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Objective: The accepted primary outcome measure for evaluating psychotic symptoms is decades old, long, and initially designed 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)., Method: 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 3 antipsychotic agents (registered and previously published) were conducted. Subjects were 118 youths receiving outpatient psychiatric treatment for schizophrenia spectrum disorders (mean age = 14.26 years, SD = 2.41 years)., Results: A 10-item short form, keeping 2 strongest items for each factor, had r = 0.89 with the full-length scale. Each of the five 2-item subscales has alphas ranging from 0.66 to 0.84. Item Response Theory (IRT) found that the 10-item scale and 2-item subscores had high reliability across the severity range typical of those for clinical trials. Criterion validity was high, with equal sensitivity to clinical changes over time., Conclusion: A 10-item PANSS version eliminates weaker items in the pediatric population while preserving coverage of 5 factors and similar sensitivity to clinical changes over time. It thus may be more appropriate for subsequent pediatric trials, and for clinical use when time and efficiency are paramount., (Copyright © 2022 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: 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., Method: 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., Results: 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., Conclusion: 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., (Copyright © 2022 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: 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)., Method: 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)., Results: 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)., Conclusion: 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., Clinical Trial Registration Information: Safety and Efficacy Study in Preschool Children Aged 4-5 Years With Attention-Deficit/Hyperactivity Disorder; http://www., Clinicaltrials: gov; NCT03260205., (Copyright © 2022 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the efficacy and safety of vortioxetine in adolescents with major depressive disorder (MDD)., Method: 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 score >2) 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., Results: 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., Conclusion: 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., Clinical Trial Registration Information: 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., (Copyright © 2022 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: 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., Method: 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., Results: 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%)., Conclusion: 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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: A recent 3-month double-blind, placebo-controlled study demonstrated efficacy and safety of pediatric prolonged-release melatonin (PedPRM) for insomnia in children with autism spectrum disorder. This study examined the long-term effects of PedPRM treatment on sleep, growth, body mass index, and pubertal development., Method: Eighty children and adolescents (2-17.5 years of age; 96% with autism spectrum disorder) who completed the double-blind, placebo-controlled trial were given 2 mg, 5 mg, or 10 mg PedPRM nightly up to 104 weeks, followed by a 2-week placebo period to assess withdrawal effects., Results: Improvements in child sleep disturbance and caregiver satisfaction with child sleep patterns, quality of sleep, and quality of life were maintained throughout the 104-week treatment period (p < .001 versus baseline for all). During the 2-week withdrawal placebo period, measures declined compared with the treatment period but were still improved compared with baseline. PedPRM was generally safe; the most frequent treatment-related adverse events were fatigue (6.3%), somnolence (6.3%), and mood swings (4.2%). Changes in mean weight, height, body mass index, and pubertal status (Tanner staging done by a physician) were within normal ranges for age with no evidence of delay in body mass index or pubertal development., Conclusion: Nightly PedPRM at optimal dose (2, 5, or 10 mg nightly) is safe and effective for long-term treatment in children and adolescents with autism spectrum disorder and insomnia. There were no observed detrimental effects on children's growth and pubertal development and no withdrawal or safety issues related to the use or discontinuation of the drug., Clinical Trial Registration Information: Efficacy and Safety of Circadin in the Treatment of Sleep Disturbances in Children With Neurodevelopment Disabilities; https://clinicaltrials.gov/; NCT01906866., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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)., (Copyright © 2018 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

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.

Objective: The Treatment of Severe Childhood Aggression (TOSCA) project examined augmentation of stimulant treatment and parent training (PT) with risperidone for severe physical aggression. This article summarizes the clinical implications; reanalyzes the data to examine the utility of 4 criteria for deciding to augment; and presents a treatment algorithm., Method: The newly analyzed 4 criteria for augmenting after 3 weeks of stimulant and PT treatment consisted of not meeting a Clinical Global Impressions-Improvement (CGI-I) score of 1 and a normal score (≤15) on the Nisonger Child Behavior Rating Form Disruptive-Total (D-Total); a CGI-I score of 1 or 2 plus 25% improvement in D-Total score; a D-Total score no higher than 15; and a CGI-Severity score of 3 (mild) or better. Effect sizes were calculated. Prior TOSCA publications were reviewed for clinically relevant findings., Results: All 4 criteria resulted in medium or better effect sizes (d = 0.59-0.72) when comparing risperidone with placebo. Providing risperidone to children who did not reach a CGI-I score of 1 plus a D-Total score no higher than 15 resulted in the greatest benefit. In addition, a review of clinically relevant data suggests that stimulant plus PT shows further improvement after 3 weeks even without augmentation., Conclusion: For those children who did not attain a CGI-I score of 1 and a D-total score no higher than 15, adding risperidone maximized the number of children benefitting from treatment and the average amount of benefit. Unless clinical circumstances dictate otherwise, practitioners should delay an antipsychotic drug for at least 1 month after the optimal stimulant dose is achieved and PT has commenced. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov; NCT00796302., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the efficacy and safety of novel pediatric-appropriate, prolonged-release melatonin minitablets (PedPRM) versus placebo for insomnia in children and adolescents with autism spectrum disorder (ASD), with or without attention-deficit/hyperactivity disorder (ADHD) comorbidity, and neurogenetic disorders (NGD)., Method: A total of 125 children and adolescents (2-17.5 years of age; 96.8% ASD, 3.2% Smith-Magenis syndrome [SMS]) whose sleep failed to improve on behavioral intervention alone were randomized (1:1 ratio), double-blind, to receive PedPRM (2 mg escalated to 5 mg) or placebo for 13 weeks. Sleep measures included the validated caregivers' Sleep and Nap Diary (SND) and Composite Sleep Disturbance Index (CSDI). The a priori primary endpoint was SND-reported total sleep time (TST) after 13 weeks of treatment., Results: The study met the primary endpoint: after 13 weeks of double-blind treatment, participants slept on average 57.5 minutes longer at night with PedPRM compared to 9.14 minutes with placebo (adjusted mean treatment difference PedPRM-placebo -32.43 minutes; p = .034). Sleep latency (SL) decreased by 39.6 minutes on average with PedPRM and 12.5 minutes with placebo (adjusted mean treatment difference -25.30 minutes; p = .011) without causing earlier wakeup time. The rate of participants attaining clinically meaningful responses in TST and/or SL was significantly higher with PedPRM than with placebo (68.9% versus 39.3% respectively; p = .001) corresponding to a number needed to treat (NNT) of 3.38. Overall sleep disturbance (CSDI) tended to decrease. PedPRM was generally safe; somnolence was more commonly reported with PedPRM than placebo., Conclusion: PedPRM was efficacious and safe for treatment of insomnia in children and adolescents with ASD with/without ADHD and NGD. The acceptability of this pediatric formulation in a population who usually experience significant difficulties in swallowing was remarkably high. Clinical trial registration information-Efficacy and Safety of Circadin in the Treatment of Sleep Disturbances in Children With Neurodevelopment Disabilities; http://clinicaltrials.gov/; NCT01906866., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Mood disorders and behavioral are broad psychiatric diagnostic categories that have different symptoms and neurobiological mechanisms, but share some neurocognitive similarities, one of which is an elevated risk for reading deficit. Our aim was to determine the influence of mood versus behavioral dysregulation on reading ability and neural correlates supporting these skills in youth, using diffusion tensor imaging in 11- to 17-year-old children and youths with mood disorders or behavioral disorders and age-matched healthy controls. The three groups differed only in phonological processing and passage comprehension. Youth with mood disorders scored higher on the phonological test but had lower comprehension scores than children with behavioral disorders and controls; control participants scored the highest. Correlations between fractional anisotropy and phonological processing in the left Arcuate Fasciculus showed a significant difference between groups and were strongest in behavioral disorders, intermediate in mood disorders, and lowest in controls. Correlations between these measures in the left Inferior Longitudinal Fasciculus were significantly greater than in controls for mood but not for behavioral disorders. Youth with mood disorders share a deficit in the executive-limbic pathway (Arcuate Fasciculus) with behavioral-disordered youth, suggesting reduced capacity for engaging frontal regions for phonological processing or passage comprehension tasks and increased reliance on the ventral tract (e.g., the Inferior Longitudinal Fasciculus). The low passage comprehension scores in mood disorder may result from engaging the left hemisphere. Neural pathways for reading differ mainly in executive-limbic circuitry. This new insight may aid clinicians in providing appropriate intervention for each disorder.

Objective: To use receiver-operating characteristics analysis to identify multilevel diagnostic likelihood ratios and provide a framework for the diagnosis of attention-deficit/hyperactivity disorder (ADHD) in children (5-10 years old) and adolescents (11-18 years old) in an outpatient setting., Method: Caregiver, teacher, and youth reports from the Achenbach System of Empirically Based Assessment (ASEBA) were obtained for 299 children and 321 adolescents with multiple imputation of missing data. The reference standard was diagnosis of ADHD based on case history and a semistructured diagnostic interview masked to the ASEBA measurements., Results: In children, caregiver-reported Attention Problems (area under the curve [AUC] = 0.74) outperformed all other subscales of the caregiver and teacher measures (AUCs ≤ 0.72). In the older sample, caregiver- and teacher-reported Attention Problems (caregiver AUC = 0.73; teacher AUC = 0.61) were best at identifying ADHD. Inclusion of caregiver and teacher reports significantly (p < .001 for all comparisons) increased prediction of ADHD diagnosis, whereas youth self-report did not., Conclusion: Caregiver-reported Attention Problems were more useful than teacher-reports and self-report in identifying ADHD. Combining caregiver and teacher reports improved identification. Multilevel likelihood ratios are provided to facilitate routine clinical use., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: This analysis examined alcohol and drug use over a 6-year follow-up of children in the Longitudinal Assessment of Manic Symptoms (LAMS) study., Method: LAMS screened 6- to 12.9-year-old children visiting 9 child outpatient mental health (MH) clinics, using the Parent General Behavior Inventory 10-item mania scale. All children with scores ≥12 and a matched group with scores ≤12 were invited to enroll. Children were assessed every 6 months. Assessments included demographics, family, MH history, child diagnoses, child stress, and alcohol and drug use. Univariate, bivariate, and interval censored survival analyses were conducted., Results: Of those >9 years at baseline, 34.9% used alcohol at least once, with 11.9% regular users; 30.1% used drugs at least once, with 16.2% regular users. Predictors of any alcohol use were parental marital status, older age at study entry, a primary diagnosis of disruptive behavior disorders at baseline, and number of impactful child life events. Predictors of regular alcohol use included parental marital status, age, and sustained high mania symptoms over the first 24 months of follow-up. Predictors of any drug use were single parent, parental substance use, and stressful child life events. Predictors of regular drug use were parental marital status, stressful child life events, and a baseline disruptive behavior disorder diagnosis. Baseline medications decreased the risk of regular drug use., Conclusion: Longitudinal data on youth with elevated manic symptoms suggest that comorbid disruptive behavior disorder, manic symptom burden, family environment, and stress are predictors of initiation and regular use of substances., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to evaluate 52-week clinical outcomes of children with co-occurring attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorder, and serious physical aggression who participated in a prospective, longitudinal study that began with a controlled, 9-week clinical trial comparing the relative efficacy of parent training + stimulant medication + placebo (Basic; n = 84) versus parent training + stimulant + risperidone (Augmented; n = 84)., Method: Almost two-thirds (n = 108; 64%) of families in the 9-week study participated in week 52 follow-ups (Basic, n = 55; Augmented, n = 53) and were representative of the initial study sample. The assessment battery included caregiver and clinician ratings and laboratory tests., Results: Only 43% of participants in the Augmented group and 36% in the Basic group still adhered to their assigned regimen (not significant [NS]); 23% of those in the Augmented group and 11% in the Basic group were taking no medication (NS). Both randomized groups improved baseline to follow-up, but the 3 primary parent-reported behavioral outcomes showed no significant between-group differences. Exploratory analyses indicated that participants in the Augmented group (65%) were more likely (p = .02) to have a Clinical Global Impressions (CGI) severity score of 1 to 3 (i.e., normal to mildly ill) at follow-up than those in the Basic group (42%). Parents rated 45% of children as impaired often or very often from ADHD, noncompliant, or aggressive behavior. The Augmented group had elevated prolactin levels, and the Basic group had decreased weight over time. Findings were generally similar whether groups were defined by randomized assignment or follow-up treatment status., Conclusion: Both treatment strategies were associated with clinical improvement at follow-up, and primary behavioral outcomes did not differ significantly. Many children evidenced lingering mental health concerns, suggesting the need for additional research into more effective interventions. Clinical trial registration information-Treatment of Severe Childhood Aggression (the TOSCA Study); http://clinicaltrials.gov/; NCT00796302., (Published by Elsevier Inc.)

Objective: To evaluate asenapine versus placebo in 403 patients aged 10 to 17 years with bipolar I disorder currently in manic or mixed episodes., Method: In this double-blind, placebo-controlled, international trial, patients were randomized 1:1:1:1 to placebo, asenapine 2.5, 5, or 10 mg b.i.d. (twice daily). Primary efficacy measure was change from baseline in Young-Mania Rating Scale (YMRS) total score at day 21. Analyses of patients with/without attention-deficit/hyperactivity disorder (ADHD) and with/without stimulant use were performed., Results: The mean difference in asenapine versus placebo in YMRS was -3.2 (p = .0008), -5.3 (p < .001), and -6.2 (p < .001) for asenapine 2.5, 5, and 10 mg b.i.d., respectively. Treatment-emergent adverse events with an incidence ≥5% and at least twice placebo were somnolence, sedation, hypoesthesia oral, paresthesia oral, and increased appetite. The asenapine groups had a higher incidence of ≥7% weight gain (range, 8.0%-12.0%) versus placebo (1.1%; p < .05). The mean change from baseline in fasting insulin was larger for patients treated with asenapine than those with placebo (asenapine 2.5 mg b.i.d.: 73.375 pmol/L; asenapine 5 mg b.i.d.: 114.042 pmol/L; asenapine 10 mg b.i.d.: 59.846 pmol/L; placebo: 3.690 pmol/L). The mean changes from baseline for lipid parameters and glucose were also larger in asenapine groups than in the placebo group. No safety differences were observed with respect to ADHD and stimulant use., Conclusion: All asenapine doses versus placebo were superior based on change in YMRS at day 21. Asenapine was generally well tolerated in patients aged 10 to 17 years with bipolar I disorder in manic or mixed states. Increases in weight and fasting insulin were associated with asenapine. Clinical trial registration information-Efficacy and Safety of Asenapine Treatment for Pediatric Bipolar Disorder; http://clinicaltrials.gov; NCT01244815., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to compare the efficacy of lamotrigine versus placebo in 10- to 17-year-olds with bipolar I disorder (BP-I) who were receiving conventional bipolar disorder treatment., Method: In this randomized withdrawal trial, patients with BP-I of at least moderate severity received lamotrigine during an ≤18-week open-label phase. Patients who maintained a stable lamotrigine dose for ≥2 weeks and Clinical Global Impression-Bipolar Severity of Illness (CGI-BP[S]) score of ≤3 for ≥6 consecutive weeks were randomized to double-blind lamotrigine or placebo for ≤36 weeks., Results: Of 301 patients enrolled, 298 comprised the open-label intention-to-treat population, with 173 (58%) randomized. Of these patients, 41 (24%) completed the study. In the open-label phase, the mean (SD) baseline CGI-BP(S) rating was 4.4 (0.57), and the mean (standard error [SE]) time to stabilization was 101 (1.6) days. During the randomized phase, mean (SE) time to occurrence of a bipolar event (TOBE) for lamotrigine versus placebo (primary endpoint) was 155 (14.7) versus 50 (3.8), 163 (12.2) versus 120 (12.2), and 136 (15.4) versus 107 (13.8) days for the 3 index mood states (depressed, manic/hypomanic, mixed). The primary stratified log-rank analysis of TOBE was not statistically significant (hazard ratio [HR] = 0.63; p = .072); however, the prespecified Cox regression analysis favored lamotrigine (p = .047). In 13- to 17-year-olds, log-rank analysis of TOBE significantly favored lamotrigine (HR = 0.46; p = .015), but not in 10- to 12-year-olds (HR = 0.93; p = .877). Dermatologic events were reported in 4% (open-label phase) and 2% (randomized phase) of patients receiving lamotrigine. Suicidality-related adverse events were reported in 7% (open-label phase) and 7% (randomized phase) of patients receiving lamotrigine., Conclusion: Although the primary analysis failed to detect a benefit of add-on lamotrigine for BP-I in 10- to 17-year-olds, lamotrigine may be effective in a subset of older adolescents. Clinical trial registration information-Lamictal as Add-on Treatment for Bipolar I Disorder in Pediatric Patients; http://clinicaltrials.gov/; NCT00723450., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the efficacy, safety, and tolerability of the selective serotonin norepinephrine inhibitor duloxetine in children and adolescents with generalized anxiety disorder (GAD)., Method: Youth aged 7 through 17 years with a primary diagnosis of GAD were treated with flexibly dosed duloxetine (30-120 mg daily, n = 135) or placebo (n = 137) for 10 weeks, followed by open-label duloxetine (30-120mg daily) for 18 weeks. Efficacy measures included the Pediatric Anxiety Rating Scale (PARS), Clinical Global Impression-Severity (CGI-Severity) scale, and Children's Global Assessment Scale (CGAS). Safety measures included the Columbia-Suicide Severity Rating Scale (C-SSRS) as well as vital signs and electrocardiographic and laboratory monitoring., Results: On the primary efficacy measure (PARS severity for GAD), mean improvement from baseline to 10 weeks was statistically significantly greater for duloxetine (-9.7) compared with placebo (-7.1, p ≤ .001, Cohen's d: 0.5). Symptomatic response (50% improvement on the PARS severity for GAD), remission (PARS severity for GAD ≤8), and functional remission (CGAS >70) rates for the duloxetine group (59%, 50%, 37%, respectively) were statistically significantly greater than for the placebo group (42%, 34%, 24%, respectively, p ≤ .05) during acute treatment. Changes in systolic and diastolic blood pressure and discontinuation because of adverse events did not statistically differ between the duloxetine and placebo groups, although gastrointestinal-related adverse events, oropharyngeal pain, dizziness, cough, and palpitations were reported with a statistically significantly greater incidence for the duloxetine group compared with the placebo group. Mean changes in pulse and weight for the duloxetine group (+6.5 beats/min, -0.1 kg, respectively) were statistically different from the placebo group (+2.0 beats/min, +1.1 kg, respectively, p ≤ .01)., Conclusion: In this study, duloxetine was superior to placebo on the primary efficacy analysis of mean change from baseline to week 10 on the PARS severity for GAD score, and safety results were consistent with the known safety profile of duloxetine in pediatric and adult patients. Clinical trial registration information-A Study in Pediatric Participants With Generalized Anxiety Disorder; http://clinicaltrials.gov; NCT01226511., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: In this study, we aimed to expand on our prior research into the relative efficacy of combining parent training, stimulant medication, and placebo (Basic therapy) versus parent training, stimulant, and risperidone (Augmented therapy) by examining treatment effects for attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) symptoms and peer aggression, symptom-induced impairment, and informant discrepancy., Method: Children (6-12 years of age; N = 168) with severe physical aggression, ADHD, and co-occurring ODD/CD received an open trial of parent training and stimulant medication for 3 weeks. Participants failing to show optimal clinical response were randomly assigned to Basic or Augmented therapy for an additional 6 weeks., Results: Compared with Basic therapy, children receiving Augmented therapy experienced greater reduction in parent-rated ODD severity (p = .002, Cohen's d = 0.27) and peer aggression (p = .02, Cohen's d = 0.32) but not ADHD or CD symptoms. Fewer children receiving Augmented (16%) than Basic (40%) therapy were rated by their parents as impaired by ODD symptoms at week 9/endpoint (p = .008). Teacher ratings indicated greater reduction in ADHD severity (p = .02, Cohen's d = 0.61) with Augmented therapy, but not for ODD or CD symptoms or peer aggression. Although both interventions were associated with marked symptom reduction, a relatively large percentage of children were rated as impaired for at least 1 targeted disorder at week 9/endpoint by parents (Basic 47%; Augmented 27%) and teachers (Basic 48%; Augmented 38%)., Conclusion: Augmented therapy was superior to Basic therapy in reducing severity of ADHD and ODD symptoms, peer aggression, and symptom-induced impairment, but clinical improvement was generally context specific, and effect sizes ranged from small to moderate. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov/; NCT00796302., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Although combination pharmacotherapy is common in child and adolescent psychiatry, there has been little research evaluating it. The value of adding risperidone to concurrent psychostimulant and parent training (PT) in behavior management for children with severe aggression was tested., Method: One hundred sixty-eight children 6 to 12 years old (mean age 8.89 ± 2.01 years) with severe physical aggression were randomized to a 9-week trial of PT, stimulant (STIM), and placebo (Basic treatment; n = 84) or PT, STIM, and risperidone (Augmented treatment; n = 84). All had diagnoses of attention-deficit/hyperactivity disorder and oppositional-defiant disorder (n = 124) or conduct disorder (n = 44). Children received psychostimulant (usually Osmotic Release Oral System methylphenidate) for 3 weeks, titrated for optimal effect, while parents received PT. If there was room for improvement at the end of week 3, placebo or risperidone was added. Assessments included parent ratings on the Nisonger Child Behavior Rating Form (Disruptive-Total subscale was the primary outcome) and Antisocial Behavior Scale; blinded clinicians rated change on the Clinical Global Impressions scale., Results: Compared with Basic treatment (PT + STIM [44.8 ± 14.6 mg/day] + placebo [1.88 mg/day ± 0.72]), Augmented treatment (PT + STIM [46.1 ± 16.8 mg/day] + risperidone [1.65 mg/day ± 0.75]) showed statistically significant improvement on the Nisonger Child Behavior Rating Form Disruptive-Total subscale (treatment-by-time interaction, p = .0016), the Nisonger Child Behavior Rating Form Social Competence subscale (p = .0049), and Antisocial Behavior Scale Reactive Aggression subscale (p = .01). Clinical Global Impressions scores were substantially improved for the 2 groups but did not discriminate between treatments (Clinical Global Impressions-Improvement score ≤2, 70% for Basic treatment versus 79% for Augmented treatment). Prolactin elevations and gastrointestinal upset occurred more with Augmented treatment; other adverse events differed modestly from Basic treatment; weight gain in the Augmented treatment group was minor., Conclusions: Risperidone provided moderate but variable improvement in aggressive and other seriously disruptive child behaviors when added to PT and optimized stimulant treatment. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study), URL: http://clinicaltrials.gov, unique identifier: NCT00796302., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Objective: Pediatric bipolar disorder involves poor social functioning, but the neural mechanisms underlying these deficits are not well understood. Previous neuroimaging studies have found deficits in emotional face processing localized to emotional brain regions. However, few studies have examined dysfunction in other regions of the face processing circuit. This study assessed hypoactivation in key face processing regions of the brain in pediatric bipolar disorder., Method: Youth with a bipolar spectrum diagnosis (n = 20) were matched to a nonbipolar clinical group (n = 20), with similar demographics and comorbid diagnoses, and a healthy control group (n = 20). Youth participated in a functional magnetic resonance imaging (fMRI) scanning which employed a task-irrelevant emotion processing design in which processing of facial emotions was not germane to task performance., Results: Hypoactivation, isolated to the fusiform gyrus, was found when viewing animated, emerging facial expressions of happiness, sadness, fearfulness, and especially anger in pediatric bipolar participants relative to matched clinical and healthy control groups., Conclusions: The results of the study imply that differences exist in visual regions of the brain's face processing system and are not solely isolated to emotional brain regions such as the amygdala. Findings are discussed in relation to facial emotion recognition and fusiform gyrus deficits previously reported in the autism literature. Behavioral interventions targeting attention to facial stimuli might be explored as possible treatments for bipolar disorder in youth., (Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS)., Method: Neurocognitive functioning of youth (ages 8 to 19 years) with schizophrenia or schizoaffective disorder was evaluated in a four-site, randomized, double-blind clinical trial comparing molindone, olanzapine, and risperidone. The primary outcomes were overall group change from baseline in neurocognitive composite and six domain scores after 8 weeks and continued treatment up to 52 weeks. Age and sex were included as covariates in all analyses., Results: Of 116 TEOSS participants, 77 (66%) had post-baseline neurocognitive data. No significant differences emerged in the neurocognitive outcomes of the three medication groups. Therefore, the three treatment groups were combined into one group to assess overall neurocognitive outcomes. Significant modest improvements were observed in the composite score and in three of six domain scores in the acute phase, and in four of six domain scores in the combined acute and maintenance phases. Partial correlation analyses revealed very few relationships among Positive and Negative Syndrome Scale (PANSS) baseline or change scores and neurocognition change scores., Conclusions: Antipsychotic intervention in youth with early-onset schizophrenia spectrum disorders (EOSS) led to modest improvement in measures of neurocognitive function. The changes in cognition were largely unrelated to baseline symptoms or symptom change. Small treatment effect sizes, easily accounted for by practice effects, highlight the critical need for the development of more efficacious interventions for the enduring neurocognitive deficits seen in EOSS. Clinical trial registry information-Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS); http://www.clinicaltrials.gov; NCT00053703., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: The primary aim of the present study was to evaluate the validity of proposed DSM-5 criteria for autism spectrum disorder (ASD)., Method: We analyzed symptoms from 14,744 siblings (8,911 ASD and 5,863 non-ASD) included in a national registry, the Interactive Autism Network. Youth 2 through 18 years of age were included if at least one child in the family was diagnosed with ASD. Caregivers reported symptoms using the Social Responsiveness Scale and the Social Communication Questionnaire. The structure of autism symptoms was examined using latent variable models that included categories, dimensions, or hybrid models specifying categories and subdimensions. Diagnostic efficiency statistics evaluated the proposed DSM-5 algorithm in identifying ASD., Results: A hybrid model that included both a category (ASD versus non-ASD) and two symptom dimensions (social communication/interaction and restricted/repetitive behaviors) was more parsimonious than all other models and replicated across measures and subsamples. Empirical classifications from this hybrid model closely mirrored clinical ASD diagnoses (90% overlap), implying a broad ASD category distinct from non-ASD. DSM-5 criteria had superior specificity relative to DSM-IV-TR criteria (0.97 versus 0.86); however sensitivity was lower (0.81 versus 0.95). Relaxing DSM-5 criteria by requiring one less symptom criterion increased sensitivity (0.93 versus 0.81), with minimal reduction in specificity (0.95 versus 0.97)., Conclusions: Results supported the validity of proposed DSM-5 criteria for ASD as provided in Phase I Field Trials criteria. Increased specificity of DSM-5 relative to DSM-IV-TR may reduce false positive diagnoses, a particularly relevant consideration for low base rate clinical settings. Phase II testing of DSM-5 should consider a relaxed algorithm, without which as many as 12% of ASD-affected individuals, particularly females, will be missed. Relaxed DSM-5 criteria may improve identification of ASD, decreasing societal costs through appropriate early diagnosis and maximizing intervention resources., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To examine lisdexamfetamine dimesylate (LDX) efficacy and safety versus placebo in adolescents with attention-deficit/hyperactivity disorder (ADHD)., Method: Adolescents (13 through 17) with at least moderately symptomatic ADHD (ADHD Rating Scale IV: Clinician Version [ADHD-RS-IV] score ≥28) were randomized to placebo or LDX (30, 50, or 70 mg/d) in a 4-week, forced-dose titration, double-blind study. Primary and secondary efficacy measures were the ADHD-RS-IV, Clinical Global Impressions-Improvement (CGI-I), and Youth QOL-Research Version (YQOL-R). Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, laboratory findings, physical examinations, and ECG., Results: Overall, 314 participants were randomized; 309 were in efficacy analyses and 49 withdrew (11 due to TEAEs). Least squares mean (SE) change from baseline at endpoint in ADHD-RS-IV total scores were -18.3 (1.25), -21.1 (1.28), -20.7 (1.25) for 30, 50, and 70 mg/d LDX, respectively; -12.8 (1.25) for placebo (p ≤ .0056 versus placebo for each). Differences in ADHD-RS-IV total scores favored all LDX doses versus placebo at all weeks (p ≤ .0076). On the CGI-I, 69.1% of participants were rated very much/much improved at endpoint with LDX all doses versus placebo (39.5%) (p < .0001). YQOL-R changes at endpoint scores for LDX groups versus placebo were not significant. Commonly reported LDX (all doses combined) TEAEs (≥5%) were decreased appetite, headache, insomnia, decreased weight, and irritability. Small mean increases in pulse and blood pressure and no clinically meaningful trends in ECG changes were noted with LDX., Conclusions: LDX at all doses was effective versus placebo in treating adolescent ADHD and demonstrated a safety profile consistent with previous LDX studies. CLINICAL TRIALS REGISTRY INFORMATION: Efficacy and Safety of Lisdexamfetamine Dimesylate (LDX) in Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD); http://www.clinicaltrials.gov; NCT00735371., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders., Method: Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks., Results: Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment., Conclusions: Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Clinical trial registry information-Treatment of Schizophrenia and Related Disorders in Children and Adolescents; URL: http://www.clinicaltrials.gov, unique identifier: NCT00053703., (2010 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: We examined the neuropsychological functioning of youth enrolled in the NIMH funded trial, Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). We compared the baseline neuropsychological functioning of youth with schizophrenia (SZ, n = 79) to those with schizoaffective disorder (SA, n = 40), and examined the relationship of different variables of illness severity and adaptive behavior to neuropsychological functioning., Method: Participants ranged in age from 8 to 19 years. Diagnostic status was confirmed via structured interview over multiple time points. Domains of neuropsychological functioning included fine-motor, attention, working memory, problem-solving efficiency, inhibitory control, and social cognition. Other variables included intelligence (IQ), academic achievement skills, adaptive behavior, and different measures of illness severity., Results: The two groups did not differ on IQ or on any of the neuropsychological domains. The SZ group performed significantly lower in spelling. A high proportion of individuals in both groups reflected significant intellectual and academic achievement skill deficits. Significant correlations were found between the neurocognitive domains and both illness severity and adaptive behavior variables., Conclusions: There were few differences between the SZ and SA groups on IQ, achievement, or neuropsychological functioning; however, both groups showed significantly high rates of deficits in IQ and basic academic skills. Correlations of the neurocognitive functions with illness severity and adaptive behavior were small to moderate in magnitude. These findings continue to implicate the importance of neurocognitive functioning as a key area of vulnerability in the study of youth with schizophrenia spectrum disorders.

Objective: To examine the short-term efficacy of methylphenidate in the treatment of youths with bipolar disorder (BD) and comorbid attention deficit/hyperactivity disorder (ADHD)., Method: A 4-week double-blind, placebo-controlled trial in youths ages 5 to 17 years was conducted. Subjects met DSM-IV criteria for bipolar disorder and ADHD, were currently receiving a stable dose of at least one thymoleptic, and while euthymic continued to have clinically significant symptoms of ADHD. Patients received 1 week each of placebo, methylphenidate 5 mg twice daily, methylphenidate 10 mg twice daily, and methylphenidate 15 mg twice daily using a crossover design. Subjects were randomly assigned to receive one of six possible dosing orders. At study's end, and before the blind being broken, a "best dose week" for each subject was determined. The primary outcome measure was the total score on the parent-completed ADHD Rating Scale-IV., Results: Sixteen patients, with a mean age of 10.43 (SD 3.14) years completed the trial. Lower scores during best dose treatment compared to the week of placebo treatment were found on the ADHD Rating Scale-IV (p < .05), suggesting a therapeutic benefit. A large effect size (Cohen's d = 0.90) was found for methylphenidate. Treatment was generally well tolerated., Conclusions: Euthymic youths with bipolar disorder and ADHD may benefit from short-term concomitant treatment with methylphenidate.

Objective: The Treatment of Early Onset Schizophrenia Spectrum Disorders Study is a publicly funded clinical trial designed to compare the therapeutic benefits, safety, and tolerability of risperidone, olanzapine, and molindone in youths with early-onset schizophrenia spectrum disorders. The rationale, design, and methods of the Treatment of Early Onset Schizophrenia Spectrum Disorders Study are described., Method: Using a randomized, double-blind, parallel-group design at four sites, youths with EOSS (ages 8-19 years) were assigned to an 8-week acute trial of risperidone (0.5-6.0 mg/day), olanzapine (2.5-20 mg/day), or molindone (10-140 mg/day). Responders continued double-blind treatment for 44 weeks. The primary outcome measure was responder status at 8 weeks, defined by a 20% reduction in baseline Positive and Negative Symptom Scale scores plus ratings of significant improvement on the Clinical Global Impressions. Secondary outcome measures included assessments of psychopathology, functional impairment, quality of life, and medication safety. An intent-to-treat analytic plan was used., Results: From February 2002 to May 2006, 476 youths were screened, 173 were further evaluated, and 119 were randomized. Several significant study modifications were required to address safety, the use of adjunctive medications, and the termination of the olanzapine treatment arm due to weight gain., Conclusions: The Treatment of Early Onset Schizophrenia Spectrum Disorders Study will inform clinical practice regarding the use of antipsychotic medications for youths with early-onset schizophrenia spectrum disorders. Important safety concerns emerged during the study, including higher than anticipated rates of suicidality and problems tapering thymoleptic agents before randomization.

Objective: We examined baseline demographic and clinical profiles of youths enrolled from 2001 to 2006 in the publicly funded multicenter, randomized controlled trial Treatment of Early-Onset Schizophrenia Spectrum Disorders., Method: Youths (8-19 years) with schizophrenia (SZ) and schizoaffective disorder were recruited at four academic sites. Diagnosis was made via structured and clinical interviews. Assessments of psychiatric symptoms and social and global functioning were included., Results: A total of 119 youths were enrolled. The mean age at illness onset was 11.1 +/- 3.5 years. Patients with SZ and schizoaffective disorder had similar ratings on the Positive and Negative Symptom Scale, Brief Psychiatric Rating Scale for Children, and Clinical Global Impression-Severity Scale. The overall level of functioning was similar in the two groups. A comparison to published reports of adults with SZ indicates that these youths may have more severe symptoms based on results of the Positive and Negative Symptom Scale., Conclusions: This is one of the largest samples of youths with SZ spectrum disorders studied to date and the largest assessment of youths with schizoaffective disorder. High rates of symptoms and general psychopathology were noted. There was a substantial degree of social and functional impairment. The symptom profiles are consistent with, but more severe than, those reported in the adult literature.

Objective: The objective of this study was to describe the prevalence and correlates of adherence to divalproex sodium (DVPX) and lithium carbonate (Li) combination treatment during the initial stabilization treatment phase., Method: Adherence to Li/DVPX combination therapy was measured by the presence or absence of minimum serum concentrations of DVPX (50 microg/mL) or Li (0.6 mmol/L). Secondary measures included pill count, patient/parent report, and clinical judgment. Correlates of adherence, including patient characteristics, medication side effects, and family variables, were evaluated., Results: One hundred seven patients (70 males and 37 females) were studied. The proportion of serum concentrations in the therapeutic range across the study period was 0.84 for DVPX and 0.66 for Li. Maternal (r = -0.31; p<.01) and paternal (r = -0.44; p < .01) hospitalization for a psychiatric disorder and less adaptive family functioning (r=-0.26; p < .05) related to treatment nonadherence for DVPX. Better treatment adherence to DVPX (r = 0.21; p < .05) and Li (r = 0.23; p < .05) was associated with a greater number of side effects, whereas male sex was associated with worse adherence to both DVPX (r= -0.24; p < .05) and Li (r = -0.22; p < .05) pharmacotherapy. Clinical response to treatment correlated with adherence to DVPX treatment (r = 0.33; p < .01)., Conclusions: Nonadherence may limit the statistical power of treatment efficacy studies and the effectiveness of pharmacotherapy treatment for juvenile BPD and necessitate strategies to evaluate and enhance levels of treatment adherence.

Objective: The safety, efficacy, and tolerability of venlafaxine extended release (ER) in subjects ages 7 to 17 years with major depressive disorder were evaluated in two multicenter, randomized, double-blind, placebo-controlled trials conducted between October 1997 and August 2001., Method: Participants received venlafaxine ER (flexible dose, based on body weight; intent to treat, n = 169) or placebo (intent to treat, n = 165) for up to 8 weeks. The primary efficacy variable was the change from baseline in the Children's Depression Rating Scale-Revised score at week 8., Results: There were no statistically significant differences between venlafaxine ER and placebo on the Children's Depression Rating Scale-Revised in either study. A post hoc age subgroup analysis of the pooled data showed greater improvement on the Children's Depression Rating Scale-Revised with venlafaxine ER than with placebo (-24.4 versus -19.9; p = .022) among adolescents (ages 12-17), but not among children (ages 7-11). The most common adverse events were anorexia and abdominal pain. Hostility and suicide-related events were more common in venlafaxine ER-treated participants than in placebo-treated participants. There were no completed suicides., Conclusions: Venlafaxine ER may be effective in depressed adolescents. However, its safety and efficacy in pediatric patients has not been established. Prescribers should monitor for signs of suicidal ideation and hostility in pediatric patients taking venlafaxine ER.

Objective: To determine whether impulsive aggression (IA) is a meaningful clinical construct and to ascertain whether it is sufficiently similar across diagnostic categories, such that parallel studies across disorders might constitute appropriate evidence for pursuing indications. If so, how should IA be assessed, pharmacological studies designed, and ethical issues addressed?, Method: Experts from key stakeholder communities, including academic clinicians, researchers, practicing clinicians, U.S. Food and Drug Administration, National Institute of Mental Health, industry sponsors, and patient and family advocates, met for a 2-day consensus conference on November 4 and 5, 2004. After evaluating summary presentations on current research evidence, participants were assigned to three workgroups, examined core issues, and generated consensus guidelines in their areas. Workgroup recommendations were discussed by the whole group to reach consensus, and then further iterated and condensed into this report postconference by the authors., Results: Conference participants agreed that IA is a substantial public health and clinical concern, constitutes a key therapeutic target across multiple disorders, and can be measured with sufficient precision that pharmacological studies are warranted. Additional areas of consensus concerned types of measures, optimal study designs, and ethical imperatives., Conclusion: Derived from scientific evidence and clinical experience, these consensus-driven recommendations can guide the design of future studies.

This practice parameter reviews the literature on the assessment and treatment of children and adolescents with bipolar disorder. The parameter focuses primarily on bipolar 1 disorder because that is the type most often studied in juveniles. The presentation of bipolar disorder in youth, especially children, is often considered atypical compared with that of the classic adult disorder, which is characterized by distinct phases of mania and depression. Children who receive a diagnosis of bipolar disorder in community settings typically present with rapid fluctuations in mood and behavior, often associated with comorbid attention-deficit/hyperactivity disorder and disruptive behavior disorders. Thus, at this time it is not clear whether the atypical forms of juvenile mania and the classic adult form of the disorder represent the same illness. The question of diagnostic continuity has important treatment and prognostic implications. Although more controlled trials are needed, mood stabilizers and atypical antipsychotic agents are generally considered the first line of treatment. Although patients may respond to monotherapy, combination pharmacotherapy is necessary for some youth. Behavioral and psychosocial therapies are also generally indicated for juvenile mania to address disruptive behavior problems and the impact of the illness on family and community functioning.

Background: Past studies have used markedly different inclusion and exclusion criteria to form samples used to evaluate diagnostic tests, making it difficult to compare results across studies. The present investigation compared eight screening algorithms in the same sample but under two different design strategies., Methods: The DSM-IV diagnoses were based on a semi-structured diagnostic interview (KSADS) with the parent and youth sequentially. Raters were blind to index test scores. Participants were 216 youths with bipolar spectrum diagnoses and 284 youths with other Axis I diagnoses or no diagnosis. T-tests evaluated whether areas under the curve (AUC) from receiver operating characteristic analyses differed under the two design conditions., Results: All of the instruments discriminated bipolar cases better when inclusion and exclusion criteria duplicated those used in phenomenological research studies selecting narrow phenotypic cases (AUCs ranging from .90 to .81). The measures performed less well when more heterogeneous clinical presentations were included [AUCs ranging from .86 to .69, t(8) = 4.99, p = 001]., Conclusions: Results indicate that checklists perform less well discriminating pediatric bipolar disorder under conditions that more closely resemble clinical practice. Test users must consider whether the sampling strategies and participant characteristics used to evaluate tests match the characteristics of their own patients.

Objective: To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD)., Method: This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale (RAAPPS), Nisonger Child Behavior Rating Form (NCBRF), and the Conners Parent Rating Scale (CPRS-48). Blood sampling for PK analyses occurred at the end of weeks 2 and 8., Results: Seventeen children (16 boys, mean age 8.9 years) were treated. The mean dose at week 8 was 4.4 mg/kg (SD = 1.1 mg/kg). Significant decreases in the baseline scores of the RAAPPS, and several subscales of the NCBRF and the CPRS were found by the end of the study (p <.05). No patients discontinued because of an adverse event. No patients experienced extrapyramidal side effects. Quetiapine disposition was linear over the dose range studied. The elimination half-life of the drug averaged 3.9 and 2.9 hours and total body clearance averaged 3.5 and 3.0 L/hr/kg after study weeks 2 and 8, respectively., Conclusions: These preliminary data suggest that aggressive children with CD may benefit from quetiapine. The PK of quetiapine supports twice-daily dosing in children with CD.

Objective: Escitalopram is a selective serotonin reuptake inhibitor antidepressant indicated for use in adults. This trial examined the efficacy and safety of escitalopram in pediatric depression., Method: Patients (6-17 years old) with major depressive disorder were randomized to receive 8 weeks of double-blind flexibly dosed treatment with escitalopram (10-20 mg/day; n = 131) or placebo (n = 133). Randomization was not stratified by age. The primary efficacy measure was the mean change from baseline to endpoint in Children's Depression Rating Scale-Revised (CDRS-R) scores, using the last observation carried forward approach., Results: A total of 82% of patients completed treatment. Escitalopram did not significantly improve CDRS-R scores compared to placebo at endpoint (least squares mean difference = -1.7, p = .31; last observation carried forward). In a post hoc analysis of adolescent (ages 12-17 years) completers, escitalopram significantly improved CDRS-R scores compared with placebo (least squares mean difference = -4.6, p = .047). Headache and abdominal pain were the only adverse events in >10% of patients in the escitalopram group. Discontinuation rates caused by adverse events were 1.5% for both groups. Potential suicide-related events were observed in one escitalopram- and two placebo-treated patients. There were no completed suicides., Conclusions: Although there were no significant differences between escitalopram and placebo in the total population, the data suggest that escitalopram may have beneficial effects in adolescent patients. Escitalopram appeared to be well tolerated.

Objective: It has been reported that bipolar disorder may become less responsive to previously effective treatment with each symptomatic relapse. The primary goal of this study was to assess the rate of re-stabilization after the resumption of lithium (Li) plus divalproex (DVPX) following relapse on either agent as monotherapy., Method: This is a prospective, 8-week, open-label outpatient Li/DVPX combination therapy trial. Patients ages 5 to 17 years with bipolar disorder type I or II, who had achieved symptom remission with Li/DVPX combination therapy and subsequently relapsed during treatment with Li or DVPX monotherapy were enrolled between January 1999 and January 2003., Results: Thirty-eight patients with a mean age of 10.5 years entered the study. Thirty-four (89.5%) patients responded to treatment with Li/DVPX mood stabilizer therapy alone, but four patients required adjunctive antipsychotic treatment to address residual symptomatology. Overall, reinitiation of Li/DVPX combination therapy was well tolerated with no subjects discontinuing because of a medication-related adverse event., Conclusions: It appears that most youths with bipolar disorder who stabilize on combination Li/DVPX therapy and subsequently relapse during monotherapy can safely and effectively be re-stabilized with the reinitiation of Li/DVPX combination treatment.

Objective: To assess the efficacy of topiramate monotherapy for acute mania in children and adolescents with bipolar disorder type I., Method: This double-blind, placebo-controlled study was discontinued early when adult mania trials with topiramate failed to show efficacy. Efficacy end points included the Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale for Children, Children's Depression Rating Scale, Children's Global Assessment Scale, and Clinical Global Impressions-Improvement., Results: Fifty-six children and adolescents (6-17 years) with a diagnosis of bipolar disorder type I received topiramate (n=29, 52%) or placebo (n=27, 48%). The only statistically significant differences in efficacy measures between treatment groups were the difference between slopes of the linear mean profiles of the YMRS (p=.003) using a post hoc repeated measures regression and the change in Brief Psychiatric Rating Scale for Children at day 28 (-14.9 versus-5.9, p=.048) using observed data. Adverse events with topiramate included decreased appetite, nausea, diarrhea, and paresthesia., Conclusions: Topiramate was well tolerated; however, the results are inconclusive because of premature termination resulting in a limited sample size. Adequately powered controlled trials are necessary to determine whether topiramate has efficacy in reducing symptoms of acute mania in children and adolescents.

Objective: To determine whether divalproex sodium (DVPX) was superior to lithium carbonate (Li+) in the maintenance monotherapy treatment of youths diagnosed with bipolar disorder who had been previously stabilized on combination Li+ and DVPX (Li+/DVPX) pharmacotherapy., Method: Youths ages 5-17 years with bipolar I or II disorder were initially treated with Li /DVPX. Patients meeting remission criteria for four consecutive weeks were then randomized in a double-blind fashion to treatment with either Li+ or DVPX for up to 76 weeks. Study participation ended if the subject required additional clinical intervention or if the subject did not adhere to study procedures., Results: Patients were recruited between July 1998 and May 2002. One hundred thirty-nine youths with a mean (SD) age of 10.8 (3.5) years were initially treated with Li+/DVPX for a mean (SD) duration of 10.7 (5.4) weeks. Sixty youths were then randomized to receive monotherapy with Li+ (n = 30) or DVPX (n = 30). The Li+ and DVPX treatment groups did not differ in survival time until emerging symptoms of relapse (p = .55) or survival time until discontinuation for any reason (p = .72)., Conclusions: DVPX was not found to be superior to Li+ as maintenance treatment in youths who stabilized on combination Li+/DVPX pharmacotherapy.

Clinicians who treat children and adolescents with bipolar disorder desperately need current treatment guidelines. These guidelines were developed by expert consensus and a review of the extant literature about the diagnosis and treatment of pediatric bipolar disorders. The four sections of these guidelines include diagnosis, comorbidity, acute treatment, and maintenance treatment. These guidelines are not intended to serve as an absolute standard of medical or psychological care but rather to serve as clinically useful guidelines for evaluation and treatment that can be used in the care of children and adolescents with bipolar disorder. These guidelines are subject to change as our evidence base increases and practice patterns evolve.

Objective: To determine the long-term safety and effectiveness of risperidone for severe disruptive behaviors in children., Method: A multisite, 1-year, open-label study of patients aged 5 to 14 years with disruptive behaviors and subaverage intelligence was conducted., Results: Seventy-three percent of the 504 patients enrolled completed the study. The mean +/- SE dose of risperidone was 1.6 +/- 0.0 mg/day. The most common adverse events were somnolence (30%), rhinitis (27%), and headache (22%). The incidence of movement disorders was low, and mean Extrapyramidal Symptom Rating Scale scores decreased during risperidone treatment. No clinically significant changes in mean laboratory values were noted, except for a transient increase in serum prolactin levels. Scores on the Nisonger Child Behavior Rating Form Conduct Problem Scale improved significantly as early as week 1, and improvement was maintained throughout the trial (p < .001 at each time point). Significant improvements were noted on positive social behavior and other Nisonger Child Behavior Rating Form subscales, Aberrant Behavior Checklist, Clinical Global Impressions scale, and tests of patients' cognitive function (each p < .001)., Conclusions: Risperidone was well tolerated and effective in the long-term treatment of disruptive behavior disorders in children with subaverage intelligence.

Of the placebo-controlled maintenance studies conducted in bipolar disorder, few have enrolled patients who present depressed. In fact, only lithium and lamotrigine have been studied over the long term with placebo-controlled designs in recently manic and recently depressed bipolar patients. Given the magnitude of the unmet medical need and the data suggesting that symptomatic patients with bipolar disorder spend the majority of their time depressed, this is unfortunate. Our review of the pre-lithium literature and more recent publications suggests that mood state at study entry predicts the polarity of relapse and the response to treatment. Accordingly, a need exists to enroll recently depressed patients in maintenance studies to elucidate the complete spectrum of efficacy of putative mood stabilizers and improve the long-term treatment of bipolar depression. Patients presenting depressed for a maintenance study tend to relapse into depression; those presenting manic, into hypomania/mania/mixed states. This is particularly true during the first several months of the randomized treatment. The polarity of the index episode tends to predict the polarity of relapse into a subsequent episode in a ratio of about 2:1 to 3:1. We conclude that putative mood stabilizers must be tested in recently manic and recently depressed patients to determine their spectrum of prophylactic efficacy.