Course And Outcome Of Bipolar Youth Research Articles

Validation of a youth suicide risk calculator in an adult sample with bipolar disorder

BackgroundBipolar disorder (BD) conveys the highest risk of suicide of all mental disorders. We sought to externally validate a risk calculator (RC) of suicide attempts developed in youth with BD from the Course and Outcome of Bipolar Youth (COBY) study in an adult sample. MethodsA prospective cohort of adults with BD from the National Institute of Mental Health Collaborative Depression Study (CDS; N = 427; mean (+/− SD) age at intake (36 +/− 13 years)) was secondarily analyzed to validate the COBY RC for one-year risk of suicide attempts/deaths. Nine of the ten predictor variables from the COBY RC were available in the CDS and used: age, age of mood disorder onset, first and second (partial) degree family history of suicide, history of psychotic symptoms, substance use disorder, prior suicide attempt, socioeconomic status, and non-suicidal self-injury (prospectively, incompletely at baseline). ResultsOver a mean (SD) follow-up of 19 (10) years, 29 % of the CDS sample attempted suicide. The RC predicted suicide attempts/deaths over one-year follow-up with an area under the receiver operating characteristic curve (AUC) of 0.78 (95 % CI 0.75–0.80). The RC performed slightly better in those with a younger age of mood disorder onset. LimitationsClinical samples may limit generalizability; the RC does not assess more acute suicide risk. ConclusionsOne-year risk of suicide attempts/deaths can be predicted with acceptable accuracy in youth and adults with BD, comparable to commonly used RCs to predict cardiovascular risk. This RC may help identify higher-risk individuals with BD for personalized treatment and research. https://cobysuicideattemptsrc.shinyapps.io/Shiny

A Risk Calculator to Predict Suicide Attempts Among Individuals With Early-Onset Bipolar Disorder.

To build a one-year risk calculator (RC) to predict individualized risk for suicide attempt in early-onset bipolar disorder. Youth numbering 394 with bipolar disorder who completed ≥2 follow-up assessments (median follow-up length = 13.1 years) in the longitudinal Course and Outcome of Bipolar Youth (COBY) study were included. Suicide attempt over follow-up was assessed via the A-LIFE Self-Injurious/Suicidal Behavior scale. Predictors from the literature on suicidal behavior in bipolar disorder that are readily assessed in clinical practice were selected and trichotomized as appropriate (presence past 6 months/lifetime history only/no lifetime history). The RC was trained via boosted multinomial classification trees; predictions were calibrated via Platt scaling. Half of the sample was used to train, and the other half to independently test the RC. There were 249 suicide attempts among 106 individuals. Ten predictors accounted for >90% of the cross-validated relative influence in the model (AUC = 0.82; in order of relative influence): (1) age of mood disorder onset; (2) non-suicidal self-injurious behavior (trichotomized); (3) current age; (4) psychosis (trichotomized); (5) socioeconomic status; (6) most severe depressive symptoms in past 6 months (trichotomized none/subthreshold/threshold); (7) history of suicide attempt (trichotomized); (8) family history of suicidal behavior; (9) substance use disorder (trichotomized); (10) lifetime history of physical/sexual abuse. For all trichotomized variables, presence in the past 6 months reliably predicted higher risk than lifetime history. This RC holds promise as a clinical and research tool for prospective identification of individualized high-risk periods for suicide attempt in early-onset bipolar disorder.Reprinted from Bipolar Disord 2022; 24:749-757, with permission from John Wiley and Sons. Copyright © 2022.

LONGITUDINAL FACTORS ASSOCIATED WITH IMPROVEMENT AND RISK IN YOUTHS AND YOUNG ADULTS WITH BIPOLAR SPECTRUM DISORDERS

This Symposium will provide an overview of updated findings from the Course and Outcome of Bipolar Youth (COBY) and Predicting Adult Outcomes of Bipolar Youth (PROBY) studies, which have followed the same cohort longitudinally. Data will be presented on improved prognosis, traumatic events, risk calculator validation, and individualized suicide risk prediction.

31.4 Continuity of Pediatric Bipolar Disorder With Mania/Hypomania in Young Adulthood

In recent years, there has been substantial controversy regarding the diagnosis of pediatric bipolar disorder (PBD) and the continuity of this diagnosis with adult bipolar I disorder (BD-I) and bipolar II disorder (BD-II). A better understanding about the prospective course of youth with PBD (especially prepubertal youth) is critical to address this clinically important controversy. In this Symposium, we present a recent analysis of the Course and Outcome of Bipolar Youth (COBY) study, which assessed the course of PBD in youth and predictors of mania/hypomania in young adulthood.

18.3 Validation of the Youth Mood Recurrences Risk Calculator in an Adult Sample with Bipolar Disorder

The ability to predict an individual’s risk of mood episode recurrence can facilitate personalized medicine in bipolar disorder (BD). We sought to externally validate, in an adult sample, a risk calculator of mood episode recurrence developed in youth/young adults with BD from the Course and Outcome of Bipolar Youth (COBY) study.

A risk calculator to predict suicide attempts among individuals with early-onset bipolar disorder.

To build a one-year risk calculator (RC) to predict individualized risk for suicide attempt in early-onset bipolar disorder. Youth numbering 394 with bipolar disorder who completed ≥2 follow-up assessments (median follow-up length=13.1 years) in the longitudinal Course and Outcome of Bipolar Youth (COBY) study were included. Suicide attempt over follow-up was assessed via the A-LIFE Self-Injurious/Suicidal Behavior scale. Predictors from the literature on suicidal behavior in bipolar disorder that are readily assessed in clinical practice were selected and trichotomized as appropriate (presence past 6months/lifetime history only/no lifetime history). The RC was trained via boosted multinomial classification trees; predictions were calibrated via Platt scaling. Half of the sample was used to train, and the other half to independently test the RC. There were 249 suicide attempts among 106 individuals. Ten predictors accounted for >90% of the cross-validated relative influence in the model (AUC=0.82; in order of relative influence): (1) age of mood disorder onset; (2) non-suicidal self-injurious behavior (trichotomized); (3) current age; (4) psychosis (trichotomized); (5) socioeconomic status; (6) most severe depressive symptoms in past 6months (trichotomized none/subthreshold/threshold); (7) history of suicide attempt (trichotomized); (8) family history of suicidal behavior; (9) substance use disorder (trichotomized); (10) lifetime history of physical/sexual abuse. For all trichotomized variables, presence in the past 6months reliably predicted higher risk than lifetime history. This RC holds promise as a clinical and research tool for prospective identification of individualized high-risk periods for suicide attempt in early-onset bipolar disorder.

Risk factors preceding new onset abuse among youth with bipolar disorder: A longitudinal prospective analysis

BackgroundChildhood abuse negatively impacts the course of Bipolar Disorder (BD). Yet, no study has examined risk factors associated with prospectively evaluated physical/sexual abuse, specifically, those preceding first abuse among BD youth. We investigate past/intake/follow-up factors preceding first physical/sexual abuse among BD youth. MethodsChildhood-onset BD participants (n = 279 youth, mean age at intake = 12, mean length of follow-up = 12 years) enrolled in the Course and Outcome of Bipolar Youth (COBY) study. Demographic, clinical and family history variables were assessed every 7 months on average using Longitudinal Interval Follow-up Evaluation and Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-PL). Abuse was evaluated at intake using the K-SADS-PL, over follow-up with a Traumatic Events Screen. Family psychopathology was assessed using Family History Screen/Structured Clinical Interview for Diagnostic Statistical Manual-IV. ResultsFifteen-percent of youth reported new-onset abuse during follow-up (62% physical, 26% sexual; 12% both). Intake predictors included more severe depressive symptoms (HR = 1.29), low socioeconomic-status (SES) in families with substance abuse (HR = 0.84) (physical abuse), and female sex (HR = 2.41) (sexual abuse). Follow-up predictors preceding physical abuse included: older age (HR = 1.42), disruptive disorders (HR = 1.39), and the interaction between low SES and family substance abuse (HR = 0.86). For sexual abuse, female sex (HR = 4.33) and a non-biologically related father presence in the household (HR = 2.76). Good relationships with friends (prospectively evaluated) protected against physical/sexual abuse (HR = 0.72/0.70, respectively). LimitationsProspective data was gathered longitudinally but assessed retrospectively at every follow-up; perpetrator information and abuse severity were not available. ConclusionsIdentifying factors temporally preceding new onset physical/sexual abuse may hold promise for identifying high-risk youth with BD.

Validation of the youth mood recurrences risk calculator in an adult sample with bipolar disorder

BackgroundThe ability to predict an individual's risk of mood episode recurrence can facilitate personalized medicine in bipolar disorder (BD). We sought to externally validate, in an adult sample, a risk calculator of mood episode recurrence developed in youth/young adults with BD from the Course and Outcome of Bipolar Youth (COBY) study. MethodsAdult participants from the National Institute of Mental Health Collaborative Depression Study (CDS; N=258; mean(SD) age=35.5(12.0) years; mean follow-up=24.9 years) were utilized as a sample to validate the youth COBY risk calculator for onset of depressive, manic, or any mood episodes. ResultsIn this older validation sample, the risk calculator predicted recurrence of any episode over 1, 2, 3, or 5-year follow-up intervals, with Area Under the Curves (AUCs) approximating 0.77. The AUC for prediction of depressive episodes was about 0.81 for each of the time windows, which was higher than for manic or hypomanic episodes (AUC=0.72). While the risk calculator was well-calibrated across the range of risk scores, it systematically underestimated risk in the CDS sample by about 20%. The length of current remission was a highly significant predictor of recurrence risk in the CDS sample. LimitationsPredominantly self-reported White samples may limit generalizability; the risk calculator does not assess more proximal risk (e.g., 1 month). ConclusionsRisk of mood episode recurrence can be predicted with good accuracy in youth and adults with BD in remission. The risk calculators may help identify higher risk BD subgroups for treatment and research.

Prospectively ascertained mania and hypomania among young adults with child- and adolescent-onset bipolar disorder.

While 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. COBY is a naturalistic, longitudinal study of 446 youth with BD (84% recruited from outpatient clinics), 7-17years old at intake, and over 11years of follow-up. Focusing on youth with BD-I/II (n=297), we examined adult mania/hypomania risk (>18years old; mean 7.9years of follow-up) according to child (<13years old) versus adolescent (13-17years old) onset. We next used penalized regression to test demographic and clinical predictors of young adult mania/hypomania. Most participants (64%) had child-onset mania/hypomania, 57% of whom also experienced mania/hypomania in adolescence. Among those who experienced an episode in adolescence, over 40% also had mania/hypomania during adulthood; the risk did not differ according to child versus adolescent onset. In contrast, 7% with mania/hypomania in childhood, but not adolescence, experienced mania/hypomania in adulthood. Family history (of mania and suicide attempts) predicted mania/hypomania in young adulthood (p-values <0.05); age of onset was not a significant predictor. Among participants with no mania/hypomania during adulthood, 53% (105/198) still experienced subthreshold manic episodes. We find substantial continuity across developmental stage indicating that, in this carefully characterized sample, children who experience mania/hypomania-particularly those who also experience mania/hypomania in adolescence-are likely to experience mania/hypomania in young adulthood.

Longitudinal course of depressive symptom severity among youths with bipolar disorders: Moderating influences of sustained attention and history of child maltreatment

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.

Emotional regulation neural circuitry abnormalities in adult bipolar disorder: dissociating effects of long-term depression history from relationships with present symptoms

Bipolar disorder (BD) is common and debilitating and confounding effects of depression history on neural activity in BD are unknown. We aimed to dissociate neural activity reflecting past depression-load vs. present symptom severity using the Course and Outcome of Bipolar Youth (COBY), a prospective longitudinal cohort study of pediatric-onset BD. In n = 54 COBY (18–32 years), we modeled depression scores over time (up to 17.5 years) using a standardized autoregressive moving average (ARMA) model, followed by k-means cluster analysis. N = 36 healthy participants (HC, 20–36 years) were included. Using two factorial analyses, we parsed the impact of ARMA-defined past depression-load on neural activity from the impact of current symptoms on neural activity (p < 0.001, k > 30) and examined relationships with past and present symptoms (ps FDR-corrected). ARMA identified three COBY groups based on past depression-load. ARMA-defined COBY participants with the greatest past depression-load vs. other groups showed greater activity in right temporoparietal junction, thalamus, insula, premotor cortex, left fusiform gyrus, bilateral precuneus and cerebellum. In contrast, BD-COBY participants vs. HC showed greater activity in left hippocampus, dorsolateral prefrontal cortex, and right somatosensory cortex, plus the above thalamus, premotor cortex and cerebellum; activity positively correlated with present symptom severity in most regions. Past depression-load was related to social cognition and salience perception network activity, potentially reflecting heightened attention to socially relevant distracters, while present symptoms were associated with emotion processing and reappraisal network activity, potentially reflecting abnormal emotional experience and regulation. Differentiating aberrant neural activity related to long-term depression vs. present affective symptoms can help target interventions to networks associated with pathophysiological processes, rather than long-term illness effects.

9.3 LITHIUM VS OTHER MOOD STABILIZERS IN YOUTH WITH BIPOLAR DISORDER: CLINICAL FINDINGS AND POTENTIAL MECHANISMS

There is strong evidence in adults with bipolar disorder (BD) that lithium (LI) reduces mood recurrence, decreases suicide deaths, and reduces hospitalization rates; however, evidence in youth is limited. We use data from the Course and Outcome of Bipolar Youth (COBY) study to assess whether LI vs other mood-stabilizing medication (OMS) is associated with improved outcomes, including mood symptoms and suicidality. Here, we discuss these recently published clinical findings, as well as potential mechanisms for these effects.

White Matter Correlates of Suicidality in Adults With Bipolar Disorder Who Have Been Prospectively Characterized Since Childhood

BackgroundPrevention of suicide in individuals with early-onset bipolar disorder (BD) remains a challenge. Diffusion magnetic resonance imaging studies in BD have identified neural correlates of emotional dysregulation implicated in BD and suicide. Using diffusion magnetic resonance imaging, we sought to identify neural signatures of suicide attempts in adults with childhood-onset BD who have been clinically followed for up to 19 years as part of the COBY (Course and Outcome of Bipolar Youth) study. MethodsDiffusion magnetic resonance imaging data were collected in 68 adults with BD: 20 in the suicide attempter (SA+) group and 48 in the non–suicide attempter (SA−) group. Multivariate analysis of covariance was used to identify the effect of group (SA+, SA−) on mean fractional anisotropy (indirect index of fiber collinearity) in key white matter tracts of emotional regulation. The effect of suicidal ideation and other clinical factors was further explored. False discovery rate was used to account for multiple comparison. Forty healthy control subjects were included. ResultsAnalyses revealed a main effect of group on fractional anisotropy (F5,59 = 3.0, p = .017). Specifically, the SA+ group showed lower fractional anisotropy than the SA− and healthy control groups in the middle portion of the forceps minor (FMIN) (F1,63 = 8.5, p = .010) and in the anterior (F1,63 = 7.8, p = .010) and posterior (F1,63 = 8.7, p = .006) portion of the right cingulum bundle (CB). Abnormalities in the FMIN, but not CB, were also associated with suicidal ideation (F1,64 = 10.6, p = .002) and levels of emotional distress at scan. ConclusionsFMIN and CB abnormalities have been associated with emotional dysregulation in BD. Our findings suggest that the FMIN may represent a generic marker of suicidal ideation and, more broadly, emotional distress, while CB may represent a specific marker of attempted suicide.

Predicting Personalized Risk of Mood Recurrences in Youths and Young Adults With Bipolar Spectrum Disorder

With each recurrence the prognosis of bipolar disorder (BD) worsens, indicating the need to identify the factors associated with increased recurrence risk. The course of BD is heterogenous and although risk factors for recurrence for the group as a whole have been reported in the literature, identification of risk factors for a specific individual are crucial for developing personalized treatments. A total of 363 recovered BD youths/young adults from the Course and Outcome of Bipolar Youth (COBY) study were included. Participants were evaluated on average every 7 months for a median of 12.5 years and interviewed with standard instruments. Risk factors of recurrence from the literature were used to build a risk calculator (RC) to predict recurrence risk at different time intervals. Approximately 80% of participants had at least one syndromal recurrence and 60% had≥2 recurrences, particularly depressions. The 6-month and 1-, 2-, 3-, and 5-year RC showed an accuracy between 72% and 82% for predicting any mood recurrences, and up to 80% for depression and 89% for hypo/mania (sensitivity/specificity both 0.74). The most influential recurrence risk factors were shorter recovery lengths, younger age at assessment, earlier mood onset, and more severe prior depression. Although important, other factors associated with recurrence risk, such as interepisodic subsyndromal mood symptoms and comorbidities, did not influence the RC score beyond factors noted above. The RC provides a useful tool for predicting an individual's recurrence risk of depression and/or hypo/mania in BD youths and for developing personalized interventions and informing research. Replication studies are warranted.

28.3 PERSON-LEVEL PREDICTION OF PROGRESSION ALONG THE BIPOLAR TRAJECTORY

Bipolar disorder (BD) rarely comes out of the blue; rather, it is generally preceded by subthreshold mood symptoms that may portend a full-threshold bipolar I disorder/bipolar II disorder (BD-I/II), particularly in youth at familial risk. Over the past several years, we and others have used longitudinal data from familial and/or clinical high-risk groups to assess predictors of progression along the trajectory to BD-I/II. These analyses are a crucial first step but do not answer the most pertinent clinical question: What is the probability that a given individual will develop BD? Recently, we have built risk calculators (RC) using data from the Pittsburgh Bipolar Offspring (BIOS) and Course and Outcome of Bipolar Youth (COBY) studies to answer this question.

Lithium works for youth with BD too: Study

Consistent with adult studies, a recent analysis of data from the Course and Outcome of Bipolar Youth (COBY) study found that lithium is associated with decreased suicidality, less depression, and better psychosocial functioning in youth.

More Evidence for Lithium’s Benefits in Youth Emerges

More Evidence for Lithium’s Benefits in Youth Emerges

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

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. 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. 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. 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.

Lithium Versus Other Mood-Stabilizing Medications in a Longitudinal Study of Youth Diagnosed With Bipolar Disorder

Lithium is the mainstay for bipolar disorder (BD) treatment in adults, but evidence in youths is limited. We used data from the Course and Outcome of Bipolar Youth (COBY) study to assess whether lithium vs other mood-stabilizing medication (OMS) was associated with improved outcomes, including mood symptoms and suicidality. COBY is a naturalistic, longitudinal study of 413 youths, 7 to 17.11 years old at intake, with BD. At each visit, medication exposure, psychiatric symptoms, and psychosocial function over the preceding follow-up period were assessed using the Adolescent Longitudinal Interval Follow-Up Evaluation. Using mixed models, we determined whether participants taking lithium vs OMS (but not lithium) differed regarding mood symptoms, suicidality, psychosocial function, hospitalization, aggression, and substance use. A total of 340 participants contributed 2,638 six-month follow-up periods (886 lithium, 1,752 OMS), over a mean follow-up of 10 years. During lithium (vs OMS) follow-up periods, participants were older, less likely to have lifetime anxiety, and less likely to be on antidepressants (p values<.005). After covariate adjustment, the lithium group (vs OMS) had half as many suicide attempts (p= .03), fewer depressive symptoms (p= .004), less psychosocial impairment (p= .003), and less aggression (p= .0004). Similar findings were observed in the subgroup of follow-up periods in which participants were<18 years old. Findings are consistent with adult studies, showing that lithium is associated with decreased suicidality, less depression, and better psychosocial functioning. Given the paucity of evidence regarding lithium in children and adolescents, these findings have important clinical implications for the pharmacological management of youths with BD.

S64. White Matter Abnormalities in the Anterior Section of the Left Cingulum Bundle Correlates With a Severe Course of Illness in Adults With Bipolar Disorder Who Have Been Prospectively Characterized Since Childhood for up to 18 Years of Illness

Different courses of Bipolar Disorder (BD) have important implications for psychosocial functioning and morbidity, yet neural correlates of these trajectories remain unclear. The Course and Outcome of Bipolar Youth (COBY) study has identified important demographic/clinical factors predicting different trajectories of BD course.