The 24-month course of manic symptoms in children.

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

Current research in child and adolescent bipolar disorder.

Although recently more research has considered children with bipolar disorder than in the past, much controversy still surrounds the validity of the diagnosis. Furthermore, questions remain as to whether or not childhood expressions of bipolarity are continuous with adult manifestations of the illness. In order to advance current knowledge of bipolar disorders in children, researchers have begun to conduct phenomenological, longitudinal, treatment, and neuroimaging studies in youths who exhibit symptoms of bipolar illness, as well as offspring of parents with bipolar disorders. Regardless of the differences between research groups regarding how bipolar disorder in children is defined, it is agreed that pediatric bipolarity is a serious and pernicious illness. With early intervention during the period of time in which youths are exhibiting subsyndromal symptoms of pediatric bipolarity, it appears that the progression of the illness to the more malignant manifestation of the disorder may be avoided. This paper will review what is currently known and what still is left to learn about clinically salient topics that pertain to bipolar disorder in children and adolescents.

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.

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.

Family conflict moderates response to pharmacological intervention in pediatric bipolar disorder.

OBJECTIVE: Family conflict affects the expression of psychopathology in youth. This study investigated whether family conflict moderates response to medication in youth with bipolar disorder. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

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.

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.

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.

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.

An open-label pilot study of St. John's wort in juvenile depression.

OBJECTIVE: This pilot study examined the effectiveness, safety, tolerability, and pharmacodynamics of Hypericum perforatum (St. John's wort) in the treatment of youths diagnosed with major depressive disorder. METHOD: Youths 6 to 16 years of age meeting DSM-IV criteria for major depressive disorder with depressive symptoms of at least moderate severity were eligible to enroll between January 1999 and January 2001 in this 8-week, prospective, open-label, outpatient study. Outcome measures included the Children's Depression Rating Scale-Revised (CDRS-R) and the Clinical Global Impressions (CGI) scale. A priori criteria for response consisted of a CDRS-R score of

A prospective, open-label trial of olanzapine in adolescents with schizophrenia.

BACKGROUND: Olanzapine is an atypical antipsychotic that has efficacy in adults with psychotic disorders. This preliminary study examined the effectiveness of olanzapine in adolescents with schizophrenia or its related conditions. METHOD: Adolescents aged 12-17 years (inclusive) with a diagnosis of schizophrenia, schizoaffective, or schizophreniform disorder were enrolled in this 8-week, open-label, outpatient study. The Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale (CGI), and the Children's Global Assessment Scale (CGAS) were administered as outcome measures. Extrapyramidal side effects were assessed at each visit. Olanzapine was initiated at a dose of 2.5 mg/day and could be increased to a maximum total daily dose of 20 mg. RESULTS: Sixteen participants with a mean age of 13.8 (SD = 1.5) years were treated. Significant improvements were found in the PANSS, CGI severity, and CGAS scores. Reductions in both positive and negative symptoms were found. Increased appetite and sedation were the most frequently reported side effects. Two subjects required treatment for extrapyramidal side effects. CONCLUSIONS: Psychotic symptoms significantly improved during study. Overall, olanzapine was well tolerated. Future studies are needed to confirm these findings, to assess long-term treatment outcomes, and to compare the effectiveness of olanzapine with that of other antipsychotics.

Elevated thyrotropin in bipolar youths prescribed both lithium and divalproex sodium.

OBJECTIVE: To examine the effect of combined lithium and divalproex sodium on thyroid-stimulating hormone (TSH) levels in children and adolescents with bipolar disorders and to identify risk factors for lithium-induced hypothyroidism. METHOD: Bipolar youths aged 5 to 17 years participating in an open-label clinical trial received treatment with lithium and divalproex sodium for up to 20 weeks. TSH levels were measured at baseline and at the end of the study. Subjects were divided into two groups for analysis: group 1 had TSH levels of less than 10.0 mU/L at the end of the study and group 2 had TSH levels of 10.0 mU/L or more at end of the study. RESULTS: Twenty of the 82 subjects (24.4%) showed TSH elevations of at least 10 mU/L within an average exposure of less than 3 months. The mean baseline TSH level for group 2 was significantly higher than for group 1 (2.97 [SD = 1.48] versus 2.05 [SD = 0.89], p <.05). Mean lithium levels at the end of the study were 1.00 mEq/L for group 2 compared to 0.76 mEq/L for group 1 (t = -2.41, p =.019). CONCLUSIONS: Lithium is associated with significant rates of thyrotropin elevation in bipolar youths. Factors associated with elevation in TSH in lithium-treated subjects include a higher baseline TSH level and a higher lithium level. Close monitoring of thyroid function in children and adolescents taking lithium is recommended.

Combination lithium and divalproex sodium in pediatric bipolarity.

OBJECTIVE: Lithium carbonate (Li) or divalproex sodium (DVPX) may be effective for some juveniles with bipolar disorder. Many youths with bipolar disorder do not respond to DVPX or Li monotherapy. An open-label study was conducted to examine the effectiveness of combination DVPX and Li therapy with youths diagnosed with bipolar disorder. METHOD: Patients meeting DSM-IV criteria for bipolar I or bipolar II disorder, ages 5 to 17 years, were treated prospectively for up to 20 weeks with DVPX + Li. Assessments included the Young Mania Rating Scale (YMRS), Children's Depression Rating Scale-Revised (CDRS-R), and the Children's Global Assessment Scale (CGAS). The a priori definition of clinical remission utilized included four contiguous weekly ratings of YMRS /=51, clinical stability, and no evidence of mood cycling. RESULTS: Ninety patients (66 males, 24 females) were treated. Significant improvement (p <.0001) in all outcome measures was observed by week 8 as well as at the end of study. The mean time in study was 11.3 weeks. Forty-seven percent (n = 42) met a priori criteria for remission. CONCLUSIONS: Symptoms of mania and depression in juvenile bipolar disorder may be safely and effectively treated acutely with DVPX + Li.

Age differences in the phenomenology of pediatric bipolar disorder.

BACKGROUND: The primary purpose of this study was to explore whether age differences in the phenomenology of bipolar disorders from 4 to 17 years of age exist. METHODS: Outcome measures included questionnaires pertaining to mood symptoms, psychosocial functioning, and family history of psychiatric illness. Phenomenology was examined in two diagnostic groups: syndromal bipolar disorder (bipolar I or II) and subsyndromal bipolar disorder (bipolar disorder not otherwise specified or cyclothymia) and across six age cohorts: 4-6, 7-8, 9-10, 11-13, and 14-17 years. Analyses examined linear and non-linear age effects on clinician-rated measures of mood and psychosocial functioning. RESULTS: Participants were 535 outpatients (339 males) ages 4-17 years. The proportion diagnosed with comorbid ADHD was significantly lower in the oldest age group. Age groups showed significant moderate decreases in motor activity, aggression, and irritability with age. Many symptoms of depression showed significant increases with age. BP I cases showed much higher manic symptoms, and BP I and BP II cases indicated slightly to moderately higher depressive symptoms, compared to subsyndromal cases. These patterns held after adjusting for comorbid ADHD, and age did not interact with syndrome status. There were also age differences in total scores for measures of mood symptoms and psychosocial functioning. LIMITATIONS: Mood ratings were completed based on the same interview that informed the research diagnoses. Also, mood episode at time of interview was not captured. CONCLUSIONS: These findings affirm the existence of bipolar disorder from pre-school children through adolescence, with a similar clinical presentation across a wide developmental age span.

An update on antidepressant use and suicidality in pediatric depression.

INTRODUCTION: In 2003, public health advisories in North America and Europe regarding suicidality associated with selective serotonin reuptake inhibitors (SSRIs) led to the addition of black box warnings to antidepressant package inserts in 2004. Subsequently, a series of events appeared to result from these regulatory actions. AREAS COVERED: This review provides an overview of the temporal associations of regulatory agencies' actions in North America and Europe with rates of depression diagnoses, pediatric antidepressant prescription rates, follow-up visits to physicians prescribing antidepressants, and rates of completed suicide and suicidal ideation in children and adolescents. In addition, evidence-based predictors of suicidal behavior and suicide risk, as provided by large, multisite studies of depressed children and adolescents, are outlined. Finally, this review considers key advancements in the study of young patients at risk for suicide and describes innovations in current research methodology, to more accurately identify suicidality and the relationship to antidepressant use within this vulnerable patient population. EXPERT OPINION: Evaluating the role of antidepressants in those youths who do not respond to evidence-based psychotherapeutic interventions may be a useful future research direction. Until more data are available, however, closely monitored antidepressant treatment in combination with CBT may provide the most benefit.

Moderators of fluoxetine treatment response for children and adolescents with comorbid depression and substance use disorders.

Our recent 8-week, randomized, placebo-controlled trial of fluoxetine in adolescents (ages 12-17 years) with comorbid depression and substance use disorder (SUD) did not detect a significant antidepressant treatment effect. The purpose of this secondary analysis was to explore moderators of the effect of fluoxetine in this sample. Static moderators measured at baseline were depression chronicity and hopelessness severity; time-varying moderators measured at baseline and weekly during the 8-week trial period were alcohol and marijuana use severity. Treatment effects on depression outcomes were examined among moderating subgroups in random effects regression models. Subjects assigned to fluoxetine treatment with chronic depression at baseline (p = .04) or no more than moderate alcohol use during the trial (p = .04) showed significantly greater decline in depression symptoms in comparison to placebo-assigned subgroups. The current analysis suggests that youth with chronic depression and no more than moderate alcohol consumption are likely to respond better to treatment with fluoxetine compared with placebo than youth with transient depression and heavy alcohol use.

Double-blind, randomized, placebo-controlled long-term maintenance study of aripiprazole in children with bipolar disorder.

BACKGROUND: This study evaluates the long-term efficacy of aripiprazole compared to placebo in children with bipolar disorders. METHOD: Outpatients aged 4 to 9 years meeting DSM-IV criteria for a bipolar disorder (I, II, not otherwise specified, cyclothymia) were eligible to receive up to 16 weeks of open-label treatment with aripiprazole (phase 1). Patients were randomized into the 72-week double-blind phase of the study once they met a priori response criteria for stabilization (phase 2). During phase 2, patients either remained on their current aripiprazole regimen or began a double-blind taper with aripiprazole discontinued and switched to placebo. The primary outcome measure for phase 2 was time to discontinuation due to a mood event. RESULTS: Patients were recruited between May 2004 and November 2008. Following phase 1, in which 96 patients received aripiprazole, 30 patients (mean age = 7.1 years) were randomly assigned to continue aripiprazole and 30 patients (mean age = 6.7 years) were randomly assigned to placebo. The mean (SD) dose of aripiprazole prior to randomization for these patients was 6.4 (2.1) mg/d. Patients randomly assigned to aripiprazole were enrolled significantly longer until time to study discontinuation due to a mood event (6.14 median weeks, SE ± 11.88 weeks; P = .005) and discontinuation for any reason (including mood events) (4.00 median weeks, SE ± 3.91 weeks; P = .003) than those randomly assigned to placebo (mood event, 2.29 median weeks, SE ± 0.38 weeks; any reason, 2.00 median weeks, SE ± 0.31 weeks). Regardless of random assignment, both the aripiprazole and placebo groups showed substantial rates of withdrawal from maintenance treatment over the initial 4 weeks (15/30 [50%] for aripiprazole; 27/30 [90%] for placebo), suggesting a possible nocebo effect (ie, knowledge of possibly switching from active medication to placebo increasing concern about relapse). The most frequently reported adverse events during double-blind aripiprazole therapy included stomach pain (n = 10, 33%), increased appetite (n = 9, 30%), and headaches (n = 9, 30%). CONCLUSIONS: Despite the possibility of a nocebo effect, these results suggest that aripiprazole may be superior to placebo in the long-term treatment of pediatric patients following stabilization with open-label aripiprazole. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00194077.

An open-label study of aripiprazole in children with a bipolar disorder.

OBJECTIVE: 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. METHOD: 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-R <29; (2) YMRS <10; and (3) CGAS >50. RESULTS: 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. CONCLUSION: APZ may be effective in the acute treatment of symptoms of children with bipolar illnesses.

Relationship of persistent manic symptoms to the diagnosis of pediatric bipolar spectrum disorders.

OBJECTIVE: The diagnosis of bipolar spectrum disorders (BPSDs [bipolar I and II disorders, cyclothymic disorder, and bipolar disorder not otherwise specified]) in youth remains controversial. The present study evaluated the possibility that the presence of persistent manic symptoms over a relatively short interval may increase the probability of a BPSD DSM diagnosis. METHOD: Data were obtained from the screening and baseline assessments collected from 2005 through 2008 of an ongoing prospective, longitudinal study (Longitudinal Assessment of Manic Symptoms) examining the diagnosis and phenomenology of youth (N = 692) presenting to outpatient centers at ages 6-12 years. Youth were assessed for elevated symptoms of mania (ESM) with the Parent General Behavior Inventory-10-Item Mania Scale (PGBI-10M), the primary outcome measure. Screening and baseline scores separated individuals into those with ESM (ESM+; PGBI-10M score ≥ 12) and a control group of youth without ESM (ESM-; PGBI-10M score < 12). Youth were classified into 4 groups: persistent ESM+, remitted ESM+, persistent ESM-, and progressed to ESM+. RESULTS: Individuals with persistent ESM+ were more likely to have a BPSD (relative risk = 3.04; 95% CI, 2.15-4.30). Using 2 administrations of the PGBI-10M spaced over a relatively brief interval (median = 4.0, mean = 6.1, SD = 5.9 weeks) improved the prediction of BPSD over using only the first administration (ΔR(2) = 0.10, Δχ(2)(1) = 50.06, P < .001). Likelihood ratios indicated that persistent ESM- substantially decreased the probability of BPSD. While high levels of persistent ESM+ increased the probability of a BPSD diagnosis, the final positive predictive value was only sufficient to signify the need for more thorough clinical evaluation. CONCLUSIONS: In many cases, obtaining repeated parent report of mania symptoms substantially altered the probability of a BPSD diagnosis and may be a useful adjunct to a careful clinical evaluation. Future waves of data collection from this longitudinal study will be crucial for devising clinically useful methods for identifying or ruling out pediatric BPSD.