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INTRODUCTION: In Turkey, there is much controversy and skepticism about the existence of mania in children and adolescents, and a paucity of rigorous data. Despite ongoing controversy, the view that pediatric Bipolar Disorder(BD) is rare or non-existent has been increasingly challenged not only by case reports but also by systematic research. METHODS: Diagnostic and Statistical Manual for Mental Disorders (DSM) criteria are usually employed in these research studies and case reports and it was strongly suggested that pediatric BD may not be rare but that it may be difficult to diagnose. RESULTS: In concordance with the current literature, euphoric mood and episodic course is rare in Turkish children and adolescents and the affective phenomenology is often mixed and dysphoric, with affective storms and temper outbursts. Comorbidity (especially with ADHD) is a big issue in accurate diagnosis and treatment. CONCLUSION: There are promising treatment studies, but we need more studies in both prepubertal children and adolescents about phenomenology, etiology, and treatment of this important condition. [ABSTRACT FROM AUTHOR]

Background: Antidepressant discontinuation syndrome refers to a cluster of symptoms that occur after abrupt dose reduction or discontinuation of antidepressant medication. Selective serotonin reuptake inhibitors (SSRIs) are increasingly being used for the treatment of depression and other psychiatric disorders in children and adolescents, but published data on SSRI discontinuation syndrome in children are limited.Objective: This paper presents 6 case reports of SSRI discontinuation syndrome in children.Results: SSRI discontinuation syndrome was diagnosed in 6 patients (4 boys, 2 girls; mean age, 11.33 +/- 1.75 years) according to established criteria. Three patients had been taking paroxetine, 2 fluvoxamine, and 1 sertraline for an average of 4.00 +/- 1.67 months (range, 3-6 months) before abrupt discontinuation or dose reduction. Dizziness/lightheadedness/drowsiness, poor concentration, nausea, headache, and fatigue were the most frequent symptoms. As in previous studies in adults, the 6 patients experienced SSRI discontinuation symptoms 1 to 5 days (mean 2.92 +/- 1.63 days) after SSRI discontinuation or dose reduction. In all patients, symptoms resolved on reinitiation of treatment with the same SSRI or a different one.Conclusions: The case reports presented in this article suggest that SSRI discontinuation syndrome can and does occur in children when treatment is stopped or the SSRI dose is reduced abruptly, and is quite similar to that reported in adults. Placebo-controlled prospective studies are needed in children to further assess the prevalence and clinical presentation of SSRI discontinuation syndrome and to develop management strategies for this condition. [ABSTRACT FROM AUTHOR]

Background: Risperidone has potent effects on serotonin and dopamine neuronal systems, both of which have been implicated in the pathophysiology of autism. Risperidone is increasingly being used to treat specific symptoms in children with autism.Objective: The purpose of this study was to investigate the efficacy and tolerability of risperidone in young children with autism.Methods: In this single-site, 6-month, open-label study, young autistic children aged 3 to 7.5 years were administered risperidone 0.5 mg/d for 15 days and then 1 mg/d until 3 months; doses were thereafter individually adjusted to a maximum of 2 mg/d between the third and sixth month. The Clinical Global Impression--Severity of Illness (CGI-SI) scale, Childhood Autism Rating Scale (CARS), and Abnormal Involuntary Movement Scale (AIMS) were used to assess efficacy. The CGI-Adverse Effect scale and the Adverse Effect Checklist were used to assess the incidence and severity of adverse events.Results: A total of 20 children (mean age, 4.95 +/- 1.18; range, 3-7.5 years) were enrolled; 16 completed the 6-month study. Two children were withdrawn due to noncompliance with the treatment protocol during the first month, and 2 children were withdrawn from the study during the first month because of marked agitation, anger, and aggression thought to be related to treatment. The mean dose of risperidone was 1.53 mg/d (range, 0.04-0.11 mg/kg per day). Thirteen of the 16 children (81%) demonstrated at least 1 grade improvement on CGI-SI scores. Mean total CARS score significantly decreased from 39.06 +/- 6.23 to 32.03 +/- 8.73 after 6 months (P = 0.001). Scores on 11 of the 15 subscales of the CARS showed significant improvement (P < 0.05). Four subjects experienced mild sedation, and 2 experienced weight gain of <10%. One child with mild sedation also experienced slight akathisia.Conclusion: In this population of young autistic children, risperidone had positive effects on most symptoms of autistic disorder. Additional double-blind, placebo-controlled studies are needed to determine the effectiveness of risperidone in the management of autism. [ABSTRACT FROM AUTHOR]

Objectives: Bipolar disorder (BD) is highly heritable and associated with increased rates of metabolic syndrome (MetS). However, little is known about MetS in offspring of parents with BD. We therefore examined this topic in the Pittsburgh Bipolar Offspring Study cohort., Methods: Participants included 199 parents (n = 116 BD, diagnosed using DSM-IV ; n = 83 non-BD) and 330 offspring (mean age 19.9 ± 5.3 years), including 198 high-risk offspring of parents with BD (n = 80 affected with a mood disorder) and 132 control offspring. We defined MetS and its components using International Diabetes Federation (IDF) guidelines (primary) and National Cholesterol Education Program (NCEP) guidelines (secondary). Multivariable analyses controlled for age and socioeconomic status in offspring. Sensitivity analyses controlled for psychotropic medications., Results: There was higher prevalence of MetS in parents with BD as compared to controls. NCEP-defined MetS was significantly more prevalent among affected high-risk offspring (16.3%) and controls (15.2%) vs unaffected high-risk offspring (6.0%; χ 2 = 6.54, P = .04). There was greater mean number of MetS components (IDF: 1.7 ± 1.1; NCEP: 1.4 ± 1.0) among affected high-risk offspring vs unaffected high-risk offspring (IDF: 1.2 ± 1.0; NCEP: 1.0 ± 1.0) and controls (IDF: 1.3 ± 1.2; NCEP: 1.1 ± 1.1; IDF: H [2] = 10.26, P = .006; NCEP: H [2] = 9.18, P = .01). Most findings became nonsignificant in multivariable analyses. Some between-group results became nonsignificant after controlling for second-generation antipsychotics., Conclusions: This preliminary study found increased risk of MetS among affected high-risk offspring, which may be attributable to socioeconomic status. Prospective studies may determine timing of MetS onset in relation to mood disorder onset, and the role of socioeconomic status in moderating this association., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Pediatric bipolar disorder (BD) is difficult to distinguish from other psychiatric disorders, a challenge which can result in delayed or incorrect interventions. Using neuroimaging we aimed to identify neural measures differentiating a rarified sample of inpatient adolescents with BD from other inpatient psychopathology (OP) and healthy adolescents (HC) during a reward task. We hypothesized reduced subcortical and elevated cortical activation in BD relative to other groups, and that these markers will be related to self-reported mania scores. We examined inpatient adolescents with diagnosis of BD-I/II (n = 29), OP (n = 43), and HC (n = 20) from the Inpatient Child and Adolescent Bipolar Spectrum Imaging study. Inpatient adolescents with BD showed reduced activity in right thalamus, left thalamus, and left amygdala, relative to inpatient adolescents with OP and HC. This reduced neural function explained 21% of the variance in past month and 23% of the variance in lifetime mania scores. Lower activity in regions associated with the reward network, during reward processing, differentiates BD from OP in inpatient adolescents and explains >20% of the variance in mania scores. These findings highlight potential targets to aid earlier identification of, and guide new treatment developments for, pediatric BD., Competing Interests: Declaration of competing interest Bertocci, Rozovsky, Abdul-waalee, Chobany, Malgireddy, Hart, Skeba, Brady, Lepore, Verace, Chase, Phillips, Diler have no financial interests or potential conflicts of interest. Birmaher has or will receive royalties from for publications from Random House, Inc (New hope for children and teens with bipolar disorder) and Lippincott Williams & Wilkins (Treating child and adolescent depression). He is employed by the University of Pittsburgh and the University of Pittsburgh Medical Center and receives research funding from NIMH. The funding agency was not involved in the conduct, analysis, or reporting of this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Disturbed sleep during early childhood predicts social-emotional problems. However, it is not known how various early childhood sleep phenotypes are associated with the development of childhood psychopathology, nor whether these relationships vary as a function of parental psychopathology. We identified sleep phenotypes among preschool youth; examined whether these phenotypes were associated with child and parent factors; and determined if early sleep phenotypes predicted later childhood psychopathology., Methods: Using data from the Pittsburgh Bipolar Offspring study, parents with bipolar disorder (BD), non-BD psychopathology, and healthy controls reported about themselves and their offspring (n = 218) when their children were ages 2-5. Offspring and parents were interviewed directly approximately every 2 years from ages 6-18. Latent class analysis (LCA) identified latent sleep classes; we compared these classes on offspring demographics, parental sleep variables, and parental diagnoses. Kaplan-Meier survival models estimated hazard of developing any new-onset Axis-I disorders, as well as BD specifically, for each class., Results: The optimal LCA solution featured four sleep classes, which we characterized as (1) good sleep, (2) wake after sleep onset problems, (3) bedtime problems (e.g., trouble falling asleep, resists going to bed), and (4) poor sleep generally. Good sleepers tended to have significantly less parental psychopathology than the other three classes. Risk of developing new-onset Axis-I disorders was highest among the poor sleep class and lowest among the good sleep class., Conclusions: Preschool sleep phenotypes are an important predictor of the development of psychopathology. Future work is needed to understand the biopsychosocial processes underlying these trajectories., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Bipolar 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., Methods: A 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)., Results: Over 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., Limitations: Clinical samples may limit generalizability; the RC does not assess more acute suicide risk., Conclusions: One-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., Competing Interests: Declaration of competing interest Dr. Fiedorowicz has received research support from the National Institute of Mental Health (NIMH) and National Center for Advancing Translational Sciences (NCATS). He receives support from Elsevier for duties as an Editor-in-Chief, and from the United States Food and Drug Administration (USFDA) for service on the Psychopharmacologic Drugs Advisory Committee. Dr. T. Goldstein has received research support from NIMH, the American Foundation for Suicide Prevention (AFSP), and The Brain and Behavior Foundation, and royalties from Guilford Press. Dr. Strober has received research support from NIMH, and support from the Resnick Endowed Chair in Eating Disorders. Dr. Hafeman has received research support from NIHM and the Klingenstein Third Generation Foundation. Dr. Keller has received research support from NIMH and the John J. McDonnell and Margaret T. O’Brien Foundation. Dr. Iyengar has received research support from NIMH. Dr. Diler has received research support from NIMH. Ms. Hower has received honoraria from the Department of Defense (DOD) and from the Department of Psychiatry, University of California at San Diego (UCSD) School of Medicine. Dr. Hunt has received honorarium from Wiley Publishers and has received support from the NIMH. Dr. B. Goldstein has received research support from the Brain and Behavior Research Foundation (NARSAD), Brain Canada, the Canadian Institutes of Health Research, the Heart & Stroke Foundation, NIMH, and the Ontario Ministry of Research and Innovation. Dr. Birmaher has received research support from the National Institute of Mental Health (NIMH), and royalties for publications from Random House, Inc., UpToDate, and Lippincott Williams and Wilkins. Mr. Merranko, Ms. Siddiqi report no financial relationships with commercial interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To assess medication adherence and factors associated with poor adherence in youth with bipolar disorder (BD) followed from adolescence through young adulthood., Method: Participants with BD recruited through the Course and Outcome of Bipolar Youth (COBY) study were included in this study if they were prescribed psychotropic medications and had at least 3 follow-up assessments of medication adherence (N= 179, ages 12-36). Medication adherence had been evaluated for a median of 8 years using a questionnaire derived from the Coronary Artery Risk Development in Young Adults (CARDIA) study. For the longitudinal evaluation, adherence was measured as the percentage of follow-up assessments in which the participants did not endorse any of the nonadherence items included in the questionnaire. Concurrent and future predictors of poor adherence were assessed using both univariate and multivariate longitudinal analyses., Results: Among the participants, 51% reported poor adherence in more than 50% of their follow-up assessments. Younger age, family conflicts, polypharmacy, lower functioning, greater severity of mood symptoms, and comorbid disorders were associated with poor adherence in the univariate analyses. In the multivariate analyses, comorbid ADHD was the single most influential factor associated with concurrent and future poor adherence in all age groups. Participants' most reported reasons for poor adherence were forgetfulness (56%), negative attitudes toward medication treatment (10.5%), and disturbed daily routine (7%)., Conclusions: Poor medication adherence is a significant problem in youth with BD with the most influential factor being the presence of comorbid ADHD. Thus, it is important to identify and appropriately treat comorbid ADHD to improve medication adherence and patients' prognosis. Providers should also recommend tools to enhance consistent medication intake and address patients' concerns and negative beliefs about their illness and treatment.

Background: To identify prospectively ascertained individual and family factors that are associated with improvement in Bipolar Disorder (BD) among youths who initially presented with poor course., Methods: 82 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., Results: Compared 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., Limitations: Predominantly self-reported White samples may limit generalizability; other factors potentially associated with outcome (e.g., treatment adherence), were not ascertained., Conclusions: In 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., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Pediatric bipolar disorder (PBD) is a serious, recurrent disorder leading to severe functional impairment. As a first mood episode, index episode could affect the long-term course of the illness. This study aimed to investigate the clinical characteristics of youth with PBD from our multicenter, nationwide, naturalistic follow-up samples and to identify (i) the effects of index mood episode and (ii) the effect of previous antidepressant treatments on the age at mania onset of PBD., Method: The study sample consisted of 271 youth with BD-I followed by the child and adolescent psychiatry clinics of seven different university hospitals and three research state hospitals, representing six geographic regions across Turkey. All diagnoses were made according to structured interviews, and all data were retrospectively obtained from clinical records by the clinicians., Results: When patients with index depressive/mixed episodes (IDE, n=129) and patients with index (hypo)manic episodes (IME, n=142) were compared, the total number of mood episodes and rapid cycling feature were significantly higher in the IDE group than in the IME group. The Cox regression analysis adjusted for sociodemographic and illness characteristics revealed female adolescents in the IDE group treated with antidepressants were more likely to have an earlier onset of mania (hazard ratio=2.03, 95% confidence interval=1.31-3.12, p=0.001)., Conclusion: This is the first large-scale nationwide follow-up study in Turkey that indicated prior antidepressant treatments were associated with an earlier onset of mania in youth, particularly in adolescent females. Larger prospective studies are needed to identify neurodevelopmental processes underlying PBD and initiate prevention approaches., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: 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., Methods: Adult 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., Results: In 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., Limitations: Predominantly self-reported White samples may limit generalizability; the risk calculator does not assess more proximal risk (e.g., 1 month)., Conclusions: Risk 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: 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., Methods: COBY 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 (<13 years old) versus adolescent (13-17 years old) onset. We next used penalized regression to test demographic and clinical predictors of young adult mania/hypomania., Results: 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., Discussion: 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., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Youth 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., Methods: We 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., Results: Poorer 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., Conclusions: Among 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., (© 2020 Association for Child and Adolescent Mental Health.)

Background: Concussion symptoms in adolescents typically resolve within 4 weeks. However, 20 - 30% of adolescents experience a prolonged recovery. Abnormalities in tracts implicated in visuospatial attention and emotional regulation (i.e., inferior longitudinal fasciculus, ILF; inferior fronto-occipital fasciculus, IFOF; uncinate fasciculus; UF) have been consistently reported in concussion; yet, to date, there are no objective markers of prolonged recovery in adolescents. Here, we evaluated the utility of diffusion MRI in outcome prediction. Forty-two adolescents (12.1 - 17.9 years; female: 44.0%) underwent a diffusion Magnetic Resonance Imaging (dMRI) protocol within the first 10 days of concussion. Based on days of injury until medical clearance, adolescents were then categorized into SHORT (<28 days; N = 21) or LONG (>28 days; N = 21) recovery time. Fractional anisotropy (FA) in the ILF, IFOF, UF, and/or concussion symptoms were used as predictors of recovery time (SHORT, LONG). Forty-two age- and sex-matched healthy controls served as reference. Higher FA in the ILF ( left : adjusted odds ratio; AOR = 0.36, 95% CI = 0.15 - 0.91, P = 0.030; right : AOR = 0.28, 95% CI = 0.10 - 0.83, P = 0.021), IFOF ( left: AOR = 0.21, 95% CI = 0.07 - 0.66, P = 0.008; right : AOR = 0.30, 95% CI = 0.11 - 0.83, P = 0.020), and UF ( left : AOR = 0.26, 95% CI = 0.09 - 0.74, P = 0.011; right: AOR = 0.28, 95% CI = 0.10 - 0.73, P = 0.010) was associated with SHORT recovery. In additional analyses, while adolescents with SHORT recovery did not differ from HC, those with LONG recovery showed lower FA in the ILF and IFOF ( P < 0.014). Notably, inclusion of dMRI findings increased the sensitivity and specificity (AUC = 0.93) of a prediction model including clinical variables only (AUC = 0.75). Our findings indicate that higher FA in long associative tracts (especially ILF) might inform a more objective and accurate prognosis for recovery time in adolescents following concussion., Competing Interests: MP declares a one-time honorarium from Sunovion in November 2016. DB receives research support from NIMH, AFSP, the Once Upon a Time Foundation, and the Beckwith Foundation, receives royalties from Guilford Press, from the electronic self-rated version of the C-SSRS from eRT, Inc., and from performing duties as an UptoDate Psychiatry Section Editor, receives consulting fees from Healthwise, and receives Honoraria from the Klingen-stein Third Generation Foundation for scientific board membership and grant review. MC is a former Co-owner and Board Member of ImPACT Applications (relationship ended 12/16/19). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lima Santos, Kontos, Mailliard, Eagle, Holland, Suss Jr., Abdul-waalee, Stiffler, Bitzer, Blaney, Colorito, Santucci, Brown, Kim, Iyengar, Skeba, Diler, Ladouceur, Phillips, Brent, Collins and Versace.)

Objective: Despite 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., Methods: A 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., Results: Females 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., Conclusions: Contrasting 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., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Objectives: Compare 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)., Methods: Participants 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)., Results: At 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., Limitations: Secondary data limited study design; groupings were based on one time point., Conclusions: Results indicate no clinically relevant longitudinal group differences., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Few 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., Method: A 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., Results: Class 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., Limitations: The study does not have a healthy control group to compare functioning findings., Conclusions: Participants 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., Competing Interests: Declaration of Competing Interest Dr.. Birmaher receives royalties for publications from Random House, Inc., UpToDate, and Lippencott Williams and Wilkins. Dr.. T. Goldstein receives royalties from Guilford Press. Dr.. Hunt receives honoraria from Wiley Publishers as a Senior Editor of the Brown University Child and Adolescent Psychopharmacology Update. Dr.. Ryan served on the Scientific Advisory Board of the Child Mind Institute. Dr.. Axelson receives royalties from UpToDate, and serves as a consultant to Janssen Research and Development, LLC. Dr.. Yen is a consultant at Janssen Research and Development, LLC. All other authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: In 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., Method: A 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., Results: The 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., Limitations: The study does not have a healthy control group to compare functioning findings., Conclusions: In 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Most 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., Method: Participants 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., Results: Of 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., Limitations: RDCyc 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., Conclusion: There 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Youth 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., Method: One 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., Results: Seventy-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)., Conclusion: If 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., (Copyright © 2018 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Patients with bipolar disorder have recurrent major depression, residual mood symptoms, and limited treatment options. Building on promising pilot data, the authors conducted a 6-week randomized double-blind placebo-controlled trial to investigate the efficacy of adjunctive bright light therapy at midday for bipolar depression. The aims were to determine remission rate, depression symptom level, and rate of mood polarity switch, as well as to explore sleep quality., Method: The study enrolled depressed adults with bipolar I or II disorder who were receiving stable dosages of antimanic medication (excluding patients with hypomania or mania, mixed symptoms, or rapid cycling). Patients were randomly assigned to treatment with either 7,000-lux bright white light or 50-lux dim red placebo light (N=23 for each group). Symptoms were assessed weekly with the Structured Interview Guide for the Hamilton Depression Scale With Atypical Depression Supplement (SIGH-ADS), the Mania Rating Scale, and the Pittsburgh Sleep Quality Index. Remission was defined as having a SIGH-ADS score of 8 or less., Results: At baseline, both groups had moderate depression and no hypomanic or manic symptoms. Compared with the placebo light group, the group treated with bright white light experienced a significantly higher remission rate (68.2% compared with 22.2%; adjusted odds ratio=12.6) at weeks 4-6 and significantly lower depression scores (9.2 [SD=6.6] compared with 14.9 [SD=9.2]; adjusted β=-5.91) at the endpoint visit. No mood polarity switches were observed. Sleep quality improved in both groups and did not differ significantly between them., Conclusions: The data from this study provide robust evidence that supports the efficacy of midday bright light therapy for bipolar depression.

Objectives: Having a parent with bipolar disorder (BP) is a very strong risk factor for developing BP. Similarly, depression among youth is a clinical risk factor for subsequent BP. We evaluated whether mood symptomatology in depressed youth is different between those at high and low familial risk to develop BP., Methods: The most severe major depressive episode in BP offspring (N=61) and community control offspring (N=20) was evaluated using expanded depression and mania rating scales derived from the Schedule for Affective Disorders and Schizophrenia for Children Present Version. The results were adjusted for any between-group significant demographic differences and for multiple comparisons., Results: The severity of depressive symptoms and the percentage of offspring with severe depressive symptoms, especially atypical depressive features, were significantly higher in the depressed offspring of BP parents compared to the depressed controls (P s <.05). The depressive symptoms were helpful to identify a high-risk group (e.g., odds ratio [OR] for hypersomnia: 22.4, 95% confidence interval [CI]: 1.3-404, P=.04). In addition, there were significantly more depressed offspring of BP parents with subsyndromal manic symptoms than controls (52.5% vs 20%, OR: 4.2, 95% CI: 1.2-14.7, P<.01)., Conclusions: Depressed BP offspring had more severe depression including atypical depressive symptoms, and were more likely to have subsyndromal mixed manic symptoms than depressed control offspring. Prospective studies to evaluate whether these youth are at high risk to develop BP are warranted. If replicated, the results of this study have important clinical (e.g., treatment of depression in depressed offspring of BP parents) and research implications., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To examine the psychometrics of the Screen for Adult Anxiety Related Disorders (SCAARED)., Methods: The SCAARED was adapted from the Screen for Child Anxiety Related Emotional Disorders. Participants (N=336) ages 18-27 years old were evaluated using the Structured Clinical Interview for DSM-IV Disorders (SCID). The SCAARED was completed at or within two-weeks before the SCID. The psychometrics of the SCAARED were analyzed using standard statistical analyses including principal components, and Receiver Operant Curve analyses. A replication was performed in an age/sex matched independent sample (N=158)., Results: The SCAARED showed four factors: somatic/panic/agoraphobia, generalized anxiety, separation anxiety, and social anxiety. The total and each factor scores demonstrated good internal consistency (α=0.86-0.97) and good discriminant validity between anxiety and other disorders and within anxiety disorders for generalized and social anxiety. Area Under the Curve for the total and each of the factor scores ranged between 0.72 and 0.84 (p<0.0001). These results were replicated in the independent sample., Conclusions: The SCAARED showed excellent psychometric properties supporting its use to screen adults for anxiety disorders, longitudinal studies following youth into adulthood and studies comparing child and adult populations. Further replication studies in larger community and clinical samples are indicated., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To identify mood symptoms that distinguishes bipolar disorder (BP) depression versus unipolar depression in youth during an acute depressive episode., Methods: Youth 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., Results: In 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., Conclusions: The 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.

Background: Previous studies have explored the role of stressful life events in the development of mood disorders. We examined the frequency and nature of stressful life events as measured by the Stressful Life Events Schedule (SLES) among 3 groups of adolescent offspring of probands with bipolar (BD), with non-BD psychiatric disorders, and healthy controls. Furthermore, we examined the relationship between stressful life events and the presence of DSM-IV Axis I disorders in these offspring. Stressful life events were characterized as dependent, independent, or uncertain (neither dependent nor independent) and positive, negative, or neutral (neither positive nor negative)., Methods: Offspring of probands with BD aged 13-18 years (n = 269), demographically matched offspring of probands with non-BD Axis I disorders (n = 88), and offspring of healthy controls (n = 81) from the Pittsburgh Bipolar Offspring Study were assessed from 2002 to 2007 with standardized instruments at intake. Probands completed the SLES for their offspring for life events within the prior year. Life events were evaluated with regard to current Axis I diagnoses in offspring after adjusting for confounds., Results: After adjusting for demographic and clinical between-group differences (in probands and offspring), offspring of probands with BD had greater independent (χ² = 11.96, P < .04) and neutral (χ² = 17.99, P < .003) life events compared with offspring of healthy controls and greater number of more severe stressful life events than offspring of healthy controls, but not offspring of probands with non-BD. Offspring of BD probands with comorbid substance use disorder reported more independent stressful life events compared to those without comorbid substance use disorder (P = .024). Greater frequency and severity of stressful life events were associated with current Axis I disorder in offspring of both probands with BD and probands with other Axis I disorders regardless of dependency or valence. Greater frequency and severity of stressful life events were associated with greater current Axis I disorder in all offspring., Conclusions: Offspring of probands with BD have greater exposure to independent and neutral life events than offspring of healthy controls. Greater frequency and severity of stressful life events were associated with Axis I disorder in offspring of both BD and non-BD affected probands., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

Objective: To provide the first longitudinal characterization of mood and psychosocial functioning in youth with comorbid bipolar (BD) and autism spectrum (ASD) disorders., Method: The 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., Results: Thirty 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., Conclusion: Youth 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., Competing Interests: Drs. Borue, Mazefesky, Keller, Yen, Diler, Axelson, Mr. Rooks, and Mss. Hower, Gill, and Liao report no biomedical financial interests or potential conflicts of interest., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Greater understanding of cognitive function in children and adolescents with bipolar disorder (BD) is of critical importance to improve our ability to design targeted treatments to help with real-world impairment, including academic performance. We sought to evaluate cognitive performance among children with either BD type I, II, or "not otherwise specified" (NOS) participating in multi-site Course and Outcome of Bipolar Youth study compared to typically developing controls (TDC) without psychopathology. In particular, we sought to test the hypothesis that BD-I and BD-II youths with full threshold episodes of mania or hypomania would have cognitive deficits, including in reversal learning, vs. those BD-NOS participants with sub-threshold episodes and TDCs. N = 175 participants (BD-I = 81, BD-II = 11, BD-NOS = 28, TDC = 55) completed Cambridge Neuropsychological Automated Testing Battery (CANTAB) tasks. A priori analyses of the simple reversal stage of the CANTAB intra-/extra-dimensional shift task showed that aggregated BD-I/II participants required significantly more trials to complete the task than either BD-NOS participants with sub-syndromal manic/hypomanic symptoms or than TDCs. BD participants across sub-types had impairments in sustained attention and information processing for emotionally valenced words. Our results align with prior findings showing that BD-I/II youths with distinct episodes have specific alterations in reversal learning. More broadly, our study suggests that further work is necessary to see the interaction between neurocognitive performance and longitudinal illness course. Additional work is required to identify the neural underpinnings of these differences as targets for potential novel treatments, such as cognitive remediation.

Objectives: To study the longitudinal course of sleep timing and circadian preferences in individuals with bipolar disorder (BP) compared to individuals with non-BP psychopathology and healthy controls., Methods: Individuals with bipolar I and bipolar II disorder (n = 257), non-BP psychopathology (n = 105), and healthy controls (n = 55) (mean age 40.2 years, 21.3% male, 85.1% Caucasian) were followed on average every 27 months for a mean of four years. Sleep timing parameters and circadian preference were reported using the Sleep Timing Questionnaire and The Composite Scale for Morningness. Group comparisons were adjusted for multiple comparisons and between-group differences in demographic variables and psychopharmacological treatment., Results: Regardless of their current mood state, individuals with BP showed more sleep onset latency (SOL), wakening after sleep onset (WASO), and evening preference in comparison to both individuals with non-BP psychopathology and healthy controls. Individuals with BP also showed less stability of bed and awakening times in comparison to the other two groups, though these results were dependent on mood state. Non-BP individuals only showed more WASO and less stability in bed and awakening times before work/school days than healthy controls. Adjusting for comorbid disorders yielded similar results. Within-group analyses found little to no effect of time and BP subtype on sleep timing and circadian preference., Conclusions: Disturbances of sleep timing are prominent in individuals with BP. These disturbances are worse during mood episodes, but still apparent during euthymic periods. Evening preference was not associated with polarity type, or mood state in BP, suggesting that this characteristic may be a trait marker., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To compare the psychopathology and longitudinal course of attention-deficit/hyperactivity disorder (ADHD) symptomatology and global functioning between the offspring with ADHD of parents with bipolar disorder and the offspring with ADHD of community control parents., Method: One hundred twenty-two offspring with ADHD of parents with bipolar disorder and 48 offspring with ADHD of control parents from the Pittsburgh Bipolar Offspring Study (BIOS) were included. DSM-IV lifetime psychiatric disorders were ascertained through the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). The outcome measures of ADHD symptoms were ascertained at intake and every other year for a period of 6 years using the ADHD section of the K-SADS-PL and the Disruptive Behavior Disorder rating scale (DBD). Global functioning was assessed using the Children's Global Assessment Scale (CGAS)., Results: The offspring with ADHD of parents with bipolar disorder showed higher lifetime prevalence of mood and anxiety disorders relative to the offspring with ADHD of control parents (P values ≤ .03). For both groups of offspring with ADHD, the hyperactivity, impulsivity, and total K-SADS-PL ADHD scores decreased over time (P values < .001) without differences between the 2 groups. There were no between- or within-group differences in the inattention scores over time. The DBD ADHD scores decreased with age in both groups (P values < .002) without differences between the 2 groups. For both groups of offspring with ADHD, the global functioning did not improve over time., Conclusions: Offspring with ADHD of parents with bipolar disorder have more psychopathology relative to offspring with ADHD of control parents. However, there were no differences in the developmental courses of ADHD symptomatology between these 2 groups of ADHD youth., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

Objective: To examine potential predictors of lifetime suicidal behaviors (SBs) in adolescents with ADHD., Method: Participants were 101 adolescents with ADHD aged 11 to 18 years, evaluated for lifetime SB and psychopathology with semistructured interviews, and for lifetime trauma exposure, parent-child conflict, ADHD symptoms, and functional impairment with child, parent, and teacher ratings., Results: Controlling for the effects of age, female sex, and comorbid depressive and other disorders, lifetime SB (n = 28) remained significantly associated (p = .001) with parent-child conflict, and to a lesser extent (p < .05) with impairment in nonacademic domains of function and breadth of exposure to victimization events. Measures related to past and current ADHD symptoms and signs were not associated with lifetime SB., Conclusion: Apart from depression, clinicians should pay particular attention to parent-child conflict, victimization trauma, and social impairment rather than levels of ADHD symptoms when weighing the likelihood of SB in youth with ADHD., (© 2012 SAGE Publications.)

Objective: In this study, we aimed to assess whether current mood state (depressed or manic/hypomanic) among parents with a mood disorder would affect their reports of their offspring's psychopathology., Method: Sixty-five parents with current depression, 42 parents with current mania/hypomania, 181 parents with mood disorder in remission, and their offspring (n = 479, aged 6-18 years) completed assessments of offspring psychopathology as part of the Pittsburgh Bipolar Offspring Study (BIOS). We compared rates of offspring psychopathology assessed using the following: a clinician-administered semi-structured interview with parent and child using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS); parent-reported Child Behavior Checklist (CBCL); offspring self-reported Youth Self Reports (YSR) for those 11 years and older (n = 250); and teachers' reports when available (n = 209)., Results: There were no between-group differences in rates of psychopathology yielded from the K-SADS, except for more depressive disorders in offspring of parents with current mania/hypomania compared to offspring of parents in remission. Conversely, using the CBCL and comparing with parents who were in remission, parents with current depression reported significantly more externalizing psychopathology in offspring, whereas parents with current mania/hypomania reported more externalizing and internalizing psychopathology in their offspring. On the YSR, offspring of parents with current mania/hypomania had more internalizing psychopathology compared to offspring of parents in remission. Teacher's reports showed no between-group differences in rates of any psychopathology., Conclusion: Parental active mood symptomatology, especially during a manic/hypomanic episode, significantly affects their reports of their offspring's psychopathology. Trained interviewers reduce potential report bias. Clinicians and studies assessing children's psychopathology should take into account parental current mood state., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: The authors sought to identify and evaluate longitudinal mood trajectories and associated baseline predictors in youths with bipolar disorder., Method: A total of 367 outpatient youths (mean age, 12.6 years) with bipolar disorder with at least 4 years of follow-up were included. After intake, participants were interviewed on average 10 times (SD=3.2) over a mean of 93 months (SD=8.3). Youths and parents were interviewed for psychopathology, functioning, treatment, and familial psychopathology and functioning., Results: Latent class growth analysis showed four different longitudinal mood trajectories: "predominantly euthymic" (24.0%), "moderately euthymic" (34.6%), "ill with improving course" (19.1%), and "predominantly ill" (22.3%). Within each class, youths were euthymic on average 84.4%, 47.3%, 42.8%, and 11.5% of the follow-up time, respectively. Multivariate analyses showed that better course was associated with higher age at onset of mood symptoms, less lifetime family history of bipolar disorder and substance abuse, and less history at baseline of severe depression, manic symptoms, suicidality, subsyndromal mood episodes, and sexual abuse. Most of these factors were more noticeable in the "predominantly euthymic" class. The effects of age at onset were attenuated in youths with lower socioeconomic status, and the effects of depression severity were absent in those with the highest socioeconomic status., Conclusions: A substantial proportion of youths with bipolar disorder, especially those with adolescent onset and the above-noted factors, appear to be euthymic over extended periods. Nonetheless, continued syndromal and subsyndromal mood symptoms in all four classes underscore the need to optimize treatment.

Objectives: Bipolar disorder (BP) has been associated with increased aggressive behaviors. However, all existing studies are cross-sectional and include forensic or inpatient populations and many do not take into account the effects of comorbid conditions. The goal of this study was to evaluate the longitudinal course of aggression among adult outpatients with BP compared with non-BP patients and healthy controls., Methods: Subjects with bipolar I disorder (BP-I)/bipolar II disorder (BP-II) (n = 255), those with non-BP psychopathology (n = 85), and healthy controls (n = 84) (average 38.9 years, 78.7% female, and 84.9% Caucasian) were evaluated at intake and after two and four years of follow-up. Aggression was self-rated using the Aggression Questionnaire (AQ). Comparisons were adjusted for any significant demographic and clinical differences and for multiple comparisons. For subjects with BP, associations of AQ with subtype of BP, current versus past mood episodes, polarity and severity of the current episode, psychosis, and current pharmacological treatment were evaluated., Results: In comparison with subjects with non-BP psychiatric disorders and healthy controls, subjects with BP showed persistently higher total and subscale AQ scores (raw and T-scores) during the four-year follow-up. There were no effects of BP subtype, severity or polarity of the current episode, psychosis, and current pharmacological treatments. Subjects in an acute mood episode showed significantly higher AQ scores than euthymic subjects., Conclusions: BP, particularly during acute episodes, is associated with increased self-reported verbal and physical aggression, anger, and hostility. These results provide further evidence of the need for treatments to prevent mood recurrences and prompt treatment of acute mood episodes in subjects with BP., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Disruptive mood dysregulation disorder (DMDD) is a new diagnosis in the DSM-5. Youth with a family history of bipolar disorder (BD) are at increased risk for BD and non-bipolar psychopathology. No studies to date have examined rates of DMDD among offspring of parents with BD. This study examines the risk for DMDD in offspring of parents with BD compared to community controls and considers rates of chronic irritability (independent of a DMDD diagnosis) across diagnoses in youth with parents with BD., Method: Modified DMDD criteria were applied post hoc to 375 offspring of parents with BD and 241 offspring, aged 6 to 17 years, of community control parents. We calculated odds ratios using generalized linear mixed models. In addition, we explored associations with a severe chronic irritability phenotype and various diagnoses in the high-risk cohort., Results: Offspring of parents with BD were more likely to meet criteria for DMDD than were the offspring of community control parents (Odds ratio [OR] = 8.3, 6.7% vs. 0.8%), even when controlling for demographic variables and comorbid parental diagnoses (OR = 5.4). They also had higher rates of chronic irritability compared to community controls (12.5% vs. 2.5%, χ(2) = 18.8, p < .005). Within the offspring of parents with BD, the chronic irritability phenotype was frequently present in offspring with diagnoses of BD, depression, attention-deficit/hyperactivity disorder, and disruptive behavior disorders., Conclusions: Like other non-BD diagnoses, family history of BD increases the risk for DMDD. Severe chronic irritability and temper tantrums are the core features of DMDD, and are associated with mood and behavioral disorders in youth at risk for BD., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Cognitive control deficits are commonly seen in Depression of Bipolar Disorder (BDd) and Unipolar Major Depressive Disorder (UDd). Because failure to differentiate BDd from UDd has significant clinical consequences we aimed to identify differential patterns of neural activity in BDd versus UDd underlying response inhibition and motor control in adolescents., Methods: Functional MRI was used to compare 12 BDd adolescents (mean age= 15.5±1.2) with age- and sex-matched ten UDd and ten healthy control (HC) adolescents during the performance of well-validated Go/NoGo task. NoGo response inhibition versus Go motor control blocks was used in whole-brain analysis and results were corrected for multiple comparisons., Results: There were no significant behavioral or neuroimaging findings between adolescents with BDd and UDd. However, both groups relative to HC showed significantly higher left superior temporal and left caudate activity during the NoGo condition. Moreover, left anterior cingulate (ACC) activity relative to HC was significantly higher only in BDd - not UDd - adolescents during the NoGo condition, and left caudate activity was higher only in UDd - not BDd - adolescents during the Go condition. In addition, several neural regions including dorsolateral prefrontal (DLPFC) were positively correlated with increased reaction time in UDd - not BDd - adolescents., Conclusions: Despite some similarities, neural correlates of depression are different in BDd and UDd relative to HC, and greater recruitment of ACC resources during response inhibition can help distinguish BDd.

Background: The purpose of this study is to compare the dimensional psychopathology, as ascertained by parental report, in preschool offspring of parents with bipolar disorder (BP) and offspring of community control parents., Methods: 122 preschool offspring (mean age 3.3 years) of 84 parents with BP, with 102 offspring of 65 control parents (36 healthy, 29 with non-BP psychopathology), were evaluated using the Child Behavior Checklist (CBCL), the CBCL-Dysregulation Profile (CBCL-DP), the Early Childhood Inventory (ECI-4), and the Emotionality Activity Sociability (EAS) survey. Teachers' Report Forms (TRF) were available for 51 preschoolers., Results: After adjusting for confounders, offspring of parents with BP showed higher scores in the CBCL total, externalizing, somatic, sleep, aggressive, and CBCL-DP subscales; the ECI-4 sleep problem scale; and the EAS total and emotionality scale. The proportion of offspring with CBCL T-scores ≥ 2 SD above the norm was significantly higher on most CBCL subscales and the CBCL-DP in offspring of parents with BP compared to offspring of controls even after excluding offspring with attention deficit hyperactivity disorder and/or oppositional defiant disorder. Compared to offspring of parents with BP-I, offspring of parents with BP-II showed significantly higher scores in total and most CBCL subscales, the ECI-4 anxiety and sleep scales and the EAS emotionality scale. For both groups of parents, there were significant correlations between CBCL and TRF scores (r = .32-.38, p-values ≤.02)., Conclusions: Independent of categorical axis-I psychopathology and other demographic or clinical factors in both biological parents, preschool offspring of parents with BP have significantly greater aggression, mood dysregulation, sleep disturbances, and somatic complaints compared to offspring of control parents. Interventions to target these symptoms are warranted., (© 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.)

Failure to distinguish bipolar depression (BDd) from the unipolar depression of major depressive disorder (UDd) in adolescents has significant clinical consequences. We aimed to identify differential patterns of functional neural activity in BDd versus UDd and employed two (fearful and happy) facial expression/ gender labeling functional magnetic resonance imaging (fMRI) experiments to study emotion processing in 10 BDd (8 females, mean age=15.1 ± 1.1) compared to age- and gender-matched 10 UDd and 10 healthy control (HC) adolescents who were age- and gender-matched to the BDd group. BDd adolescents, relative to UDd, showed significantly lower activity to both intense happy (e.g., insula and temporal cortex) and intense fearful faces (e.g., frontal precentral cortex). Although the neural regions recruited in each group were not the same, both BDd and UDd adolescents, relative to HC, showed significantly lower neural activity to intense happy and mild happy faces, but elevated neural activity to mild fearful faces. Our results indicated that patterns of neural activity to intense positive and negative emotional stimuli can help differentiate BDd from UDd in adolescents., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Depressive mood in adolescents with bipolar disorder (BDd) is associated with significant morbidity and mortality, but we have limited information about neural correlates of depression and treatment response in BDd. Ten adolescents with BDd (8 females, mean age = 15.6 ± 0.9) completed two (fearful and happy) face gender labeling fMRI experiments at baseline and after 6-weeks of open treatment. Whole-brain analysis was used at baseline to compare their neural activity with those of 10 age and sex-matched healthy controls (HC). For comparisons of the neural activity at baseline and after treatment of youth with BDd, region of interest analysis for dorsal/ventral prefrontal, anterior cingulate, and amygdala activity, and significant regions identified by wholebrain analysis between BDd and HC were analyzed. There was significant improvement in depression scores (mean percentage change on the Child Depression Rating Scale-Revised 57 % ± 28). Neural activity after treatment was decreased in left occipital cortex in the intense fearful experiment, but increased in left insula, left cerebellum, and right ventrolateral prefrontal cortex in the intense happy experiment. Greater improvement in depression was associated with baseline higher activity in ventral ACC to mild happy faces. Study sample size was relatively small for subgroup analysis and consisted of mainly female adolescents that were predominantly on psychotropic medications during scanning. Our results of reduced negative emotion processing versus increased positive emotion processing after treatment of depression (improvement of cognitive bias to negative and away from positive) are consistent with the improvement of depression according to Beck's cognitive theory.

Objectives: Early identification of bipolar disorder (BP) symptomatology is crucial for improving the prognosis of this illness. Increased mood lability has been reported in BP. However, mood lability is ubiquitous across psychiatric disorders and may be a marker of severe psychopathology and not specific to BP. To clarify this issue, this study examined the prevalence of mood lability and its components in offspring of BP parents and offspring of community control parents recruited through the Pittsburgh Bipolar Offspring Study., Methods: Forty-one school-age BP offspring of 38 BP parents, 257 healthy or non-BP offspring of 174 BP parents, and 192 offspring of 117 control parents completed a scale that was developed to evaluate mood lability in youth, i.e., the Children's Affective Lability Scale (CALS)., Results: A factor analysis of the parental CALS, and in part the child CALS, revealed Irritability, Mania, and Anxiety/Depression factors, with most of the variance explained by the Irritability factor. After adjusting for confounding factors (e.g., parental and offspring non-BP psychopathology), BP offspring of BP parents showed the highest parental and child total and factor scores, followed by the non-BP offspring of BP parents, and then the offspring of the controls., Conclusions: Mood lability overall and mania-like, anxious/depressed, and particularly irritability symptoms may be a prodromal phenotype of BP among offspring of parents with BP. Prospective studies are warranted to clarify whether these symptoms will predict the development of BP and/or other psychopathology. If confirmed, these symptoms may become a target of treatment and biological studies before BP develops., (© 2013 John Wiley and Sons A/S. Published by Blackwell Publishing Ltd.)

Objective: Abnormal prefrontal and subcortical activity during cognitive control tasks is identified in non-depressed adolescents with bipolar disorder (BD); however, little is known about the neural correlates of bipolar adolescents in a depressed state (BDd). We aimed to investigate baseline versus after-treatment patterns of neural activity underlying motor response and response inhibition in adolescents with BDd., Methods: In this functional magnetic resonance imaging (fMRI) study, 10 adolescents with BDd relative to 10 age- and sex-matched healthy controls (HC) completed a well-validated go/no go block-design cognitive control task at baseline and after 6 weeks of naturalistic treatment. We used whole-brain analysis and controlled our results for multiple comparisons., Results: There was significant improvement in depression scores (mean change: 57%±28). There was no behavioral difference in BDd baseline versus HC and after treatment. BDd adolescents relative to HC had higher baseline cortical, but not subcortical, neural activity (e.g., bilateral ventrolateral prefrontal during both the go [motor control] and the no go [response inhibition] conditions, and left superior temporal during the no go condition). However, after-treatment activity relative to baseline neural activity during response inhibition was significantly increased in subcortical (e.g., right hippocampus and left thalamus), but not cortical, regions. In addition, at baseline, lower left thalamus activity was correlated with higher depression scores., Conclusions: Adolescents with BDd had baseline prefrontal and temporal hyperactivity underlying motor control and response inhibition that did not change after treatment in contrast to relatively decreased baseline subcortical activity underlying response inhibition associated with the depressive state that was increased after the treatment.

This review focuses mainly on published articles regarding the treatment of school-aged children and adolescents with pediatric bipolar disorder. In light of systematic reviews, large randomized controlled trial data are emphasized wherever possible. This review addresses the treatment of acute manic/mixed episodes, including combination treatment, the preliminary literature regarding bipolar depression among youth, treatment in the face of comorbid conditions, and maintenance treatment. Suggestions regarding future directions are offered. A clinical vignette describing a teen with bipolar disorder is presented and bipolar medications, dosing, efficacy, side effects, contraindications, and succinct comments on each medication are summarized., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To compare the dimensional psychopathology in offspring of parents with bipolar disorder (BP) with offspring of community control parents as assessed by the Child Behavior Checklist (CBCL)., Methods: Offspring of parents with BP, who were healthy or had non-BP disorders (any psychiatric disorder other than BP; n = 319) or who had bipolar spectrum disorders (n = 35), and offspring of community controls (n = 235) ages 6-18 years were compared using the CBCL, the CBCL-Dysregulation Profile (CBCL-DP), and a sum of the CBCL items associated with mood lability. The results were adjusted for multiple comparisons and for any significant between-group demographic and clinical differences in both biological parents and offspring., Results: With few exceptions, several CBCL (e.g., Total, Internalizing, and Aggression Problems), CBCL-DP, and mood lability scores in non-BP offspring of parents with BP were significantly higher than in offspring of control parents. In addition, both groups of offspring showed significantly lower scores in most scales when compared with offspring of parents with BP who had already developed BP. Similar results were obtained when analyzing the rates of subjects with CBCL T-scores that were two standard deviations or higher above the mean., Conclusions: Even before developing BP, offspring of parents with BP had more severe and higher rates of dimensional psychopathology than offspring of control parents. Prospective follow-up studies in non-BP offspring of parents with BP are warranted to evaluate whether these dimensional profiles are prodromal manifestations of mood or other disorders, and can predict those who are at higher risk to develop BP., (© 2011 John Wiley and Sons A/S.)

Background: Offspring of parents with bipolar disorder are at increased risk for a range of psychopathology, including bipolar disorder. It is not clear if they also have impairments in their psychosocial functioning., Methods: We compared the psychosocial functioning of three groups of children enrolled in the Pittsburgh Bipolar Offspring Study (BIOS): offspring of probands with bipolar disorder (n=388), offspring of probands with other types of psychopathology (n=132), and offspring of healthy probands (n=118). Psychosocial functioning was assessed at study intake using the schedule of the Adolescent Longitudinal Interval Follow-Up Evaluation (A-LIFE), the Child Behavior Check List (CBCL) and the Children's Global Assessment Scale (CGAS)., Results: Offspring of probands with bipolar disorder exhibited impairments in various aspects of psychosocial functioning. On all measures, they had worse functioning in comparison with offspring of healthy probands. Offspring of probands with bipolar disorder generally exhibited more impairment than offspring of probands with nonbipolar psychopathology. After adjusting for proband parent functioning and the child's Axis I psychopathology, functioning of offspring of probands with bipolar disorder was similar to that of offspring of healthy probands., Limitations: Data are cross-sectional and therefore do not allow for causal conclusions about the association between parental psychopathology, child psychopathology and offspring psychosocial functioning., Conclusions: Offspring of parents with bipolar disorder exhibit impairments in psychosocial functioning which appear largely attributable to proband parent functional impairment and the child's own psychopathology. As such, interventions to improve parental functioning, as well as early interventions to treat the child's psychopathology may help reduce the risk for long-term functional impairment in offspring., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The authors describe a new variant of guanosine triphosphate (GTP)- cyclohydrolase deficiency in a young man with severe and disabling major depressive disorder with multiple near-lethal suicide attempts. His cerebrospinal fluid levels showed that the concentration of tetrahydrobiopterin (BH4), neopterin, 5-hydroxyindoleacetic acid and homovanillic acid were below the reference range, suggesting a defect in the pterin biosynthetic pathway and in synthesis of dopamine and serotonin indicative of GTP-cyclohydrolase deficiency. Patient was started on sapropterin, a BH4 replacement protein, for the defect in the above pathway. In addition, the authors started 5-hydroxytryptophan titrated to 400 mg orally twice daily with concomittant carbidopa 37.5 mg orally four times a day, and he responded with remission of suicidal ideation and significant improvement in depression and function.

[This corrects the article DOI: 10.1136/bcr.03.2011.3927.].

Depression is a common, potentially devastating comorbidity in youth with attention-deficit/hyperactivity disorders (ADHD). Various environmental adversities are well-described as correlates of depression in general pediatric populations, but not in youth with ADHD. In 104 adolescents with ADHD, we examined potential environmental correlates of lifetime depression, including trauma exposure, recent negative life events and current parent-child conflict, along with current and past ADHD severity and current impairment. Controlling for demographic variables, comorbid disorders, and ADHD severity, we noted significant associations between lifetime depression and environmental adversities, including victimization trauma, parent-child conflict, and behaviorally-independent negative life events. Current impairment but not ADHD severity was also highly associated with lifetime depression, controlling for the same covariates. Findings from this preliminary, cross-sectional study suggest that environmental adversities and impairment in youth with ADHD should also be targeted along with the ADHD when contemplating strategies to treat or prevent comorbid depression.

Objectives: Previous studies have suggested that the sum of Attention, Aggression, and Anxious/Depressed subscales of Child Behavior Checklist (CBCL-PBD; pediatric bipolar disorder phenotype) may be specific to pediatric bipolar disorder (BP). The purpose of this study was to evaluate the usefulness of the CBCL and CBCL-PBD to identify BP in children <12 years old., Methods: A sample of children with BP I, II, and not otherwise specified (NOS) (n = 157) ascertained through the Course and Outcome for Bipolar Disorder in Youth (COBY) study were compared with a group of children with major depressive/anxiety disorders (MDD/ANX; n = 101), disruptive behavior disorder (DBD) (n = 127), and healthy control (HC) (n = 128). The CBCL T-scores and area under the curve (AUC) scores were calculated and compared among the above-noted groups., Results: Forty one percent of BP children did not have significantly elevated CBCL-PBD scores (>or=2 standard deviations [SD]). The sensitivity and specificity of CBCL-PBD >or= 2 SD for diagnosis of BP was 57% and 70-77%, respectively, and the accuracy of CBCL-PBD for identifying a BP diagnosis was moderate (AUC = 0.72-0.78)., Conclusion: The CBCL and the CBCL-PBD showed that BP children have more severe psychopathology than HC and children with other psychopathology, but they were not useful as a proxy for Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) diagnosis of BP.