Clinical, cortical thickness and neural activity predictors of future affective lability in youth at risk for bipolar disorder: initial discovery and independent sample replication.

We aimed to identify markers of future affective lability in youth at bipolar disorder risk from the Pittsburgh Bipolar Offspring Study (BIOS) (n = 41, age = 14, SD = 2.30), and validate these predictors in an independent sample from the Longitudinal Assessment of Manic Symptoms study (LAMS) (n = 55, age = 13.7, SD = 1.9). We included factors of mixed/mania, irritability, and anxiety/depression (29 months post MRI scan) in regularized regression models. Clinical and demographic variables, along with neural activity during reward and emotion processing and gray matter structure in all cortical regions at baseline, were used to predict future affective lability factor scores, using regularized regression. Future affective lability factor scores were predicted in both samples by unique combinations of baseline neural structure, function, and clinical characteristics. Lower bilateral parietal cortical thickness, greater left ventrolateral prefrontal cortex thickness, lower right transverse temporal cortex thickness, greater self-reported depression, mania severity, and age at scan predicted greater future mixed/mania factor score. Lower bilateral parietal cortical thickness, greater right entorhinal cortical thickness, greater right fusiform gyral activity during emotional face processing, diagnosis of major depressive disorder, and greater self-reported depression severity predicted greater irritability factor score. Greater self-reported depression severity predicted greater anxiety/depression factor score. Elucidating unique clinical and neural predictors of future-specific affective lability factors is a step toward identifying objective markers of bipolar disorder risk, to provide neural targets to better guide and monitor early interventions in bipolar disorder at-risk youth.

A Randomized Comparison of Two Psychosocial Interventions on Family Functioning in Adolescents with Bipolar Disorder.

Impairments in family functioning are associated with more severe depressive and manic symptoms, earlier recurrences, and more suicidal behaviors in early-onset bipolar disorder. This study examined whether family-focused treatment for adolescents (FFT-A) with BD I or II disorder led to greater increases in family cohesion and adaptability and decreases in conflict over 2 years compared to a briefer psychoeducational treatment (enhanced care, EC). Participants were 144 adolescents (mean age: 15.6 ± 1.4 years) with BD I or II with a mood episode in the previous 3 months. Adolescents and parents were randomized to either FFT-A (21 sessions) or EC (three sessions). Patients received guideline-based pharmacotherapy throughout the 2-year study. Trajectories of adolescent- and parent-rated family cohesion, adaptability, and conflict were analyzed over 2 years. FFT-A had greater effects on adolescent-rated family cohesion compared to EC over 2 years. Participants in FFT-A and EC reported similar improvements in family conflict across the 2 years. In the FFT-A group, low-conflict families had greater adolescent-rated family cohesion throughout the study compared to high-conflict families. High-conflict families in both treatment groups tended to show larger reductions in conflict over 2 years than low-conflict families. Family psychoeducation and skills training may improve family cohesion in the early stages of BD. Measuring levels of family conflict at the start of treatment may inform treatment responsiveness among those receiving FFT-A.

Los problemas en el funcionamiento familiar están asociados con síntomas depresivos y maníacos más graves, recidivas en periodos más breves y más conductas suicidas en el trastorno bipolar de inicio precoz. Este estudio analizó si el "Tratamiento centrado en la familia para adolescentes" (Family-Focused Treatment for Adolescents, FFT-A) con trastorno bipolar tipo I y tipo II condujo a mayores aumentos en la cohesión familiar y en la adaptabilidad y a disminuciones en el conflicto durante dos años en comparación con un tratamiento psicoeducativo más breve (atención optimizada; Enhanced Care: EC). Los participantes fueron 144 adolescentes (edad promedio: 15.6±1.4 años) con trastorno bipolar tipo I o tipo II con un episodio de alteración del humor en los tres meses previos. Los adolescentes y los padres fueron asignados aleatoriamente al FFT-A (21 sesiones) o a la EC (3 sesiones). Los pacientes recibieron farmacoterapia pautada durante todo el estudio de dos años. Las trayectorias de la cohesión familiar evaluada por los adolescentes y los padres, la adaptabilidad y el conflicto se analizaron durante dos años. El FFT-A tuvo mayores efectos en la cohesión familiar evaluada por los adolescentes en comparación con la EC durante dos años. Los participantes del FFT-A y de la EC informaron mejoras similares en el conflicto familiar durante los dos años. Las familias con un alto nivel de conflicto en el FFT-A tuvieron una menor cohesión evaluada por los adolescentes y una menor adaptabilidad durante dos años en comparación con las familias con un bajo nivel de conflicto en el FFT-A. Las familias con un alto nivel de conflicto en ambos grupos de tratamiento tendieron a mostrar reducciones más grandes en el conflicto durante dos años que las familias con un bajo nivel de conflicto. La psicoeducación familiar y la capacitación en habilidades pueden mejorar la cohesión familiar en las etapas iniciales del trastorno bipolar. La medición de los niveles de conflicto familiar al comienzo del tratamiento puede respaldar la capacidad de respuesta al tratamiento entre aquellos que reciben el FFT-A.

Diagnostic Accuracy of the CASI-4R Psychosis Subscale for Children Evaluated in Pediatric Outpatient Clinics.

Diagnostic accuracy of the Diagnostic and Statistical Manual of Mental Disorders-oriented Child and Adolescent Symptom Inventory (CASI-4R) Psychotic Symptoms scale was tested using receiver operating characteristic analyses to identify clinically significant psychotic symptoms. Participants were new outpatients (N = 700), ages 6.0 to 12.9 years (M = 9.7, SD = 1.8) at 9 child outpatient mental health clinics, who participated in the Longitudinal Assessment of Manic Symptoms (LAMS) Study baseline assessment. Because LAMS undersampled participants with low mania scores by design, present analyses weighted low scorers to produce unbiased estimates. Psychotic symptoms, operationally defined as a score of 3 or more for hallucinations or 4 or more for delusions based on the Schedule for Affective Disorders and Schizophrenia (K-SADS) psychosis items, occurred in 7% of youth. K-SADS diagnoses for those identified with psychotic symptoms above threshold included major depressive disorder, bipolar spectrum disorder, attention deficit/hyperactivity disorder, posttraumatic stress disorder, psychotic disorders, and autism spectrum disorder. The optimal psychosis screening cut score (maximizing sensitivity and specificity) was 2.75+ (corresponding diagnostic likelihood ratio [DiLR] = 4.29) for the parent version and 3.50+ (DiLR = 5.67) for the teacher version. The Area under the Curve for parent and teacher report was .83 and .74 (both p < .001). Parent report performed significantly better than teacher report for identifying psychotic symptoms above threshold (p = .03). The CASI-4R Psychosis subscale (J) appears clinically useful for identifying psychotic symptoms in children because of its brevity and accuracy.

Diagnostic Efficiency of the Child and Adolescent Symptom Inventory (CASI-4R) Depression Subscale for Identifying Youth Mood Disorders.

This study examined the diagnostic and clinical utility of the Child and Adolescent Symptom Inventory-4 R (CASI-4 R) Depressive and Dysthymia subscale for detecting mood disorders in youth (ages 6-12; M = 9.37) visiting outpatient mental health clinics. Secondary analyses (N = 700) utilized baseline data from the Longitudinal Assessment of Manic Symptoms study. Semistructured interviews with youth participants and their parents/caregivers determined psychiatric diagnoses. Caregivers and teachers completed the CASI-4 R. CASI-4 R depressive symptom severity and symptom count scores each predicted mood disorder diagnoses. Both caregiver scores (symptom severity and symptom count) of the CASI-4 R subscale significantly identified youth mood disorders (areas under the curve [AUCs] = .78-.79, ps < .001). The symptom severity version showed a small but significant advantage. Teacher symptom severity report did not significantly predict mood disorder diagnosis (AUC = .56, p > .05), whereas the teacher symptom count report corresponded to a small effect size (AUC = .61, p < .05). The CASI-4 R Depression scale showed strong incrememental validity even controlling for the other CASI-4 R scales. Caregiver subscale cutoff scores were calculated to assist in ruling in (diagnostic likelihood ratio [DLR] = 3.73) or ruling out (DLR = 0.18) presence of a mood disorder. The CASI-4 R Depressive subscale caregiver report can help identify youth mood disorders, and using DLRs may help improve diagnostic accuracy.

Diagnostic Efficiency of Caregiver Report on the SCARED for Identifying Youth Anxiety Disorders in Outpatient Settings.

This study investigated the diagnostic and clinical utility of the parent-rated Screen for Child Anxiety Related Emotional Disorders (SCARED-P) for detecting youth anxiety disorders. Youth ages 6 to 12 years, 11 months were recruited from 9 outpatient mental health clinics (N = 707). Consensus diagnoses were based on semistructured interviews (Schedule for Affective Disorders and Schizophrenia for School-Age Children) with youth and caregivers; 31% were diagnosed with at least one anxiety disorder. Caregivers completed the SCARED-P to describe youth anxiety levels. SCARED-P scores were not considered during the consensus diagnoses. Areas under the curve (AUCs) from receiver operating characteristic analyses and diagnostic likelihood ratios (DLRs) quantified performance of the SCARED-P total score and subscale scores (generalized anxiety disorder and separation anxiety disorder). SCARED-P total scores had variable efficiency (AUCs = .69-.88), and Generalized Anxiety Disorder and Separation Anxiety subscale scores were excellent (AUCs = .86-.89) for identifying specific anxiety disorders. Optimal subscale cutoff scores were computed to help rule in (DLRs = 2.7-5.4) or rule out (DLRs < 1.0) anxiety disorders among youth. Results suggest that the Generalized Anxiety Disorder and Separation Anxiety SCARED-P subscales accurately identify their respective matched diagnoses. DLRs may aid clinicians in screening for youth anxiety disorders and improve accuracy of diagnosis.

The International Society for Bipolar Disorders Task Force report on pediatric bipolar disorder: Knowledge to date and directions for future research.

OBJECTIVES: Over the past two decades, there has been tremendous growth in research regarding bipolar disorder (BD) among children and adolescents (ie, pediatric BD [PBD]). The primary purpose of this article is to distill the extant literature, dispel myths or exaggerated assertions in the field, and disseminate clinically relevant findings. METHODS: An international group of experts completed a selective review of the literature, emphasizing areas of consensus, identifying limitations and gaps in the literature, and highlighting future directions to mitigate these gaps. RESULTS: Substantial, and increasingly international, research has accumulated regarding the phenomenology, differential diagnosis, course, treatment, and neurobiology of PBD. Prior division around the role of irritability and of screening tools in diagnosis has largely abated. Gold-standard pharmacologic trials inform treatment of manic/mixed episodes, whereas fewer data address bipolar depression and maintenance/continuation treatment. Adjunctive psychosocial treatment provides a forum for psychoeducation and targets primarily depressive symptoms. Numerous neurocognitive and neuroimaging studies, and increasing peripheral biomarker studies, largely converge with prior findings from adults with BD. CONCLUSIONS: As data have accumulated and controversy has dissipated, the field has moved past existential questions about PBD toward defining and pursuing pressing clinical and scientific priorities that remain. The overall body of evidence supports the position that perceptions about marked international (US vs elsewhere) and developmental (pediatric vs adult) differences have been overstated, although additional research on these topics is warranted. Traction toward improved outcomes will be supported by continued emphasis on pathophysiology and novel therapeutics.

Ten-year updated meta-analysis of the clinical characteristics of pediatric mania and hypomania.

OBJECTIVES: The phenomenology and diagnosis of pediatric bipolar disorder has been controversial. We aimed to update a 2005 meta analysis of the prevalence of manic symptoms in youth, in order to determine whether the picture of pediatric mania has changed as research on pediatric bipolar disorder has grown. METHODS: We conducted literature reviews in PsycINFO and PubMed; studies with the prevalence of manic symptoms in youth were included. Two raters coded each study; kappa was 0.86-1.0. RESULTS: Twenty studies were meta-analyzed (N = 2,226 youths). The most common symptoms across bipolar subtypes, using a random-effects model, were: increased energy 79%, irritability 77%, mood lability 76%, distractibility 74%, goal-directed activity 72%, euphoric/elated mood 64%, pressured speech 63%, hyperactive 62%, racing thoughts 61%, poor judgment 61%, grandiosity 57%, inappropriate laughter 57%, decreased need for sleep 56%, and flight of ideas 54%. Symptom rates were heterogeneous across samples; potential predictors were explored but no clear patterns were found. CONCLUSIONS: Debate continues about the definitions of pediatric bipolar disorder; the results of this meta-analysis suggest that there is significant heterogeneity of symptom prevalence between studies, and that symptoms vary widely across individuals. Understanding the roots of this heterogeneity could broaden understanding of the complex clinical presentation of pediatric mania, and aid in diagnosis.

Cognitive flexibility and performance in children and adolescents with threshold and sub-threshold bipolar disorder.

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.

Phenomenology of bipolar disorder not otherwise specified in youth: a comparison of clinical characteristics across the spectrum of manic symptoms.

OBJECTIVES: Controversy surrounds the diagnostic categorization of children with episodic moods that cause impairment, but do not meet DSM-IV criteria for bipolar I (BD-I) or bipolar II (BD-II) disorder. This study aimed to characterize the degree to which these children, who meet criteria for bipolar disorder not otherwise specified (BD-NOS), are similar to those with full syndromal BD, versus those with no bipolar spectrum diagnosis (no BSD). METHODS: Children aged 6-12 years were recruited from nine outpatient clinics, preferentially selected for higher scores on a 10-item screen for manic symptoms. Interviews with the children and their primary caregivers assessed a wide array of clinical variables, as well as family history. RESULTS: A total of 707 children [mean ± standard deviation (SD) 9.4 ± 1.9 years old] were evaluated at baseline, and were diagnosed with BD-I (n = 71), BD-II (n = 3), BD-NOS (including cyclothymia; n = 88), or no BSD (n = 545). Compared to BD-I, the BD-NOS group had less severe past functional impairment. However, current symptom severity and functional impairment did not differ between BD-NOS and BD-I, even though both groups were significantly more symptomatic and impaired than the no BSD group. Parental psychiatric history was similar for the BD-NOS and BD-I groups, and both were more likely than the no BSD group to have a parent with a history of mania. Rates of elated mood did not differ between BD-NOS and BD-I youth. CONCLUSIONS: Children with BD-NOS and BD-I are quite similar, but different from the no BSD group, on many phenomenological measures. These findings support the hypothesis that BD-NOS is on the same spectrum as BD-I.

The 24-month course of manic symptoms in children.

OBJECTIVES: The Longitudinal Assessment of Manic Symptoms (LAMS) study was designed to investigate phenomenology and establish predictors of functional outcomes in children with elevated manic symptoms. The purpose of this series of analyses was to determine whether the participants demonstrated different trajectories of parent-reported manic and biphasic symptoms over the first 24 months of follow-up and to describe the clinical characteristics of the trajectories. METHODS: The 707 participants were initially aged 6-12 years and ascertained from outpatient clinics associated with the four university-affiliated LAMS sites. There were 621 children whose parents/guardians' ratings scored ≥ 12 on the Parent General Behavior Inventory-10-item Mania Form (PGBI-10M) and a matched random sample of 86 children whose parents/guardians' ratings scored ≤ 11 on the PGBI-10M. Participants were seen every six months after the baseline and their parents completed the PGBI-10M at each visit. RESULTS: For the whole sample, manic symptoms decreased over 24 months (linear effect B = -1.15, standard error = 0.32, t = -3.66, p < 0.001). Growth mixture modeling revealed four unique trajectories of manic symptoms. Approximately 85% of the cohort belonged to two classes in which manic symptoms decreased. The remaining ~15% formed two classes (high and rising and unstable) characterized by the highest rates of diagnostic conversion to a bipolar disorder (all p-values < 0.001). CONCLUSIONS: Outcomes are not uniform among children with symptoms of mania or at high risk for mania. A substantial minority of clinically referred children shows unstable or steadily increasing manic symptoms, and these patterns have distinct clinical correlates.

What differentiates children visiting outpatient mental health services with bipolar spectrum disorder from children with other psychiatric diagnoses?

OBJECTIVES: To determine the contribution of parent-reported manic symptoms, family history, stressful life events, and family environment in predicting diagnosis of bipolar spectrum disorders (BPSD) in youth presenting to an outpatient psychiatric clinic. METHODS: A total of 707 6- to 12-year-old children [621 with elevated symptoms of mania (ESM+) based on screening via the Parent General Behavior Inventory 10-item Mania Scale (PGBI-10M) and 86 without ESM (ESM-)] received a comprehensive assessment. RESULTS: Of the 629 with complete data, 24% (n = 148) had BPSD. Compared to those without BPSD (n = 481), children with BPSD: were older (Cohen's d = 0.44) and more likely to be female (Cohen's d = 0.26); had higher parent-endorsed manic symptom scores at screening (Cohen's d = 0.36) and baseline (Cohen's d = 0.76), more biological parents with a history of manic symptoms (Cohen's d = 0.48), and greater parenting stress (Cohen's d = 0.19). Discriminating variables, in order, were: baseline PGBI-10M scores, biological parent history of mania, parenting stress, and screening PGBI-10M scores. Absence of all these factors reduced risk of BPSD from 24% to 2%. CONCLUSIONS: History of parental manic symptoms remains a robust predictor of BPSD in youth seeking outpatient care, even after accounting for parent report of manic symptoms in the child at screening. However, the risk factors identified as associated with BPSD, together had limited value in accurately identifying individual participants with BPSD, highlighting the need for careful clinical assessment.

Development of a Symptom-Focused Model to Guide the Prescribing of Antipsychotics in Children and Adolescents: Results of the First Phase of the Safer Use of Antipsychotics in Youth (SUAY) Clinical Trial.

OBJECTIVE: To develop a new approach to prescribing guidelines as part of a pragmatic trial, Safer Use of Antipsychotics in Youth (SUAY; ClinicalTrials.gov Identifier: NCT03448575), which supports prescribers in delivering high-quality mental health care to youths. METHOD: A nominal group technique was used to identify first- to nth-line treatments for target symptoms and potential diagnoses. The panel included US pediatricians, child and adolescent psychiatrists, and psychopharmacology experts. Meeting materials included information about Medicaid review programs, systematic reviews, prescribing guidelines, and a description of the pragmatic trial. Afterward, a series of 4 webinar discussions were held to achieve consensus on recommendations. RESULTS: The panel unanimously agreed that the guideline should focus on target symptoms rather than diagnoses. Guidance included recommendations for first- to nth-line treatment of target mental health symptoms, environmental factors to be addressed, possible underlying diagnoses that should first be considered and ruled out, and general considerations for pharmacological and therapeutic treatments. CONCLUSION: Prescribing guidelines are often ignored because they do not incorporate the real-world availability of first-line psychosocial treatments, comorbid conditions, and clinical complexity. Our approach addresses some of these concerns. If the approach proves successful in our ongoing pragmatic trial, Safer Use of Antipsychotics in Youth (SUAY), it may serve as a model to state Medicaid programs and health systems to support clinicians in delivering high-quality mental health care to youths. CLINICAL TRIAL REGISTRATION INFORMATION: Safer Use of Antipsychotics in Youth; http://clinicaltrials.gov/; NCT03448575.

Pediatric bipolar spectrum disorder and ADHD: comparison and comorbidity in the LAMS clinical sample.

OBJECTIVE: To compare attention-deficit hyperactivity disorder (ADHD), bipolar spectrum disorders (BPSDs), and comorbidity in the Longitudinal Assessment of Manic Symptoms (LAMS) study. METHODS: Children ages 6-12 were recruited at first visit to clinics associated with four universities. A BPSD diagnosis required that the patient exhibit episodes. Four hypotheses were tested: (i) children with BPSD + ADHD would have a younger age of mood symptom onset than those with BPSD but no ADHD; (ii) children with BPSD + ADHD would have more severe ADHD and BPSD symptoms than those with only one disorder; (iii) global functioning would be more impaired in children with ADHD + BPSD than in children with either diagnosis alone; and (iv) the ADHD + BPSD group would have more additional diagnoses. RESULTS: Of 707 children, 421 had ADHD alone, 45 had BPSD alone, 117 had both ADHD and BPSD, and 124 had neither. Comorbidity (16.5%) was slightly less than expected by chance (17.5%). Age of mood symptom onset was not different between the BPSD + ADHD group and the BPSD-alone group. Symptom severity increased and global functioning decreased with comorbidity. Comorbidity with other disorders was highest for the ADHD + BPSD group, but higher for the ADHD-alone than the BPSD-alone group. Children with BPSD were four times as likely to be hospitalized (22%) as children with ADHD alone. CONCLUSIONS: The high rate of BPSD in ADHD reported by some authors may be better explained as a high rate of both disorders in child outpatient settings rather than ADHD being a risk factor for BPSD. Co-occurrence of the two disorders is associated with poorer global functioning, greater symptom severity, and more additional comorbidity than for either single disorder.

First-dose pharmacokinetics of lithium carbonate in children and adolescents.

This study examines the pharmacokinetics of oral doses of lithium carbonate immediate-release capsules after administration of 600 or 900 mg in children and adolescents with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, bipolar I disorder. Lithium plasma concentrations were followed over 48 to 72 hours in 39 subjects (20 male and 19 female subjects; ages, 7-17 years) with mixed or manic episodes enrolled at 7 clinical sites participating in the Collaborative Lithium Trials. Population pharmacokinetic modeling was performed using NONMEM, and influences of patient covariates on pharmacokinetics parameters were examined. The pharmacokinetics of lithium was best described using a 2-compartment model with a lag time and first-order absorption. There was considerable variability in lithium exposures. Lithium clearance related best to fat-free mass. Inclusion of fat-free mass as a covariate reduced the between-subject variability from 52% to 42%. Lithium clearances did not vary systematically with age group, dose, sex, or creatinine clearances. Allometrically scaled clearance and volume of distribution from the population analysis were within the range reported in adults. Single-dose profiles of lithium in young patients with BP-1 show marked variability. Therefore, ongoing serum monitoring is needed during continued therapy. The developed population pharmacokinetic model may be used to predict other dosage regimens, support scaling from adult to pediatric pharmacokinetics, and support the design of future clinical trials.

Classifying Mood Symptom Trajectories in Adolescents With Bipolar Disorder.

OBJECTIVE: The Course and Outcome of Bipolar Youth study found that children and adolescents with bipolar spectrum disorders followed 1 of 4 distinct mood trajectories over 8 years of follow-up, with as many as 25% of participants showing a predominantly euthymic course. We evaluated whether similar patterns of illness course are observed in adolescents with bipolar I and II disorder who participated in a 2-year clinical trial. METHOD: A total of 144 adolescents with bipolar I or II disorder, identified shortly after a mood episode, were assessed over a 2-year period. Participants were randomly assigned to one of 2 psychosocial family treatments during the first 9 months of the study, and pharmacotherapy was provided throughout the 2 years. Using latent class growth analyses, we classified participants into distinct courses of illness based on mood ratings collected over the 2 years. We examined demographic and illness variables as predictors of these course classifications. RESULTS: Latent class growth analyses indicated four mood trajectories: "predominantly euthymic" (29.9% of sample), "ill with significantly improving course" (11.1%), "moderately euthymic" (26.4%), and "ill with moderately improving course" (32.6%). Adolescents in these classes were euthymic 77.7%, 53.6%, 44.1%, and 18.6% of the weeks of follow-up, respectively. Psychosocial treatment condition and baseline medication exposure were not associated with trajectories. However, youth with more severe baseline depressive symptoms, suicidality, lower quality of life scores, and minority race/ethnicity had more symptomatic courses of illness over time. CONCLUSION: A substantial proportion (25%-30%) of youth with bipolar I or II disorder maintain euthymic states over extended periods of follow-up. Identifying youth who are more and less likely to remain stable over time may help guide psychosocial and pharmacological treatments after an illness episode. CLINICAL TRIAL REGISTRATION INFORMATION: Effectiveness of Family-Focused Treatment Plus Pharmacotherapy for Bipolar Disorder in Adolescents; https://clinicaltrials.gov/; NCT00332098.

Comorbid disorders as moderators of response to family interventions among adolescents with bipolar disorder.

BACKGROUND: While family interventions have shown efficacy in improving mood symptoms and family functioning in pediatric bipolar disorder, few studies have examined the effects of comorbid psychiatric conditions on patients' symptomatic or functional responses to treatment. METHODS: 145 adolescents with bipolar I or II disorder were randomly assigned to family-focused therapy (FFT-A) or a brief psychoeducational therapy (enhanced care; EC) and followed over 2 years. Participants received pharmacotherapy for the study's duration. We examined whether comorbid anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and disruptive behavior disorders (DBDs; i.e., oppositional defiant and conduct disorder) predicted the proportion of weeks that participants experienced mood symptoms during follow-up, and whether comorbid disorders moderated the effects of treatment assignment on mood symptoms and family conflict. RESULTS: Comorbid anxiety was associated with a greater proportion of weeks with depressive symptoms, more severe (hypo)manic symptoms during follow-up, and greater family conflict over the 2-year study. Comorbid ADHD was associated with a greater proportion of weeks with (hypo)manic symptoms, more severe (hypo)manic symptoms, and greater family conflict. Additionally, youth with comorbid ADHD who received FFT-A had more favorable trajectories of (hypo)manic symptoms and family functioning than youth with comorbid ADHD who received EC. Comorbid DBDs were consistently associated with more severe depressive symptoms and greater family conflict throughout the study. LIMITATIONS: Randomization to treatments was not stratified on comorbid disorders. The longitudinal trajectories of anxiety, attentional, and disruptive behavior symptoms were not examined. CONCLUSIONS: The course of bipolar disorder in adolescents is strongly affected by comorbid disorders. Future research should examine whether adolescents with more complex presentations of bipolar disorder should be treated with different or more intensive psychosocial protocols than adolescents without these presentations.

Lithium for the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Discontinuation Study.

OBJECTIVE: This study examined the role of lithium in the maintenance treatment of pediatric patients with bipolar I disorder (BP-I). METHOD: Participants aged 7 to 17 years who presented with a manic or mixed episode received 24 weeks of lithium treatment in one of two multiphase studies, the Collaborative Lithium Trials (CoLT 1 and CoLT 2). Responders were randomized to continue lithium or to be cross-titrated to placebo for up to 28 weeks. The primary outcome measure was relative risk of study discontinuation for any reason. RESULTS: A Cox regression analysis found that those who continued treatment with lithium (n = 17) had a lower hazard ratio compared to those who received placebo (n = 14) (p = .015)]. The vast majority of discontinuations were due to mood symptom exacerbations, with most of these occurring in the placebo-treated group. Discontinuation for other reasons occurred at similarly low rates across both group. Most adverse events were mild to moderate in severity, and only one study participant was discontinued from the trial owing to a serious adverse event (aggression). There was no statistically significant difference with respect to weight gain in participants receiving lithium compared to those receiving placebo. CONCLUSION: This randomized, double-blind, placebo-controlled Discontinuation Trial builds support for the role of lithium as a maintenance treatment in pediatric patients with bipolar disorder and for the safety and tolerability of 28 weeks of maintenance lithium treatment. CLINICAL TRIAL REGISTRATION INFORMATION: Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT00442039 (CoLT 1). Safety and Efficacy Study of Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT01166425 (CoLT 2).

Mood instability as a predictor of clinical and functional outcomes in adolescents with bipolar I and bipolar II disorder.

BACKGROUND: Traditional assessment and treatment of bipolar disorder (BD) often overlooks an important feature of the illness, mood instability (MI). MI - the presence of intense, rapidly shifting emotional states - is associated with a number of poor prognostic outcomes. This study examined whether MI among adolescents with BD was cross-sectionally related to bipolar subtype (I vs. II) and prognostically associated with symptoms and functioning over 3 months. METHODS: Participants included 145 adolescents (mean age: 15.6 years ±â€¯1.4) with BD I or II with a mood episode in the previous 3 months. Depression and (hypo)mania instability were computed using the root mean square successive difference (rMSSD) score, reflecting both the size and temporal order of changes in weekly depression and (hypo)mania scores (over 12 weeks) from the Adolescent Longitudinal Interval Follow-Up Evaluation. RESULTS: Greater depression instability was associated with BD II, whereas greater (hypo)mania instability was associated with BD I. Baseline MI, particularly depression, predicted more instability, a higher percentage of weeks in a clinical mood state, and poorer global functioning over 3 months, even when covarying concurrent mood severity scores. LIMITATIONS: The clinical measure of symptoms used retrospective reports of clinically significant symptoms only. We were unable to standardize medication use or adherence. CONCLUSIONS: MI differs by diagnostic subtype, is relatively stable over time, and predicts clinical and functional outcomes. Targeting MI should be considered a clinical focus to augment traditional methods of assessing and treating BD during adolescence to enhance clinical and functional outcomes.

Decreased functional connectivity in the fronto-parietal network in children with mood disorders compared to children with dyslexia during rest: An fMRI study.

Background: The DSM-5 separates the diagnostic criteria for mood and behavioral disorders. Both types of disorders share neurocognitive deficits of executive function and reading difficulties in childhood. Children with dyslexia also have executive function deficits, revealing a role of executive function circuitry in reading. The aim of the current study is to determine whether there is a significant relationship of functional connectivity within the fronto-parietal and cingulo-opercular cognitive control networks to reading measures for children with mood disorders, behavioral disorders, dyslexia, and healthy controls (HC). Method: Behavioral reading measures of phonological awareness, decoding, and orthography were collected. Resting state fMRI data were collected, preprocessed, and then analyzed for functional connectivity. Differences in the reading measures were tested for significance among the groups. Global efficiency (GE) measures were also tested for correlation with reading measures in 40 children with various disorders and 17 HCs. Results: Significant differences were found between the four groups on all reading measures. Relative to HCs and children with mood disorders or behavior disorders, children with dyslexia as a primary diagnosis scored significantly lower on all three reading measures. Children with mood disorders scored significantly lower than controls on a test of phonological awareness. Phonological awareness deficits correlated with reduced resting state functional connectivity MRI (rsfcMRI) in the cingulo-opercular network for children with dyslexia. A significant difference was also found in fronto-parietal global efficiency in children with mood disorders relative to the other three groups. We also found a significant difference in cingulo-opercular global efficiency in children with mood disorders relative to the Dyslexia and Control groups. However, none of these differences correlate significantly with reading measures. Conclusions/significance: Reading difficulties involve abnormalities in different cognitive control networks in children with dyslexia compared to children with mood disorders. Findings of the current study suggest increased functional connectivity of one cognitive control network may compensate for reduced functional connectivity in the other network in children with mood disorders. These findings provide guidance to clinical professionals for design of interventions tailored for children suffering from reading difficulties originating from different pathologies.

Olanzapine versus placebo in the treatment of adolescents with bipolar mania.

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of olanzapine for the treatment of acute manic or mixed episodes associated with bipolar disorder in adolescents. METHOD: A 3-week multicenter, parallel, double-blind, randomized placebo-controlled trial was conducted at 24 sites in the United States and two sites in Puerto Rico. The participants were outpatient and inpatient male and female adolescents 13-17 years of age with an acute manic or mixed episode. Subjects received either olanzapine (2.5-20 mg/day [N=107]) or placebo (N=54). The mean change from baseline to endpoint in the Young Mania Rating Scale total score was the primary outcome measure. RESULTS: The mean baseline-to-endpoint change in the Young Mania Rating Scale total score was significantly greater for patients receiving olanzapine relative to patients receiving placebo, and a greater proportion of olanzapine-treated patients met response and remission criteria (44.8% versus 18.5% and 35.2% versus 11.1%, respectively). The mean baseline-to-endpoint weight change was significantly greater for patients receiving olanzapine relative to patients receiving placebo (3.7 kg versus 0.3 kg), and the incidence of treatment-emergent weight gain > or =7% of baseline was higher for olanzapine-treated patients (41.9% versus 1.9%). The mean baseline-to-endpoint changes in prolactin, fasting glucose, fasting total cholesterol, uric acid, and the hepatic enzymes aspartate transaminase and alanine transaminase were significantly greater in patients treated with olanzapine relative to patients receiving placebo. CONCLUSIONS: Olanzapine was effective in the treatment of bipolar mania in adolescent patients. Patients treated with olanzapine, however, had significantly greater weight gain and increases in the levels of hepatic enzymes, prolactin, fasting glucose, fasting total cholesterol, and uric acid.