PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Clin Psychiatry. Author manuscript; available in PMC Mar 18, 2013.
Published in final edited form as:
PMCID: PMC3600866
NIHMSID: NIHMS437349
Factors Associated With the Persistence and Onset of New Anxiety Disorders in Youth With Bipolar Spectrum Disorders
Dr Regina Sala, MD, Dr David A. Axelson, MD, Dr Josefina Castro-Fornieles, MD, PhD, Dr Tina R. Goldstein, PhD, Dr Benjamin I. Goldstein, MD, PhD, Dr Wonho Ha, PhD, Ms Fangzi Liao, MS, Ms Mary Kay Gill, MSN, Dr Satish Iyengar, PhD, Dr Michael A. Strober, PhD, Dr Shirley Yen, PhD, Ms Heather Hower, MSW, Dr Jeffrey I. Hunt, MD, Dr Daniel P. Dickstein, MD, Dr Neal D. Ryan, MD, Dr Martin B. Keller, MD, and Dr Boris Birmaher, MD
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine (Drs Sala, Axelson, T. R. Goldstein, Ha, Ryan, and Birmaher and Mss Liao and Gill); Department of Statistics, University of Pittsburgh (Dr Iyengar), Pittsburgh, Pennsylvania; Department of Child and Adolescent Psychiatry and Psychology, IDIBAPS, CIBERSAM, Neurosciences Institute, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain (Dr Castro-Fornieles); Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada (Dr B. I. Goldstein); Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, (Dr Strober); and Department of Psychiatry and Butler Hospital, Brown University School of Medicine, Providence, Rhode Island (Drs Yen, Hunt, Dickstein, and Keller and Ms Hower)
Corresponding author: Regina Sala, MD, Department of Psychiatry, New York State Psychiatric Institute, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, Unit 69, New York, NY 10032 (salareg/at/pi.cpmc.columbia.edu)
Objective
Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder, but, to our knowledge, no studies examined the course of anxiety disorders in youth and adults with bipolar disorder.
Method
As part of the Course and Outcome of Bipolar Youth study, 413 youth, ages 7 to 17 years who met criteria for Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) bipolar I disorder (n = 244), bipolar II disorder (n = 28), and operationally defined bipolar disorder not otherwise specified (n = 141) were recruited primarily from outpatient clinics. Subjects were followed on average for 5 years using the Longitudinal Interval Follow-Up Evaluation. We examined factors associated with the persistence (> 50% of the follow-up time) and onset of new anxiety disorders in youth with bipolar disorder.
Results
Of the 170 youth who had anxiety at intake, 80.6% had an anxiety disorder at any time during the follow-up. Most of the anxiety disorders during the follow-up were of the same type as those present at intake. About 50% of the youth had persistent anxiety, particularly generalized anxiety disorder (GAD). Persistence was associated with multiple anxiety disorders, less follow-up time in euthymia, less conduct disorder, and less treatment with antimanic and antidepressant medications (all P values ≤ .05). Twenty-five percent of the sample who did not have an anxiety disorder at intake developed new anxiety disorders during follow-up, most commonly GAD. The onset of new anxiety disorders was significantly associated with being female, lower socioeconomic status, presence of attention-deficit/hyperactivity disorder and substance use disorder, and more follow-up time with manic or hypomanic symptoms (all P values ≤ .05)
Conclusions
Anxiety disorders in youth with bipolar disorder tend to persist, and new-onset anxiety disorders developed in a substantial proportion of the sample. Early identification of factors associated with the persistence and onset of new anxiety disorders may enable the development of strategies for treatment and prevention.
Youth with bipolar disorder are among the most psychosocially impaired of psychiatrically ill youth, and the presence of comorbidity compounds disability, complicates treatment, and appears to worsen the prognosis of bipolar disorder.1 Comorbid conditions frequently associated with pediatric bipolar disorder include attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorders, substance use disorders, anxiety disorders, and pervasive developmental disorders.2 However, the presence of anxiety disorders in patients who suffer from bipolar disorder has been underrecognized and understudied.1
Clinical and epidemiologic studies have documented high rates of comorbid anxiety disorders in youth with bipolar disorder.35 The existent longitudinal studies of comorbid anxiety in youth6,7 and adults with bipolar disorder811 have shown that anxiety disorders are associated with greater severity of bipolar disorder. For example, Masi and colleagues6 followed a group of 224 children and adolescents with bipolar disorder spectrum disorder for at least 6 months. They reported that, compared to bipolar disorder youth without panic disorder, those with panic disorder showed less mood improvement during the follow-up. In addition, DelBello and colleagues7 followed a group of 71 adolescents with bipolar I disorder 1 year after discharge from the hospital. They found that adolescents with bipolar disorder and comorbid anxiety disorder had more severe mood symptoms and lower rates of recovery than adolescents without anxiety.
Studies in adults with bipolar disorder have also found that the presence of comorbid anxiety is associated with shorter euthymic periods, higher depression severity, rapid cycling, longer time to remission from the index episode, increased risk for recurrence, more time with depressive mood, suicidal behavior, substance abuse, lower quality of life, diminished role functioning, and poor response to treatment.814
The above-noted studies focused on the effect of anxiety on the course of bipolar disorder, but, to our knowledge, there are no studies examining the course of anxiety disorders in youth and adults with bipolar disorder. It is important to examine the course and factors associated with anxiety disorders in youth with bipolar disorder because the early identification and management of the anxiety may improve the prognosis of bipolar disorder.
In a prior publication,3 as part of the Course and Outcome of Bipolar Youth study, we analyzed the presence of lifetime anxiety disorders in a large group of youth with bipolar disorder. Forty-four percent (194/446) of youth with bipolar disorder met DSM-IV criteria for at least 1 lifetime anxiety disorder (mainly separation anxiety disorders and generalized anxiety disorders [GAD]), and 18% met criteria for 2 or more anxiety disorders. The main goal of the current study was to evaluate the longitudinal course of the anxiety disorders of the bipolar disorder youth who had anxiety disorders at intake. More specifically, we sought to evaluate whether the anxiety disorders present during the follow-up were the same as those present at intake (homotypic continuity) and to identify the intake and follow-up factors associated with the persistence of anxiety disorders. In addition, we evaluated the factors at intake and follow-up that were associated with the development of new anxiety disorders during the follow-up period in youth without any anxiety disorders at intake.
Subjects
The sample included in this article consists of 413 youth, ages 7 to 17 years 11 months (mean ± SD, 12.6 ± 3.3 years) who met criteria for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) bipolar I disorder (n = 244), bipolar II disorder (n = 28), and operationally defined bipolar disorder not otherwise specified (NOS) (n = 141) and who had at least 1 follow-up assessment. The sample was recruited primarily though clinical referrals from 3 academic medical centers (University of Pittsburgh [Pennsylvania], Brown University [Providence, Rhode Island], and University of California at Los Angeles). Institutional review board approval was obtained at each site prior to subject enrollment.
To date, subjects have been prospectively interviewed weekly for a mean ± SD of 37.13 ± 20.4 weeks for 261.7 ± 94.1 weeks (approximately 5 years). At present, subject retention rate is 84.8%.
Procedures
Children and parents were 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),15 the Kiddie Mania Rating Scale,16 and the depression section of the K-SADS-PL.
Parents were interviewed at intake about their personal psychiatric history by using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I),17 and about their first- and second-degree psychiatric family history by using a modified version of the Family History Screen.18 Socioeconomic status was measured using the Hollingshead 4-Factor Scale.19 Functional impairment was assessed by using the Child Global Assessment Scale,20 and the child and parent Screen for Child Anxiety Related Emotional Disorder21 was used to evaluate severity of anxiety.
Longitudinal changes in psychiatric symptoms, functioning, and treatment exposure since the previous evaluation were assessed by using the Longitudinal Interval Follow-Up Evaluation.22,23 The Longitudinal Interval Follow-Up Evaluation evaluates the course of symptoms by identifying change points, frequently anchored by memorable dates for the subject (eg, holidays, beginning of school). The severity of ongoing symptoms, onset of new symptoms, and episode polarity for bipolar disorder since the last appointment are tracked by using weekly Longitudinal Interval Follow-Up Evaluation Psychiatric Status Rating scores. For DSM-IV mood disorders, the Psychiatric Status Rating scores range from 1 for no symptoms, to 2 to 4 for varying levels of sub-threshold symptoms and impairment, to 5 or 6 for full criteria with different degrees of severity or impairment. Most of the anxiety disorders were also rated on a 6-point scale of 1 to 6, on which 5 and 6 indicate presence of DSM-threshold symptoms. Some anxiety disorders (anxiety NOS and separation anxiety disorder), other comorbid disorders, and psychosis were assigned weekly scores on a 3-point scale of 1 to 3, on which 3 indicates presence of DSM-threshold symptoms. A past history of subsyndromal anxiety was defined as youth with 75% of the DSM-IV criteria for any anxiety disorder and functional impairment and was ascertained through K-SADS-PL completed at intake. Youth with only specific phobia (eg, fear of the dark) were excluded because simple phobias are ubiquitous.3 At intake, information about past and current pharmacologic treatment was obtained. Information about pharmacologic treatment during the follow-up was ascertained by using the Psychotropic Treatment Record of the Longitudinal Interval Follow-Up Evaluation. Each specific type of treatment and dose was recorded on a weekly basis.
Definition of Persistence of Anxiety Disorders
The mean ± SD of the distribution of time with anxiety disorders during the follow-up was 56.9 ± 33 weeks, with a median of 55.4 weeks. On the basis of this distribution, persistence of anxiety disorders over the follow-up period was defined as at least 50% of follow-up time meeting full-threshold DSM-IV anxiety disorders criteria.
Definition of Remission
Neither the DSM-IV nor the pediatric literature provides a definition of remission for anxiety disorders. Therefore, we used the criteria described in the adult literature of remission for anxiety disorders that is similar to the definition used for depression, namely, at least 8 consecutive weeks with only 1 or 2 symptoms to a mild degree.2426 To avoid overlap with the anxiety disorders present at intake, onset of new anxiety disorders were counted only if they started more than 8-weeks after intake.
Statistical Analyses
Analyses of the persistence of anxiety disorders included between-group comparisons using t tests or χ2 tests as appropriate. As is customary,27 and given that this is the first study prospectively evaluating anxiety disorders in youth with bipolar disorder, intake and follow-up variables with P values < .1 associated with the persistence of anxiety disorder were entered into a stepwise logistic regression and controlled for between-group significant demographic variables.
Analyses of the factors associated with the onset of new anxiety disorders in bipolar disorder youth were performed by using the log-rank test or Cox proportional hazards regressions. A Cox proportional hazards regression with time-varying covariates was used to identify factors that occurred during prospective follow-up and were associated with onset of new anxiety disorders. Data for the time-varying covariates were ascertained with the Longitudinal Interval Follow-Up Evaluation. Weekly values on the Psychiatric Status Rating for individual diagnostic factors were aggregated over 8-week time intervals. A stepwise multivariate Cox regression analysis was performed including all variables with significance (P < .1) and controlled for any between-group significant demographic variables.
Odds ratios (ORs) and confidence intervals (CIs) were computed. All P values are based on 2-tailed tests, with α = .05.
Before analyzing the persistence of anxiety during the follow-up, we performed analyses to ascertain the presence of any anxiety at any time during the follow-up and whether the anxiety disorders during the follow-up were of the same type as those present at intake. At any time during the follow-up, 80.6% (137/170) of the youth had an anxiety disorder (GAD, 49.6%; separation anxiety disorder, 44.5%; social phobia, 34.3%; OCD, 27.7%; panic disorder, 21.2%; PTSD, 15.3%; anxiety NOS, 15.3%; and agoraphobia, 11%). Fifty-three-percent of youth with any anxiety disorders had ≥ 2 anxiety disorders. Youth diagnosed with a given anxiety disorder at intake tended to have the same disorder over the follow-up (OCD, 90.5%; social phobia, 85.7%; GAD, 83.6%; anxiety NOS, 80%; agoraphobia, 77.8%; panic disorder, 73.7%; separation anxiety disorder, 69.7%; and PTSD, 57.9%).
Of the 137 youth who continued to have any anxiety disorder, 67 subjects spent ≤ 50% of the follow-up time with anxiety disorders, and 70 subjects spent more than 50% of the follow-up time with anxiety disorders.
Intake and Follow-Up Factors Associated With the Persistence of Anxiety
For the intake factors, univariate analyses showed that bipolar disorder youth with persistent anxiety were significantly more likely to have ≥ 2 comorbid anxiety disorders, GAD, and less lifetime treatment with antimanic medications (Table 1; all P values ≤ .05). In addition, analyses of medication used at intake showed less treatment with anti-manic medications (80.6% vs 62.9%; χ2 = 5.3; P = .02; data not included in the Table).
Table 1
Table 1
Demographic and Clinical Characteristics at Intake Associated With the Persistence of Anxiety Disorders in Youth With Bipolar Disorder Based on the Percentage of Time Spent With Anxiety Disorders
For the follow-up factors, univariate analyses showed that bipolar disorder youth with persistent anxiety had significantly less follow-up time in euthymia, more subthreshold and threshold mood symptoms, more full-threshold depression, and more follow-up time spent with any comorbid disorder (Table 2; all P values ≤ .05).
Table 2
Table 2
Follow-Up Factors Associated With the Persistence of Anxiety Disorders in Youth With Bipolar Disorder Based on the Percentage of Time Spent With Anxiety Disordersa
Multivariate regression analyses for the intake and follow-up factors showed that persistent anxiety was associated with having ≥ 2 comorbid anxiety disorders (OR = 2.14; 95% CI, 1.03–4.47; P = .04), less antimanic treatment at intake (OR = 0.37; 95% CI, 0.16–0.85; P = .02), less follow-up time spent euthymic (OR = 0.97; 95% CI, 0.96–0.99; P = .0004), less ongoing conduct disorder (OR = 0.96; 95% CI, 0.94–0.99; P = .01), and less follow-up time receiving antidepressant medications (OR = 0.99; 95% CI, 0.98–1.00; P = .04).
Prevalence of Onset of New Anxiety Disorders
Of the 243 youth who at intake did not have any lifetime DSM-IV anxiety disorders, 60 (24.7%) had an onset of new disorders, including GAD, 31.7%; anxiety NOS, 28.3%; PTSD, 20%; social phobia, 18.3%; OCD, 15%; panic disorder, 11.7%; separation anxiety disorder, 10%; and agoraphobia, 3.3%. Eighteen percent of subjects with any new anxiety disorder had new onset of ≥ 2 anxiety disorders.
Intake and Follow-Up Factors Associated With Onset of New Anxiety Disorders
For the intake factors, univariate analyses showed that new-onset anxiety disorders were significantly associated with lower socioeconomic status, not living with both natural parents, and higher total scores on the child’s and parent’s Screen for Child Anxiety Related Emotional Disorder. In addition, conduct disorder, substance use disorders, history of physical or sexual abuse, history of subsyndromal anxiety, and less lifetime antimanic medications were significantly associated with new onset of anxiety (Table 3; all P values ≤ .05). Additional analyses of medications used at the time of the intake showed that use of stimulants was associated with the onset of more new anxiety disorders (36.7 vs 24.2; χ2=3.9; P = .05; data not included Table 3).
Table 3
Table 3
Demographic and Clinical Characteristics at Intake Associated With the Onset of New Anxiety Disorders in Youth With Bipolar Disorder
For the follow-up factors, univariate analyses showed that onset of new anxiety disorders was significantly associated with less time euthymic, more time in depression and mania/hypomania, ADHD, conduct disorder, substance use disorders, and less time receiving antimanic medications (Table 4; all P values ≤ .05).
Table 4
Table 4
Follow-Up Factors Associated With the Onset of New Anxiety Disorders in Youth With Bipolar Disordera
Multivariate regression analyses for the intake and follow-up factors showed that onset of new anxiety disorders was associated with being female (hazard ratio [HR]: 1.81; 95% CI, 1.05–3.11; P = .03), lower socioeconomic status (HR: 0.8; 95% CI, 0.65–0.99; P = .05), stimulant treatment at intake (HR: 1.91; 95% CI, 1.09–3.34; P = .02), ongoing ADHD (HR: 1.01; 95% CI, 1.002–1.01; P = .01) and substance use disorders (HR: 1.01; 95% CI, 1.003–1.02; P = .004), and more follow-up time with manic/hypomanic symptoms (HR: 1.01; 95% CI, 1.001–1.02; P = .04).
As noted above, use of stimulants was 1 of the intake factors associated with onset of new anxiety disorders. To disentangle the effects of stimulants and ADHD, both variables were entered into a regression. In this analysis, only ADHD was associated with the onset of new of anxiety disorders (P = .05).
To our knowledge, this is the first study examining the long-term outcome of anxiety disorders and the factors that predict onset of new anxiety disorders among youth with bipolar disorder. Present findings indicate that most anxiety disorders diagnosed at intake continued during the follow-up and were of the same type. Moreover, about 50% of the youth had persistent anxiety, particularly GAD. The persistence of anxiety disorders was associated with multiple anxiety disorders, less follow-up time euthymic, less comorbid conduct disorder, and less treatment with antimanic and antidepressant medications. Twenty-five percent of the sample who did not have an anxiety disorder at intake developed new anxiety disorders during follow-up, most commonly GAD. The onset of new anxiety disorders was significantly associated with being female, lower socioeconomic status, presence of ADHD and substance use disorders, and more follow-up time with manic or hypomanic symptoms.
Since no other pediatric and adult longitudinal studies that have assessed the outcome of anxiety disorders in bipolar disorder, we compared our results with existing literature on the course of anxiety disorders in youth and adults without bipolar disorder. Similar to our findings, results from longitudinal studies in youth with anxiety disorders have also shown that, with the exception of separation anxiety disorder, most anxiety disorders, and especially GAD,24,25,28,29 tend to continue into adulthood.2932 Also, evidence for the homotypic continuation of the anxiety disorders has been reported,33,34 and, in concordance with our results, multiple anxiety disorders35 predicted higher persistence of anxiety disorders. In contrast with other studies36,37 which mainly included males, we found that persistence of anxiety was associated with less comorbid conduct disorder. This finding might be explained by the fact that there were no differences in the proportion of males and females in the Course of Outcome of Bipolar Youth study.38 The persistence of anxiety over time may explain in part the high association between anxiety disorders and bipolar disorder and could be a unique factor that negatively influences bipolar disorder severity and prognosis68,11 compared to other comorbid conditions such as ADHD and substance use disorders. Furthermore, our results and those of 1 epidemiologic study in youth39 give evidence that the relationship between anxiety disorders and bipolar disorder severity may be bidirectional, as ongoing symptoms of mania or hypomania are associated with persistence and the onset of new anxiety disorders.
The results of our study together with the fact that pediatric anxiety disorders may continue into adulthood and that anxiety disorders worsen the course of bipolar disorder6,7 indicate the need for early identification and treatment of these disorders in youth with bipolar disorder. Current evidence-based treatments for anxiety disorders show that cognitive-behavioral therapy (CBT) and the selective serotonin reuptake inhibitors (SSRIs), and in particular their combination, are efficacious for the acute treatment of anxiety in youth.40 Although we know that CBT is efficacious for youth with anxiety disorders, youth with comorbid bipolar disorder have been excluded from these trials, and thus we do not have data on its efficacy for this population. Moreover, even if the SSRIs are efficacious and well tolerated for youth with anxiety, we do not know the efficacy and tolerability of these medications for youth with bipolar disorder and anxiety. Since there are no randomized controlled trials comparing CBT, SSRIs, or the combination of both treatments in youth (and adults) with anxiety and bipolar disorder, we feel these studies are necessary. Such studies would inform clinical practice, and answer a very important question about the relative efficacy of CBT, SSRIs, and/or the combination, for youth with the common and impairing presentation of comorbid bipolar disorder and anxiety.
About one-quarter of the sample developed new anxiety disorders during the follow-up. Similar to findings in the pediatric and adult literature, female sex41,42 and lower socioeconomic status41,43 increased the risk for new anxiety disorders, particularly GAD.41,44 Our findings are also consistent with the epidemiologic literature in which anxiety disorders are more prevalent in females,30,43 especially GAD in adolescent females.41,45
Epidemiologic as well as clinical studies have shown that youth4649 and adults50,51 with bipolar disorder are at high risk for substance use disorders. Also, both bipolar disorder and substance use disorders are strongly associated with anxiety.52 Similarly, our findings showed that bipolar disorder youth with substance use disorders or ADHD53 were at high risk for onset of new anxiety disorders, suggesting that early recognition and treatment of these disorders may prevent the development of new anxiety disorders.
These above-noted results need to be taken in the context of the limitations of this study. First, no psychiatric control group was included. Thus, we cannot conclude that anxiety disorders are more common in youth with bipolar disorder than in youth with other childhood psychiatric disorders (eg, major depressive disorder). However, other pediatric and adults studies have consistently shown that anxiety disorders are more common in bipolar disorder than in other psychiatric disorders.54,55 Second, the effects of treatment were not analyzed. Finally, since subjects were a referred sample, findings may not apply to other populations.
In summary, most anxiety disorders persisted during the follow-up and a substantial group of subjects developed new anxiety disorders. Consistent with the literature for other disorders (eg, major depressive disorder),56 we found that different factors were associated with the persistence and the onset of new anxiety disorders. Early identification and appropriate management of these risk factors may improve the course of bipolar disorder youth. Randomized controlled trials are warranted to evaluate whether existing treatments known to be efficacious for anxiety disorders particularly psychosocial treatments, such as CBT, that are not associated with inducing mood instability, are equally efficacious and tolerable for youth with comorbid bipolar disorder and anxiety disorders.
Clinical Points
  • Anxiety disorders in youth with bipolar disorder tended to persist, and a substantial proportion of subjects developed new anxiety disorders.
  • Different factors, including the presence of severe or multiple anxiety disorders, ongoing mood symptoms, and comorbid disorders, were associated with the persistence and the onset of anxiety disorders. Early identification of factors may enable the development of strategies for treatment and prevention of anxiety disorders in bipolar youth.
  • Randomized controlled trials are warranted to evaluate the efficacy and tolerability of pharmacologic and psychosocial treatments for youth with comorbid bipolar disorder and anxiety disorders.
Acknowledgments
Funding/support: NIMH grants MH59929 (Dr Birmaher), MH59977 (Dr Strober), and MH59691 (Dr Keller).
Role of sponsor: The NIMH had no 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
Previous presentation: Preliminary findings were presented in poster form at the 57th Annual Meeting of the American Academy of Child and Adolescent Psychiatry; October 26–31, 2010; New York, New York.
Potential conflicts of interest: Dr Hunt has received honoraria from Wiley Publishing. Dr Keller has been a consultant to or has received honoraria from Medtronic and Sierra Neuropharmaceuticals and has received grant/research support from Pfizer. Dr Birmaher is currently employed by the University of Pittsburgh and The University of Pittsburgh Medical Center/Western Psychiatric Institute and Clinic; receives research funding from the National Institute of Mental Health (NIMH); is a consultant to Schering-Plough; has participated in forums in the past 12 months sponsored by Dey Pharma; and has received or will receive royalties for publications from Random House and Lippincott Williams & Wilkins. Drs Sala, Axelson, Castro-Fornieles, T. R. Goldstein, B. I. Goldstein, Ha, Iyengar, Strober, Yen, Dickstein, and Ryan and Mss Liao, Gill, and Hower do not have any commercial associations that might pose a conflict of interest in connection with this article. Dr Sala was supported by a grant from the Alicia Koplowitz Foundation.
1. Joshi G, Wilens T. Comorbidity in pediatric bipolar disorder. Child Adolesc Psychiatr Clin N Am. 2009;18(2):291–319. vii–viii. doi: 10.1016/j.chc.2008.12.005. [vii–viii.] [PMC free article] [PubMed] [Cross Ref]
2. 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. [vii.]. [PMC free article] [PubMed] [Cross Ref]
3. Sala R, Axelson DA, Castro-Fornieles J, et al. Comorbid anxiety in children and adolescents with bipolar spectrum disorders: prevalence and clinical correlates. J Clin Psychiatry. 2010;71(10):1344–1350. doi: 10.4088/JCP.09m05845gre. [PMC free article] [PubMed] [Cross Ref]
4. 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. doi: 10.1016/j.jad.2005.05.016. [PubMed] [Cross Ref]
5. 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. doi: 10.1034/j.1399-5618.2000.20309.x. [PubMed] [Cross Ref]
6. 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. doi: 10.1016/j.psychres.2006.10.010. [PubMed] [Cross Ref]
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. doi: 10.1176/appi.ajp.164.4.582. [PubMed] [Cross Ref]
8. Otto MW, Simon NM, Wisniewski SR, et al. STEP-BD Investigators. Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders. Br J Psychiatry. 2006;189(1):20–25. doi: 10.1192/bjp.bp.104.007773. [PubMed] [Cross Ref]
9. 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. doi: 10.4088/JCP.v65n0813. [PubMed] [Cross Ref]
10. 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. doi: 10.1002/da.20053. [PubMed] [Cross Ref]
11. Coryell W, Solomon DA, Fiedorowicz JG, et al. Anxiety and outcome in bipolar disorder. Am J Psychiatry. 2009;166(11):1238–1243. doi: 10.1176/appi.ajp.2009.09020218. [PMC free article] [PubMed] [Cross Ref]
12. 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. doi: 10.1176/appi.ajp.157.6.956. [PubMed] [Cross Ref]
13. 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. doi: 10.1001/archpsyc.59.10.905. [PubMed] [Cross Ref]
14. 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. doi: 10.1176/appi.ajp.161.12.2222. [PubMed] [Cross Ref]
15. 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. doi: 10.1097/00004583-199707000-00021. [PubMed] [Cross Ref]
16. 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. doi: 10.1089/104454603322724850. [PubMed] [Cross Ref]
17. First MB, Sr, Williams JBW, Gibbon M. Structured Clinical Interview for DSM-IV (SCID) Washington, DC: American Psychiatric Association; 1995.
18. 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. doi: 10.1001/archpsyc.57.7.675. [PubMed] [Cross Ref]
19. Hollingshead AB. Four-Factor Index of Social Status. New Haven, CT: Dept of Sociology, Yale University; 1975.
20. Shaffer D, Gould MS, Brasic J, et al. A children’s global assessment scale (CGAS) Arch Gen Psychiatry. 1983;40(11):1228–1231. [PubMed]
21. Birmaher B, Khetarpal S, Brent D, et al. The Screen for Child Anxiety Related Emotional Disorders (SCARED): scale construction and psychometric characteristics. J Am Acad Child Adolesc Psychiatry. 1997;36(4): 545–553. doi: 10.1097/00004583-199704000-00018. [PubMed] [Cross Ref]
22. Keller MB, Lavori PW, Friedman B, et al. The Longitudinal Interval Follow-up Evaluation: a comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry. 1987;44(6):540–548. [PubMed]
23. Warshaw MG, Dyck I, Allsworth J, et al. Maintaining reliability in a long-term psychiatric study: an ongoing inter-rater reliability monitoring program using the Longitudinal Interval Follow-up Evaluation. J Psychiatr Res. 2001;35(5):297–305. doi: 10.1016/S0022-3956(01)00030-9. [PubMed] [Cross Ref]
24. Bruce SE, Yonkers KA, Otto MW, et al. Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a 12-year prospective study. Am J Psychiatry. 2005;162(6):1179–1187. doi: 10.1176/appi.ajp.162.6.1179. [PMC free article] [PubMed] [Cross Ref]
25. Yonkers KA, Dyck IR, Warshaw M, et al. Factors predicting the clinical course of generalised anxiety disorder. Br J Psychiatry. 2000;176(6): 544–549. doi: 10.1192/bjp.176.6.544. [PubMed] [Cross Ref]
26. Yonkers KA, Bruce SE, Dyck IR, et al. Chronicity, relapse, and illness—course of panic disorder, social phobia, and generalized anxiety disorder: findings in men and women from 8 years of follow-up. Depress Anxiety. 2003;17(3):173–179. doi: 10.1002/da.10106. [PubMed] [Cross Ref]
27. Hoaglin D, Mosteller F, Rukey JW. Understanding Robust and Exploratory Data Analysis. New York, NY: John Wiley & Sons; 1983.
28. Cantwell DP, Baker L. Stability and natural history of DSM-III childhood diagnoses. J Am Acad Child Adolesc Psychiatry. 1989;28(5):691–700. doi: 10.1097/00004583-198909000-00009. [PubMed] [Cross Ref]
29. Cohen P, Cohen J, Brook J. An epidemiological study of disorders in late childhood and adolescence, 2: persistence of disorders. J Child Psychol Psychiatry. 1993;34(6):869–877. doi: 10.1111/j.1469-7610.1993.tb01095.x. [PubMed] [Cross Ref]
30. 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. doi: 10.1001/archpsyc.55.1.56. [PubMed] [Cross Ref]
31. Essau CA, Conradt J, Petermann F. Course and outcome of anxiety disorders in adolescents. J Anxiety Disord. 2002;16(1):67–81. doi: 10.1016/S0887-6185(01)00091-3. [PubMed] [Cross Ref]
32. Keller MB, Lavori PW, Wunder J, et al. Chronic course of anxiety disorders in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1992;31(4):595–599. doi: 10.1097/00004583-199207000-00003. [PubMed] [Cross Ref]
33. Costello EJ, Mustillo S, Erkanli A, et al. Prevalence and development of psychiatric disorders in childhood and adolescence. Arch Gen Psychiatry. 2003;60(8):837–844. doi: 10.1001/archpsyc.60.8.837. [PubMed] [Cross Ref]
34. Gregory AM, Caspi A, Moffitt TE, et al. Juvenile mental health histories of adults with anxiety disorders. Am J Psychiatry. 2007;164(2):301–308. doi: 10.1176/appi.ajp.164.2.301. [PubMed] [Cross Ref]
35. Last CG, Hansen C, Franco N. Anxious children in adulthood: a prospective study of adjustment. J Am Acad Child Adolesc Psychiatry. 1997;36(5): 645–652. doi: 10.1097/00004583-199705000-00015. [PubMed] [Cross Ref]
36. Lahey BB, Loeber R, Burke J, et al. Waxing and waning in concert: dynamic comorbidity of conduct disorder with other disruptive and emotional problems over 7 years among clinic-referred boys. J Abnorm Psychol. 2002;111(4):556–567. doi: 10.1037/0021-843X.111.4.556. [PubMed] [Cross Ref]
37. Nock MK, Kazdin AE, Hiripi E, et al. Prevalence, subtypes, and correlates of DSM-IV conduct disorder in the National Comorbidity Survey Replication. Psychol Med. 2006;36(5):699–710. doi: 10.1017/S0033291706007082. [PMC free article] [PubMed] [Cross Ref]
38. Axelson DA, Birmaher B, Strober M, et al. Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry. 2006;63(10):1139–1148. doi: 10.1001/archpsyc.63.10.1139. [PubMed] [Cross Ref]
39. 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. doi: 10.1176/appi.ajp.157.10.1679. [PubMed] [Cross Ref]
40. 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. doi: 10.1056/NEJMoa0804633. [PMC free article] [PubMed] [Cross Ref]
41. 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. doi: 10.1016/j.psc.2009.06.002. [PMC free article] [PubMed] [Cross Ref]
42. Merikangas KR. Vulnerability factors for anxiety disorders in children and adolescents. Child Adolesc Psychiatr Clin N Am. 2005;14(4): 649–679. vii–vii. doi: 10.1016/j.chc.2005.06.005. [PubMed] [Cross Ref]
43. Wittchen HU, Nelson CB, Lachner G. Prevalence of mental disorders and psychosocial impairments in adolescents and young adults. Psychol Med. 1998;28(1):109–126. doi: 10.1017/S0033291797005928. [PubMed] [Cross Ref]
44. Blazer D, Hughes D, George LK. Stressful life events and the onset of a generalized anxiety syndrome. Am J Psychiatry. 1987;144(9):1178–1183. [PubMed]
45. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593–602. doi: 10.1001/archpsyc.62.6.593. [PubMed] [Cross Ref]
46. Goldstein BI, Strober MA, Birmaher B, et al. Substance use disorders among adolescents with bipolar spectrum disorders. Bipolar Disord. 2008;10(4):469–478. doi: 10.1111/j.1399-5618.2008.00584.x. [PMC free article] [PubMed] [Cross Ref]
47. 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. doi: 10.1097/00004583-199504000-00012. [PubMed] [Cross Ref]
48. Wilens TE, Biederman J, Kwon A, et al. Risk of substance use disorders in adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2004;43(11):1380–1386. doi: 10.1097/01.chi.0000140454.89323.99. [PubMed] [Cross Ref]
49. Wilens TE, Biederman J, Millstein RB, et al. Risk for substance use disorders in youths with child- and adolescent-onset bipolar disorder. J Am Acad Child Adolesc Psychiatry. 1999;38(6):680–685. doi: 10.1097/00004583-199906000-00014. [PubMed] [Cross Ref]
50. Chengappa KN, Levine J, Gershon S, et al. Lifetime prevalence of substance or alcohol abuse and dependence among subjects with bipolar I and II disorders in a voluntary registry. Bipolar Disord. 2000;2(3 pt 1):191–195. doi: 10.1034/j.1399-5618.2000.020306.x. [PubMed] [Cross Ref]
51. Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004;61(8):807–816. doi: 10.1001/archpsyc.61.8.807. [PubMed] [Cross Ref]
52. 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. doi: 10.1111/j.1399-5618.2008.00461.x. [PubMed] [Cross Ref]
53. Kim-Cohen J, Caspi A, Moffitt TE, et al. Prior juvenile diagnoses in adults with mental disorder: developmental follow-back of a prospective-longitudinal cohort. Arch Gen Psychiatry. 2003;60(7):709–717. doi: 10.1001/archpsyc.60.7.709. [PubMed] [Cross Ref]
54. Jolin EM, Weller EB, Weller RA. Anxiety symptoms and syndromes in bipolar children and adolescents. Curr Psychiatry Rep. 2008;10(2):123–129. doi: 10.1007/s11920-008-0022-5. [PubMed] [Cross Ref]
55. 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. doi: 10.1016/S0165-0327(00)00299-8. [PubMed] [Cross Ref]
56. Lewinsohn PM, Rohde P, Seeley JR. Major depressive disorder in older adolescents: prevalence, risk factors, and clinical implications. Clin Psychol Rev. 1998;18(7):765–794. doi: 10.1016/S0272-7358(98)00010-5. [PubMed] [Cross Ref]