 71. It has been well-documented that anxious youth experience somatic complaints and tend to consult primary care physicians or pediatricians before mental health clinicians 72. 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 BP.
It is important to note the limitations of this study. First, as most subjects were Caucasian and were recruited primarily from outpatient clinical settings, the generalizability of the findings remains uncertain. However, a community-based study of non-referred adolescents with BP reported similarly high rates of comorbid anxiety disorders 73. Second, subjects were ascertained for bipolarity. Thus, results may not apply to subjects whose primary diagnosis is anxiety and then develop BP. Third, this study is cross-sectional and data was 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 BP than in youth with other childhood psychiatric disorders (e.g., major depressive disorder).
In summary, anxiety disorders usually predate the onset of BP and are very common in youth with BP, especially those with BP-II, 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 BP are needed. Finally, longitudinal studies to determine the impact of comorbid anxiety disorder on the course and outcome of pediatric BP spectrum disorders are warranted.
Acknowledgments
Dr. Sala was supported by a grant from the Alicia Koplowitz Foundation. Funding for this study was provided by National Institute of Mental Health Grants MH59929 (Dr. Birmaher), MH59977 (Dr. Strober), and MH59691 (Dr. Keller). The NIMH had no further role in 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.
Footnotes
The authors of this paper do not have any commercial associations that might pose a conflict of interest in connection with this manuscript.
Preliminary findings were presented in poster form at the 56th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, October 2009, Hawai’i, HI, USA.
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 Apr;18(2):273–289. vii. [PMC free article] [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 Sep;44(9):846–871. [PubMed]
3. Axelson D, Birmaher B, Strober M, et al. Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry. 2006 Oct;63(10):1139–1148. [PubMed]
4. Joshi G, Wilens T. Comorbidity in pediatric bipolar disorder. Child Adolesc Psychiatr Clin N Am. 2009 Apr;18(2):291–319. vii–viii. [PMC free article] [PubMed]
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 Sep;32(3):483–524. [PMC free article] [PubMed]
6. Kowatch RA, Youngstrom EA, Danielyan A, Findling RL. Review and meta-analysis of the phenomenology and clinical characteristics of mania in children and adolescents. Bipolar Disord. 2005 Dec;7(6):483–496. [PubMed]
7. DelBello MP, Hanseman D, Adler CM, Fleck DE, Strakowski SM. Twelve-month outcome of adolescents with bipolar disorder following first hospitalization for a manic or mixed episode. [see comment] American Journal of Psychiatry. 2007;164(4):582–590. [PubMed]
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 Feb;36(2):214–223. [PubMed]
9. Dickstein DP, Rich BA, Binstock AB, et al. Comorbid anxiety in phenotypes of pediatric bipolar disorder. J Child Adolesc Psychopharmacol. 2005 Aug;15(4):534–548. [PubMed]
10. Tillman R, Geller B, Bolhofner K, Craney JL, Williams M, Zimerman B. 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 Dec;42(12):1486–1493. [PubMed]
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 Mar;66(3):287–296. [PMC free article] [PubMed]
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 Aug 30;173(2):113–120. [PMC free article] [PubMed]
13. Henin A, Biederman J, Mick E, et al. Psychopathology in the offspring of parents with bipolar disorder: a controlled study. Biological Psychiatry. 2005 Oct 1;58(7):554–561. [PubMed]
14. Grigoroiu-Serbanescu M, Christodorescu D, Jipescu I, Totoescu A, Marinescu E, Ardelean V. Psychopathology in children aged 10–17 of bipolar parents: psychopathology rate and correlates of the severity of the psychopathology. J Affect Disord. 1989 Mar–Jun;16(2–3):167–179. [PubMed]
15. Hammen C, Burge D, Burney E, Adrian C. Longitudinal study of diagnoses in children of women with unipolar and bipolar affective disorder. Archives of General 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 Feb;152(2):280–282. [PubMed]
17. Chen YW, Dilsaver SC. Comorbidity for obsessive-compulsive disorder in bipolar and unipolar disorders. Psychiatry Res. 1995 Nov 29;59(1–2):57–64. [PubMed]
18. Kessler RC, Rubinow DR, Holmes C, Abelson JM, Zhao S. The epidemiology of DSM-III-R bipolar I disorder in a general population survey. Psychol Med. 1997 Sep;27(5):1079–1089. [PubMed]
19. Masi G, Perugi G, Millepiedi S, et al. Clinical and research implications of panic-bipolar comorbidity in children and adolescents. Psychiatry Res. 2007 Sep 30;153(1):47–54. [PubMed]
20. Keller MB. Prevalence and impact of comorbid anxiety and bipolar disorder. J Clin Psychiatry. 2006;67( Suppl 1):5–7. [PubMed]
21. Freeman MP, Freeman SA, McElroy SL. The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues. J Affect Disord. 2002 Feb;68(1):1–23. [PubMed]
22. Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008 Dec 25;359(26):2753–2766. [PMC free article] [PubMed]
23. Birmaher B, Axelson DA, Monk K, et al. Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2003 Apr;42(4):415–423. [PubMed]
24. Allgulander C, Dahl AA, Austin C, et al. Efficacy of sertraline in a 12-week trial for generalized anxiety disorder. Am J Psychiatry. 2004 Sep;161(9):1642–1649. [PubMed]
25. Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Antidepressants in bipolar disorder: the case for caution. Bipolar Disord. 2003 Dec;5(6):421–433. [PubMed]
26. 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]
27. Birmaher B, Axelson D, Strober M, et al. Clinical course of children and adolescents with bipolar spectrum disorders. Archives of General Psychiatry. 2006;63:175–183. [PMC free article] [PubMed]
28. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder. 4. Washington, DC: American Psychiatric Association; 1994.
29. 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. [see comment] Journal of the American Academy of Child & Adolescent Psychiatry. 1997 Jul;36(7):980–988. [PubMed]
30. 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. Journal of Child & Adolescent Psychopharmacology. 2003;13:463–470. [PubMed]
31. First MBSR, Williams JBW, Gibbon M. Structured Clinical Interview for DSM-IV (SCID) Washington, DC: American Psychiatric Association; 1995.
32. Weissman MM, Wickramaratne P, Adams P, Wolk S, Verdeli H, Olfson M. Brief screening for family psychiatric history: the family history screen. Archives of General Psychiatry. 2000 Jul;57(7):675–682. [PubMed]
33. Petersen AC, Crockett L, Richards M, Boxer A. A self-report measure of pubertal status: Reliability, validity, and initial norms. Journal of Youth and Adolescence. 1988 [PubMed]
34. Hollingshead AB. Index of Social Status. In: Mangen DJ, Peterson WA, editors. Research instruments in social gerontology: Vol. 2. Social roles and social participation. Minneapolis, MN: University of Minnesota Press; 1982.
35. Shaffer D, Gould MS, Brasic J, et al. A children’s global assessment scale (CGAS) Arch Gen Psychiatry. 1983 Nov;40(11):1228–1231. [PubMed]
36. Klein RG. Anxiety disorders. J Child Psychol Psychiatry. 2009 Jan;50(1–2):153–162. [PubMed]
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 May;115(12):11–17. [PubMed]
38. Carleton RN, Abrams MP, Asmundson GJ, Antony MM, McCabe RE. Pain-related anxiety and anxiety sensitivity across anxiety and depressive disorders. J Anxiety Disord. 2009 Aug;23(6):791–798. [PubMed]
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 Sep;88(1):19–26. [PubMed]
40. Masi G, Toni C, Perugi G, Mucci M, Millepiedi S, Akiskal HS. Anxiety disorders in children and adolescents with bipolar disorder: a neglected comorbidity. Can J Psychiatry. 2001 Nov;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 Mar;158(3):420–426. [PubMed]
42. Pini S, Cassano GB, Simonini E, Savino M, Russo A, Montgomery SA. Prevalence of anxiety disorders comorbidity in bipolar depression, unipolar depression and dysthymia. J Affect Disord. 1997 Feb;42(2–3):145–153. [PubMed]
43. Boylan KR, Bieling PJ, Marriott M, Begin H, Young LT, MacQueen GM. Impact of comorbid anxiety disorders on outcome in a cohort of patients with bipolar disorder. J Clin Psychiatry. 2004 Aug;65(8):1106–1113. [PubMed]
44. Henry C, Van den Bulke D, Bellivier F, Etain B, Rouillon F, Leboyer M. Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer. J Clin Psychiatry. 2003 Mar;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 Apr;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 Jan–Feb;33(1):53–61. [PubMed]
47. Cassano GB, Pini S, Saettoni M, Dell’Osso L. Multiple anxiety disorder comorbidity in patients with mood spectrum disorders with psychotic features. Am J Psychiatry. 1999 Mar;156(3):474–476. [PubMed]
48. Doughty CJ, Wells JE, Joyce PR, Olds RJ, Walsh AE. Bipolar-panic disorder comorbidity within bipolar disorder families: a study of siblings. Bipolar Disord. 2004 Jun;6(3):245–252. [PubMed]
49. Lee JH, Dunner DL. The effect of anxiety disorder comorbidity on treatment resistant bipolar disorders. Depress Anxiety. 2008;25(2):91–97. [PubMed]
50. Bauer MS, Altshuler L, Evans DR, Beresford T, Williford WO, Hauger R. Prevalence and distinct correlates of anxiety, substance, and combined comorbidity in a multi-site public sector sample with bipolar disorder. J Affect Disord. 2005 Apr;85(3):301–315. [PubMed]
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 Jun;157(6):956–962. [PubMed]
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 Oct;59(10):905–911. [PubMed]
53. Gaudiano BA, Miller IW. Anxiety disorder comobidity in Bipolar I Disorder: relationship to depression severity and treatment outcome. Depress Anxiety. 2005;21(2):71–77. [PubMed]
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 Dec;62(12):1322–1330. [PubMed]
55. Angst J. The course of affective disorders. Psychopathology. 1986;19( Suppl 2):47–52. [PubMed]
56. Henin A, Biederman J, Mick E, et al. Childhood antecedent disorders to bipolar disorder in adults: a controlled study. J Affect Disord. 2007 Apr;99(1–3):51–57. [PubMed]
57. Pine DS, Cohen P, Gurley D, Brook J, Ma Y. The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch Gen Psychiatry. 1998 Jan;55(1):56–64. [PubMed]
58. Merikangas KR, Zhang H, Avenevoli S, Acharyya S, Neuenschwander M, Angst J. Longitudinal trajectories of depression and anxiety in a prospective community study: the Zurich Cohort Study. Arch Gen Psychiatry. 2003 Oct;60(10):993–1000. [PubMed]
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 Dec;161(12):2222–2229. [PubMed]
60. Perlis RH, Miyahara S, Marangell LB, et al. 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 May 1;55(9):875–881. [PubMed]
61. 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 Oct;157(10):1679–1681. [PubMed]
62. Birmaher BAD, Pavuluri MN. Pediatric Bipolar Disorder, in Lewis’ Child and Adolescent Psychiatric. In: Martin A, Volkmar FR, editors. A Comprehensive Textbook. 4. Baltimore: Lippincott Williams 7 Wilkins; 2007.
63. Wozniak J, Biederman J, Monuteaux MC, Richards J, Faraone SV. Parsing the comorbidity between bipolar disorder and anxiety disorders: a familial risk analysis. J Child Adolesc Psychopharmacol. 2002 Summer;12(2):101–111. [PubMed]
64. Goldstein TR, Birmaher B, Axelson D, et al. History of suicide attempts in pediatric bipolar disorder: factors associated with increased risk. Bipolar Disord. 2005 Dec;7(6):525–535. [PMC free article] [PubMed]
65. Goldstein BI, Strober MA, Birmaher B, et al. Substance use disorders among adolescents with bipolar spectrum disorders. Bipolar Disord. 2008 Jun;10(4):469–478. [PMC free article] [PubMed]
66. Steinbuchel PH, Wilens TE, Adamson JJ, Sgambati S. Posttraumatic stress disorder and substance use disorder in adolescent bipolar disorder. Bipolar Disord. 2009 Mar;11(2):198–204. [PMC free article] [PubMed]
67. Goldstein BI, Levitt AJ. The specific burden of comorbid anxiety disorders and of substance use disorders in bipolar I disorder. Bipolar Disord. 2008 Feb;10(1):67–78. [PubMed]
68. Beck AT, Brown GK, Steer RA, Dahlsgaard KK, Grisham JR. Suicide ideation at its worst point: a predictor of eventual suicide in psychiatric outpatients. Suicide Life Threat Behav. 1999 Spring;29(1):1–9. [PubMed]
69. Brown GK, Beck AT, Steer RA, Grisham JR. Risk factors for suicide in psychiatric outpatients: a 20-year prospective study. J Consult Clin Psychol. 2000 Jun;68(3):371–377. [PubMed]
70. Fawcett J, Scheftner WA, Fogg L, et al. Time-related predictors of suicide in major affective disorder. Am J Psychiatry. 1990 Sep;147(9):1189–1194. [PubMed]
71. 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 Oct;117(3):151–156. [PMC free article] [PubMed]
72. Bell-Dolan DB, TJ Separation anxiety disorder, overanxious disorder, and school refusal. Child Adolesc Psychiatr Clin N Am. 1993;2:563–580.
73. Lewinsohn PM, Klein DN, Seeley JR. Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar Disorders. 2000;2:281–293. [PubMed]