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

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

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

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

A 6-Month Open-Label Extension Study of Vortioxetine in Pediatric Patients with Depressive or Anxiety Disorders.

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.

Adherence to pharmacological treatment for juvenile bipolar disorder.

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.

Methylphenidate in the treatment of children and adolescents with bipolar disorder and attention-deficit/hyperactivity disorder.

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.

Treatment of early-onset schizophrenia spectrum disorders (TEOSS): demographic and clinical characteristics.

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.

A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type.

BACKGROUND: Disturbances in N-methyl-D-aspartate (NMDA) receptor activity may play a role in attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE: This study is a preliminary evaluation of the safety, pharmacokinetics, and effectiveness of the NMDA receptor antagonist memantine in pediatric ADHD. METHODS: An open-label, dose-finding, 8-week, trial in outpatients 6-12 years old with ADHD combined type. Memantine oral solution (2 mg/mL) was titrated to 10 mg/day (n = 8) or 20 mg/day (n = 8). Safety data and blood samples for pharmacokinetic analyses were collected. The ADHD Rating Scale-IV (ADHD-IV) and Clinical Global Impression of Severity (CGI-S) scale measured the effectiveness of memantine. RESULTS: There were no discontinuations due to adverse events (AEs), serious AEs, deaths, or suicides. Most AEs were mild and occurred during the first week of treatment. The 20 mg/day memantine dose was associated with a higher rate of completion and larger mean improvement on the ADHD-IV and CGI-S than 10 mg/day memantine. Pharmacokinetic analyses suggest response to memantine may be dose-dependent beyond an initial threshold concentration. CONCLUSIONS: This pilot study suggests that a memantine dose of 20 mg/day may be a safe and possibly effective treatment for pediatric ADHD. Further investigations of memantine in ADHD appear to be warranted.

A 26-week open-label study of quetiapine in children with conduct disorder.

OBJECTIVE: The aim of this study was to describe the long-term safety and effectiveness of quetiapine in conduct disorder (CD). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Evaluation and comparison of psychometric instruments for pediatric bipolar spectrum disorders in four age groups.

The primary objective of this study was to evaluate the psychometric characteristics of the Young Mania Rating Scale (YMRS), the K-SADS Mania Rating Scale (KMRS), and the Children's Depression Rating Scale-Revised (CDRS-R) across four age groups (4-7, 8-10, 11-13, and 14-17 years). The interrater reliability of K-SADS diagnoses was also examined. Participants included 1,014 youths (62.1% male) presenting to an outpatient clinical research center. Diagnoses were based upon semistructured K-SADS interviews. Symptomatic assessments and ratings of psychosocial functioning were completed following the diagnostic interview. Mania measures showed unifactorial structure and good internal consistency reliability (alpha = 0.79-0.95) across all ages groups. The CDRS-R factor structure shifted from one to two factors in adolescents. For all ages and symptom measures, reliability was excellent in the range where differential diagnosis is most difficult. Efficiencies in discriminating bipolar spectrum disorders from other disorders were excellent (areas under the curve, AUCs = 0.92-0.99) for mania measures, with comparable discrimination across age groups. Interrater reliability of K-SADS diagnoses was excellent across age groups (smallest kappa = 0.95). Results indicate that mania measures are useful for assessing symptoms across a wide range of ages. The CDRS-R may be better conceptualized as a two-factor measure in older adolescents. The semistructured K-SADS interview can be used to generate reliable diagnoses across a broad age range.

Venlafaxine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: The objectives of this pilot study were to explore the changes in symptom severity, tolerability, and the pharmacodynamics of venlafaxine treatment in youths with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was a 2-week, open-label, outpatient trial of venlafaxine in children and adolescents, ages 5-17 years, with ADHD. Three dosing strata, 0.5, 1.0, and 2.0 mg/kg per day, were examined. ADHD symptom severity and improvement assessments included the ADHD Rating Scale (ARS-IV) and the Clinical Global Impressions Scale (CGI). During this study, venlafaxine, O-desmethylvenlafaxine (ODV), norepinephrine, and serotonin concentrations were obtained. RESULTS: Thirty-eight participants (33 males) were treated in this trial. Overall, parent-completed and teacher-completed ARS-IV total scores showed a statistically significant positive change at the end of the study when compared to baseline (p < 0.05). Significant increases in plasma venlafaxine concentrations were observed at day 15 when compared to day 8 (p = 0.04). In addition, plasma norepinephrine and serotonin concentrations were found to be significantly decreased from baseline at end of study (p < 0.05). Four patients ended participation in the study prematurely: lost to follow up (n = 2), withdrawal of consent (n = 1), and worsening of ADHD symptoms after 8 days of treatment (n = 1). There were no discontinuations due to other adverse events. CONCLUSIONS: Venlafaxine appeared to offer some benefit and appears to be relatively safe for the short-term treatment of ADHD in this open-label trial. The pharmacodynamics of venlafaxine in youths are consistent with serotonergic and neuradrenergic modulation.

A Double-Blind and Placebo-Controlled Trial of Aripiprazole in Symptomatic Youths at Genetic High Risk for Bipolar Disorder.

OBJECTIVE: 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." METHODS: 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. RESULTS: 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]). CONCLUSION: This double-blind trial found that APZ was significantly more efficacious than placebo in reducing symptoms of mania in children and adolescents with cyclotaxia.

Risperidone Added to Psychostimulant in Children with Severe Aggression and Attention-Deficit/Hyperactivity Disorder: Lack of Effect on Attention and Short-Term Memory.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: Similar to other studies, we found no deleterious effects on attention and short-term memory associated with short-term use of risperidone. NCT00796302.

The Treatment of Severe Childhood Aggression Study: 12 Weeks of Extended, Blinded Treatment in Clinical Responders.

OBJECTIVES: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Combination lithium and divalproex sodium in pediatric bipolar symptom re-stabilization.

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.

Effectiveness, safety, and pharmacokinetics of quetiapine in aggressive children with conduct disorder.

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.

The relevance of pharmacokinetic studies in designing efficacy trials in juvenile major depression.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder.

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.

Comorbid anxiety and social avoidance in treatment of severe childhood aggression: response to adding risperidone to stimulant and parent training; mediation of disruptive symptom response.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRY: Treatment of Severe Childhood Aggression (The TOSCA Study). NCT00796302. clinicaltrials.gov.

Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study.

BACKGROUND: Lithium is a benchmark treatment for bipolar disorder in adults. Definitive studies of lithium in pediatric bipolar I disorder (BP-I) are lacking. METHODS: This multicenter, randomized, double-blind, placebo-controlled study of pediatric participants (ages 7-17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus placebo (n = 28) for up to 8 weeks. The a priori primary efficacy measure was change from baseline to the end of study (week 8/ET) in the Young Mania Rating Scale (YMRS) score, based on last-observation-carried-forward analysis. RESULTS: The change in YMRS score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03). Overall Clinical Global Impression-Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03). A statistically significant increase in thyrotropin concentration was seen with lithium (3.0 ± 3.1 mIU/L) compared with placebo (-0.1 ± 0.9 mIU/L; P < .001). There was no statistically significant between-group difference with respect to weight gain. CONCLUSIONS: Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder.

Participant satisfaction in a study of stimulant, parent training, and risperidone in children with severe physical aggression.

OBJECTIVE: The purpose of this study was to examine the satisfaction of families who participated in the Treatment of Severe Childhood Aggression (TOSCA) study. METHODS: 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). RESULTS: 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 (p<0.001) and future (p<0.005) problem behaviors. CONCLUSIONS: 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. TRIAL REGISTRY: Treatment of Severe Childhood Aggression (The TOSCA Study), NCT00796302, clinicaltrials.gov .