High Prevalence of Metabolic Syndrome Among Adolescents and Young Adults With Bipolar Disorder.

OBJECTIVE: Despite abundant literature demonstrating increased metabolic syndrome (MetS) prevalence and important clinical correlates of MetS among middle-age adults with bipolar disorder, little is known about this topic among adolescents and young adults early in their course of bipolar disorder. We therefore examined this topic in the Course and Outcome of Bipolar Youth (COBY) study. METHODS: A cross-sectional, retrospective study was conducted of 162 adolescents and young adults (mean ± SD age = 20.8 ± 3.7 years; range, 13.6-28.3 years) with bipolar disorder (I, II, or not otherwise specified, based on DSM-IV) enrolled in COBY between 2000 and 2006. MetS measures (blood pressure, glucose, high-density lipoprotein cholesterol [HDL-C], triglycerides, and waist circumference), defined using the International Diabetes Federation criteria, were obtained at a single timepoint. Mood, comorbidity, and treatment over the 6 months preceding the MetS assessment were evaluated using the Longitudinal Interval Follow-Up Evaluation. RESULTS: The prevalence of MetS in the sample was 19.8% (32/162). Low HDL-C (56.5%) and abdominal obesity (46.9%) were the most common MetS criteria. MetS was nominally associated with lower lifetime global functioning at COBY intake (odds ratio [OR] = 0.97, P = .06). MetS was significantly associated with percentage of weeks in full-threshold pure depression (OR = 1.07, P = .02) and percentage of weeks receiving antidepressant medications (OR = 1.06, P = .001) in the preceding 6 months. MetS was not associated with manic symptoms or medications other than antidepressants. CONCLUSIONS: The prevalence of MetS in this sample was at least double compared to the general population. Moreover, MetS is associated with increased burden of depression symptoms in this group. Management of early-onset bipolar disorder should integrate strategies focused on modifying MetS risk factors.

Differentiating weight-restored anorexia nervosa and body dysmorphic disorder using neuroimaging and psychometric markers.

Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are potentially life-threatening conditions whose partially overlapping phenomenology-distorted perception of appearance, obsessions/compulsions, and limited insight-can make diagnostic distinction difficult in some cases. Accurate diagnosis is crucial, as the effective treatments for AN and BDD differ. To improve diagnostic accuracy and clarify the contributions of each of the multiple underlying factors, we developed a two-stage machine learning model that uses multimodal, neurobiology-based, and symptom-based quantitative data as features: task-based functional magnetic resonance imaging data using body visual stimuli, graph theory metrics of white matter connectivity from diffusor tensor imaging, and anxiety, depression, and insight psychometric scores. In a sample of unmedicated adults with BDD (n = 29), unmedicated adults with weight-restored AN (n = 24), and healthy controls (n = 31), the resulting model labeled individuals with an accuracy of 76%, significantly better than the chance accuracy of 35% ([Formula: see text]). In the multivariate model, reduced white matter global efficiency and better insight were associated more with AN than with BDD. These results improve our understanding of the relative contributions of the neurobiological characteristics and symptoms of these disorders. Moreover, this approach has the potential to aid clinicians in diagnosis, thereby leading to more tailored therapy.

Inflammatory markers among adolescents and young adults with bipolar spectrum disorders.

OBJECTIVE: Despite burgeoning literature in middle-aged adults, little is known regarding proinflammatory markers (PIMs) among adolescents and young adults with bipolar disorder. Similarly, few prior studies have considered potential confounds when examining the association between PIMs and bipolar disorder characteristics. We therefore retrospectively examined these topics in the Course and Outcome of Bipolar Youth (COBY) study. METHOD: Subjects were 123 adolescents and young adults (mean [SD] = 20.4 ± 3.8 years; range, 13.4-28.3 years) in COBY, enrolled between October 2000 and July 2006. DSM-IV diagnoses were determined using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). Clinical characteristics during the preceding 6 months, including mood, comorbidity, and treatment, were evaluated using the Longitudinal Interval Follow-Up Evaluation (LIFE). Serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and high-sensitivity C-reactive protein (hsCRP) were assayed. Primary analyses examined the association of PIMs with bipolar disorder characteristics during the preceding 6 months. RESULTS: Several lifetime clinical characteristics were significantly associated with PIMs in multivariable analyses, including longer illness duration (P = .005 for IL-6; P = .0004 for hsCRP), suicide attempts (P = .01 for TNF-α), family history of suicide attempts or completion (P = .01 for hsCRP), self-injurious behavior (P =.005 for TNF-α), substance use disorder (SUD) (P < .0001 for hsCRP), and family history of SUD (P = .02 for TNF-α; P = .01 for IL-6). The following bipolar disorder characteristics during the preceding 6 months remained significantly associated with PIMs in multivariable analyses that controlled for differences in comorbidity and treatment: for TNF-α, percentage of weeks with psychosis (χ(2) = 5.7, P =.02); for IL-6, percentage of weeks with subthreshold mood symptoms (χ(2)= 8.3, P = .004) and any suicide attempt (χ(2) = 6.1, P = .01); for hsCRP, maximum severity of depressive symptoms (χ(2) = 8.3, P =.004). CONCLUSION: Proinflammatory markers may be relevant to bipolar disorder characteristics as well as other clinical characteristics among adolescents and young adults with bipolar disorder. Traction toward validating PIMs as clinically relevant biomarkers in bipolar disorder will require repeated measures of PIMs and incorporation of relevant covariates.

Effects of comorbid anxiety disorders on the longitudinal course of pediatric bipolar disorders.

OBJECTIVE: To examine the longitudinal effects of comorbid anxiety disorders in youth with bipolar spectrum disorder (BP). METHOD: As part of the Course and Outcome of Bipolar Youth study, 413 youth, who were 7 through 17 years or age and who met criteria for DSM-IV BP-I (n = 244), BP-II (n = 28), and operationally defined bipolar disorder not otherwise specified (BP-NOS) (n = 141) were included. Subjects were followed on average 5 years using the Longitudinal Interval Follow-up Evaluation. Effects of anxiety on the time to mood recovery and recurrence and percentage of time with syndromal and subsyndromal mood symptomatology during the follow-up period were analyzed. RESULTS: At intake and during the follow-up, 62% of youth with BP met criteria for at least 1 anxiety disorder. About 50% of the BP youth with anxiety had ≥2 anxiety disorders. Compared to BP youth without anxiety, those with anxiety had significantly more depressive recurrences and significantly longer median time to recovery. The effects of anxiety on recovery disappeared when the severity of depression at intake was taken into account. After adjusting for confounding factors, BP youth with anxiety, particularly those with ≥2 anxiety disorders, spent significantly less follow-up time asymptomatic and more time with syndromal mixed/cycling and subsyndromal depressive symptomatology compared to those without anxiety. CONCLUSIONS: Anxiety disorders are common and adversely affect the course of BP in youth, as characterized by more mood recurrences, longer time to recovery, less time euthymic, and more time in mixed/cycling and depressive episodes. Prompt recognition and the development of treatments for BP youth with anxiety are warranted.

Factors associated with the persistence and onset of new anxiety disorders in youth with bipolar spectrum disorders.

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.

Course of subthreshold bipolar disorder in youth: diagnostic progression from bipolar disorder not otherwise specified.

OBJECTIVE: To determine the rate of diagnostic conversion from an operationalized diagnosis of bipolar disorder not otherwise specified (BP-NOS) to bipolar I disorder (BP-I) or bipolar II disorder (BP-II) in youth over prospective follow-up and to identify factors associated with conversion. METHOD: Subjects were 140 children and adolescents recruited from clinical referrals or advertisement who met operationalized criteria for BP-NOS at intake and participated in at least one follow-up evaluation (91% of initial cohort). Diagnoses were assessed at follow-up interviews using the Longitudinal Interval Follow-Up Evaluation. The mean duration of follow-up was 5 years and the mean interval between assessments was 8.2 months. RESULTS: Diagnostic conversion to BP-I or BP-II occurred in 63 subjects (45%): 32 (23%) to BP-I (nine of whom had initially converted to BP-II) and 31 to only BP-II (22%). Median time from intake to conversion was 58 weeks. First- or second-degree family history of mania or hypomania was the strongest baseline predictor of diagnostic conversion (p = .006). Over follow-up, conversion was associated with greater intensity of hypomanic symptoms and with greater exposure to specialized, intensive outpatient psychosocial treatments. There was no association between conversion and exposure to treatment with particular medication classes. CONCLUSIONS: Children and adolescents referred with mood symptoms that meet operationalized criteria for BP-NOS, particularly those with a family history of BP, frequently progress to BP-I or BP-II. Efforts to identify these youth and effectively intervene may have the potential to curtail the progression of mood disorders in this high-risk population.

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.

Negative life events in children and adolescents with bipolar disorder.

OBJECTIVE: To study the relationship between negative life events and demographic and clinical variables in youth with bipolar I disorder, bipolar II disorder, and bipolar disorder not otherwise specified (NOS), as well as to compare the rates of life events in youth with bipolar disorder, depressive and/or anxiety disorders (DEP-ANX), and healthy controls. METHOD: Subjects included 446 youth, aged 7 to 17 years, meeting DSM-IV criteria for bipolar I, bipolar II, or an operationalized definition of bipolar disorder NOS, and were enrolled in the Course and Outcome of Bipolar Illness in Youth study. Subjects completed the Life Events Checklist. Sixty-five DEP-ANX and 65 healthy youth were obtained from previous studies using similar methodology. The study was conducted from October 2000 to July 2006. RESULTS: Older age, lower socioeconomic status, living with nonintact family, non-Caucasian race, anxiety, and disruptive disorders were associated with greater number of total negative life events. Specifically, increased independent, dependent, and uncertain negative life events were associated with lower socioeconomic status, nonintact family, and comorbid disruptive disorders. Increased independent negative life events were additionally associated with non-Caucasian race and comorbid anxiety disorders. Increased dependent and uncertain negative life events were also associated with older age. DEP-ANX youth reported a similar rate of negative life events as bipolar youth, and both groups had more negative life events than the healthy controls. Bipolar youth reported fewer total and dependent positive life events compared to DEP-ANX and healthy youths. CONCLUSIONS: Similar to DEP-ANX youth, bipolar youth are exposed to excessive negative independent and dependent life events, which may have implications in the long-term outcome and negative consequences associated with this disorder.

Family environment and suicidal ideation among bipolar youth.

The objective of this study was to examine the association between family environment and suicidal ideation among youth with bipolar disorder. Subjects included 446 bipolar (BP) youth (age 7-17) enrolled in the Course and Outcome of Bipolar Youth study. Current suicidal ideation, family functioning and family stress were assessed at intake. BP youth with current suicidal ideation reported more conflict with their mother and less family adaptability. Ideators endorsed more stressful family events over the prior year and higher rates of specific familial stressors. Clinicians treating bipolar youth should consider family stress when conducting suicide risk assessment. Treatment goals may include enhancing family communication and addressing issues of loss.

Psychosocial functioning among bipolar youth.

BACKGROUND: Evidence indicates that children and adolescents with bipolar disorder (BP) experience significant functional impairment. However, little is known about the association between psychosocial functioning and episodes of illness, demographic, and clinical variables in this population. METHODS: Subjects included 446 patients aged 7 to 17 diagnosed with DSM-IV bipolar disorder via the K-SADS for the Course and Outcome of Bipolar Youth (COBY) study. The Psychosocial Functioning Schedule of the Adolescent Longitudinal Interval Follow-Up Assessment (A-LIFE) was administered at study intake. RESULTS: Mild to moderate levels of psychosocial impairment were evident in work (includes academics), interpersonal, and overall domains of functioning among BP youth. Multivariate analyses indicated that the strongest predictors of psychosocial impairment were adolescence (regardless of age of onset), current mood episode, current affective symptom severity, current psychotic symptoms, and current comorbid conduct disorder. Bipolar youth in-episode were significantly more impaired than those in partial remission/recovery in every functional domain examined and were less satisfied with their functioning. Yet, BP youth in partial remission/recovery reported significant psychosocial impairment. LIMITATIONS: Limitations include the reliance on patient and parent retrospective report of psychosocial functioning. Additionally, we did not account for the impact of psychosocial and pharmacological interventions on functioning. CONCLUSIONS: Findings suggest pediatric BP is associated with significant impairment in psychosocial functioning during and between episodes, with greater impairment during mood episodes than during partial remission/recovery. Additionally, functional impairment in BP appears to increase during adolescence regardless of age of onset. Clinicians should carefully assess and address psychosocial impairment during and between mood episodes, with particular attention to the functioning of BP adolescents.

Prevalence and correlates of physical and sexual abuse in children and adolescents with bipolar disorder.

OBJECTIVE: Adult bipolar disorder (BP) has been associated with lifetime history of physical and sexual abuse. However, there are no reports of the prevalence of abuse in BP youth. The objective of this study was to examine the prevalence and correlates of physical and/or sexual abuse among youth with BP spectrum disorders. METHODS: Four hundred forty-six youths, ages 7 to 17 years (12.7+/-3.2), meeting DSM-IV criteria for BP-I (n=260), BP-II (n=32) or operationalized definition of BP-NOS (n=154) were assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime version (K-SADS-PL). Abuse was ascertained using the K-SADS. RESULTS: Twenty percent of the sample experienced physical and/or sexual abuse. The most robust correlates of any abuse history were living with a non-intact family (OR=2.6), lifetime history of posttraumatic stress disorder (PTSD) (OR=8.8), psychosis (OR=2.1), conduct disorder (CD) (OR=2.3), and first-degree family history of mood disorder (OR=2.2). After adjusting for confounding demographic factors, physical abuse was associated with longer duration of BP illness, non-intact family, PTSD, psychosis, and first-degree family history of mood disorder. Sexual abuse was associated with PTSD. Subjects with both types of abuse were older, with longer illness duration, non-intact family, and greater prevalence of PTSD and CD as compared with the non-abused group. LIMITATIONS: Retrospective data. Also, since this is a cross-sectional study, no inferences regarding causality can be made. CONCLUSION: Sexual and/or physical abuse is common in youth with BP particularly in subjects with comorbid PTSD, psychosis, or CD. Prompt identification and treatment of these youth is warranted.

Preliminary findings regarding overweight and obesity in pediatric bipolar disorder.

OBJECTIVE: Overweight/obesity is highly prevalent among adults with bipolar disorder and has been associated with illness severity. Little is known regarding overweight/obesity among youth with bipolar disorder. METHOD: Subjects were 348 youths aged 7 to 17 years who met DSM-IV criteria for bipolar I or bipolar II disorder or study-operationalized criteria for bipolar disorder not otherwise specified and were enrolled in the Course and Outcome of Bipolar Illness in Youth study. Age- and sex-adjusted body mass index was computed according to International Obesity Task Force cut points, based on self- and parent-reported height and weight, to determine overweight/obesity. The study was conducted from October 2000 to July 2006. RESULTS: Overweight/obesity was prevalent among 42% of subjects. The most robust predictors of overweight/obesity in a logistic regression model were younger age, nonwhite race, lifetime physical abuse, substance use disorders, psychiatric hospitalizations, and exposure to ≥ 2 medication classes associated with weight gain. CONCLUSIONS: The prevalence of overweight/obesity among youth with bipolar disorder may be modestly greater than in the general population. Moreover, similar to adults, overweight/obesity among youth with bipolar disorder may be associated with increased psychiatric burden. These preliminary findings underscore the importance of early identification of overweight/obesity among youth with bipolar disorder. Future studies are needed to clarify the direction of the associations between overweight/obesity and the identified predictors and to compare the prevalence of overweight/obesity among youth with bipolar disorder versus other psychiatric disorders.

Significance of cigarette smoking among youths with bipolar disorder.

Cigarette smoking among adults with bipolar disorder (BP) correlates with psychosis, substance use disorders (SUD), and suicidality. Little is known regarding smoking among youths with BP. Youths with BP (n = 441) were divided into three smoking groups: Never, Ever, and Daily. Twenty-five percent reported any smoking (11% daily, 14% ever). Ever and Daily subjects had significantly greater lifetime prevalence of suicide attempts, physical abuse, conduct disorder, and SUD compared to Never subjects. Daily heavy smokers had greater prevalence of SUD and suicide attempts, and worse depression versus daily light smokers. Smoking among youths with BP is independently associated with suicide attempts and SUD.

Substance use disorders among adolescents with bipolar spectrum disorders.

OBJECTIVE: We set out to examine the prevalence and correlates of substance use disorders (SUD) in a large sample of adolescents with bipolar disorder (BP). METHODS: Subjects were 249 adolescents ages 12 to 17 years old who fulfilled DSM-IV criteria for bipolar I disorder [(BPI), n = 154], or bipolar II disorder [(BPII), n = 25], or operationalized criteria for BP not otherwise specified [(BP NOS), n = 70], via the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS). As part of the multi-site Course and Outcome of Bipolar Youth study, demographic, clinical, and family history variables were measured via intake clinical interview with the subject and a parent/guardian. RESULTS: The lifetime prevalence of SUD among adolescents with BP was 16% (40/249). Results from univariate analyses indicated that subjects with, as compared to without, SUD were significantly less likely to be living with both biological parents, and that there was significantly greater lifetime prevalence of physical abuse, sexual abuse, suicide attempts, conduct disorder, and posttraumatic stress disorder among subjects with SUD. Subjects with SUD reported significantly greater 12-month prevalence of trouble with police, and females with SUD reported significantly greater 12-month prevalence of pregnancy and abortion. Significant predictors of SUD in a logistic regression model included living with both biological parents (lower prevalence), conduct disorder and suicide attempts (increased prevalence). In logistic regression analyses controlling for demographic differences and conduct disorder, SUD remained significantly associated with trouble with police, whereas the association of SUD with pregnancy and abortion was reduced to a statistical trend. The prevalence of SUD was not significantly different among child- versus adolescent-onset BP subjects. CONCLUSIONS: SUD among adolescents with BP is associated with profound hazards including suicide attempts, trouble with police, and teenage pregnancy and abortion.

History of suicide attempts in pediatric bipolar disorder: factors associated with increased risk.

BACKGROUND: Despite evidence indicating high morbidity associated with pediatric bipolar disorder (BP), little is known about the prevalence and clinical correlates of suicidal behavior among this population. OBJECTIVE: To investigate the prevalence of suicidal behavior among children and adolescents with BP, and to compare subjects with a history of suicide attempt to those without on demographic, clinical, and familial risk factors. METHODS: Subjects were 405 children and adolescents aged 7-17 years, who fulfilled DSM-IV criteria for BPI (n = 236) or BPII (n = 29), or operationalized criteria for BP not otherwise specified (BP NOS; n = 140) via the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. As part of a multi-site longitudinal study of pediatric BP (Course and Outcome of Bipolar Youth), demographic, clinical, and family history variables were measured at intake via clinical interview with the subject and a parent/guardian. RESULTS: Nearly one-third of BP patients had a lifetime history of suicide attempt. Attempters, compared with non-attempters, were older, and more likely to have a lifetime history of mixed episodes, psychotic features, and BPI. Attempters were more likely to have a lifetime history of comorbid substance use disorder, panic disorder, non-suicidal self-injurious behavior, family history of suicide attempt, history of hospitalization, and history of physical and/or sexual abuse. Multivariate analysis found that the following were the most robust set of predictors for suicide attempt: mixed episodes, psychosis, hospitalization, self-injurious behavior, panic disorder, and substance use disorder. CONCLUSIONS: These findings indicate that children and adolescents with BP exhibit high rates of suicidal behavior, with more severe features of BP illness and comorbidity increasing the risk for suicide attempt. Multiple clinical factors emerged distinguishing suicide attempters from non-attempters. These clinical factors should be considered in both assessment and treatment of pediatric BP.