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BackgroundTo identify prospectively ascertained individual and family factors that are associated with improvement in Bipolar Disorder (BD) among youths who initially presented with poor course.Methods82 youths with BD with persistent poor mood symptomatology ("predominantly ill course") were compared to 70 youths with BD who at intake had poor course, but showed improvement during the follow-up ("ill with improving course"), (ages 12.3 ± 3.3, vs. 11.7 ± 3.3 years old, at intake). Improvement was measured by the percentage of time euthymic during a mean follow-up of 12.8 years. Youths and parents were interviewed to assess psychopathology, functioning, treatment, and familial functioning and psychopathology.ResultsCompared to the ill group, since intake, the improving group showed significantly lower subthreshold depression and hypo/mania, Attention Deficit Hyperactivity Disorder, and Disruptive Behavior Disorders. Parental Socioeconomic Status (SES) remained unchanged over time in the ill group, but progressively increased in the improving group. Importantly, the change in SES predated the improvement in the mood trajectory. The most influential variables that predicted improvement were higher SES, and absence of parental BD and Substance Use Disorder (SUD). Parental SUD also negatively affected the parental SES, which was directly associated with worse mood course.LimitationsPredominantly self-reported White samples may limit generalizability; other factors potentially associated with outcome (e.g., treatment adherence), were not ascertained.ConclusionsIn addition to treating mood/comorbid psychopathology in symptomatic BD youths, to improve their prognosis, it is crucial to address their parent's BD and SUD and promote parental education/employment.

Neurocognitive deficits, such as cognitive flexibility impairments, are common in bipolar disorder (BD) and predict poor academic, occupational, and functional outcomes. However, the association between neurocognition and illness trajectory is not well understood, especially across developmental transitions. This study examined cognitive flexibility and subsequent mood symptom and suicidal ideation (SI) course in young adults with childhood-onset BD-I (with distinct mood episodes) vs. BD-not otherwise specified (BD-NOS) vs. typically-developing controls (TDCs). Sample included 93 young adults (ages 18-30) with prospectively verified childhood-onset DSM-IV BD-I (n = 34) or BD-NOS (n = 15) and TDCs (n = 44). Participants completed cross-sectional neuropsychological tasks and clinical measures. Then participants with BD completed longitudinal assessments of mood symptoms and SI at 6-month intervals (M = 39.18 ± 16.57 months of follow-up data). Analyses included ANOVAs, independent-samples t tests, chi-square analyses, and multiple linear regressions. Participants with BD-I had significant deficits in cognitive flexibility and executive functioning vs. BD-NOS and TDCs, and impaired spatial working memory vs. TDCs only. Two significant BD subtype-by-cognitive flexibility interactions revealed that cognitive flexibility deficits were associated with subsequent percentage of time depressed and with SI in BD-I but not BD-NOS, regardless of other neurocognitive factors (full-scale IQ, executive functioning, spatial working memory) and clinical factors (current and prior mood and SI symptoms, age of BD onset, global functioning, psychiatric medications, comorbidity). Thus, cognitive flexibility may be an important etiological brain/behavior mechanism, prognostic indicator, and intervention target for childhood-onset BD-I, as this deficit appears to endure into young adulthood and is associated with worse prognosis for subsequent depression and SI.

Facial emotion recognition deficits are common in bipolar disorder (BD) and associated with impairment. However, the relationship between facial emotion recognition and mood course is not well understood. This study examined facial emotion recognition and subsequent mood symptoms in young adults with childhood-onset BD versus typically developing controls (TDCs). The sample included 116 young adults (ages 18-30, 58% male, 78% White) with prospectively verified childhood-onset BD (n = 52) and TDCs (n = 64). At baseline, participants completed a facial emotion recognition task (Diagnostic Analysis of Non-Verbal Accuracy-2) and clinical measures. Then, participants with BD completed mood symptom assessments every 6 months (M = 8.7 ± 5.2 months) over two years. Analyses included independent-samples t tests and mixed-effects regression models. Participants with BD made significantly more recognition errors for child expressions than TDCs. There were no significant between-group differences for recognition errors for adult expressions, or errors for specific child or adult emotional expressions. Participants had moderate baseline mood symptoms. Significant time-by-facial emotion recognition interactions revealed more recognition errors for child emotional expressions predicted lower baseline mania and stable/consistent trajectory; fewer recognition errors for child expressions predicted higher baseline mania and decreasing trajectory. In addition, more recognition errors for adult sad expressions predicted stable/consistent depression trajectory and decreasing mania; fewer recognition errors for adult sad expressions predicted decreasing depression trajectory and stable/consistent mania. Effects remained when controlling for baseline demographics and clinical variables. Facial emotion recognition may be an important brain/behavior mechanism, prognostic indicator, and intervention target for childhood-onset BD, which endures into young adulthood and is associated with mood trajectory.

ObjectivesWhile adults with bipolar disorder (BD) often report symptoms starting in childhood, continuity of mania and/or hypomania (mania/hypomania) from childhood to adulthood has been questioned. Using longitudinal data from the Course and Outcome of Bipolar Youth (COBY) study, we assessed threshold mania/hypomania in young adults who manifested BD as youth.MethodsCOBY is a naturalistic, longitudinal study of 446 youth with BD (84% recruited from outpatient clinics), 7-17 years old at intake, and over 11 years of follow-up. Focusing on youth with BD-I/II (n = 297), we examined adult mania/hypomania risk (>18 years old; mean 7.9 years of follow-up) according to child (

BackgroundYouth with bipolar disorder (BD) are at high risk for suicidal thoughts and behaviors and frequently experience interpersonal impairment, which is a risk factor for suicide. Yet, no study to date has examined the longitudinal associations between relationship quality in family/peer domains and suicidal thoughts and behaviors among youth with BD. Thus, we investigated how between-person differences - reflecting the average relationship quality across time - and within-person changes, reflecting recent fluctuations in relationship quality, act as distal and/or proximal risk factors for suicidal ideation (SI) and suicide attempts.MethodsWe used longitudinal data from the Course and Outcome of Bipolar Youth Study (N = 413). Relationship quality variables were decomposed into stable (i.e., average) and varying (i.e., recent) components and entered, along with major clinical covariates, into separate Bayesian multilevel models predicting SI and suicide attempt. We also examined how the relationship quality effects interacted with age and sex.ResultsPoorer average relationship quality with parents (β = -.33, 95% Bayesian highest density interval (HDI) [-0.54, -0.11]) or friends (β = -.33, 95% HDI [-0.55, -0.11]) was longitudinally associated with increased risk of SI but not suicide attempt. Worsening recent relationship quality with parents (β = -.10, 95% HDI [-0.19, -0.03]) and, to a lesser extent, friends (β = -.06, 95% HDI [-0.15, 0.03]) was longitudinally associated with increased risk of SI, but only worsening recent relationship quality with parents was also associated with increased risk of suicide attempt (β = -.15, 95% HDI [-0.31, 0.01]). The effects of certain relationship quality variables were moderated by gender but not age.ConclusionsAmong youth with BD, having poorer average relationship quality with peers and/or parents represents a distal risk factor for SI but not suicide attempts. Additionally, worsening recent relationship quality with parents may be a time-sensitive indicator of increased risk for SI or suicide attempt.

BackgroundPediatric bipolar disorders are often characterized by disruptions in cognitive functioning, and exposure to child maltreatment (e.g., physical and sexual abuse) is associated with a significantly poorer course of illness. Although clinical and developmental research has shown maltreatment to be robustly associated with poorer cognitive functioning, it is unclear whether maltreatment and cognitive function jointly influence the clinical course of bipolar symptoms.MethodsThis secondary analysis examined moderating effects of lifetime childhood physical and sexual abuse, and cognitive disruptions (sustained attention, affective information processing), on longitudinal ratings of depression symptom severity in youths from the Course and Outcome of Bipolar Youth (COBY) study, examined from intake (M = 12.24 years) through age 22 (N = 198; 43.9% female; Mean age of bipolar onset = 8.85 years).ResultsA significant moderating effect was detected for sustained attention and maltreatment history. In the context of lower sustained attention, maltreatment exposure was associated with higher depression symptom severity during childhood, but not late adolescence. There was no association between maltreatment and symptom severity in the context of higher sustained attention, and no association between attention and depression symptom severity for non-maltreated youths.LimitationsDepression symptom ratings at each assessment were subject to retrospective recall bias despite the longitudinal design. Cognitive assessments were administered at different ages across youths.ConclusionsDepressive symptoms in pediatric bipolar may be jointly moderated by impairments in attention and exposure to maltreatment. Assessment of these risks, particularly in childhood, may be beneficial for considering risk of recurrence or chronicity of depressive symptoms.

BackgroundExposure to severe Traumatic Events (TEs) has been associated with poor course and outcomes among individuals with Bipolar Disorder (BD). However, there is limited research on TEs among youth with BD, and few studies are longitudinal. This study prospectively followed a large sample of BD youth, examining the associations of lifetime TEs with their mood and functioning.MethodsBD participants (n=375; mean age=17; range 8-25y) were assessed, on average, every 7 months for a median 8.7 years. Psychopathology and lifetime trauma history were prospectively evaluated using the Longitudinal Interval Follow-Up Evaluation, and a traumatic events screening.ResultsAccounting for covariates, participants with one or more lifetime TEs (84%) showed earlier BD onset, poorer psychosocial functioning, worse mood symptoms, and more suicidal ideation, comorbidities, and family psychopathology than those without TEs. TEs during recovery periods increased recurrence risk (p

ObjectivesCompare longitudinal trajectories of youth with Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV Bipolar Disorder (BD), grouped at baseline by presence/absence of increased energy during their worst lifetime mood episode (required for DSM-5).MethodsParticipants from the parent Course and Outcome of Bipolar Youth study (N = 446) were assessed utilizing The Schedule for Affective Disorders and Schizophrenia for School-Age Children (KSADS), KSADS Mania Rating Scale (KMRS), and KSADS Depression Rating Scale (KDRS). Youth were grouped at baseline into those with increased energy (meeting DSM-5 Criteria A for mania) vs. without increased energy (meeting DSM-IV, but not DSM-5, Criteria A for mania), for those who had worst lifetime mood episode recorded (n = 430). Youth with available longitudinal data had the presence/absence of increased energy measured, as well as psychiatric symptomatology/clinical outcomes (evaluated via the Adolescent Longitudinal Interval Follow-Up Evaluation), at each follow-up for 12.5 years (n = 398).ResultsAt baseline, the increased energy group (based on endorsed increased energy during worst lifetime mood episode; 86% of participants) vs. the without increased energy group, were more likely to meet criteria for BD-I and BD Not Otherwise Specified, had higher KMRS/KDRS total scores, and displayed poorer family/global psychosocial functioning. However, frequency of increased energy between groups was comparable after 5 years, and no significant group differences were found on clinical/psychosocial functioning outcomes after 12.5 years.LimitationsSecondary data limited study design; groupings were based on one time point.ConclusionsResults indicate no clinically relevant longitudinal group differences.

ObjectivesFew studies have examined domain-specific psychosocial functioning in Bipolar Disorder (BD) youths. This prospective study examines (1) Interpersonal Relationships with Family; (2) Interpersonal Relationships with Friends; (3) School/Work; (4) Recreation; (5) Life Satisfaction, in BD youths.MethodA Course and Outcome of Bipolar Youth subsample (n = 367; mean intake age = 12.6 years, SD = 3.3; 46.6% female) was previously grouped into 4 Classes based on their illness trajectories and percentage of time euthymic using Latent Class Growth Analysis: Class 1 Predominantly Euthymic; Class 2 Moderately Euthymic; Class 3 Ill with Improving Course; Class 4 Predominantly Ill. Psychosocial functioning within the domains were examined for greater than 10 years using the Adolescent Longitudinal Interval Follow-Up Evaluation.ResultsClass 1 demonstrated better functioning across all domains; Class 4 demonstrated worse functioning across all domains. Class 2 showed worsening relationships and recreation, and improvement in work/schoolwork. Class 3 showed variable domain declines and improvements. Despite symptomatic remission, 13%-20% of Class 1 and 20-47% of Classes 1/3 still had impairments across different domains. Early age of BD onset impacted impairment across most domains, and low SES significantly predicted impairment in family relationships.LimitationsThe study does not have a healthy control group to compare functioning findings.ConclusionsParticipants with more symptomatic mood trajectories had greater impairment across domains. Moreover, even with symptomatic remission, participants still exhibited impairment. Each Class and domain had different trajectories for impairment. Results suggest the importance of examining specific (vs. global) domains for targeted treatment, even when symptomatically remitted.

This study examines how relationship quality in family and peer domains are associated with suicidal ideation (SI) in youth with bipolar disorder (BP). We assessed 404 Course and Outcome of Bipolar Youth study participants for psychiatric disorders and SI at intake and for family/peer relationships the month after intake. Multivariate logistic regression examined associations between relationships and SI, controlling for significant covariates. There were 144 youth (36%) who reported SI at intake; bivariate analyses indicated they had significantly worse family/peer relationships. Multivariate analyses showed that family/peer relationships were associated with current SI, controlling for significant covariates. Results support associations between poor relationships and SI in BP youth, regardless of current mood symptom severity. Clinicians should assess relationships when completing risk assessments with BP youth.

ObjectiveDespite substantial literature on sex differences in adults with bipolar disorder (BD), little is known about this topic in youth; this study examines sex differences in mood symptomatology and psychiatric comorbidity in prospectively followed youth with BD.MethodsA subsample of the Course and Outcome of Bipolar Youth study (N = 370; female n = 199, male n = 171) enrolled October 2000-July 2006 (age at intake = 7-17.11 years) who met DSM-IV criteria for bipolar I disorder (BD-I; n = 221), bipolar II disorder (BD-II; n = 26), or operationalized BD not otherwise specified (BD-NOS; n = 123) with ≥ 4 years follow-up was included. Analyses examined sex differences at intake and, prospectively, in mood symptomatology and psychiatric comorbidity for a mean ± SD follow-up of 10.5 ± 1.72 years.ResultsFemales were older than males at intake (mean ± SD age = 13.33 ± 3.32 vs 12.04 ± 3.16 years; P = .0002) and at age at mood onset (9.33 ± 4.22 vs 7.53 ± 3.74 years; P < .0001). After adjustment for confounders, males spent more time with syndromal ADHD (Padjusted = .001) and females spent more time with syndromal anxiety (Padjusted = .02). There were trends toward males spending more time with substance use disorder and females having more non-suicidal self-injurious behavior (Padjusted = .07 and .09, respectively). There were no sex differences on outcome variables, including rate of or time to recovery and recurrence.ConclusionsContrasting with adult literature, this study identified minimal sex differences in the course of youth with BD. Longer-term studies are needed to clarify if youth-onset BD remains a "sex neutral" subtype of BD or diverges according to sex in adulthood.

ObjectivesIn a sample of participants diagnosed with Bipolar Disorder (BD) in youth, we aim: (1) to examine longitudinal psychosocial functioning; (2) to determine whether psychosocial impairment remains in those who remitted from mood disorders during later periods of follow-up; (3) to examine predictors of psychosocial impairment despite symptomatic remission.MethodA Course and Outcome of Bipolar Youth subsample of 367 (≥ 4 years follow-up data) were grouped into mood trajectories: Class 1 Predominantly Euthymic; Class 2 Moderately Euthymic; Class 3 Ill with Improving Course; Class 4 Predominantly Ill. Psychosocial functioning was assessed via Children's Global Assessment Scale (C-GAS) for those under age 22; Global Assessment of Functioning (GAF) scale after 22. Current school, employment, and disability status were examined. Established predictors of symptomatic impairment were analyzed.ResultsThe Predominantly Euthymic Class had better psychosocial functioning, and were more likely to be in school/employed. The Persistently Ill Class had worse psychosocial functioning, and were more likely to receive disability. However, 44% of Predominantly Euthymic and 93% of Ill with Improving Course participants continued to experience current psychosocial impairment. Early BD onset, low Socioeconomic Status (SES), and current comorbidity, predicted poor psychosocial functioning. Low SES, and current comorbidity, predicted no school enrollment/unemployment.LimitationsThe study does not have a healthy control group to compare functioning findings.ConclusionsIn general, youth with persistent mood symptoms had worse psychosocial functioning, moreover, those with remitted symptoms still exhibited current psychosocial functioning deficits. High risk individuals with predictors of impairment should be targeted for functioning interventions.

ObjectiveDespite 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.MethodsA 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.ResultsThe 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.ConclusionsThe 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.

ObjectiveMost studies of pediatric bipolar disorder (BP) combine youth who have manic symptoms, but do not meet criteria for BP I/II, into one "not otherwise specified" (NOS) group. Consequently, little is known about how youth with cyclothymic disorder (CycD) differ from youth with BP NOS. The objective of this study was to determine whether youth with a research diagnosis of CycD (RDCyc) differ from youth with operationalized BP NOS.MethodParticipants from the Course and Outcome of Bipolar Youth study were evaluated to determine whether they met RDCyc criteria. Characteristics of RDCyc youth and BP NOS youth were compared at baseline, and over eight-years follow-up.ResultsOf 154 youth (average age 11.96 (3.3), 42% female), 29 met RDCyc criteria. RDCyc youth were younger (p = .04) at baseline. Over follow-up, RDCyc youth were more likely to have a disruptive behavior disorder (p = .01), and were more likely to experience irritability (p = .03), mood reactivity (p = .02), and rejection sensitivity (p = .03). BP NOS youth were more likely to develop hypomania (p = .02), or depression (p = .02), and tended to have mood episodes earlier in the eight-year follow-up period.LimitationsRDCyc diagnoses were made retrospectively and followed stringent criteria, which may highlight differences that, under typical clinical conditions and more vague criteria, would not be evident.ConclusionThere were few differences between RDCyc and BP NOS youth. However, the ways in which the groups diverged could have implications; chronic subsyndromal mood symptoms may portend a severe, but ultimately non-bipolar, course. Longer follow-up is necessary to determine the trajectory and outcomes of CycD symptoms.

ObjectiveYouth with subthreshold mania are at increased risk of conversion to bipolar disorder (BP) I/II. Predictors for conversion have been published for the group as a whole. However, risk factors are heterogeneous, indicating the need for personalized risk assessment.MethodOne hundred forty youth with BP not otherwise specified (BP-NOS; 6-17 years old) followed through the Course and Outcome of Bipolar Youth (COBY) study with at least 1 follow-up assessment before conversion to BP-I/II were included. Youths were assessed on average every 7 months (median 11.5 years) using standard instruments. Risk predictors reported in the literature were used to build a 5-year risk calculator. Discrimination was measured using the time-dependent area under the curve after 1,000 bootstrap resamples. Calibration was evaluated by comparing observed with predicted probability of conversion. External validation was performed using an independent sample of 58 youths with BP-NOS recruited from the Pittsburgh Bipolar Offspring Study.ResultsSeventy-five (53.6%) COBY youths with BP-NOS converted to BP-I/II, of which 57 (76.0%) converted within 5 years. Earlier-onset BP-NOS, familial hypomania/mania, and high mania, anxiety, and mood lability symptoms were important predictors of conversion. The calculator showed excellent consistency between the predicted and observed risks of conversion, good discrimination between converters and non-converters (area under the curve 0.71, CI 0.67-0.74), and a proportionally increasing rate of converters at each successive risk class. Discrimination in the external validation sample was good (area under the curve 0.75).ConclusionIf replicated, the risk calculator would provide a useful tool to predict personalized risk of conversion from subsyndromal mania to BP-I/II and inform individualized interventions and research.

ObjectiveThere is substantial interest in delineating the course of cognitive functioning in bipolar (BP) youth. However, there are no longitudinal studies aimed at defining subgroups of BP youth based on their distinctive cognitive trajectories and their associated clinical variables.MethodCognitive functioning was measured in 135 participants from the Course and Outcome of BP Youth (COBY) study using several subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Youth were prospectively evaluated three times on average every 13.75 months over 2.5 years. Clinical and functional outcomes were assessed using the Longitudinal Interval Follow-Up Evaluation (LIFE).ResultsLatent class growth analysis identified three longitudinal patterns of cognitive functioning based on a general cognitive index: class 1, "persistently high" (N=21; 15.6%); class 2, "persistently moderate" (N=82; 60.74%); and class 3, "persistently low" (N=32; 23.7%). All classes showed normal cognitive functioning when compared with the CANTAB normative data. After adjustment for confounders, youth from class 3 had a significantly greater percentage of time with overall, manic, and depressive syndromal symptoms than youth in the other two classes. Also, after adjustment for confounders, youth from class 3 had significantly poorer global, academic, and social functioning than youth from class 1.ConclusionsBP youth showed normal overall cognitive functioning that remained stable during the follow-up within each class. However, 24% of BP youth showed poorer cognitive functioning than the other BP youth. This subgroup had poorer mood course and functioning, and may benefit from cognitive remediation and early management with evidence-based pharmacological treatments.

ObjectivesTo identify mood symptoms that distinguishes bipolar disorder (BP) depression versus unipolar depression in youth during an acute depressive episode.MethodsYouth with BP (N = 30) were compared with youth with unipolar depression (N = 59) during an acute depressive episode using the depression and mania items derived from the Schedule for Affective Disorders and Schizophrenia for Children (K-SADS)-Present Version. The results were adjusted for multiple comparisons, and any significant between-group differences in demographic, nonmood comorbid disorders, and psychiatric family history.ResultsIn comparison with unipolar depressed youth, BP depressed youth had significantly higher scores in several depressive symptoms and all subsyndromal manic symptoms, with the exception of increased goal-directed activity. Among the depressive symptoms, higher ratings of nonsuicidal physical self-injurious acts and mood reactivity, and lower ratings of aches/pains, were the symptoms that best discriminated BP from unipolar depressed youth. Subsyndromal manic symptoms, particularly motor hyperactivity, distractibility, and pressured speech, were higher in BP depressed youth and discriminated BP depressed from unipolar depressed youth.ConclusionsThe results of this study suggest that it is possible to differentiate BP depression from unipolar depression based on depressive symptoms, and in particular subsyndromal manic symptoms. If replicated, these results have important clinical and research implications.

ObjectiveTo provide the first longitudinal characterization of mood and psychosocial functioning in youth with comorbid bipolar (BD) and autism spectrum (ASD) disorders.MethodThe Course and Outcome of Bipolar Youth study followed 368 youth (aged 7-17 years) with DSM-IV bipolar I (BP-I), BP-II, or Not Otherwise Specified (NOS) for, on average, 9 years using the Longitudinal Interval Follow-up Evaluation. This subgroup analysis compared youth with and without ASD on clinical presentation, percentage of time with mood symptomatology, and psychosocial functioning.ResultsThirty youth (∼8%) met DSM-IV criteria for Asperger's disorder or pervasive developmental disorder-NOS (referred to here as ASD). Lifetime worst episode severity was similar in both groups, but youth with both BD and ASD (BD+ASD) had elevated rates of comorbid attention-deficit/hyperactivity and obsessive-compulsive disorders, were younger at intake, and had an earlier onset of mood symptoms. Over time, in both groups, the proportion of predominantly euthymic youth increased, and episode recurrence decreased. Compared to youth with BD, the clinical presentation of youth with BD+ASD more frequently involved distractibility, racing thoughts, depressed mood, social withdrawal, and low reactivity of negative mood states. ASD-related symptomatic differences were generally strongest early and decreased over time. Youth with BD+ASD had significantly greater impairment in friendships throughout follow-up.ConclusionYouth with BD+ASD exhibit typical BD mood symptoms but with earlier onset, mixed symptom presentation, and additive functional impairments. Significant amelioration of clinical symptoms occurred over time, suggesting that early recognition and treatment of mood disorders in youth with ASD may improve clinical outcomes.

ObjectiveDespite 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.MethodSubjects 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.ResultsSeveral 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).ConclusionProinflammatory 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.

ObjectiveTo examine the longitudinal effects of comorbid anxiety disorders in youth with bipolar spectrum disorder (BP).MethodAs 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.ResultsAt 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.ConclusionsAnxiety 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.

Systematic screening of depression in primary care settings that have adequate follow-up and treatment is recommended. The Patient Health Questionnaire (PHQ-9) was developed as a depression screening measure for use [...]