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Background: Multiple clinical trials of modern antipsychotics have failed in pediatric samples. One possibility for these failures is the use of a primary outcome measure that was developed for adults. Surprisingly, the psychometric properties of primary outcome measures have never been reported for a pediatric sample using modern methods. The present study’s aim is to use a pediatric sample to evaluate the psychometrics of the most used primary outcome measure in pediatric schizophrenia trials, the Positive and Negative Syndrome Scale (PANSS). Methods: To evaluate the factor structure, item characteristics, and treatment sensitivity of the PANSS in a pediatric sample, secondary analyses of PANSS data at baseline and weekly throughout an 8-week randomized double-blind study of three antipsychotic agents (registered and previously published) were conducted. Subjects were 118 youths receiving outpatient psychiatric treatment for schizophrenia spectrum disorders (Mage=14.26(2.41) years). Outcomes: A 10-item short form, keeping two strongest items for each factor, had r=.89 with the full-length scale. Each of the 5 2-item subscales has alphas ranging from .66 to .84. Item Response Theory (IRT) found that the 10-item scale and 2-item subscores had high reliability across the severity range typical of clinical trials. Criterion validity was high, with equal sensitivity to treatment effects. Interpretation: The short version eliminates weaker items in the pediatric population without loss of sensitivity to treatment effects and thus may be more appropriate for subsequent pediatric trials. Funding: NIMH funded the original protocol; NDA archived the data; Signant paid for secondary statistical analyses. Declaration of Interest: Dr. Findling receives or has received research support, acted as a consultant and/or has received honoraria from Acadia, Adamas, Aevi, Afecta, Akili, Alkermes, Allergan, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Arbor, Axsome, Daiichi-Sankyo, Emelex, Gedeon Richter, Genentech, Idorsia, Intra-Cellular Therapies, Kempharm, Luminopia, Lundbeck, MedAvante-ProPhase, Merck, MJH Life Sciences,NIH, Neurim, Otsuka, PaxMedica, PCORI, Pfizer, Physicians Postgraduate Press, Q BioMed, Receptor Life Sciences, Roche, Sage, Signant Health, Sunovion, Supernus Pharmaceuticals, Syneos, Syneurx, Takeda, Teva, Tris, and Validus. Dr. Youngstrom has received royalties from the American Psychological Association and Guilford Press, consulted with Signant Health about psychological assessment, and received funding from NIMH. He is the founder and Executive Director of Helping Give Away Psychological Science (HGAPS.org). Dr. Sikich receives or has received research support from NIMH, NICHD, and Roche. She has received partial salary support from Tris. She has a patent submission through Duke University for a new formulation of intranasal oxytocin. Dr. Frazier receives or has received funding from NIMH, NICHD, Autism Speaks, Roche pharmaceuticals, and Fulcrum. Dr. McClellan receives or has received funding from NIMH. Dr. Daniel is an employee and equity holder in Signant Health. Dr. Busner is an employee and equity holder in Signant Health. Ethical Approval: The secondary analyses were reviewed and approved by the UNC Chapel Hill IRB.

Impairing emotional outbursts, defined by extreme anger or distress in response to relatively ordinary frustrations and disappointments, impact all mental health care systems, emergency departments, schools, and juvenile justice programs. However, the prevalence, outcome, and impact of outbursts are difficult to quantify because they are transdiagnostic and not explicitly defined by current diagnostic nosology. Research variably addresses outbursts under the rubrics of tantrums, anger, irritability, aggression, rage attacks, or emotional and behavioral dysregulation. Consistent methods for identifying and assessing impairing emotional outbursts across development or systems of care are lacking.The American Academy of Child and Adolescent Psychiatry Presidential Task Force (2019-2021) conducted a narrative review addressing impairing emotional outbursts within the limitations of the existing literature and independent of diagnosis.Extrapolating from the existing literature, best estimates suggest that outbursts occur in 4%-10% of community children (preschoolers through adolescents). Impairing emotional outbursts may respond to successful treatment of the primary disorder, especially for some children with attention-deficit/hyperactivity disorder whose medications have been optimized. However, outbursts are generally multi-determined and often represent maladaptive or deficient coping strategies and responses.Evidence-based strategies are necessary to address factors that trigger, reinforce, or excuse the behaviors and to enhance problem-solving skills. Currently available interventions yield only modest effect sizes for treatment effect. More specific definitions and measures are needed to track and quantify outbursts and to design and assess the effectiveness of interventions. Better treatments are clearly needed.

Identifying substance use disorders (SUDs) early and accurately improves case formulation and treatment. Previous studies have investigated validity and reliability of the Child and Adolescent Symptom Inventory (CASI) for anxiety, mood, and behavior problems. The present study's aim was to test if the embedded CASI Substance Use (SU) subscale can discriminate adolescents and young adults (AYA) with and without a SUD diagnosis accurately enough to justify clinical application within an evidence-based assessment framework.

Objectives: Irritability and anhedonia are cardinal symptoms of depression for children and adolescents. However, anhedonia may be more strongly associated with illness severity compared with irritability. The present study evaluated the impact of irritability and anhedonia on symptom severity and functional impairment among depressed children and adolescents. Methods: Participants were 383 children and adolescents presenting for outpatient treatment at a community mental health center or academic medical center. Children and adolescents were diagnosed with unipolar depression or bipolar disorder. Regression models predicted depression severity and functional impairment from irritability and anhedonia after covarying age, gender, depressive and hypomanic symptoms, and diagnosis. Results: Greater irritability and anhedonia were associated with more severe depression symptoms. Greater irritability, but not anhedonia, was associated with lower global functioning and family quality of life (QoL), and more externalizing problems. Greater anhedonia was associated with lower overall, emotional, self-esteem, and social QoL. Neither irritability nor anhedonia was associated with school or physical QoL, nonsuicidal self-injury, suicidal ideation, number of comorbid diagnoses, or internalizing problems. Conclusions: Irritability was associated with more markers of depression severity, whereas anhedonia was associated with indicators of functional impairment. This study used a cross-sectional observational design and therefore cannot provide information about cause and effect relationships between variables. Irritability and anhedonia were derived from their respective subscales of the General Behavior Inventory and included only caregiver-reported symptoms but not child- or adolescent-reported symptoms. Identifying the impact of specific symptoms of depression may assist clinicians in delivering more individualized interventions to target symptoms that result in greater impairment.

Although hopelessness has been linked to depression for centuries, the diagnostic criteria for depression are inconsistent with regard to the status of hopelessness. Most research on hopelessness and depression has focused on adults. The current study examined this relation in children and adolescents. Integrative data analyses with a pooled sample (N = 2466) showed that clinical levels of hopelessness multiplied the odds of having a clinical diagnosis of depression 10-fold. Conversely, not having clinical levels of hopelessness multiplied the odds of endorsing no clinical level of depressive symptoms 28-fold. Moreover, results differed by levels of depression: (a) among youths with clinical levels of depression, hopelessness was associated with six depressive symptoms; (b) among youths without clinical levels of depression, hopelessness was associated with nine depressive symptoms. We found that hopelessness helps to explain the heterogeneity of depressive presentations. Our finding supports the consideration of hopelessness in the diagnosis (if not treatment and prevention) of depression in children and adolescents. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

biObjective:/i/bTo describe the longer-term effectiveness, safety, and tolerability of open-label ziprasidone in children and adolescents with bipolar I disorder (BD-I).biMethods:/i/bA subset of 23 participants aged 10-17 years, who were previously treated in a multi-site, 4-week randomized controlled trial received open-label ziprasidone (20-80 mg twice a day) for up to 26 weeks.biResults:/i/bThe most common adverse events (AEs) were fatigue (30%), somnolence (17%), and nausea (13%). Effects on weight, body mass index, and metabolic parameters (glucose, cholesterol, and triglycerides) were minimal. No participant had a Fridericia-corrected QT interval ≥ 460 msec or a change from baseline of ≥60 msec, and there were no cardiac-related AEs. Both the participants who continued ziprasidone and those who initiated ziprasidone in the open-label extension showed improvements in their symptoms of mania.biConclusions:/i/bThe overall findings of the study are consistent with the accumulating knowledge on the safety profile of ziprasidone in the acute and long-term treatment of children and adolescents with BD-I, in the midst of a manic episode. ClinicalTrial.gov ID: NCT03768726.

Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

Supplemental digital content is available in the text., Purpose This phase 3 clinical trial evaluated the efficacy and safety of viloxazine extended-release capsules (VLX-ER) as a monotherapy for attention-deficit/hyperactivity disorder (ADHD) in adolescents (12–17 years). Methods Eligible subjects (n = 310) were randomized to receive once-daily 200 and 400 mg VLX-ER, or placebo for 6 weeks. The primary efficacy end point was change from baseline (CFB) at the end of study (EOS) in ADHD Rating Scale-5 Total score. Key secondary end points were Clinical Global Impression—Improvement score at EOS, CFB at EOS in Conners 3—Parent Short Form Composite T-score, and CFB at EOS in Weiss Functional Impairment Rating Scale—Parent Total average score. Results In the 200-mg/d and 400-mg/d VLX-ER treatment groups, a significant improvement was found in the CFB at EOS in ADHD Rating Scale-5 Total (P = 0.0232, P = 0.0091) and Inattention (P = 0.0424, P = 0.0390) and Hyperactivity/Impulsivity (P = 0.0069, P = 0.0005) subscale scores versus placebo. The Clinical Global Impression—Improvement score was significantly improved at EOS in the 200-mg/d and 400-mg/d VLX-ER groups versus placebo (P = 0.0042, P = 0.0003). The Conners 3—Parent Short Form composite T-score and Weiss Functional Impairment Rating Scale—Parent Total average score exhibited improvement in both VLX-ER groups; however, the difference versus placebo was not statistically significant. The most common treatment-related adverse events were somnolence, headache, decreased appetite, nausea, and fatigue. The adverse event–related discontinuation rates were

Neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention-deficit/hyper-activity disorder (ADHD), represent a group of conditions that manifest early in child development and produce impairments across multiple domains of functioning. Although a number of pharmacological and psychosocial treatments exist to improve the symptoms associated with these syndromes, treatment advances have lagged. The Precision Medicine Initiative was launched with the goal of revolutionizing medicine by progressing beyond the historical one-size-fits-all approach. In this review, we evaluate current research efforts to personalize treatments for ASD and ADHD. Most pharmacogenetic testing has focused on the cytochrome P450 enzyme family with a particular focus on CYP2D6 and CYP2C19 , which are genes that produce an enzyme that acts as a key metabolizer of many prescribed medications. This article provides an update on the state of the field of pharmacogenetics and “therapy-genetics” in the context of ASD and ADHD, and it also encourages clinicians to follow US Food and Drug Administration recommendations regarding pharmacogenetic testing. [ Psychiatr Ann . 2021;50(4):175–184.]

Rates of treatment utilization decline as adolescents make the transition to adulthood even though young adults are particularly vulnerable to the negative outcomes of untreated mental illness. Although a variety of factors have been explored to explain decreased treatment utilization in this age group, previous research has almost exclusively employed cross-sectional methods rather than following a group of youth as they enter adulthood. The current study aims to address this methodological limitation by assessing treatment utilization in emerging adults who began participating in a longitudinal study during childhood. One hundred and thirty seven youth who turned 18 during the 96-month follow-up period were included in the current analyses. Demographic and socioeconomic variables such as sex, race, and insurance status and clinical variables such as psychiatric diagnoses and perceptions of treatment effectiveness were investigated as factors potentially associated with outpatient treatment use before and after age 18. Prior to age 18, youth reported using outpatient services at 75% of their visits, but after age 18, outpatient treatment utilization dropped to around 50%. White race, increased parental stress, and increased parental perception of treatment usefulness were associated with greater treatment use prior to age 18, whereas only increased youth perception of symptom-related dysfunction were associated with increased treatment use after age 18. Findings point to the importance of including youth preferences and perceptions of dysfunction in treatment decisions across adolescence in order to optimize treatment use following the transition to adulthood.

It is vital to identify substance use disorders (SUDs) in youths and adults early and accurately. Previous studies have investigated the validity and reliability of the Achenbach Child Behavior Checklist (CBCL) and Youth Self Report (YSR) for other related anxiety, mood, and behavior problems. The present study tested if the CBCL and YSR substance use items can discriminate adolescents with versus without a SUD diagnosis accurately enough to justify clinical application within an evidence-based assessment framework.

BackgroundMinimal long-term benefit: Risk data are available regarding antipsychotic treatments for schizophrenia in pediatric populations. This study evaluated the long-term safety, tolerability, and effectiveness of lurasidone in adolescents with schizophrenia.MethodsPatients aged from 13 to 17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose (20-80 mg/day) lurasidone treatment study. Safety was assessed via spontaneous reporting, rating scales, body weight measurement, metabolic, and prolactin testing. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score.ResultsAbout 271 patients completed 6 weeks of DB treatment and entered the 2-year OL extension study. Altogether, 42.4% discontinued prematurely, 10.7% due to adverse events. During OL treatment, the most common adverse events were headache (24.0%); anxiety (12.9%), schizophrenia, and nausea (12.5%); sedation/somnolence (12.2%); and nasopharyngitis (8.9%). Minimal changes were observed on metabolic parameters and prolactin. Mean change from DB baseline in weight at week 52 and week 104 was +3.3 kg and + 4.9 kg, respectively, compared to an expected weight gain of +3.4 kg and + 5.7 kg, respectively, based on the sex- and age-matched US Center for Disease Control normative data. Continued improvement was observed in PANSS total score, with mean change from OL baseline of −15.6 at week 52 and −18.4 at week 104.ConclusionIn adolescents with schizophrenia, long-term lurasidone treatment was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin. Continued improvement in symptoms of schizophrenia was observed over 2 years of lurasidone treatment.

Objective: To evaluate the efficacy and long-term safety of vilazodone in children and adolescent outpatients with major depressive disorder (MDD). Methods: Children and adolescents aged 7–17 years of age with MDD were randomized 2:2:1 to 8 weeks of double-blind placebo, vilazodone 15 or 30 mg/day or fluoxetine 20 mg/day, respectively. The primary and secondary efficacy outcomes, respectively, were change from baseline to week 8 in Children's Depression Rating Scale-Revised (CDRS-R) score total score and Clinical Global Impressions-Severity (CGI-S) score analyzed using a mixed model for repeated measurement approach. Patients who completed the 8-week randomized controlled trial (RCT), as well as new (de novo) patients, could participate in a 26-week, vilazodone-only, open-label extension (OLE) study. Results: The RCT enrolled 473 patients (60% female) with an average age of 13 years. Change in CDRS-R and CGI-S scores from baseline to week 8 did not differ between patients who received vilazodone and those randomized to placebo. The least-squares mean change from baseline in CDRS-R scores was similar for vilazodone and placebo (−20.7 vs. −20.3, p = 0.77; least-squares mean difference [LSMD] = −0.40). For fluoxetine, the LSMD versus placebo was −2.3 (p = 0.14). The OLE enrolled 330 patients (60% female) with an average age of 13–14 years. Overall, no new safety concerns were identified compared to what is known in adults. Conclusions: Similar improvements in depressive symptoms were observed in all arms. This study does not support the efficacy of vilazodone 15 or 30 mg/day for pediatric patients with MDD. No new or unexpected safety concerns were detected during the RCT or OLE studies.

Background Despite the well-documented negative impact of untreated bipolar illness, approaches to early intervention in childhood-onset bipolar and related disorders are not well delineated. Methods We reviewed the extant treatment literature on children at high risk for bipolar disorder, with definitions based on family history, childhood adversity, and prodromal symptoms. Results A panoply of approaches have been described, but most interventions are based on an inadequate database to support their routine implementation. We classify early stage interventions as a function of their safety and tolerability with the hope that these might generate more rigorous study and a stronger database. Limitations Critics may rightly argue that identifying viable treatment methods is premature given our lack of ability to reliably predict illness trajectory in very young children. However, many of the psychosocial and pharmacological interventions we present could have nonspecific positive effects across a variety of symptoms, syndromes, and diagnoses, further enhancing the rationale for more rigorous study. Conclusions Early stage interventions have the potential to improve functioning in prodromal illness and exert long-term positive effects on the course of illness. Many of the safest interventions deserve consideration for implementation and dissemination studies.

Objective Previous studies of Tai Chi or mindfulness-based interventions in attention-deficit/hyperactivity disorder (ADHD) have relied on self- or parent-reported outcome measures; however, there is a critical need for the validation of objective biomarkers of treatment. Therefore, we implemented a mindful movement intervention for children with ADHD, hypothesizing that an ADHD-relevant motor control measure could serve as a predictive biomarker of treatment-related improvement. Methods Thirty-four participants were included, 8 to 12 year olds diagnosed with DSM-5 ADHD. Participants engaged in the mindful movement treatment, an 8-week program with 2 classes a week for 60 minutes. At pre- and post-treatment, ADHD symptoms and associated impairment and motor control via the Physical and Neurological Examination for Subtle Signs (PANESS) were assessed. Results The results showed a significant reduction for PANESS Gaits and Station (p ≤ 0.001), total overflow (p = 0.009), and total score (p = 0.001) after treatment, with the largest effect for Gaits and Stations. The results also showed a significant reduction in symptoms of inattention (p ≤ 0.001), hyperactivity/impulsivity (p ≤ 0.001), oppositional defiant disorder (p = 0.001), and executive dysfunction (p ≤ 0.001). There were significant positive correlations between change in PANESS Gaits and Stations and change in both inattentive (p = 0.02) and hyperactive/impulsive symptoms (p = 0.02). There was also a significant positive correlation between change in the PANESS total score and change in inattentive (p = 0.007) and hyperactive/impulsive symptoms (p = 0.042). The change in the PANESS total score (β = 0.295, p = 0.002) predicted post-treatment ADHD severity above the change in inattentive or hyperactive/impulsive symptoms. Conclusion The results suggest the effectiveness of a mindful movement treatment on ADHD symptoms and suggest the PANESS as a candidate motor biomarker for future mindful movement trials. Clinical trial registration ClinicalTrials.gov, NCT02234557, https://clinicaltrials.gov/ct2/show/NCT02234557.

Objectives: Describe the safety and tolerability of lisdexamfetamine dimesylate (LDX) and provide data on clinical effects for efficacy-related endpoints and pharmacokinetics in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD). Methods: This phase 2, multicenter, open-label, dose-optimization study (ClinicalTrials.gov registry: NCT02402166) was conducted at seven U.S. sites between April 15, 2015, and June 30, 2016. Children (4–5 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for ADHD and having ADHD Rating Scale-IV Preschool version (ADHD-RS-IV-PS) total scores ≥28 (boys) or ≥24 (girls) were eligible. Open-label LDX (8-week duration) was initiated at 5 mg and titrated to 30 mg until achieving an optimal dose. Assessments included treatment-emergent adverse events (TEAEs), vital sign changes, ADHD-RS-IV-PS total score changes, and pharmacokinetic evaluations. Results: Among 24 participants, the most frequently reported TEAE was decreased appetite (8/24; 33%). At week 8/early termination, mean (standard deviation) systolic and diastolic blood pressure and pulse changes from baseline were −1.1 (7.31) and 1.5 (6.93) mmHg and −0.8 (12.75) bpm, respectively. The mean (95% confidence interval) change from baseline ADHD-RS-IV-PS total score at the final on-treatment assessment was −26.1 (−32.2 to −20.0). Pharmacokinetic parameters of d-amphetamine, a major active metabolite of LDX, were characterized: d-amphetamine exposure increased with LDX dose; mean tmax and t1/2, respectively, ranged from 4.00 to 4.23 hours and 7.18 to 8.46 hours. Conclusions: In preschool-aged children with ADHD, LDX was generally well tolerated and reduced ADHD symptoms, consistent with observations in children 6–17 years of age. Based on these findings, a starting LDX dose as low as 5 mg in phase 3 studies in preschool-aged children is supported.

Schizophrenia is a leading cause of disease burden in youth and can significantly impair an adolescent’s peer and familial relationships and academic functioning. Therefore, safe and effective treatments are needed. This article reviews the pharmacological treatment of adolescents with schizophrenia, when possible, with a focus on the past five years of research. There are relatively few randomized controlled trials (RCTs) and head-to-head trials informing selection of a medication in pediatric schizophrenia. However, recent literature focusing on the efficacy and tolerability of atypical antipsychotics has led to the Food and Drug Administration (FDA) approval of multiple agents, specifically risperidone, olanzapine, quetiapine, aripiprazole, paliperidone, and lurasidone, for the treatment of pediatric schizophrenia. Asenapine has also been studied in a large RCT within the past five years, but participants randomized to asenapine treatment did not do statistically significantly better than those assigned to receive placebo. Comparison RCTs on clozapine have indicated benefit in treatment-resistant pediatric schizophrenia, but at the cost of significant side effect burden. Common adverse events with atypical antipsychotics include weight gain, akathisia, hyperprolactinemia, and somnolence. Atypical antipsychotics remain first-line treatment for children and adolescents with early onset schizophrenia. However, further study is required to develop more effective and better tolerated treatment options, and in addition to pharmacologic management, current guidelines recommend combination treatment with psychotherapy and psychoeducation.

Objective: To explore blinded observational outcomes in the Treatment of Severe Childhood Aggression (TOSCA) study. Methods: During a 9-week acute trial, children with severe physical aggression and attention-deficit/hyperactivity disorder received parent training + titrated psychostimulant for 3 weeks, and those who failed to show an optimal response during Week 4 through Week 6 received in addition either randomly assigned placebo (Basic treatment) or titrated risperidone (Augmented treatment). Child and parent behaviors were videotaped in a Standardized Observation Analogue Procedure (SOAP) designed to elicit problems and strengths in child and parent interactions. SOAPs were collected at baseline and Week 9 and 52 follow-up. Results: During the acute 9-week trial, augmented treatment was associated with better outcomes than basic treatment for 3 of 13 measures: increased Child Compliance (p = 0.004; significant after correction for multiple tests), greater use of positive Parent Reinforcement (p = 0.03), and more Shared Enjoyment (p = 0.04). At follow-up, when medication was no longer by randomized assignment, parents used more Alpha Commands and displayed fewer Parent Negative Behaviors, and the dyads showed more Shared Enjoyment regardless of original randomization. Thus, there were better parent-child interactions with Augmented treatment, and interactions improved overall at follow-up regardless of original treatment assignment. Conclusions: The SOAP demonstrated sensitivity to behavior changes between short-term treatments for a few (but not most) measures. The acute treatment differences for Child Compliance and Child Negative Behavior are generally consistent with the moderate superiority of Augmented over Basic treatment previously reported for the primary study outcome.

An increasing number of antipsychotic medications have demonstrated efficacy in randomized placebo-controlled trials in the treatment of children and adolescents with schizophrenia. This review summarizes and synthesizes relevant antipsychotic medication studies, with particular emphasis on second-generation agents, and discusses other clinical considerations that may influence medication selection. With the exception of clozapine demonstrating superior efficacy in the improvement of psychotic symptoms in treatment-resistant patients, many antipsychotic agents have been shown to be similarly efficacious, including first-generation medications. Consideration of the side-effect profile, which can differ substantially from medication to medication, is essential when choosing treatment options.

Approximately 60% of patients with bipolar disorder who present with depression are misdiagnosed as having recurrent unipolar depression, which may lead to inappropriate treatment and potential worsening of symptoms. Bipolar depression in youth has a negative effect on numerous domains of life. Early treatment is crucial, yet diagnosis is difficult. The standard of treatment often requires life-long psychopharmacologic management, and treatments have various adverse effects that should be considered when the clinician tailors the regimen for each patient. By facilitating effective communication with patients, referring to diagnostic criteria, and using assessment tools before diagnosis and as treatment continues, clinicians can identify indicators of the disorder, recommend individualized treatment, and help patients work toward greater success in relationships, at home, and at school or work.

To evaluate the efficacy and safety of vortioxetine in adolescents with major depressive disorder (MDD).After 4 weeks of single-blind lead-in treatment with a Brief Psychosocial Intervention (BPI) plus placebo, patients (aged 12-17 years) with MDD (DSM-5) who did not meet response criteria (Children's Depression Rating Scale-Revised [CDRS-R]; total score ≥40 plus 40% reduction and a Parent Global Assessment score2) were randomized 1:1:1:1 to 8 weeks of BPI plus double-blind treatment with vortioxetine 10 mg, vortioxetine 20 mg, fluoxetine 20 mg, or placebo. The primary endpoint was change from randomization in CDRS-R total score at week 8; the primary comparison was the average effect of 2 vortioxetine doses vs placebo.Of 784 patients enrolled in the lead-in, 616 were randomized. At week 8, the mean change in CDRS-R total score averaged for vortioxetine doses was -18.01 (SE = 0.98) and the mean difference vs placebo was 0.21 (P = .878; not significant). For fluoxetine, the mean change in CDRS-R total score was -21.95 and the mean difference vs placebo was -3.73 (P = .015). Treatment-emergent adverse events occurring in ≥5% of patients in either vortioxetine arm and at least twice more frequently than placebo were nausea, headache, vomiting, and dizziness.Patients in all groups showed reduction in CDRS-R scores by the end of the study, with no difference between combined doses of vortioxetine and placebo. The primary endpoint was not met, thereby rendering the study negative. The overall favorable safety profile of vortioxetine in an adolescent patient population was consistent with that seen in adults.Active Reference (Fluoxetine) Fixed-Dose Study of Vortioxetine in Paediatric Patients Aged 12 to 17 Years With Major Depressive Disorder (MDD); http://clinicaltrials.gov; NCT02709746.

Background Treatment of a child who has an anxiety disorder usually begins with the question of which treatment to start first, medication or psychotherapy. Both have strong empirical support, but few studies have compared their effectiveness head-to-head, and none has investigated what to do if the treatment tried first isn’t working well—whether to optimize the treatment already begun or to add the other treatment. Methods This is a single-blind Sequential Multiple Assignment Randomized Trial (SMART) of 24 weeks duration with two levels of randomization, one in each of two 12-week stages. In Stage 1, children will be randomized to fluoxetine or Coping Cat Cognitive Behavioral Therapy (CBT). In Stage 2, remitters will continue maintenance-level therapy with the single-modality treatment received in Stage 1. Non-remitters during the first 12 weeks of treatment will be randomized to either [1] optimization of their Stage 1 treatment, or [2] optimization of Stage 1 treatment and addition of the other intervention. After the 24-week trial, we will follow participants during open, naturalistic treatment to assess the durability of study treatment effects. Patients, 8–17 years of age who are diagnosed with an anxiety disorder, will be recruited and treated within 9 large clinical sites throughout greater Los Angeles. They will be predominantly underserved, ethnic minorities. The primary outcome measure will be the self-report score on the 41-item youth SCARED (Screen for Child Anxiety Related Disorders). An intent-to-treat analysis will compare youth randomized to fluoxetine first versus those randomized to CBT first (“Main Effect 1”). Then, among Stage 1 non-remitters, we will compare non-remitters randomized to optimization of their Stage 1 monotherapy versus non-remitters randomized to combination treatment (“Main Effect 2”). The interaction of these main effects will assess whether one of the 4 treatment sequences (CBT➔CBT; CBT➔med; med➔med; med➔CBT) in non-remitters is significantly better or worse than predicted from main effects alone. Discussion Findings from this SMART study will identify treatment sequences that optimize outcomes in ethnically diverse pediatric patients from underserved low- and middle-income households who have anxiety disorders. Trial registration This protocol, version 1.0, was registered in ClinicalTrials.gov on February 17, 2021 with Identifier: NCT04760275.

Bipolar depression in youth has a negative effect on numerous domains, including physical and emotional well-being, school and family functioning, friendships, and academic success. Early treatment is crucial, yet diagnosis is difficult. The standard of treatment often requires life-long psychopharmacological management, and most treatments increase risk of adverse effects. Pediatric patients who have at least 1 parent with bipolar disorder are considered to be at higher risk for also developing bipolar depression, although there is currently no clear evidence of efficacious pharmacotherapy for these patients.

Objective: To establish the validity and reliability of a provisional 30-item impulsive aggression (IA) diary in children (ages 6–12 years, inclusive) with attention-deficit/hyperactivity disorder (ADHD). Methods: The provisional 30-item IA diary was administered for 14 days to parents of children with ADHD and IA symptoms (n = 103). Key inclusion criteria: confirmed ADHD diagnosis; signs of IA as measured by a Retrospective-Modified Overt Aggression Scale (R-MOAS) score ≥20 and an Aggression Questionnaire score of −2 to −5. Analyses included inter-item correlations, exploratory factor analysis (EFA), item response theory (IRT) modeling, internal consistency, test–retest reliability (TRT), concurrent validity (estimated by correlation between the IA diary and the R-MOAS/Nisonger Child Behavior Rating Form), and known-groups methods. Results: The prevalence rates of 15 (50.0%) items were found to be too low (

Objective To examine development of bipolar spectrum disorders (BPSD) and other disorders in prospectively followed children with attention-deficit/hyperactivity disorder (ADHD). Method In the Longitudinal Assessment of Manic Symptoms (LAMS) study, 531 of 685 children age 6-12 (most selected for scores > 12 on General Behavior Inventory 10-item Mania scale) had ADHD, 112 with BPSD, and 419 without. With annual assessments for 8 years, retention averaged 6.2 years. Chi-square analyses compared rate of new BPSD and other comorbidity between those with versus without baseline ADHD and between retained versus resolved ADHD diagnosis. Cox regression tested factors influencing speed of BPSD onset. Results Of 419 with baseline ADHD but not BPSD, 52 (12.4%) developed BPSD, compared with 16 of 110 (14.5%) without either baseline diagnosis. Those who developed BPSD had more nonmood comorbidity over the follow-up than those who did not develop BPSD (p = .0001). Of 170 who still had ADHD at eight-year follow-up (and not baseline BPSD), 26 (15.3%) had developed BPSD, compared with 16 of 186 (8.6%) who had ADHD without BPSD at baseline but lost the ADHD diagnosis (χ2 = 3.82, p = .051). There was no statistical difference in whether ADHD persisted or not across new BPSD subtypes (χ2 = 1.62, p = .446). Of those who developed BPSD, speed of onset was not significantly related to baseline ADHD (p = .566), baseline anxiety (p = .121), baseline depression (p = .185), baseline disruptive behavior disorder (p = .184), age (B = -.11 p = .092), maternal mania (p = .389), or paternal mania (B = .73, p = .056). Those who started with both diagnoses had more severe symptoms/impairment than those with later developed BPSD and reported having ADHD first. Conclusions In a cohort selected for symptoms of mania at age 6-12, baseline ADHD was not a significant prospective risk factor for developing BPSD. However, persistence of ADHD may marginally mediate risk of BPSD, and early comorbidity of both diagnoses increases severity/impairment.

Objectives: The purpose of this pilot study was to evaluate changes in adiposity, carotid intima media thickness (CIMT), and hepatic fat content measured via magnetic resonance imaging-estimated hepatic proton density fat fraction (PDFF) in antipsychotic (AP)-treated youth versus nonpsychiatric (NP) participants during participation in a 16-week behavioral weight loss (BWL) intervention. Subjects/Methods: Overweight/obese AP-treated youth (n = 26) were randomized 2:1 to weekly treatment versus recommended care (RC) over 16 weeks. NP controls (n = 21) were assigned to weekly treatment. Dual-energy X-ray absorptiometry (DEXA)-measured adiposity, CIMT, and PDFF were measured at baseline and 16 weeks. Analyses assessed group differences in the effect of BWL on adiposity, CIMT, and PDFF. Results: BWL was well tolerated in both AP-treated and NP groups. DEXA-measured fat decreased significantly in the NP group (F[1,16] = 11.81, p = 0.003), with modest improvements in adiposity and hepatic fat in the AP-treated group, while an increase in adiposity was observed in the RC group. Significant differences in endpoint DEXA total fat (F[2,34] = 4.81, p = 0.01) and PDFF (F[2,30] = 3.60, p = 0.04) occurred across treatment groups, explained by larger improvements in NP versus RC youth in DEXA total fat (p = 0.03) and PDFF (p = 0.04). Conclusions: Intensive, family-based BWL treatment can improve whole-body adiposity and liver fat in obese youth, with decreases or attenuation of additional fat gain observed in AP-treated youth.

Objectives: We examined the association of parent training (PT)-related factors with therapeutic success in the Treatment of Severe Childhood Aggression (TOSCA) study. Our aims were (1) to evaluate demographic and clinical characteristics as predictors of parent attendance and engagement in PT and (2) to examine the associations of parent attendance and engagement in PT with study-targeted child behavior outcomes (i.e., attention-deficit/hyperactivity disorder [ADHD] and disruptive behavior symptoms). TOSCA was a randomized clinical trial evaluating the effect of placebo versus risperidone when added to PT and psychostimulant for childhood ADHD with severe aggression. Methods: Data for 167 parents and children 6–12 years old with ADHD, oppositional defiant disorder (ODD) or conduct disorder, and severe physical aggression were examined. Analyses used generalized linear models. Results: Most parents (72%) attended seven or more of nine sessions. The average parental engagement, that is, the percentage of PT elements fully achieved across participants and sessions, was 85%. The average therapist rating of goal completion was 92%. Parents of non-white and/or Hispanic children (p = 0.01) and children with lower intelligence quotient (p = 0.02) had lower PT attendance; parents with lower family incomes (p = 0.01) were less engaged. Attendance and engagement predicted better scores on the primary child behavior outcomes of disruptive behavior (Nisonger Child Behavior Rating Form Disruptive Behavior Total) and ADHD and ODD symptoms, adjusting for baseline severity. Conclusions: When the clinical picture is sufficiently severe to warrant prescribing an atypical antipsychotic, PT is feasible for families of children with ADHD and co-occurring severe aggression. The promotion of attendance and engagement in PT is important to enhance clinical outcomes among this challenging population. Methods for overcoming barriers to participation in PT deserve vigorous investigation, particularly for those with low family income, non-white race, Hispanic ethnicity, or when children have lower cognitive level.

Objective: A recent double-blind randomized placebo-controlled study demonstrated 3-month efficacy and safety of a novel pediatric-appropriate prolonged-release melatonin (PedPRM) for insomnia in children and adolescents with autism spectrum disorder (ASD) and neurogenetic disorders (NGD) with/without attention-deficit/hyperactivity disorder comorbidity. Long-term efficacy and safety of PedPRM treatment was studied. Methods: A prospective, open-label efficacy and safety follow-up of nightly 2, 5, or 10 mg PedPRM in subjects who completed the 13-week double-blind trial (51 PedPRM; 44 placebo). Measures included caregiver-reported Sleep and Nap Diary, Composite Sleep Disturbance Index (CSDI), caregiver's Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, and quality of life (WHO-5 Well-Being Index). Results: Ninety-five subjects (74.7% males; mean [standard deviation] age, 9 [4.24]; range, 2–17.5 years) received PedPRM (2/5 mg) according to the double-blind phase dose, for 39 weeks with optional dose adjustment (2, 5, or 10 mg/day) after the first 13 weeks. After 52 weeks of continuous treatment (PedPRM-randomized group) subjects slept (mean [SE]) 62.08 (21.5) minutes longer (p = 0.007); fell asleep 48.6 (10.2) minutes faster (p 50% decrease; p = 0.001); and better sleep quality (p

The use of atypical antipsychotic medications in pediatric patients has become more prevalent in recent years. The purpose of this review is to provide a clinically relevant update of recent selected key publications regarding the use of atypical antipsychotics in this population.Studies reviewed included randomized, double-blind, placebo-controlled medication trials conducted within the past 5 years. A PubMed search was conducted for each of the 11 second-generation antipsychotic medications currently approved by the Food and Drug Administration for use in the United States: clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, paliperidone, asenapine, iloperidone, lurasidone, and cariprazine. Trials published in English with subjects 18 years of age and younger were included in this review. Additional studies, chosen for their significance to clinical practice, were also included at the discretion of the authors.This review demonstrates that more empiric data are available regarding both the acute efficacy and, to a lesser extent, the longer-term efficacy and tolerability for several of the considered antipsychotic medications. The clinical conditions for which these medications have been studied include schizophrenia, bipolar disorder, Tourette's disorder, and autism spectrum disorder. They have also been used as an adjunctive treatment for disruptive behavior disorders with aggression, which have not responded to treatment with stimulants.Evidence regarding the efficacy and tolerability of antipsychotic medications for mental health disorders in children and adolescents has expanded exponentially in recent years. However, more information is needed so that evidence-based comparisons between medications can be made. In the future, data enabling the selection of medications based upon individual patient characteristics could potentially lead to greater efficacy and efficiency in treating what are frequently debilitating medical conditions. Maladaptive aggression in children, often treated with antipsychotics, is one such area in which there is a dearth of actual information available to the clinician. It is to be hoped that additional, longer-term studies of these medications will further inform evidence-based practice in clinical settings.

To evaluate the acute efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) vs placebo (PBO) in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD).This phase 3, double-blind, fixed-dose study randomly assigned children (aged 4-5 years) with ADHD to 6 weeks of LDX (5, 10, 20, 30 mg) or PBO. The prespecified primary (change from baseline at week 6 in ADHD Rating Scale IV, Preschool version, total score [ADHD-RS-IV-PS-TS]) and key secondary (Clinical Global Impression-Improvement [CGI-I] score at week 6) efficacy endpoints were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and changes in pulse and blood pressure (BP).The study comprised 199 participants randomly asigned 5:5:5:5:6 to receive 5, 10, 20, 30 mg LDX or PBO, respectively. Least squares (LS) mean (95% CI) treatment difference at week 6 between pooled LDX (10, 20, 30 mg) and PBO was statistically significant for ADHD-RS-IV-PS-TS change (-5.9 [-11.01, -0.78], p = .0242; effect size [ES], -0.43). CGI-I scores improved (ie, 1-2 on CGI-I) in 41.7% for pooled LDX and 24.3% for PBO (p = .0857). The LS mean (95% CI) treatment difference between pooled LDX and PBO for CGI-I score at week 6 was -0.6 (-1.03, -0.16; p = .0074; ES, -0.52). Frequency of TEAEs was 46.6% across all 4 LDX doses vs 42.2% with PBO; the most frequent TEAEs were decreased appetite (13.7% vs 8.9%, respectively) and irritability (9.6% vs 0%). Discontinuations because of TEAEs were 5.5% for all LDX doses and 4.4% for PBO. Mean ± SD pulse/BP changes from baseline at week 6/early termination were numerically greater with LDX vs PBO (pulse beats/min: 2.7 ± 10.79 vs 1.2 ± 9.90; systolic BP, mm Hg: 1.0 ± 7.51 vs 0.3 ± 6.06; diastolic BP, mm Hg: 1.7 ± 5.90 vs 0.0 ± 6.88).In children aged 4 to 5 years with ADHD, LDX was more efficacious than PBO in reducing symptoms. The observed ES for change in ADHD-RS-IV-PS-TS appears to be smaller in magnitude than has been reported for studies of LDX conducted in older children and adolescents. LDX was generally well tolerated, and no new safety signals were identified.Safety and Efficacy Study in Preschool Children Aged 4-5 Years With Attention-Deficit/Hyperactivity Disorder; http://www.gov; NCT03260205.

Objective To test differential prospective prediction of growth in externalizing behavior, including oppositional defiant disorder, conduct disorder, and substance use disorders, by earlier hyperactive-impulsive (HI) vs inattentive (IN) symptoms of attention-deficit/hyperactivity disorder (ADHD). Method Participants in the Longitudinal Assessment of Manic Symptoms (LAMS) Study (N = 685 at study entry), including 458 boys and 227 girls ages 6–12, completed full parent report and self-report assessments every year for 8 years on the Schedule for Affective Disorders and Schizophrenia for School-Age Children. Three sets of analyses were conducted. First, hierarchal regression (block entry) was used to test independent associations between HI symptoms and later externalizing outcomes, controlling for IN symptoms, and IN symptoms and later externalizing outcomes, controlling for HI symptoms. Second, logistic regression was used to test progression of DSM externalizing disorders. Third, tests of mediation were used to assess potentiation of externalizing progression through environmental risk mediators (eg, family environment, neighborhood violence). Results Consistent with hypotheses derived from trait impulsivity theories of externalizing behavior, HI symptoms of ADHD were associated independently with long-term externalizing outcomes, whereas IN symptoms were not. Between months 48 and 96, ADHD-HI/combined symptom subtype diagnoses predicted later oppositional defiant disorder diagnoses, oppositional defiant disorder diagnoses predicted later conduct disorder diagnoses, and conduct disorder diagnoses predicted later substance use disorder diagnoses. Evidence for environmental risk mediation (eg, parental monitoring, neighborhood violence) was also found. Conclusion Findings support trait impulsivity models of externalizing progression, whereby ADHD-HI/combined symptoms subtypes predispose to increasingly severe externalizing behaviors, which are magnified in contexts of environmental risk.

OBJECTIVE: Describe hospitalization rates in children with elevated symptoms of mania and determine predictors of psychiatric hospitalizations during 96 month follow-up. METHODS: Eligible 6–12.9 year olds and their parents visiting 9 outpatient mental health clinics were invited to be screened with the Parent General Behavior Inventory 10-item Mania Scale. Of 605 children with elevated symptoms of mania eligible for follow-up, 538 (88.9%) had ≥1 of 16 possible follow-up interviews and are examined herein. RESULTS: Multivariate Cox regression indicated only four factors predicted hospitalizations: parental mental health problems (HR=1.80; 95% CI=1.21, 2.69); hospitalization prior to study entry (HR=3.03; 95% CI=1.80, 4.43); continuous outpatient mental health service use (HR=3.73; 95% CI=2.40, 5.50); and low parental assessment of how well treatment matched child’s needs (HR=3.97; 95% CI=2.50, 6.31). CONCLUSIONS. Parental perspectives on mental health services should be gathered routinely, as they can signal treatment failures.

Background The affective go/no-go (AGN) task has been used to assess affective biases in attention set-shifting and deficits in inhibitory control of emotional information among depressed youth, but results have been inconsistent. We aimed to test AGN robustness and clarify temporal relationships between depressive symptoms and affective processing in youth. Methods We evaluated AGN performance twice (Time 1 N = 306; Time 2 N = 238) in relation to current, previous, and future depression in the same children/adolescents with depression and those without diagnoses who participated in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Mixed repeated ANCOVAs were powered to detect small-medium group by valence interactions in response latency and errors. Supplemental regression analyses examined depressive symptoms as a continuous variable in relation to AGN performance. Results No clear pattern emerged, mirroring the broader AGN literature. In primary analyses, group by valence interactions were only observed at one AGN administration; none replicated across administrations. Similarly, in regression analyses depressive symptoms had no relation to affective processing biases/deficits at AGN Time 1, though some relationships were detected between symptoms and AGN Time 2. Limitations Relatively few youth met criteria for a depressive disorder, though analyses were appropriately powered and supplemental analyses examined depressive symptoms continuously. Comparison groups were not healthy controls at recruitment but were free from any Axis I disorder at AGN administration. Conclusions Given the inconsistency of AGN findings, attention should be focused on tasks that provide more sensitive, robust measures of emotional information processing in depressed youth.

Disruptive mood dysregulation disorder (DMDD) was introduced in DSM-5 to distinguish a subset of chronically irritable youth who may be incorrectly diagnosed and/or treated for pediatric bipolar disorder (BPD). This study characterized the rate of new treatment episodes and treated prevalence of BPD and DMDD from a longitudinal electronic health record database and examined the impact of DMDD on prescription trends.A retrospective cohort study using 2008-2018 Optum electronic health record data was conducted. Youth aged 10 to 18 years with ≥ 183 days of database enrollment before the study cohort entry were included. Annual new treatment episode rates per 1,000 patient-years and treated prevalence (%) were estimated. Prescriptions for medications, concomitant diagnoses, and acute mental health service use for 2016-2018 were evaluated.There were 7,677 youths with DMDD and 6,480 youths with BPD identified. Mean age (13-15 years) and ethnicity were similar for both groups. A rise in new treatment episode rates (0.87-1.75 per 1,000 patient-years, p .0001) and treated prevalence (0.08%-0.35%, p .0001) of DMDD diagnoses (2016-2018) following diagnosis inception was paralleled by decreasing new treatment episode rates (1.22-1.14 per 1,000 patient-years, p .01) and treated prevalence (0.42%-0.36%, p .0001) of BPD diagnoses (2015-2018). More youth in the DMDD group were prescribed medications compared with the BPD group (81.9% vs 69.4%), including antipsychotics (58.9% vs 51.0%). Higher proportions of youth with DMDD vs youth with BPD had disruptive behavior disorders (eg, 35.9% vs 20.5% had oppositional defiant disorder), and required inpatient hospitalization related to their mental health disorder (45.0% vs 33.0%).Diagnosis of DMDD has had rapid uptake in clinical practice but is associated with increased antipsychotic and polypharmacy prescriptions and higher rates of comorbidity and inpatient hospitalization in youth with a DMDD diagnosis compared with a BPD diagnosis.

Impulsive aggressive (IA, or impulsive aggression) behavior describes an aggregate set of maladaptive, aggressive behaviors occurring across multiple neuropsychiatric disorders. IA is reactive, eruptive, sudden, and unplanned; it provides information about the severity, but not the nature, of its associated primary disorder. IA in children and adolescents is of serious clinical concern for patients, families, and physicians, given the detrimental impact pediatric IA can have on development. Currently, the ability to properly identify, monitor, and treat IA behavior across clinical populations is hindered by two major roadblocks: (1) the lack of an assessment tool designed for and sensitive to the set of behaviors comprising IA, and (2) the absence of a treatment indicated for IA symptomatology. In this review, we discuss the clinical gaps in the approach to monitoring and treating IA behavior, and highlight emerging solutions that may improve clinical outcomes in patients with IA.

Objective: Study goals were to (1) provide a rationale for developing a composite primary outcome score that includes symptom severity for attention-deficit/hyperactivity disorder (ADHD) and emotional dysregulation, plus symptom-induced impairment; (2) demonstrate weighting methods to calculate the composite score using a sample of children diagnosed with ADHD and aggression; and (3) identify the optimal weighting method most sensitive to change, as measured by effect sizes. Methods: We conducted secondary data analyses from the previously conducted Treatment of Severe Childhood Aggression (TOSCA) study. Children aged 6-12 years were recruited through academic medical centers or community referrals. The composite primary outcome comprised the ADHD, oppositional defiant disorder, disruptive mood dysregulation disorder, and peer conflict subscales from the Child and Adolescent Symptom Inventory (CASI), a DSM (Diagnostic and Statistical Manual)-referenced rating scale of symptom severity and symptom-induced impairment. Five weighting methods were tested based on input from senior statisticians. Results: The composite score demonstrated a larger (Cohen's d) effect size than the individual CASI subscales, irrespective of the weighting method (10%-55% larger). Across all weighting methods, effect sizes were similar and substantial: approximately a two-standard deviation symptom reduction (range: -1.97 to -2.04), highest for equal item and equal subscale weighting, was demonstrated, from baseline to week 9, among all TOSCA participants. The composite score showed a medium positive correlation with the Clinical Global Impressions-Severity scores, 0.46-0.47 for all weighting methods. Conclusions: A composite score that included severity and impairment ratings of ADHD and emotional dysregulation demonstrated a more robust pre-post change than individual subscales. This composite may be a more useful indicator of clinically relevant improvement in heterogeneous samples with ADHD than single subscales, avoiding some of the statistical limitations associated with multiple comparisons. Among the five similar weighting methods, the two best appear to be the equal item and equal subscale weighting methods.

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.

Objective Risk calculators (RC) to predict clinical outcomes are gaining interest. An RC to estimate risk of bipolar spectrum disorders (BPSD) could help reduce the duration of undiagnosed BPSD and improve outcomes. Our objective was to adapt an RC previously validated in the Pittsburgh Bipolar Offspring Study (BIOS) sample to achieve adequate predictive ability in both familial high-risk and clinical high-risk youths. Method Participants (aged 6−12 years at baseline) from the Longitudinal Assessment of Manic Symptoms (LAMS) study (N = 473) were evaluated semi-annually. Evaluations included a Kiddie Schedule for Affective Disorders (K-SADS) interview. After testing an RC that closely approximated the original, we made modifications to improve model prediction. Models were trained in the BIOS data, which included biennial K-SADS assessments, and tested in LAMS. The final model was then trained in LAMS participants, including family history of BPSD as a predictor, and tested in the familial high-risk sample. Results Over follow-up, 65 youths newly met criteria for BPSD. The original RC identified youths who developed BPSD only moderately well (area under the curve [AUC] = 0.67). Eliminating predictors other than the K-SADS screening items for mania and depression improved accuracy (AUC = 0.73) and generalizability. The model trained in LAMS, including family history as a predictor, performed well in the BIOS sample (AUC = 0.74). Conclusion The clinical circumstances under which the assessment of symptoms occurs affects RC accuracy; focusing on symptoms related to the onset of BPSD improved generalizability. Validation of the RC under clinically realistic circumstances will be an important next step.

Awareness of the prevalence and impact of bipolar disorder in pediatric patients has grown in recent years. Youths with this disorder are at risk for poor long-term outcomes, but with careful screening, clinicians may be able to detect early signs or subthreshold symptoms and provide a timely diagnosis and effective treatment. Although several pharmacologic options are available for patients aged 10 years and up, they differ in their safety and tolerability profiles. Clinicians should select the agent that best balances benefit and risk-at the lowest efficacious dose-and provide careful monitoring for adverse events throughout treatment.

OBJECTIVE: We compared the diagnostic efficiency of the Child Behavior Checklist (CBCL) Thought Problems subscale and the rationally derived DSM-oriented Psychotic Symptoms Scale (DOPSS) to identify clinically concerning psychosis in a multi-site sample of youths seeking outpatient mental health services (N = 694). METHOD: We operationally defined clinically concerning psychosis as the presence of clinically significant hallucinations or delusions, assessed by the Schedule for Affective Disorders and Schizophrenia (K-SADS) psychosis items. RESULTS: Both the Thought Problems and DOPSS scores showed significant areas under the curve (AUCs=.65 and .70, respectively), but the briefer DOPSS showed statistically significantly better diagnostic efficiency for any clinically concerning psychosis, but the difference was small enough that it would not be clinically meaningful. The optimal psychosis screening cut-off score (maximizing sensitivity and specificity) was 68.5+ [corresponding diagnostic likelihood ratio (DiLR)=1.59] for the Thought Problems subscale and 1.67+ (DiLR=1.97) for the DOPSS. CONCLUSIONS: Both the CBCL Thought Problems and DOPSS are clinically useful for identifying psychotic symptoms in children, and although the DOPSS showed statistically better discriminating power, the difference was small so we would not necessarily recommend the DOPSS over standard scoring.