Children's Bipolar Network Treatment Trial I

Study Overview
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Brief Summary
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This is a naturalistic treatment and follow-up study of youth with bipolar spectrum disorders (BSDs) across four US sites of The Childhood Bipolar Network (CBN). CBN sites have expertise in diagnosing, assessing, and treating BSDs in youth. The primary aims of this study are to (1) identify and reliably diagnose youth (ages 9 to 19 yrs) with full bipolar disorder (BD) and BSDs, and (2) examine predictors (e.g., mood instability, inflammatory marker C-reactive protein) of clinical outcome over a 12 month period. Participating youth will initially complete a screening that includes a structured diagnostic interview and a baseline blood draw to measure inflammatory processes. Youth with BSD and parents (80 families) will be asked to participate in multiple follow up research visits with interviews, rating instruments, and questionnaires. Per established CBN guidelines, study psychiatrists will provide and track medication management and sites will also track psychosocial treatments. This study ultimately aims to further understanding of best practice pediatric BSD psychiatric and psychosocial treatments and development of a standardized and validated set of clinical tools for patient assessment, diagnosis, and tracking.

Detailed Description
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Study Background and Significance Cross-site research networks for specific childhood diseases have led to important treatment advances, such as guidance of optimizing treatments for individual patients and significant reductions in childhood mortality. The Childhood Bipolar Network (CBN) is a similar type of research collaboration developed to support advancements to the understanding and treatment of pediatric bipolar spectrum disorders (BSDs), starting with this first study. The study builds on recent advances in the early identification and reliable diagnosis of pediatric BSDs. It also builds on advances in treatment for youth with or at high risk for BSD, such as the finding from randomized clinical trials showing that family intervention plus pharmacotherapy is consistently associated with superior symptomatic, suicidal, and functional outcomes compared with either usual care or supportive therapy plus pharmacotherapy. Specific Aims of the Study The aims of the first study with 80 youth are to (1) identify and reliably diagnose diverse youth (9 to 19 yrs) with BSD I, II, and Other Specified Bipolar Disorder (OSBD, formerly called Bipolar Disorder Not Otherwise Specified) across collaborative clinics in the US; and (2) examine predictors of 1-year treatment response in youth with BSDs, using treatment methods and instrumentation harmonized across four sites. This study will examine mood instability and an inflammatory marker based on a blood test (C-reactive protein) as primary predictors of outcomes. Study phases and outcomes include: I. Recruitment and screening, II. Intake (blood draw, medical history, structured diagnostic interview, youth mood symptom and instability measures, youth and family functioning measures), III. Weekly parent online reporting on youth symptoms and functioning, IV. Follow-up at 6 and 12 months for repeated measures and relevant updates. Study milestones will include cross-site harmonization of assessment and treatment methods, validation of a mood instability phenotype, and development of an open trial infrastructure for novel treatments for youth with or at risk for BSD. The development of a standardized BSD clinical assessment and care procedure across US centers is critical to the broader effort to develop robust treatment algorithms and empirically based guidelines for use in a wide variety of national and international health care settings with culturally heterogeneous populations of youth with or at risk for BSD.

Official Title
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A Collaborative Treatment Network for Youth With or at High Risk for Bipolar Disorder

Conditions
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Bipolar Disorder, Bipolar I Disorder, Bipolar II Disorder, Other Specified Bipolar and Related Disorder, Mood Instability, Child Mental Disorder, Adolescent - Emotional Problem

Intervention / Treatment
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* Other: Medication or psychosocial treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Youth 9-19 years old Youth diagnosed with Bipolar disorder (I, II, Other Specified) or Cyclothymic Disorder by the study team during the diagnostic interview screening Youth is able to read and communicate in English to the degree necessary to be able to assent and participate (with help) in their treatment and assessments appropriate for ages 9 and up Youth has a caregiver able to participate in ongoing basis in assessment and treatment The participating caregiver can reliably read and communicate in English for purposes of study consenting, assessment, and treatment, unless preferred language translation services are regularly available. Exclusion Criteria: Youth has DSM-5 diagnosis of autism spectrum disorder Youth has DSM-5 diagnosis of substance or alcohol abuse with impairment within 3 mos. Youth has a medical or psychiatric disorder that is life-threatening or requires immediate hospitalization or emergency medical or therapeutic treatment Evidence of recent sexual or physical abuse of the youth by legally responsible caregivers Evidence of recent intimate partner violence between caregivers responsible for the youth's care

Ages Eligible for Study
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Minimum Age: 9 Years
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Youth with or at clinical high risk for Bipolar Spectrum Disorder<br>Youth included in the study will have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of Bipolar I or II, Cyclothymic Disorder, or Other Specified Bipolar Disorder (per Course and Outcome of Bipolar Youth study definition) | Other: Medication or psychosocial treatment<br>* Youth included in this naturalistic study will be offered medication management from study psychiatrists. The study's Network Oversight Committee, consisting of PI psychiatrists and consultants, has created guidelines on best practice medications, dosing, and adjustments for the study. The Network Oversight Committee will also offer ongoing consultation to study psychiatrists. The treating physician will take these guidelines and recommendations under consideration but will use clinical judgment and have the final say, in consultation with the parents and child, as to what treatments are prescribed. While psychosocial interventions are of interest as a predictor of outcomes, no universal psychotherapy or other psychosocial treatment will be provided by sites. There is no limitation on participant enrollment in psychosocial treatments. Investigators and their clinical partners may offer these interventions based on clinical judgment and availability.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Adolescent Longitudinal Interval Follow-up Evaluation (A-LIFE) Psychiatric Status Ratings | The A-LIFE is a measure of severity of youth mood symptoms and episodes, including first episode onset, duration, recovery, and recurrence. Independent evaluators administer the A-LIFE interview to the youth and one parent, and rate each week of the prior 6 month interval (i.e., 6 months prior to intake) on Psychiatric Status Ratings (PSRs) of depression, hypomania, mania, and suicidality. The minimum and maximum Psychiatric Status Ratings values are 0 and 6 respectively, with higher Psychiatric Status Ratings meaning worse psychiatric severity. | The measure will be administered at 0, 6, and 12 months. | 
| Change in Children's Affective Lability Scale (CALS), Child and Parent Report forms | CALS is a measure of youth mood lability and yields subscores for elevation/activation, irritability, and anxiety-depression. It consists of 20 items covering the prior 3 months: Suddenly becomes tense or anxious…has bursts of being overly affectionate or silly….starts to laugh or cry…suddenly appears sad, depressed, for no reason. The CALS uses a five level Likert scale, from 0 (never or rarely occurs) to 4 (occurs 1 or more times a day). Total score for the 20 items can vary from 0 to 80, with lower scores indicating a lesser degree of affective lability. | The measure will be administered at 0, 6, and 12 months. | 
| Change in Conflict Behavior Questionnaire (CBQ) scores, Child and Parent Report forms | The CBQ assesses the degree of aversive communication and conflict experienced in a child/parent dyad over the prior 3 months. The 20 scale items are rated true/false and cover argumentativeness (e.g., At least three times a week, we get angry at each other), frustration in communication, degree of empathy (e.g., My mother understands me), and relationship quality (e.g. I don't think we get along very well). The child fills out separate CBQs regarding conflict with each primary caregiver. Total scores range from 0 to 20. Higher scores represent more conflict including negative communications. | The measure will be administered at 0, 6, and 12 months. | 
| Kiddo-KINDL Quality of Life Questionnaire for Children, Child and Parent Reports forms | This Kiddo-KINDL is a measure of youth quality of life in five domains (Emotional Well-being, Self-esteem, Family, Social Contacts, School). Items (e.g., I did things together with my friends) are rated by the adolescent and parent on a Likert scale from 1 (never) to 5 (all the time) for the past week. The parent form contains items that pertain to the youth's quality of life while the child form pertains to the youth patient. Subscales represent each domain with scores range from 4 to 20. Total scale scores range from 20 to 100. Higher scores on subscales or the total scale mean greater quality of life. | The measure will be administered at 0, 6, and 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Parents' Online Weekly Evaluation and Rating Scale (POWERS), Parent Report form | The POWERS is a measure of the severity of youth psychopathology across several symptom domains. Parents rate six symptom domains (anxiety, depression, attention deficit hyperactivity disorder, oppositional defiance, manic, overall symptoms) on symptom severity (0=none to 3=severe) and frequency (0= rarely to 3= almost all of the time) for the past week. Total scale score ranges from 0 to 36, while symptom severity and frequency subscales each range from 0 to 18. Higher scores represent greater psychopathology. | The measure will be administered at 0 months and then weekly through 12 months. | 
| Change in General Behavior Inventory, Parent Version Short form (P-GBI) | The P-GBI Mania scale is a measure of youth hypomanic/biphasic symptom severity. An example item is Has your child's mood or energy shifted rapidly back and forth from happy to sad or high to low? 10 items are each rated by parents on a Likert scale ranging from 1 (never or hardly ever) to 4 (very often or almost constantly) for the past six months. Total scores range from 10 to 40, with higher scores representing greater youth hypomanic/biphasic symptom severity. | The measure will be administered at 0, 6, and 12 months. | 
| Change in Mood and Feelings Questionnaire (MFQ), Child and Parent Report forms | The MFQ is a measure of severity of youth suicidal ideation and depression. Example items include I didn't enjoy anything at all, I thought about death or dying, and I slept a lot more than usual. The youth or parent rates 33 items as not true (0), sometimes true (1) or true (2) for the past two weeks. Total scores range from 0 to 66, with higher scores representing greater severity of suicidal ideation and depression. | The measure will be administered at 0, 6, and 12 months. | 
| Change in Self-Report for Childhood Anxiety Related Disorders (SCARED), Child Report form | The SCARED is a measure of severity of youth anxiety severity and types of anxiety or worry. An example item is When I feel frightened, it is hard to breathe. The 41-items are rated by as Not True or Hardly Ever True (0), Somewhat True or Sometimes True (1), or Very True or Often True (2). Total scores range from 0 to 82, with higher scores representing greater severity of anxiety and worry. A total score of ≥ 25 may indicate the presence of an Anxiety Disorder | The measure will be administered at 0, 6, and 12 months. | 
| Drug Use Screening Inventory, Revised (DUSI-R), Child Report form | DUSI-R is a measure of frequency and severity of drug and alcohol use for the prior month. Participants are instructed to darken the circle that applies to the number of times you have used each of the drugs listed below in the last month. Item ratings range from 0=no times to 4=More than 20 times. The youth rates 15 additional severity items as yes (0) or no (1), with an example item being Have you had a craving or very strong desire for alcohol or drugs? The interviewer may assist with form completion to ensure understanding and completion. Total severity scale scores range from 0 to 15, with higher scores representing more severe substance use. | The measure will be administered at 0, 6, and 12 months. | 
| Change in Positive and Negative Affect Schedule for Children (PANAS-C-SF), Child Report Short form | PANAS-C-SF is a measure of youth positive and negative affect. Instructions are to Please indicate how much you have felt this way over the past 15 minutes, with youth asked to rate eight emotions on 5-point Likert scales from 1=Not much at all to 5=a lot for six consecutive days. Four items comprise the positive affect subscale (joyful, happy, lively, proud) while another four items comprise the negative affect subscale (miserable, mad, scared, sad). Subscale scores range from 4 to 20, with higher scores representing more affect. | The measure will be administered at 0, 6, and 12 months. | 
| Change in Perceived Criticism on Perceived Criticism Scale (PC), Child Report form | The Perceived Criticism (PC) scale measures severity of perceived parental criticism. Youth make a weekly rating for any primary parental figures of How critical is your parent of you? and When this parent criticizes you, how upset do you get? on scales ranging from 1 (not at all) to 10 (extremely). Total scores range from 2 to 20 with higher scores representing greater perceived criticism. | The measure will be administered at 0, 6, and 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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medication, psychosocial, treatment, longitudinal, naturalistic, assessment