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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.

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.

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.

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.

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.

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 (

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.

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.

Objectives: In this 6-month open-label extension (OLE) of NCT01491035 (a 14-day, open-label, pharmacokinetic/safety lead-in study), the long-term safety and tolerability of vortioxetine (5–20 mg/day) were investigated in children and adolescents with a DSM-IV-TR™ diagnosis of depressive or anxiety disorder in the United States or Germany. The study also was designed to provide data to inform dose selection and titration in future pediatric studies with vortioxetine. Methods: Safety evaluations included spontaneously reported adverse events (AEs), the Columbia Suicide Severity Rating Scale (C-SSRS), and the Pediatric Adverse Events Rating Scale (PAERS; clinician administered). Clinical effectiveness was determined by Clinical Global Impressions. Comorbid attention-deficit/hyperactivity disorder was permitted, including concomitant use of stimulant medication (US sites only). Results: Of the 47 patients who completed the lead-in period, 41 continued into the OLE. Most patients (n = 39 [95%]) continued their previous dose regimen. Twenty-one patients (51%) withdrew during the OLE; the most common primary reasons were administrative [n = 8], AEs [n = 4], and lack of efficacy [n = 3]. Thirty-five patients (85%) had ≥1 AE, 86% of which were mild or moderate in severity. Five patients (12%) reported a severe AE, none of which was considered related to study medication. The most common AEs (≥10%) were headache (27%), nausea (20%), dysmenorrhea (females; 19%), and vomiting (15%), with no relationship between AE intensity and age or dose. Five patients reported instances of suicidal ideation during the OLE, one of whom also reported this during the lead-in period. Two patients had nonsuicidal self-injurious behavior; one had a nonfatal suicide attempt. Throughout the study, there was a decrease over time in the incidence and intensity of AEs collected using the PAERS. Effectiveness assessment indicated a trend toward improvement based on numeric results. Conclusion: This OLE confirms the findings from the lead-in study, which concluded that a dosing strategy of 5–20 mg/day is safe, well tolerated, and suitable for future clinical studies of vortioxetine in pediatric patients.

Objective: To evaluate the short-term efficacy and safety of desvenlafaxine versus placebo in the treatment of children and adolescents with major depressive disorder (MDD). Methods: Outpatient children (7–11 years) and adolescents (12–17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8 weeks of treatment with placebo, low exposure desvenlafaxine (20, 30, or 35 mg/day based on baseline weight), or higher exposure desvenlafaxine (25, 35, or 50 mg/day based on baseline weight). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy assessments included Clinical Global Impressions-Severity and Clinical Global Impressions-Improvement scales. Safety assessments included adverse events and the Columbia-Suicide Severity Rating Scale. Results: The safety population included 363 patients (children, n = 109; adolescents, n = 254). No statistical separation from placebo was observed for either desvenlafaxine group for CDRS-R total score or for any secondary efficacy endpoint. At week 8, adjusted mean (standard error) changes from baseline in CDRS-R total score for the desvenlafaxine low exposure, desvenlafaxine high exposure, and placebo groups were −23.7 (1.1), −24.4 (1.1), and −22.9 (1.1), respectively. The incidence of adverse events was similar among groups. Conclusion: Low and high exposure desvenlafaxine groups did not demonstrate efficacy for the treatment of MDD in children and adolescents in this double-blind, placebo-controlled trial. Desvenlafaxine (20–50 mg/day) was generally safe and well tolerated with no new safety signals identified in pediatric patients with MDD in this study.

To determine if acute treatment with aripiprazole (APZ) would be superior to treatment with placebo in reducing dysfunctional symptoms of elevated mood and/or irritability in symptomatic children and adolescents at familial high risk for bipolar disorder (BPD) whose mood episodes occur spontaneously. These are patients we have previously referred to as suffering from "cyclotaxia."This was single-site, randomized, double-blind, placebo-controlled outpatient clinical trial in which youths aged 5-17 years who met diagnostic criteria for either cyclothymic disorder (CYC) or BPD not otherwise specified (BP-NOS) were randomly assigned to receive either APZ or placebo. Eligible participants had at least one parent with BPD, another first- or second-degree relative afflicted with a mood disorder, and also had not responded to psychotherapy. Treatment with APZ was initiated at a dose of approximately 0.1 mg/kg/day and could be increased by approximately 0.05 mg/kg/day at each study visit. Patients were seen weekly for 4 weeks and then every other week thereafter for 12 weeks. The primary outcome measure was mean change from baseline on Young Mania Rating Scale (YMRS) total score.A total of 59 patients (30 APZ, 29 placebo) aged 11.8 (SD = 2.7) years were randomized and returned for at least one postbaseline assessment. The mean total daily doses of active APZ and placebo were 7.1 mg (SD = 3.7) and 7.4 mg (SD = 4.2), respectively. At the 12-week time point, APZ was superior to placebo on the primary outcome measure (p 0.005). Most adverse events were mild and transient in nature. There was a significant difference in weight gain from baseline between patients who received APZ (2.3 kg [SD = 3.3]) and those who received placebo (0.7 kg [SD = 1.8]).This double-blind trial found that APZ was significantly more efficacious than placebo in reducing symptoms of mania in children and adolescents with cyclotaxia.

Objective: To evaluate the efficacy and safety of lurasidone in acutely symptomatic adolescent patients with schizophrenia. Methods: Patients aged 13–17 years were randomly assigned to 6 weeks of double-blind, fixed-dose lurasidone (40 or 80 mg/day) or placebo. Primary and key secondary efficacy measures were change from baseline to week 6 in the Positive and Negative Symptom Scale (PANSS) total score and Clinical Global Impressions-Severity (CGI-S) score, respectively, using mixed model for repeated measurement (MMRM) analysis. The proportion of patients achieving treatment response at endpoint, based on ≥20% reduction in PANSS total score, was analyzed using a logistic regression model. Results: Least-squares (LS) mean change in PANSS total score from baseline to week 6 was −18.6 with lurasidone 40 mg/day (N = 108; p

Professionals have periodically expressed concern that atypical antipsychotics may cause cognitive blunting in treated patients. In this study, we report data from a double-blind, randomized, controlled study of stimulant plus placebo versus combined stimulant and risperidone to evaluate the effects of the atypical antipsychotic on attention and short-term memory.A total of 165 (n = 83 combined treatment; n = 82 stimulant plus placebo) children with attention-deficit/hyperactivity disorder and severe physical aggression, aged 6-12 years, were evaluated with Conners' Continuous Performance Test (CPT-II) and the Wechsler Intelligence Scale for Children-III (WISC) Digit Span subscale at baseline, after 3 weeks of stimulant-only treatment, and after six additional weeks of randomized treatment (stimulant+placebo vs. stimulant+risperidone).At 3 weeks, improvement on CPT-II performance (Commissions and Reaction Time Standard Error; p 0.001) and on Digit Span memory performance (p 0.006) was noted for the full sample. At study week 9, no difference in CPT-II or Digit Span performance was observed between the randomized groups (ps = 0.41 to 0.83).Similar to other studies, we found no deleterious effects on attention and short-term memory associated with short-term use of risperidone. NCT00796302.

Previous "Treatment of Severe Childhood Aggression" (TOSCA) reports demonstrated that many children with severe physical aggression and attention-deficit/hyperactivity disorder (ADHD) responded well to two randomized treatments (parent training [PT]+stimulant+placebo = Basic vs. PT+stimulant+risperidone = Augmented) for 9 weeks. An important clinical question is whether these favorable outcomes are maintained over longer times.Clinical responders to the 9-week trial (n = 103/168), defined as Clinical Global Impressions (CGI)-Improvement of much/very much improved plus substantial reduction in parent ratings of disruptiveness, were followed another 12 weeks (21 weeks total) while remaining on blinded treatment. Outcome measures included Clinical Global Impressions scale, Nisonger Child Behavior Rating Form (NCBRF), other parent/teacher-rated scales, laboratory tests, clinician ratings of abnormal movement, and other adverse events (AEs).Parent ratings of problem behavior showed minimal worsening of behavior from end of the 9-week acute trial (expected from regression to the mean after selecting best responders), but outcomes at Extension endpoint were meaningfully improved compared with acute study baseline. As expected, outcomes for Basic and Augmented treatment did not differ among these children selected for good clinical response. During Extension, more Augmented subjects had elevated prolactin; there were no clinically confirmed cases of tardive dyskinesia. Delayed sleep onset was the most frequent Basic AE. We also conducted a last-observation-carried-forward analysis, which included both nonresponders and responders. We found that, at the end of Extension, Augmented subjects had more improvement than Basic subjects on the NCBRF Positive Social subscale (p = 0.005; d = 0.44), the Antisocial Behavior Scale Reactive Aggression subscale (p = 0.03; d = 0.36), and marginally so on the Disruptive Behavior Total subscale (p = 0.058; d = 0.29, the primary outcome).The medium-term outcomes were good for the participants in both treatment groups, perhaps because they were selected for good response. When nonresponders were included in ITT analyses, there was some indication that Augmented surpassed Basic treatment.

To investigate the safety and pharmacokinetic profile of ascending doses of desvenlafaxine in children and adolescents with major depressive disorder. Assessment of the effect of desvenlafaxine on depression symptoms was exploratory.The 8-week, open-label study included an initial 3.5-day inpatient period followed by a 7.5-week outpatient period. Children (7-11 years) received a single desvenlafaxine dose of 10, 25, 50, or 100 mg on day 1; adolescents (12-17 years) received desvenlafaxine 25, 50, 100, or 200 mg/day. Plasma and urine samples were collected over the initial 72-hour inpatient period. Evaluations included treatment-emergent adverse events (TEAEs), physical examinations (including Tanner Staging), vital signs, laboratory assessments, 12-lead electrocardiogram, Columbia-Suicide Severity Rating Scale, and the Children's Depression Rating Scale-Revised (CDRS-R).In all, 29 children and 30 adolescents took at least one dose of desvenlafaxine and were included in the safety population (children: 10 mg, n = 6; 25 mg, n = 7; 50 mg, n = 9; 100 mg, n = 7; adolescents: 25 mg, n = 7; 50 mg, n = 7; 100 mg, n = 8; 200 mg, n = 8). Total area under the drug concentration-time curve from 0 to infinity (AUC) appeared to increase linearly with increasing dose. Mean (standard deviation [SD]) AUC ranged from 628 (346) ng/mL (desvenlafaxine 10 mg) to 6732 (3031) ng/mL (100 mg) in children and from 1123 (361) ng/mL (25 mg) to 11,730 (3113) ng/mL (200 mg) in adolescents. During the combined inpatient and outpatient period, 16/29 (55%) children and 21/30 (70%) adolescents reported at least one TEAE. One serious adverse event (suicidal behavior) was reported. Mean (SD) change from baseline in CDRS-R total scores at week 8 was -19.00 (9.87) for children and -21.57 (11.50) for adolescents.Desvenlafaxine AUC values increased linearly with dose; body weight alone provided an adequate prediction for dose-normalized AUC. Desvenlafaxine was generally safe and well tolerated in children and adolescents for treatment up to 8 weeks.

Objective: Impulsive aggression (IA) is a maladaptive form of aggressive behavior that is an associated feature of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). As one of the most common forms of aggressive behavior, IA is a serious clinical concern. Recognition, monitoring, and management of IA symptoms are complicated by the lack of IA-specific psychometric instruments and evidence-based treatments. A recently developed electronic observer-reported outcome instrument has been validated in children for monitoring the frequency of 15 IA-related behaviors in the context of ADHD. This study seeks to first determine if the behaviors included in the pediatric IA diary are applicable to adolescents with ADHD, and second, compare the reliability of adolescent versus parent reporters. Methods: We evaluated the utility of the pediatric IA diary through concept elicitation and cognitive interviews with 17 pairs of parents and adolescents (aged 13-17 years) with IA and ADHD, supplemented with 15 new behaviors potentially applicable to adolescents. Results: The behaviors most frequently reported by adolescents included arguing (93.8%), raising their voice/shouting/yelling (93.8%), hitting others (87.5%), slamming (87.5%), pushing/shoving (81.3%), breaking (75.0%), fighting (75.0%), throwing (75.0%), and cursing (68.8%). The behaviors most commonly reported by parents included raising their voice/shouting/yelling (94.1%), arguing (88.2%), being disrespectful/mean/rude (88.2%), slamming (88.2%), throwing (88.2%), cursing (82.4%), hitting others (82.4%), pushing/shoving (82.4%), breaking (76.5%), name-calling (76.5%), and threatening (70.6%). Of all commonly reported behaviors, only being "disrespectful/mean/rude" and "breaking" are not part of the pediatric IA diary, likely due to the imprecision of these terms. No significant usability issues were found for the IA diary device. Conclusions: These findings suggest that the 15-item pediatric IA diary should be applicable to adolescent populations to appropriately characterize IA behaviors in individuals with ADHD. Furthermore, this study indicated that parents may be more reliable reporters of IA behavior than adolescents.

Dasotraline is a potent inhibitor of presynaptic dopamine and norepinephrine reuptake with a pharmacokinetic profile characterized by slow absorption and a long elimination half-life. The aim of this study was to evaluate the efficacy and safety of dasotraline in children with attention-deficit/hyperactivity disorder (ADHD).Children aged 6-12 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD were randomized to 6 weeks of double-blind once-daily treatment with dasotraline (2 or 4 mg) or placebo. The primary efficacy endpoint was change from baseline in the ADHD Rating Scale Version IV-Home Version (ADHD RS-IV HV) total score at week 6.A total of 342 patients were randomized to dasotraline or placebo (mean age 9.1 years, 66.7% male). Treatment with dasotraline was associated with significant improvement at study endpoint in the ADHD RS-IV HV total score for the 4 mg/day dose versus placebo (-17.5 vs. -11.4; p 0.001; effect size [ES], 0.48), but not for the 2 mg/day dose (-11.8 vs. -11.4; ns; ES, 0.03). A regression analysis confirmed a significant linear dose-response relationship for dasotraline. Significant improvement for dasotraline 4 mg/day dose versus placebo was also observed across the majority of secondary efficacy endpoints, including the Clinical Global Impression (CGI)-Severity score, the Conners Parent Rating Scale-Revised scale (CPRS-R) ADHD index score, and subscale measures of hyperactivity and inattentiveness. Discontinuation rates due to adverse events (AEs) were higher in the dasotraline 4 mg/day group (12.2%) compared with the 2 mg/day group (6.3%) and placebo (1.7%). The most frequent AEs associated with dasotraline were insomnia, decreased appetite, decreased weight, and irritability. Psychosis-related symptoms were reported as AEs by 7/219 patients treated with dasotraline in this study. There were no serious AEs or clinically meaningful changes in blood pressure or heart rate on dasotraline.In this placebo-controlled study, treatment with dasotraline 4 mg/day significantly improved ADHD symptoms and behaviors, including attention and hyperactivity, in children aged 6-12 years. The most frequently reported AEs observed on dasotraline included insomnia, decreased appetite, decreased weight, and irritability.

Research on adults with cyclothymic disorder (CycD) suggests that irritability and impulsive aggression (IA) are highly prevalent among this population. Less is known about whether these behaviors might also distinguish youth with CycD from youth without CycD. Additionally, little is known about how irritability and IA relate to one another, and whether they are associated with different outcomes. This study aimed to compare irritability and IA across diagnostic subtypes to determine whether CycD is uniquely associated with these behaviors, and to assess how irritability and IA relate to youth social and general functioning.Participants (n = 459), 11-18 years of age, were recruited from an urban community mental health center and an academic outpatient clinic; 25 had a diagnosis of CycD. Youth and caregivers completed measures of IA and irritability. Youth and caregivers also completed an assessment of youth friendship quality. Clinical interviewers assessed youth social, family, and school functioning.Youth with CycD had higher scores on measures of irritability and IA than youth with nonbipolar disorders, but scores were not different from other youth with bipolar spectrum disorders. Measures of irritability and IA were correlated, but represented distinct constructs. Regression analyses indicated that irritability was related to friendship quality (p 0.005). Both IA and irritability were related to social impairment (ps 0.05-0.0005) and Child Global Assessment Scale (C-GAS) scores (ps = 0.05-0.005). CycD diagnosis was associated with poorer caregiver-rated friendship quality and social functioning (ps0.05).We found that irritability and aggression were more severe among youth with CycD than among youth with nonbipolar diagnoses, but did not differ across bipolar disorder subtypes. Among youth seeking treatment for mental illness, irritability and IA are prevalent and nonspecific. Irritability and IA were uniquely related to our outcomes of social and general functioning, suggesting that it is worthwhile to assess each separately, in order to broaden our understanding of the characteristics and correlates of each.

The purpose of this study was to examine the satisfaction of families who participated in the Treatment of Severe Childhood Aggression (TOSCA) study.TOSCA was a randomized clinical trial of psychostimulant plus parent training plus placebo (basic treatment) versus psychostimulant plus parent training plus risperidone (augmented treatment) for children with severe physical aggression, disruptive behavior disorder, and attention-deficit/hyperactivity disorder. Parents completed a standardized Parent Satisfaction Questionnaire (PSQ).Of the 168 families randomized, 150 (89.3%) provided consumer satisfaction data. When they were asked if they would join the study again if they had the option to repeat, 136 (91%) said "yes," 11 (7%) said "maybe," and one (1%) said "no." When asked if they would recommend the study to other parents with children having similar problems, 147 (98%) said "yes" and 3 (2%) said "maybe." Between 71% (rating one aspect of the Parent Training) and 96% (regarding the diagnostic interview) endorsed study procedures using the most positive response option. Asked if there were certain aspects of the study that they especially liked, 64 (43%) spontaneously reported parent training. Treatment assignment (basic vs. augmented) and responder status were not associated with reported satisfaction. However, responder status was strongly associated with parent confidence in managing present (p0.001) and future (p0.005) problem behaviors.These findings indicate high levels of satisfaction with TOSCA study involvement and, taken together with previous pediatric psychopharmacology social validity studies, suggest high levels of support for the research experience. These findings may inform research bioethics and may have implications for deliberations of institutional review boards.Treatment of Severe Childhood Aggression (The TOSCA Study), NCT00796302, clinicaltrials.gov .

OBJECTIVE: In this study, we evaluated parent and child characteristics as predictors and moderators of response in the four-site Treatment of Severe Childhood Aggression (TOSCA) study. METHODS: A total of 168 children with severe aggression, disruptive behavior disorder, and attention-deficit/hyperactivity disorder (ADHD) were enrolled in a 9-week trial of basic treatment (n=84, stimulant+parent training+placebo) versus augmented treatment (n=84, stimulant+parent training+risperidone). In the initial report, augmented treatment surpassed basic treatment in reducing the primary outcome of disruptive behavior (D-Total) scores. In the current study, we evaluated parent (income, education, family functioning, employment) and child variables (intelligence quotient [IQ], aggression type, comorbid symptomatology) as predictors or moderators, using linear mixed models and the MacArthur guidelines. RESULTS: Higher scores on ADHD symptom severity and callous/unemotional traits predicted better outcome on D-Total regardless of treatment assignment. Two moderators of D-Total were found: Higher anger/irritability symptoms and lower mania scores were associated with faster response, although not better overall effect at endpoint, in the augmented but not the basic group. Several variables moderated response on secondary outcomes (ADHD severity and prosocial behavior), and were characterized by faster response, although not better outcome, in the augmented but not in the basic group. Maternal education moderated outcome on the measure of positive social behavior; children of mothers with less education benefited more from augmented treatment relative to basic than those with more education. CONCLUSION: Although these findings require validation, they tentatively suggest that augmented treatment works equally well across the entire sample. Nevertheless, certain child characteristics may be useful indicators for the speed of response to augmented treatment. Language: en

Objective: The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials. Methods: This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20 mg q.d. for 14 days. The total treatment period lasted 14–20 days with patients in the higher dose cohorts uptitrated over 2–6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing. Results: Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration–time curve from time 0 to 24 hours, was 30%–40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults. Conclusion: The results suggest that the dosages of vortioxetine evaluated (5–20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials.

The purpose of this study was to assess the effect of guanfacine extended release (GXR) adjunctive to a psychostimulant on oppositional symptoms in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).A multicenter, double-blind, placebo-controlled dose-optimization study of GXR (1-4 mg/d) or placebo administered morning (a.m.) or evening (p.m.) adjunctive to psychostimulant was conducted in subjects ages 6-17 with suboptimal response to psychostimulant alone. Suboptimal response was defined as treatment with a stable dose of psychostimulant for ≥4 weeks with ADHD Rating Scale IV total score ≥24 and Clinical Global Impressions-Severity of Illness score ≥3, as well as investigator opinion. Primary efficacy and safety results have been reported previously. Secondary efficacy measures included the oppositional subscale of the Conners' Parent Rating Scale-Revised: Long Form (CPRS-R:L); these are reported herein.Significant reductions from baseline to the final on-treatment assessment on the oppositional subscale of the CPRS-R:L were seen with GXR plus psychostimulant compared with placebo plus psychostimulant, both in the overall study population (placebo-adjusted least squares [LS] mean change from baseline to the final on-treatment assessment: GXR a.m.+psychostimulant, -2.4, p=0.001; GXR p.m.+psychostimulant, -2.2, p=0.003) as well as in the subgroup of subjects with significant baseline oppositional symptoms (GXR a.m.+psychostimulant, -3.6, p=0.001; GXR p.m.+psychostimulant, -2.7, p=0.013). Treatment-emergent adverse events were reported by 77.3%, 76.3%, and 63.4% of subjects in the GXR a.m., GXR p.m., and placebo groups, respectively, in the overall study population.GXR adjunctive to a psychostimulant significantly reduced oppositional symptoms compared with placebo plus a psychostimulant in subjects with ADHD and a suboptimal response to psychostimulant alone.

The purpose of this study was to evaluate the short- and long-term efficacy, safety, and tolerability of ziprasidone in adolescents with schizophrenia.Subjects ages 13-17 years with schizophrenia (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. [DSM-IV]) were enrolled in a 6 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized in a 2:1 ratio to flexible-dose oral ziprasidone (40-160 mg/day, based on weight) or placebo. Primary end-point was change from baseline in Brief Psychiatric Rating Scale-Anchored (BPRS-A) total score. Safety assessments included adverse events, vital signs, laboratory measures, electrocardiograms, weight and body mass index, and movement disorder ratings.Planned interim analysis for the primary end-point in the RCT resulted in early termination of both studies because of futility. In the RCT, 283 subjects received ziprasidone (n=193) or placebo (n=90). In the intent-to-treat analysis population, the least squares mean (SE) BPRS-A score decrease from baseline at week 6 was not significantly different (p=0.15; -14.16 [0.78] for ziprasidone and -12.35 [1.05] for placebo). Per-protocol analysis was significant (p=0.02). In the OLE, 221 subjects entered the OLE and received ziprasidone for a median of 99 days. The mean (SD) change in BPRS-A score from end of RCT to end of OLE (last observation carried forward) was -6.9 (8.9). The most common treatment-emergent adverse events (≥ 10%) for all causalities during the RCT were somnolence and extrapyramidal disorders, and during OLE was somnolence only. No subjects had Fridericia's corrected QT (QTcF) ≥ 500 ms in the RCT or OLE phases. One completed suicide occurred during the OLE phase. For RCT and OLE, no clinically significant changes were reported in metabolic indices and laboratory measures.Ziprasidone failed to separate from placebo in treatment of schizophrenia in adolescents. Ziprasidone was generally well tolerated with an overall neutral weight and metabolic profile.NCT00257192 and NCT00265382 at ClinicalTrials.gov .

The purpose of this study was to evaluate the short- and long-term efficacy and safety of ziprasidone in children and adolescents with bipolar I disorder.Subjects 10-17 years of age with a manic or mixed episode associated with bipolar I disorder participated in a 4 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized 2:1 to initially receive flexible-dose ziprasidone (40-160 mg/day, based on weight) or placebo. Primary outcome was the change in Young Mania Rating Scale (YMRS) scores from baseline. Safety assessments included weight and body mass index (BMI), adverse events (AEs), vital signs, laboratory measures, electrocardiograms, and movement disorder ratings.In the RCT, 237 subjects were treated with ziprasidone (n=149; mean age, 13.6 years) or placebo (n=88; mean age, 13.7 years). The estimated least squares mean changes in YMRS total (intent-to-treat population) were -13.83 (ziprasidone) and -8.61 (placebo; p=0.0005) at RCT endpoint. The most common AEs in the ziprasidone group were sedation (32.9%), somnolence (24.8%), headache (22.1%), fatigue (15.4%), and nausea (14.1%). In the OLE, 162 subjects were enrolled, and the median duration of treatment was 98 days. The mean change in YMRS score from the end of the RCT to the end of the OLE (last observation carried forward) was -3.3 (95% confidence interval, -5.0 to -1.6). The most common AEs were sedation (26.5%), somnolence (23.5%), headache (22.2%), and insomnia (13.6%). For both the RCT and the OLE, no clinically significant mean changes in movement disorder scales, BMI z-scores, liver enzymes, or fasting lipids and glucose were observed. One subject on ziprasidone in the RCT and none during the OLE had Fridericia-corrected QT interval (QTcF) ≥ 460 ms.These results demonstrate that ziprasidone is efficacious for treating children and adolescents with bipolar disorder. Ziprasidone was generally well tolerated with a neutral metabolic profile.NCT00257166 and NCT00265330 at ClinicalTrials.gov.

The purpose of this study was to describe the safety, tolerability, and efficacy of quetiapine monotherapy continued for up to 26-weeks in youth with schizophrenia or bipolar I disorder.Medically healthy boys and girls with a baseline Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) diagnosis of schizophrenia (ages 13-17 years) or a manic episode of bipolar I disorder (ages 10-17 years) who participated in one of two acute, double-blind, placebo-controlled studies of immediate-release quetiapine were potentially eligible to enroll in a 26-week, open-label study. During the open-label study, quetiapine was flexibly dosed at 400-800 mg/day, with options to reduce dosing to 200 mg/day based on tolerability. Safety and tolerability outcomes assessed from open-label baseline to week 26 included adverse events (AEs), metabolic/laboratory parameters, extrapyramidal symptoms, suicidality, and vital signs.Of 381 patients enrolled in the open-label study (n=176, schizophrenia; n=205, bipolar disorder diagnosis), 237 patients (62.2%) completed the 26-week study period (71.0%, schizophrenia; 54.6%, bipolar disorder). The most common AEs reported during the study included somnolence, headache, sedation, weight increase, and vomiting. A total of 14.9% of patients experienced a shift to potentially clinically significant low levels of high-density lipoprotein cholesterol and 10.2% of patients experienced a shift to potentially clinically significant high triglyceride levels. Weight gain ≥ 7% was reported in 35.6% of patients between open-label baseline and final visit. After adjustment for normal growth, 18.3% of study participants experienced clinically significant weight gain (i.e., increase in body mass index ≥ 0.5 standard deviations from baseline).In this 26-week study, quetiapine flexibly dosed at 400-800 mg/day, with options to reduce dosing based on tolerability, was generally safe and well tolerated in youth. Clinicians should monitor lipid profiles and weight gain in youth with schizophrenia or bipolar disorder during treatment with quetiapine.

This study examined the long-term effectiveness of lithium for the treatment of pediatric bipolar disorder within the context of combination mood stabilizer therapy for refractory mania and pharmacological treatment of comorbid psychiatric conditions.Outpatients, ages 7-17 years, meeting American Psychiatric Association, diagnostic and statistical manual of mental disorders, 4th ed. (DSM-IV) diagnostic criteria for bipolar disorder I (BP-I) (manic or mixed) who demonstrated at least a partial response to 8 weeks of open-label treatment with lithium (phase I) were eligible to receive open-label lithium for an additional 16 weeks (phase II). Up to two adjunctive medications could be prescribed to patients experiencing residual symptoms of mania or comorbid psychiatric conditions, following a standardized algorithm.Forty-one patients received continued open-label long-term treatment with lithium for a mean of 14.9 (3.0) weeks during phase II. The mean weight-adjusted total daily dose at end of phase II was 27.8 (6.7) mg/kg/day, with an average lithium concentration of 1.0 (0.3) mEq/L. Twenty-five of the 41 patients (60.9%) were prescribed adjunctive psychotropic medications for residual symptoms. The most frequent indications for adjunctive medications were refractory mania (n=13; 31.7%) and attention-deficit/hyperactivity disorder (ADHD) (n=15; 36.6%). At the end of this phase 28 (68.3%) patients met a priori criteria for response (≥50% reduction from phase I baseline in young mania rating scale [YMRS] summary score and a clinical global impressions-improvement [CGI-I] score of 1 or 2), with 22 (53.7%) considered to be in remission (YMRS summary score≤12 and CGI-severity score of 1 or 2). These data suggest that patients who initially responded to lithium maintained mood stabilization during continuation treatment, but partial responders did not experience further improvement during Phase II, despite the opportunity to receive adjunctive medications. The most commonly reported (≥20%) adverse events associated with lithium treatment were vomiting, headache, abdominal pain, and tremor.Lithium may be a safe and effective longer-term treatment for patients with pediatric bipolar disorder who respond to acute treatment with lithium. Partial responders to acute lithium did not appear to experience substantial symptom improvement during the continuation phase, despite the possibility that adjunctive medications could be prescribed.

The purpose of this open-label study was to describe the effectiveness of aripiprazole (APZ) in the treatment of children with bipolar disorders suffering from manic symptomatology.Symptomatic outpatients (Young Mania Rating Scale [YMRS] score ≥15) meeting strict, unmodified, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic symptom criteria for a bipolar disorder, ages 4-9 years, were eligible. Subjects were treated prospectively with flexible doses of APZ (maximum daily dose of 15 mg/day), for up to 16 weeks or until a priori response criteria were met. Outcome measures included the YMRS, Clinical Global Impressions Scale-Severity, Children's Global Assessment Scale (CGAS), and the Children's Depression Rating Scale-Revised (CDRS-R). A priori response criteria consisted of 3 of 4 consecutive weeks with (1) CDRS-R29; (2) YMRS10; and (3) CGAS50.Ninety-six children (62 males; mean age of 6.9 (SD = 1.7), received APZ for an average length of treatment of 12.5 (SD = 3.9) weeks. Significant improvements in YMRS, CDRS-R, CGAS, and Clinical Global Impressions Scale-Severity scores (p 0.001) were noted at the end of study participation. Sixty of the subjects (62.5%) met a priori response criteria at study's end. The most common side effects noted were stomachache, increased appetite, and headache. Two subjects were removed from the study due to side effects [epistaxis (n = 1); akathisia (n = 1)]. Subjects experienced an average weight gain of 2.4 (SD = 1.9) kg.APZ may be effective in the acute treatment of symptoms of children with bipolar illnesses.

This study explored the demographic and diagnostic features of children who were currently receiving antipsychotics compared to children who were receiving other psychotropics in a cohort of children with and without elevated symptoms of mania (ESM). Participants were recruited from 10 child outpatient mental health clinics associated with four universities. Guardians with children between 6–12 years who presented for new clinical evaluations completed the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M). All children who scored ≥12 on the PGBI-10M and a select demographically matched comparison group of patients who scored ≤11 were invited to participate. Children were divided into two groups: those receiving at least one antipsychotic medication and those receiving other psychotropic medications. The groups were compared on demographics, diagnoses, psychiatric symptoms, functioning, and past hospitalizations. Of the 707 children enrolled in the Longitudinal Assessment of Manic Symptoms (LAMS) study, 443 (63%) were prescribed psychotropic medication at baseline: 157 (35%) were receiving an antipsychotic and 286 (65%) were prescribed other agents. Multivariate results indicated that being prescribed antipsychotics was related to being white, previous hospitalization, having a psychotic or bipolar 1 disorder and the site where the child was receiving services (p

The primary goal of this exploratory study was to obtain data that could lead to evidence-based dosing strategies for lithium in children and adolescents suffering from bipolar I disorder.Outpatients aged 7-17 years meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic criteria for bipolar I disorder (manic or mixed) were eligible for 8 weeks of open label treatment with lithium in one of three dosing arms. In Arm I, participants began treatment at a dose of 300 mg of lithium twice daily. The starting dose of lithium in Arms II and III was 300 mg thrice daily. Patients in Arms I and II could have their dose increased by 300 mg/day, depending on clinical response, at weekly visits. Patients in Arm III also had mid-week telephone interviews after which they could also have their dose of lithium increased by 300 mg per day. Youths weighing30 kg were automatically assigned to Arm I, whereas youths weighing ≥30 kg were randomly assigned to Arm I, II, or III. Randomization was balanced by age (7-11 years, 12-17 years) and sex in approximately equal numbers. A priori response criteria were defined as a Clinical Global Impressions-Improvement scale score of ≤ 2 and a 50% decrease from baseline on the Young Mania Rating Scale.Of the 61 youths [32 males (52.5%)] who received open-label lithium, 60 youths completed at least 1 week of treatment and returned for a postbaseline assessment. Most patients had a ≥ 50% improvement in Young Mania Rating Scale score, and more than half of the patients (58%) achieved response. Overall, lithium was well tolerated. All three treatment arms had similar effectiveness, side effect profiles, and tolerability of lithium.On the basis of these results, a dosing strategy in which pediatric patients begin lithium at a dose of 300 mg thrice daily (with an additional 300 mg increase during the first week), followed by 300 mg weekly increases until a priori stopping criteria are met, will be used in an upcoming randomized, placebo-controlled trial.

To assess the effects of lisdexamfetamine dimesylate (LDX) on executive function (EF) behaviors in children with attention-deficit/hyperactivity disorder (ADHD).This observational, open-label, 7-week, dose-optimization study of LDX (20-70 mg/day) in children with ADHD evaluated efficacy with the ADHD Rating Scale IV; safety measures included adverse events (AEs). EF was assessed with the Behavior Rating Inventory of Executive Function (BRIEF). Post hoc analyses examined BRIEF scores by sex, ADHD subtype, comorbid psychiatric symptoms, and common treatment-emergent AEs (TEAEs). ADHD Rating Scale IV scores were assessed in subjects categorized by baseline BRIEF global executive composite T scores with clinically significant (≥65) or not clinically significant (65) impairment in EF.Mean (standard deviation) change from baseline to endpoint for BRIEF of -17.9 (12.5) for Global Executive Composite, -15.4 (12.6) for Behavioral Regulation Index, and -17.6 (12.3) for Metacognition Index demonstrated improvement with LDX (pooled doses; p 0.0001 for all). Improvements in BRIEF scores were seen regardless of sex, ADHD subtype, comorbid psychiatric symptoms, common TEAEs, or baseline EF impairment category. TEAEs included decreased appetite, decreased weight, irritability, insomnia, headache, upper abdominal pain, and initial insomnia.Improvements were demonstrated in EF behaviors and ADHD symptoms with LDX. LDX safety profile was consistent with long-acting stimulant use.

The aim of this study was to assess the effectiveness and safety of lisdexamfetamine dimesylate (LDX) in children with attention-deficit/hyperactivity disorder (ADHD).This was a 7-week, open-label study evaluating 20, 30, 40, 50, 60, or 70 mg/day LDX in 318 children aged 6-12 years with ADHD. The ADHD Rating Scale IV (ADHD-RS-IV) was the primary efficacy assessment. Secondary measures included the Clinical Global Impressions-Improvement (CGI-I), Expression and Emotion Scale for Children (EESC), and Behavior Rating Inventory of Executive Function (BRIEF). Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms.At end point, mean (standard deviation [SD]) improvement from baseline in ADHD-RS-IV total score was 28.6 (10.9) (p0.0001). Most subjects (89.9%) were rated "improved" (i.e., CGI-I 1 or 2). Improvements from baseline were observed in the EESC total and subscale scores (por = 0.0002). LDX treatment resulted in significant improvement on the Global Executive Composite, Behavioral Regulation, and Metacognition indices of the BRIEF (p0.0001). TEAEs (incidencesor =10%) were decreased appetite, decreased weight, irritability, insomnia, headache, upper abdominal pain, and initial insomnia.LDX was effective and generally well tolerated with a safety profile consistent with long-acting stimulant use. There was overall improvement in ADHD symptoms and executive function measures and no worsening of emotional expression measures.clinicaltrials.gov Identifier: NCT00500071.

The 2006 Research Forum addressed the goal of formulating a research agenda for early-onset bipolar disorder (EOBP) and improving outcome by understanding the risk and protective factors that contribute to its severity and chronicity.Five work groups outlined barriers and research gaps in EOBP genetics, neuroimaging, prodromes, psychosocial factors, and pharmacotherapy.There was agreement that the lack of consensus on the definition and diagnosis of EOBP is the primary barrier to advancing research in BP in children and adolescents. Related issues included: the difficulties in managing co-morbidity both statistically and clinically; acquiring adequate sample sizes to study the genetics, biology, and treatment; understanding the EOBP's developmental aspects; and identifying environmental mediators and moderators of risk and protection. Similarly, both psychosocial and medication treatment strategies for children with BP are hamstrung by diagnostic issues. To advance the research in EOBP, both training and funding mechanisms need to be developed with these issues in mind.EOBP constitutes a significant public health concern. Barriers are significant but identifiable and thus are not insurmountable. To advance the understanding of EOBP, the field must be committed to resolving diagnostic and assessment issues. Once achieved, with adequate personnel and funding resources, research into the field of EOBP will doubtless be advanced at a rapid pace.

Children and adolescents who are the offspring of a bipolar parent and who first present with major depressive disorder (MDD) are at high risk for eventually developing bipolar disorder. In this report, the authors describe a group of 9 such high-risk children and adolescents with MDD, aged 7–16 years, who were randomized to receive treatment with either paroxetine monotherapy or combination paroxetine-divalproex sodium therapy. In the long-term management of depressive symptomatology in these patients, neither treatment appeared to be particularly effective. As a result, future treatment studies in this population appear to be warranted, not only due to the putative impending risk of developing bipolar disorder, but also the manifest risk of current depressive episodes.

Family conflict affects the expression of psychopathology in youth. This study investigated whether family conflict moderates response to medication in youth with bipolar disorder.Youth ages 5-17 years diagnosed with bipolar I or II disorder were recruited from a trial of combination therapy with divalproex and lithium. Mania and depression were assessed at baseline and after 8 weeks of treatment using the Young Mania Rating Scale (YMRS) and the Children's Depression Rating Scale-Revised (CDRS-R). Parents completed the Family Assessment Device (FAD). Ordinary least-squares regression evaluated whether family conflict contributed to YMRS/CDRS-R outcomes controlling for severity of baseline mood.In 55 youths, the model examining family conflict and CDRS-R outcomes showed that family conflict variables accounted for 10% of the variance in CDRS-R scores after 8 weeks of treatment. The final model was statistically significant. The FAD Problem Solving subscale was the only uniquely significant predictor of CDRS-R scores after 8 weeks of treatment. Family conflict did not predict YMRS outcomes.There is a significant relationship between family problem solving and depressive symptoms that persist despite pharmacotherapy. Although depression severity was mild at baseline, it persisted despite pharmacological treatment in youths whose families endorsed higher levels of conflict.

Recent developments in the field of neuroscience have illuminated the understanding of the neural circuits impaired in attention-deficit/hyperactivity disorder (ADHD) and the mechanism of action of treatments used to treat this condition. There is an exciting confluence between emerging studies in basic neurobiology and the genetic, neuroimaging, and neuropsychological analyses of ADHD. The following provides a brief review of this field, explaining how compounds like guanfacine and the traditional stimulant medications can reduce the core symptoms of ADHD by optimizing the neurochemical environment in the prefrontal cortex (PFC). Knowledge of these basic mechanisms may inform our medication choices and facilitate treatment of ADHD and related disorders.

The aim of this study was to describe the long-term safety and effectiveness of quetiapine in conduct disorder (CD).This was an 18-week outpatient follow-up study of an acute trial that enrolled aggressive children ages 6-12 years with a primary diagnosis of CD. To be enrolled into this study, subjects had to have successfully completed participation in the initial 8-week, open-label, outpatient quetiapine trial. Psychometric measures included the Rating of Aggression Against People and/or Property Scale (RAAPP), the Nisonger Child Behavior Rating Form (NCBRF), the Conners' Parent Rating Scale (CPRS-48), the Clinical Global Impressions Scale of Severity (CGI-S), and the Children's Global Assessment Scale.Nine males with a mean age of 8.9 (SD = 1.2) years were treated. The median quetiapine dose at end of study was 150 mg/day (range 75-350). Mean psychometric scores did not change substantively from baseline. No patients experienced extrapyramidal side effects. Three subjects discontinued due to study nonadherence. No patients discontinued treatment due to an adverse event.These preliminary data suggest that quetiapine might be a generally safe and effective maintenance treatment for aggressive children with CD who initially respond to an acute therapeutic trial of quetiapine. More research is needed to confirm or refute these initial findings.

The purpose of this study was to evaluate the safety and efficacy of asenapine in adolescents with schizophrenia.In an 8 week, randomized, double-blind placebo-controlled trial, subjects (12-17 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria for schizophrenia were randomized 1:1:1 to placebo, asenapine 2.5 mg b.i.d., or asenapine 5 mg b.i.d. Subjects who completed the 8 week acute study could participate in a 26 week flexible-dose asenapine-only open-label extension (OLE).A similar percentage of subjects completed treatment on day 56 (2.5 mg b.i.d. (n=98): 83%; 5 mg b.i.d. [n=106]: 79%; placebo [n=102]: 79%). In the mixed model for repeated measures analysis of the primary end-point (with Hochberg correction for multiplicity), least squares (LS) mean differences between asenapine and placebo on the Positive and Negative Syndrome Scale (PANSS) total score at day 56 were not significant (-4.8 for 2.5 mg b.i.d., p=0.070; -5.6 for 5 mg b.i.d., p=0.064). Significant improvement in the Clinical Global Impressions-Severity score was observed in the 5 mg b.i.d. group versus placebo on day 56 (LS mean -0.3, p=0.024). In the acute phase, ≥7% weight gain and the composite event of somnolence, sedation, and hypersomnia were more common in both asenapine groups than in the placebo group. Akathisia, fasting glucose elevation, and extrapyramidal syndrome were more common in the 5 mg b.i.d. group than in the placebo group. There were no unexpected adverse events in the OLE, and PANSS total scores decreased by -16.1 points in the group previously treated with placebo (n=62) and by -11.2 points in the continuous asenapine group (n=131) from OLE baseline to week 26.Although improvements in PANSS total score at day 56 of the acute phase were numerically greater for both asenapine 2.5 and 5 mg b.i.d. than for placebo and were maintained in the OLE, the primary end-point did not achieve statistical significance in the acute phase. No new or unexpected safety concerns were detected during the acute phase or after an additional 26 weeks of asenapine treatment in the adolescent population with schizophrenia.NCT01190254 and NCT1190267 at ClinicalTrials.gov.

In the four-site Treatment of Severe Childhood Aggression (TOSCA) study, addition of risperidone to stimulant and parent training moderately improved parent-rated disruptive behavior disorder (DBD) symptoms. This secondary study explores outcomes other than DBD and attention-deficit/hyperactivity disorder (ADHD) as measured by the Child and Adolescent Symptom Inventory-4R (CASI-4R).A total of 168 children ages 6-12 with severe aggression (physical harm), DBD, and ADHD were randomized to parent training plus stimulant plus placebo (basic treatment) or parent training plus stimulant plus risperidone (augmented treatment) for 9 weeks. All received only parent training plus stimulant for the first 3 weeks, then those with room for improvement received a second drug (placebo or risperidone) for 6 weeks. CASI-4R category item means at baseline and week 9 were entered into linear mixed-effects models for repeated measures to evaluate group differences in changes. Mediation of the primary DBD outcome was explored.Parent ratings were nonsignificant with small/negligible effects, but teacher ratings (n=46 with complete data) showed significant augmented treatment advantage for symptoms of anxiety (p=0.013, d=0.71), schizophrenia spectrum (p=0.017, d=0.45), and impairment in these domains (p=0.02, d=0.26), all remaining significant after false discovery rate correction for multiple tests. Improvement in teacher-rated anxiety significantly (p=0.001) mediated the effect of risperidone augmentation on the primary outcome, the Disruptive-total of the parent-rated Nisonger Child Behavior Rating Form.Addition of risperidone to parent training plus stimulant improves not only parent-rated DBD as previously reported, but also teacher-rated anxiety-social avoidance. Improvement in anxiety mediates improvement in DBD, suggesting anxiety-driven fight-or-flight disruptive behavior with aggression, with implications for potential treatment strategies. Clinicians should attend to possible anxiety in children presenting with aggression and DBD.Treatment of Severe Childhood Aggression (The TOSCA Study). NCT00796302. clinicaltrials.gov.

Identifying evidence-based dosing strategies is a key part of new drug development in pediatric populations. Pharmacokinetic (PK) studies can provide important information regarding how best to dose medications in children and adolescents. Utilizing scientifically supported dosing strategies provides the best chance for any given drug to demonstrate both efficacy and acceptable tolerability in definitive, placebo-controlled studies.Results of both PK studies and randomized, placebo-controlled efficacy trials (RPCTs) in juvenile major depressive disorder (MDD) are reviewed. The degree to which the medication dosing strategies that were employed in the efficacy studies were supported by the extant PK data is considered. Medications that are reviewed include fluoxetine, sertraline, paroxetine, citalopram, escitalopram, venlafaxine, nefazodone, and mirtazapine.In many instances, the dosing paradigms that were used in the RPCTs differed, sometimes substantially, from the dosing strategies that would have been supported based on the results of PK studies.Medication dosing regimens may have contributed to the failure of several RPCTs to show drug efficacy in the treatment of pediatric MDD. In addition, the doses of medication used in these RPCTs may also have contributed to the safety and tolerability concerns that have been raised with these drugs. PK and dose-ranging studies should be performed prior to the initiation of definitive efficacy trials so that empirically supported dosing strategies can be incorporated into the design of RPCTs of antidepressants in children and adolescents suffering from MDD.

The aim of this study was to examine the effectiveness of quetiapine in adolescents suffering from autistic disorder (AD).This was a 12-week, open-label study, for which medically healthy patients with AD between the ages of 10 and 17 years were eligible. Quetiapine treatment was gradually increased over the first 6 weeks of the study, to a total daily dose of 300 mg/day. Doses could then be increased to a maximum daily dose of 750 mg/day. Outcome measures included the Children's Psychiatric Rating Scale (CPRS) and the Clinical Global Impressions (CGI) scale.Nine (9) males were enrolled. Six (6) patients had previously been treated with other psychotropic agents. Although improvements in several symptom domains were observed on quetiapine, only 2 patients met a priori criteria for response ("much" or "very much improved" on the Clinical Global Impressions-Improvement Scale). In addition, only these same 2 patients' parents/guardians chose to continue quetiapine pharmacotherapy after study participation.These data suggest that quetiapine may not be a particularly effective agent in the treatment of adolescent patients with AD. However, should future studies be performed, it seems reasonable that they be conducted with more rigor, less treatment-resistant cohorts, and, possibly, a different dosing strategy.

To achieve consensus among researchers, pharmaceutical industry representatives, federal regulatory agency staff, and family advocates on a template for clinical trials of acute mania/bipolar disorder in children and adolescents.The American Academy of Child and Adolescent Psychiatry, in collaboration with Best Practice, convened a group of experts from the key stakeholder communities (including adult psychiatrists with expertise in bipolar disorder) and assigned them to workgroups to examine core methodological issues surrounding the design of clinical trials and, ultimately, to generate a consensus statement encompassing: (1) inclusion/exclusion criteria, (2) investigator training needs and site selection, (3) assessment and outcome measures, (4) protocol design and ethical issues unique to trials involving children/adolescents, and (5) regulatory agency perspectives on these deliberations.Conference participants reached agreement on 18 broad methodological questions. Key points of consensus were to assign priority to placebo-controlled studies of acute manic episodes in children and adolescents aged 10-17 years, who may or may not be hospitalized, and who may or may not suffer from common comorbid psychiatric disorders; to require that specialist diagnostic "gatekeepers" screen youths' eligibility to participate in trials; to monitor interviewer and rater competency over the course of the trial using agreed upon standards; and to develop new tools for assessment, including scales to measure aggression/rage and cognitive function, while using the best available instruments (e.g., Young Mania Rating Scale) in the interim.Methodologically rigorous, large-scale clinical trials of treatment of acute mania are urgently needed to provide information regarding the safety and efficacy, in youth, of diverse agents with potential mood-stabilizing properties.

The purpose of this study was to assess long-term improvement in quality of life (QOL) in adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with lisdexamfetamine dimesylate (LDX).Adolescents with ADHD treated for ≥3 weeks in a 4 week, placebo-controlled study entered a 1 year, open-label study. After the 4 week dose optimization (30, 50, and 70 mg/day LDX) period, treatment was maintained for 48 additional weeks. Change from baseline (of prior study) to week 52/early termination (ET) (of open-label study) in ADHD Rating Scale IV (ADHD-RS-IV) assessed effectiveness, and the Youth QOL-Research Version (YQOL-R) assessed participant-perceived QOL. Post-hoc analyses described effectiveness and QOL for participants with self-perceived poor QOL at baseline (≥1 SD below the mean) versus all others, and for study completers versus study noncompleters.These post-hoc analyses included 265 participants. Participants with baseline self-perceived poor QOL (n=32) versus all others (n=232) exhibited robust YQOL-R perceptual score changes (improvement) with LDX, emerging by week 28 and maintained to week 52/ET. Week 52/ET mean change score ranged from +9.8 to +17.6 for participants with baseline self-perceived poor QOL and +0.4 to +5.1 for all others; week 52/ET improvements in ADHD-RS-IV total scores were similar, regardless of baseline YQOL-R total score. At week 52/ET, study completers had greater YQOL-R improvements than did noncompleters; ADHD-RS-IV total score changes were also numerically larger at week 52/ET for completers than for noncompleters.Participant-perceived QOL and ADHD symptoms improved from baseline with LDX in adolescents with ADHD; greatest improvements occurred among participants with baseline self-perceived poor QOL.

Risperidone is an atypical antipsychotic drug that has been used in the treatment of numerous psychiatric disorders in children and adolescents. The question of whether risperidone-induced weight gain is associated with steatohepatitis has recently been raised. The purpose of this chart review was to ascertain: (1) the rate of liver dysfunction observed during risperidone treatment in children and adolescents; and (2) the clinical factors associated with liver dysfunction. For purposes of this chart review study, abnormal liver function was defined by serum transaminase or bilirubin values falling outside the normal laboratory ranges. Chart reviews were completed on 38 youths with ages ranging from 5-17 years with a variety of psychiatric diagnoses. The mean length of risperidone treatment was 15.2 months at a mean dose of 2.5 mg/day. It was found that 37 of the 38 youths treated with risperidone had no liver enzyme abnormalities at the end of study. One subject had an alanine aminotransferase (ALT) level of 46 U/L which was 7 U/L above the upper limit of normal for this laboratory test. This isolated value was not considered clinically significant. These data were noted in spite of weight gain and the use of numerous concomitant psychotropic medications. These findings suggest that risperidone in short term treatment does not commonly lead to evidence of abnormal liver function at therapeutic doses in children and adolescents. Larger-scale, prospective studies are needed in order to confirm these findings.

The purpose of this study was to investigate associations between body weight and illness characteristics, including weight gain and therapeutic efficacy, in adolescents with schizophrenia.Adolescents ages 13-17 years (n = 107) with American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) schizophrenia enrolled in a 6 week, double-blind, placebo-controlled trial comparing olanzapine and placebo. Therapeutic response was assessed by the Brief Psychiatric Rating Scale for Children (BPRS-C). Secondary outcomes included the Clinical Global Impressions-Severity (CGI-S) scale and Positive and Negative Syndrome Scale (PANSS). Obesity was defined as sex-/age-adjusted body mass index (BMI) ≥ 95th percentile. Linear regression was used to analyze the relationship between weight gain and psychiatric symptom improvement; logistic regression was conducted to identify predictors of baseline obesity.Weight gain was significantly correlated with greater BPRS-C reduction among olanzapine-treated subjects (r = -0.31, p0.01), whereas a trend was observed among placebo-treated subjects (r = -0.31, p = 0.08). However, this relationship became nonsignificant when analyses were controlled for duration of olanzapine treatment (p=0.12), and a treatment by weight gain interaction did not emerge in a repeated-measures mixed model analysis that included time in the study (t = 1.27, p = 0.21). Additionally, weight gain ≥ 7% was not significantly associated with response or remission. Among 17 adolescents (16%) with obesity at study entry, obesity was not significantly associated with endpoint BPRS-C illness severity. However, girls (p = 0.03), individuals hospitalized within the past year (p = 0.02), and those with less severe overall (p = 0.03) and negative symptoms (p = 0.003) according to the CGI-S and PANSS negative subscale, respectively, were more likely to be obese at baseline.Baseline obesity was associated with lower illness severity, which could be mediated by greater treatment adherence, leading to more weight gain. Olanzapine-related weight gain was not independently associated with symptomatic outcome when controlling for treatment duration. Additional studies are needed to extend these findings to other disorders and medications.

The purpose of this study was to evaluate the extended efficacy, safety, and tolerability of escitalopram relative to placebo in adolescents with major depressive disorder (MDD).Adolescents (12-17 years) who completed an 8-week randomized, double-blind, flexible-dose, placebo-controlled, lead-in study of escitalopram 10-20 mg versus placebo could enroll in a 16-24-week, multisite extension trial; patients maintained the same lead-in randomization (escitalopram or placebo) and dosage (escitalopram 10 or 20 mg/day, or placebo) during the extension. The primary efficacy was Children's Depression Rating Scale-Revised (CDRS-R) change from the lead-in study baseline to treatment week 24 (8-week lead-in study plus 16-week extension); the secondary efficacy was Clinical Global Impressions-Improvement (CGI-I) score at week 24. All efficacy analyses used the last observation carried forward (LOCF) approach; sensitivity analyses used observed cases (OC) and mixed-effects model for repeated measures (MMRM). Safety was evaluated via adverse event (AE) reports and the clinician-rated Columbia-Suicide Severity Rating Scale (C-SSRS).Following lead-in, 165 patients enrolled in the double-blind extension (82 placebo; 83 escitalopram); 40 (48.8%) placebo and 37 (44.6%) escitalopram patients completed treatment. CDRS-R total score improvement was significantly greater for escitalopram than for placebo (p=0.005, LOCF; p=0.014; MMRM). Response rates (CDRS-R ≥ 40% reduction from baseline [adjusted and unadjusted] and CGI-I ≤ 2) were significantly higher for escitalopram than for placebo (LOCF); remission rates (CDRS-R ≤ 28) were 50.6% for escitalopram and 35.7% for placebo (p=0.002). OC analyses were not significantly different between groups. The most frequent escitalopram AEs (≥ 5% and more frequent than placebo) were headache, nausea, insomnia, vomiting, influenza-like symptoms, diarrhea, and urinary tract infection. Most AEs were mild/moderate and not related to the study drug. AEs suggestive of self-harm occurred in 5.7% and 7.1% of placebo and escitalopram patients. Occurrence of suicidal behavior and/or suicidal ideation assessed by C-SSRS was 10.9% (14/128) for placebo and 14.5% (19/131) for escitalopram.Extended use of escitalopram was generally safe and resulted in modest improvement in efficacy in adolescents with MDD.

The purpose of this study was to assess lisdexamfetamine dimesylate (LDX) treatment effects based on baseline emotional control dysfunction in children with attention-deficit/hyperactivity disorder (ADHD) categorized with or without impairments of executive function (EF) emotional control.Post-hoc analyses of a 7 week, open-label LDX study in children with ADHD (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision [DSM-IV-TR] defined) and impairments in EF control of emotional response. At baseline, participants were dichotomized by Behavior Rating Inventory of EF (BRIEF) emotional control domain T-scores of ≥65 (with impairment) or65 (without impairment). ADHD Rating Scale-IV (ADHD-RS-IV), BRIEF Global Executive Composite and emotional control domain, Expression and Emotion Scale for Children (EESC) scores, Pearson correlations for BRIEF versus ADHD-RS-IV and EESC, and Clinical Global Impressions scores were assessed at baseline and end of study (week 7)/early termination (EOS/ET) by baseline category of BRIEF emotional control impairment. Safety assessments included treatment-emergent adverse events (TEAEs).At baseline and EOS/ET, respectively, 53.0% and 20.7% met criteria for emotional control impairment. Participants with and without emotional control impairments had similar ADHD-RS-IV change scores. Mean (SD) change from baseline for those with and without emotional control impairments were -20.8 (12.89) and -14.6 (11.25) for BRIEF global scores and -16.0 (13.19) and -5.0 (9.48) for BRIEF emotional control domain scores. Participants with emotional control impairments had greater mean EESC total score changes. BRIEF emotional control domain and all ADHD-RS-IV scores indicated moderate correlations between change scores (all p0.0001). Overall, 84.9% of participants had TEAEs (mostly mild-to-moderate in severity); 3.8% discontinued because of TEAEs.The proportion of children with behavioral impairments in EF control of emotional response decreased during LDX treatment. ADHD symptoms improved in both groups. The moderate correlations between EF behaviors and ADHD symptoms suggest there may be utility in evaluating behavioral domains beyond core ADHD symptoms.