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Anxiety disorders are common among children but can be difficult to diagnose. An actuarial approach to the diagnosis of anxiety may improve the efficiency and accuracy of the process. The objectives of this study were to determine the clinical utility of the Achenbach Child Behavior Checklist (CBCL) and Youth Self Report (YSR), two widely used assessment tools, for diagnosing anxiety disorders in youth and to aid clinicians in incorporating scale scores into an actuarial approach to diagnosis through a clinical vignette. Demographically diverse youth, 5 to 18 years of age, were drawn from two samples; one (N = 1,084) was recruited from a research center, and the second (N = 651) was recruited from an urban community mental health center. Consensus diagnoses integrated information from semistructured interview, family history, treatment history, and clinical judgment. The CBCL and YSR internalizing problems T scores discriminated cases with any anxiety disorder or with generalized anxiety disorder from all other diagnoses in both samples (ps .0005); the two scales had equivalent discriminative validity (ps .05 for tests of difference). No other scales, nor any combination of scales, significantly improved on the performance of the Internalizing scale. In the highest risk group, Internalizing scores greater than 69 (CBCL) or greater than 63 (YSR) resulted in a Diagnostic Likelihood Ratio of 1.5; low scores reduced the likelihood of anxiety disorders by a factor of 4. Combined with other risk factor information in an actuarial approach to assessment and diagnosis, the CBCL and YSR Internalizing scales provide valuable information about whether a youth is likely suffering from an anxiety disorder.

This report evaluates whether classification tree algorithms (CTA) may improve the identification of individuals at risk for bipolar spectrum disorders (BPSD). Analyses used the Longitudinal Assessment of Manic Symptoms (LAMS) cohort (629 youth, 148 with BPSD and 481 without BPSD). Parent ratings of mania symptoms, stressful life events, parenting stress, and parental history of mania were included as risk factors. Comparable overall accuracy was observed for CTA (75.4%) relative to logistic regression (77.6%). However, CTA showed increased sensitivity (0.28 vs. 0.18) at the expense of slightly decreased specificity and positive predictive power. The advantage of CTA algorithms for clinical decision making is demonstrated by the combinations of predictors most useful for altering the probability of BPSD. The 24% sample probability of BPSD was substantially decreased in youth with low screening and baseline parent ratings of mania, negative parental history of mania, and low levels of stressful life events (2%). High screening plus high baseline parent-rated mania nearly doubled the BPSD probability (46%). Future work will benefit from examining additional, powerful predictors, such as alternative data sources (e.g., clinician ratings, neurocognitive test data), these may increase the clinical utility of CTA models further.

BackgroundNeuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging.MethodA total of 61 youth (9–17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy.ResultsThere were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n = 22) and low and decreasing (LowD; n = 39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p p's ConclusionsPatterns of function in lateral prefrontal cortical–amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.

This study evaluated demographic and clinical correlates and predictors of polypharmacy at baseline assessment in the Longitudinal Assessment of Manic Symptoms (LAMS) sample, a cohort of children age six to 12 years at their first outpatient mental health visit at university-affiliated clinics.Use of medications in four classes (mood stabilizers, antidepressants, antipsychotics, and stimulants) was assessed, and the Service Assessment for Children and Adolescents classified lifetime and current use of various services. Analyses examined correlates of the number of medications prescribed and odds of polypharmacy, defined as use of two or more concurrent medications.In the total sample, 201 of 698 participants (29%) were prescribed two or more medications. These participants had lower Children's Global Assessment Scale scores, more comorbid disorders, and higher baseline parent-reported mood symptoms than those prescribed no or one medication. White youths were three times as likely as nonwhite youths to be receiving two or more psychotropics, even after adjustment for other demographic and clinical characteristics. Of 262 participants (38% of sample) not being treated with medications, 252 (96%) had a diagnosis of at least one psychiatric disorder (74% had two or more).Findings suggest that patients with greater severity and comorbidity were more likely to receive two or more medications. However, 38% of these children with serious disorders were not receiving psychotropic medication at the time of this assessment. Results counter findings suggesting overtreatment with medications of children with psychiatric disorders in the community.

Youth receiving mental health services often experience numerous mania-like symptoms (1, 2). Furthermore, although symptoms of mania are, by definition, present in youth suffering from bipolar disorder, prior data have noted that many youth who experience manic symptomatology do not suffer from bipolar disorder (3-7). Whether or not a youth has suffered from a bipolar disorder, it has been noted that elevated symptoms of mania (ESM) are associated with substantial psychosocial impairments and notable degrees of psychopathology (7-9). Despite these initial investigations of children who experience ESM, very little is known about the phenomenology or symptomatic course of ESM in youth. Data from a pilot study suggested that the presence of ESM in children with attention-deficit hyperactivity disorder (ADHD) may be associated with a poorer outcome (9, 10). The National Institute of Mental Health (NIMH)-supported Longitudinal Assessment of Manic Symptoms (LAMS) study was designed to better understand the phenomenology and determinants of outcome (e.g., psychosocial functioning, diagnoses, medications, and service utilization) in children with ESM. LAMS used an epidemiological approach to assemble a cohort of 6–12-year-old children at their first outpatient mental health visit at university-affiliated clinics (11). The LAMS design used a low, sensitive threshold on a screening instrument for manic symptoms, both to capture a large portion of those already showing symptoms of bipolarity, but also to include a substantial number of cases without bipolarity who were also experiencing similar emotional and behavioral dysregulation. Initial results have confirmed the finding that ESM in clinical mental health settings for youth are, in fact, common and that the majority of children with ESM indeed do not meet DSM-IV criteria for a bipolar spectrum disorder at baseline (5). The most common diagnoses are ADHD, oppositional defiant disorder, conduct disorder, and depression, often in various combinations (3, 5, 12). A specific goal of the LAMS study was to examine the course of children’s manic symptoms over time. To this end, we evaluated whether or not children who participated demonstrated different trajectories of parent-reported manic and biphasic symptoms over the first 24 months of follow-up. Based on prior longitudinal investigations of diagnostic status, combined with the choice of a low threshold of ESM to capture a heterogeneous group of youths in terms of clinical issues, we anticipated that there would be several distinct symptom trajectories, including at least one group that showed persistent symptoms of mania and at least one group that remitted. We also anticipated that a third group might show intermediate levels of mood symptoms, but whether this would be a stable pattern, or whether manic symptoms would fluctuate, was an empirical question. We next investigated what baseline determinants differentiated these distinct trajectories. Finally, we investigated what factors occur over the span of an initial 24-month observation period that could lead to categorization into these distinct classes.

Applying specific techniques and tools of project management has become an important issue of concern in the context of New Public Management and a practice for the public administration reform and integration, in an expanded European context and particularly in the case of Romania, where projects of various sizes (national programs and strategies and sectoral policies) are implemented by different structures. This paper aims to examine the application and integration of the project management instruments and techniques in the Romanian public administration practice. The research objectives are: (1) to present and analyze the using of projects and project management by public administration, and (2) to identify the effects of implementing project management on the development of the organizational capacity of the public sector. This paper presents (1) the results obtained from the study of the relevant literature and (2) the results of a questionnaire survey conducted among civil servants with the purpose of identifying the effects of using project management in Romanian public administration.

Irritable mood and temper outbursts are common in youth referred for psychiatric treatment.1,2 They are also the core features of the proposed diagnosis disruptive mood dysregulation disorder (DMDD) in DSM-5.3 DMDD is characterized primarily by frequent, severe, recurrent temper outbursts and chronically irritable and/or angry mood, both of which must be present for at least a year. The DSM-5 Work Groups raised concerns that many youth with severe, nonepisodic irritable mood are inappropriately diagnosed with bipolar disorder.4 The DMDD diagnosis was constructed to capture the phenomenology of youth with severe, chronic irritability, with the goal of reducing the chance that youth with this phenotype would receive a bipolar diagnosis. The DSM-5 Work Groups note that there is currently relatively limited research to support the DMDD diagnosis.4 Most available studies focus on an overlapping but not identical construct called severe mood dysregulation (SMD). SMD includes the core criteria of DMDD, but also requires symptoms of chronic hyperarousal such as insomnia, agitation, distractibility, racing thoughts, flight of ideas, pressured speech, and intrusiveness.5 Published research on SMD has primarily been from a carefully phenotyped cohort of 146 youth referred to the National Institute of Mental Health (NIMH) Intramural Program.6 The youth with SMD were predominantly male (66%) and had high lifetime rates of attention-deficit/hyperactivity disorder (ADHD; 85%), oppositional defiant disorder (86%), and anxiety disorders (58%). About 16% met lifetime criteria for major depressive disorder (MDD). The youth with SMD were shown to be different from youth with a specified phenotype of bipolar I disorder (requiring distinct episodes of manic symptoms, including either elated mood or grandiosity) on a number of domains, including lower familial rates of bipolar disorder, lower onset rates of manic and hypomanic episodes over prospective follow-up, and differences on several neuropsychological domains and measures of brain structure and functioning.6 Other studies relevant to the SMD/DMDD phenotype have been post hoc analyses of large datasets in which a retrospective diagnosis of SMD was derived from the existing phenotypic variables. In the Great Smoky Mountains Study, 1.8% of the sample met SMD criteria with severe functional impairment, which made it much more common than bipolar disorder (0.1% of the sample).7 The severely impaired SMD youth from this community sample were predominantly male (66%), but differed from those in the NIMH studies, as only about 32% met criteria for ADHD; 42%, for oppositional defiant disorder; and 21%, for any anxiety disorder. In addition, there was very little longitudinal stability of the SMD diagnosis (83% met SMD criteria at only 1 wave). A retrospective SMD diagnosis was applied to 4 large aggregated community samples and 2 large clinical samples, which were assessed using the NIMH Diagnostic Interview Schedule-IV.6 Preliminary analyses indicated that in the community samples, 15% of youth with oppositional defiant disorder met SMD criteria, as did about 25% of the youth with oppositional defiant disorder in the clinical samples. Additional data specific to the DMDD diagnosis are needed; however, given the time constraints involved with the release of the upcoming DSM-5, carefully performed prospective studies are not possible. One way to evaluate DMDD is to take data from existing cohorts and retrospectively construct a DMDD diagnosis, similar to what was done for SMD. The Longitudinal Assessment of Manic Symptoms (LAMS) study is one source that can provide suitable data, as participants were sampled from all children presenting for new evaluation at 9 different university-affiliated clinics and were carefully assessed using semistructured interviews. In order to evaluate the validity of the DMDD diagnosis, it is useful to keep in mind the 5 phases of systematic study proposed by Robins and Guze8 that are necessary to validate a particular diagnostic classification in psychiatry. Using the LAMS cohort, we can provide relevant data on 4 of these phases: (1) clinical description, (2) delimitation from other disorders, (3) follow-up study, and (4) family study. In this article, we examine the clinical phenomenology of LAMS participants who met a DMDD diagnostic phenotype at intake and evaluate whether the DMDD phenotype can be delimited from other diagnoses, is stable over a 2-year follow-up period, and predicts new onset of DSM-IV diagnoses. Lastly, we assess the association of the DMDD phenotype with parental history of different psychiatric disorders.

Fristad MA, Frazier TW, Youngstrom EA, Mount K, Fields BW, Demeter C, Birmaher B, Kowatch RA, Arnold LE, Axelson D, Gill MK, Horwitz SM, Findling RL. What differentiates children visiting outpatient mental health services with bipolar spectrum disorder from children with other psychiatric diagnoses? Bipolar Disord 2012: 14: 497–506. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: To determine the contribution of parent-reported manic symptoms, family history, stressful life events, and family environment in predicting diagnosis of bipolar spectrum disorders (BPSD) in youth presenting to an outpatient psychiatric clinic. Methods: A total of 707 6- to 12-year-old children [621 with elevated symptoms of mania (ESM+) based on screening via the Parent General Behavior Inventory 10-item Mania Scale (PGBI-10M) and 86 without ESM (ESM–)] received a comprehensive assessment. Results: Of the 629 with complete data, 24% (n = 148) had BPSD. Compared to those without BPSD (n = 481), children with BPSD: were older (Cohen’s d = 0.44) and more likely to be female (Cohen’s d = 0.26); had higher parent-endorsed manic symptom scores at screening (Cohen’s d = 0.36) and baseline (Cohen’s d = 0.76), more biological parents with a history of manic symptoms (Cohen’s d = 0.48), and greater parenting stress (Cohen’s d = 0.19). Discriminating variables, in order, were: baseline PGBI-10M scores, biological parent history of mania, parenting stress, and screening PGBI-10M scores. Absence of all these factors reduced risk of BPSD from 24% to 2%. Conclusions: History of parental manic symptoms remains a robust predictor of BPSD in youth seeking outpatient care, even after accounting for parent report of manic symptoms in the child at screening. However, the risk factors identified as associated with BPSD, together had limited value in accurately identifying individual participants with BPSD, highlighting the need for careful clinical assessment.

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.

Robust screening measures that perform well in different populations could help improve the accuracy of diagnosis of pediatric bipolar disorder. Changes in sampling could influence the performance of items and potentially influence total scores enough to alter the predictive utility of scores. Additionally, creating a brief version of a measure by extracting items from a longer scale might cause differential functioning due to context effects. The authors of current study examined both sampling and context effects of a brief measure of pediatric mania. Caregivers of 813 youths completed the parent-reported version of the General Behavior Inventory (PGBI) at an academic medical center sample enriched for mood disorders. Caregivers of 481 youths completed the PGBI at a community mental health center. Caregivers of 799 youths completed 10 items extracted from the PGBI at a community setting. Caregivers of 159 youths completed both versions of the PGBI and a semistructured diagnostic interview. Differential item functioning indicated that across samples some items functioned differently; however, total observed scores were similar across all levels of mania. Receiver operating characteristic analysis indicated that the 10 extracted items discriminated bipolar disorder from nonbipolar behavior as well as when the items were embedded within the full measure. Findings suggest that the extracted items perform similarly to the embedded items in the community setting. Measurement properties appear sufficiently robust across settings to support clinical applications.

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

OBJECTIVE The aim of the Longitudinal Assessment of Manic Symptoms (LAMS) study is to examine differences in psychiatric symptomatology, diagnoses, demographics, functioning, and psychotropic medication exposure in children with elevated symptoms of mania (ESM) compared to youth without ESM. This article describes the initial demographic information, diagnostic and symptom prevalence, and medication exposure for the LAMS cohort that will be followed longitudinally. METHOD Guardians of consecutively ascertained new outpatients 6 to 12 years of age presenting for treatment at one of 10 university-affiliated mental health centers were asked to complete the Parent General Behavior Inventory-10-Item Mania Scale (PGBI-10M). Patients with scores ≥ 12 on the PGBI-10M (ESM+) and a matched sample of patients who screened negative (ESM-) were invited to participate. Patients were enrolled from December 13, 2005, to December 18, 2008. RESULTS 707 children (621 ESM+, 86 ESM-; mean [SD] age = 9.4 [2.0] years) were evaluated. The ESM+ group, compared to the ESM- group, more frequently met DSM-IV criteria for a mood disorder (P < .001), bipolar spectrum disorders (BPSD; P < .001), and disruptive behavior disorders (P < .01). Furthermore, they showed poorer overall functioning and more severe manic, depressive, attention-deficit/hyperactivity, disruptive behavioral, and anxiety symptoms. Nevertheless, rates of BPSD were relatively low in the ESM+ group (25%), with almost half of these BPSD patients (12.1% of ESM+ patients) meeting DSM-IV criteria for bipolar disorder not otherwise specified. ESM+ children with BPSD had significantly more of the following: current prescriptions for antipsychotics, mood stabilizers, and anticonvulsants (P < .001 for each); psychiatric hospitalizations (P < .001); and biological parents with elevated mood (P = .001 for mothers, P < .013 for fathers). ESM+ children with BPSD were also lower functioning compared to ESM+ children without BPSD. CONCLUSIONS Although ESM+ was associated with higher rates of BPSD than ESM-, 75% of ESM+ children did not meet criteria for BPSD. Results suggest that longitudinal assessment is needed to examine which factors are associated with diagnostic evolution to BPSD in children with elevated symptoms of mania.

Pediatric bipolarity is a debilitating, chronic disorder that impairs afflicted youths’ developmental and emotional growth. Furthermore, pediatric bipolar disorder has been associated with high rates of suicide, school failure, aggression, and risk-taking behaviors such as sexual promiscuity and substance abuse (1, 2). Often, investigators have attempted to identify risk factors that may lead to the development of bipolar disorders in children and adolescents (3, 4). One complication in diagnosing pediatric bipolarity is that there is an overlap in symptoms of bipolar disorder (hyperactivity, dysphoria, irritability, and aggressive behavior) with other common psychiatric conditions in youths such as attention-deficit hyperactivity disorder (ADHD), depression, and conduct disorder (5–8). Juvenile bipolar disorder is commonly misdiagnosed, due to the high rates of psychiatric comorbidity, high rates of rapid cycling without inter-episode recovery, and brief periods of euthymia (9). These challenges in combination with changes in diagnostic practices to improve recognition of bipolar I disorder (BP I) may contribute to the varying rates of BP I among youths in community, epidemiological, and pediatric research centers. Given the lack of knowledge of the phenomenology, course, or symptomatic evolution of BP I, it is not surprising that some youths with BP I are treated with stimulants or antidepressants. Concerns have been raised about the effects of stimulant and antidepressant treatment in children with BP I (10,11). One theory is that prior stimulant and antidepressant exposure may put youths at higher risk for developing bipolar disorder (12–14). More specifically, the higher rate of BP I in the United States may be related to the greater use of antidepressants and stimulants by US children (13). The aim of this study is twofold: (i) to examine the initiation of antidepressant and stimulant treatment in relation to the onset of BP I; and (ii) to examine the clinical presentation of youths prescribed stimulant and antidepressant medication before and after the onset of BP I.

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.

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.

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.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.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).Nonadherence may limit the statistical power of treatment efficacy studies and the effectiveness of pharmacotherapy treatment for juvenile BPD and necessitate strategies to evaluate and enhance levels of treatment adherence.

Objective: To determine if divalproex sodium was superior to placebo in the treatment of symptomatic youths who suffer from a bipolar spectrum disorder and who also have a parent with a diagnosis of a bipolar illness. Method: Youths, ages 5 to 17 years, meeting DSM-IV criteria for bipolar disorder not otherwise specified (NOS) or cyclothymia who also had at least 1 biological parent with bipolar illness were randomly assigned in a double-blind fashion to receive treatment with either divalproex sodium or placebo for up to 5 years. Study participation ended if the subject required additional clinical intervention, if the patient developed treatment-related adverse events, or if the participant was not adherent with study procedures. The primary outcome measure was time to study discontinuation for any reason. The study was conducted from August 1997 to April 2003. Results: Fifty-six youths with a mean (SD) age of 10.7 (3.1) years were randomly assigned and received either divalproex sodium (N = 29) or placebo (N = 27). In spite of statistical power of 80% to detect hazard ratios of 2.2 or larger, the treatment groups did not significantly differ in survival time for discontinuation for any reason (p = .93) or discontinuation due to a mood event (p = .55). Changes in mood symptom ratings and psychosocial functioning from baseline to study discontinuation did not differ between groups (most significant p >.14). However, both groups did show improvements in mood symptoms and psychosocial functioning over time (all p values

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.

Objectives: The objectives of this study were to: (i) describe the phenomenology of youths diagnosed with subsyndromal bipolar disorders; (ii) describe the phenomenology of youngsters who are the children of bipolar parents, who are also experiencing subsyndromal symptoms of bipolar disorder (patients with ‘cyclotaxia’); and (iii) explore which symptoms may be most useful in identifying youths with cyclotaxia. Methods: Four hundred outpatients between the ages of 5 and 17 years received a diagnostic assessment and psychometric questionnaires pertaining to mood symptomatology and psychosocial functioning. Parental diagnostic information was also obtained. Children and adolescents were assigned to one of three diagnostic groups: a ‘syndromal bipolar disorder (BP)’ group (n = 118), a ‘sub-syndromal bipolar (SUB-BP)’ group (n = 75), or a ‘non-bipolar (NON-BP)’ group (n = 207). In addition, based on parental diagnoses, youths were assigned to either a high genetic risk group (n = 167) or a low genetic risk group (n = 233). Results: Youths with subsyndromal bipolar disorders were found to have intermediate degrees of manic symptoms than youths with bipolar disorder and youths without a bipolar diagnosis. Offspring of parents having a bipolar disorder were more likely to show symptoms of hypomania and mania than youths without a bipolar parent. Youths at genetic risk for developing a bipolar disorder were not found to be at higher risk for having a diagnosis of attention-deficit hyperactivity disorder or a disruptive behavior disorder. Finally, results suggest that elevated mood with irritability and rapid mood fluctuations are the key distinguishing characteristics of ‘cyclotaxia’. Conclusions: There exists a group of youngsters who are the offspring of a parent/parents with a bipolar disorder who do not suffer from BP 1 or BP 2, yet have elevated mood symptoms and psychosocial dysfunction. As a result of these observations, treatment studies are needed for youths with ‘cyclotaxia’.

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 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.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.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).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.

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 ≤12.5, CDRS-R ≤40, CGAS ≥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.

Importance: Psychiatric disorders in youth characterized by behavioral and emotional dysregulation are often comorbid and difficult to distinguish. An alternative approach to conceptualizing these disorders is to move toward a diagnostic system based on underlying pathophysiologic processes that may cut across conventionally defined diagnoses. Neuroimaging techniques have potentials for the identification of these processes.Objective: To determine whether diffusion imaging, a neuroimaging technique examining white matter (WM) structure, can identify neural correlates of emotional dysregulation in a sample of youth with different psychiatric disorders characterized by behavioral and emotional dysregulation.Design, Setting, And Participants: Using global probabilistic tractography,we examined relationships betweenWMstructure in key tracts in emotional regulation circuitry (ie, cingulum, uncinate fasciculus, and forceps minor) and (1) broader diagnostic categories of behavioral and emotional dysregulation disorders (DDs) and (2) symptom dimensions cutting across conventional diagnoses in 120 youth with behavioral and/or emotional DDs, a referred sample of the Longitudinal Assessment of Manic Symptoms (LAM) study. Thirty age- and sex-matched typically developing youth (control participants) were included. Multivariate multiple regression models were used. The study was conducted from July 1, 2010, to February 28, 2014.Main Outcomes And Measures: Fractional anisotropy aswell as axial and radial diffusivity were estimated and imported into a well-established statistical package.We hypothesized that (1) youth with emotional DDs and those with both behavioral and emotional DDs would show significantly lower fractional anisotropy compared with youth with behavioral DDs in these WM tracts and (2) that there would be significant inverse relationships between dimensional measures of affective symptom severity and fractional anisotropy in these tracts across all participants.Results: Multivariate multiple regression analyses revealed decreased fractional anisotropy and decreased axial diffusivity within the uncinate fasciculus in youth with emotional DDs vs those with behavioral DDs, those with both DDs, and the controls (F6,160 = 2.4; P = .032; all pairwise comparisons, P < .002). In the same model, greater severity of manic symptomswas positively associated with higher fractional anisotropy across all affected youth (F3,85 = 2.8; P = .044).Conclusions And Relevance: These findings suggest that abnormal uncinate fasciculus and cingulumWMstructure may underlie emotional, but not behavioral, dysregulation in pediatric psychiatric disorders and that a different neural mechanism may exist for comorbid emotional and behavioral DDs.

Objectives: The primary purpose of this study was to describe the clinical presentation of bipolar I disorder (BP-I) as it occurs in children and adolescents and to assess whether the manifestations of BP-I were similar in both age groups. Method: Ninety youths between the ages of 5 and 17 years meeting full diagnostic symptom criteria for BP-I were included in this study. The diagnosis of BP-I was established for these youths based on the results of a semi-structured diagnostic interview and a clinical assessment by a child and adolescent psychiatrist. The course of a subset of these youngsters’ illnesses was assessed using the Life Charting Method (LCM). Data regarding the clinical presentation, longitudinal history, psychiatric co-morbidities and parental psychopathology were also obtained. Results: The clinical presentation of BP-I was similar in children and adolescents. Youths meeting diagnostic criteria for BP-I developed an average of approximately 5.8 of the 7 symptoms of mania during periods of elevated or irritable mood. BP-I was found to be a cyclic disorder characterized by high rates of rapid cycling (50%) with almost no inter-episode recovery. Almost 75% of these subjects also met diagnostic symptom criteria for a disruptive behavior disorder. High rates of mood disorders were found in fathers. Conclusions: These data suggest that the presentation of juvenile BP-I is a cyclic and valid clinical condition with manifestations on a continuum with the later-onset forms of this illness.

Objective This study aims to examine trajectories of attention-deficit/hyperactivity disorder (ADHD) symptoms in the Longitudinal Assessment of Manic Symptoms (LAMS) sample. Method The LAMS study assessed 684 children aged 6 to 12 years with the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS) and rating scales semi-annually for 3 years. Although they were selected for elevated manic symptoms, 526 children had baseline ADHD diagnoses. With growth mixture modeling (GMM), we separately analyzed inattentive and hyperactive/impulsive symptoms, covarying baseline age. Multiple standard methods determined optimal fit. The χ 2 and Kruskal–Wallis analysis of variance compared resulting latent classes/trajectories on clinical characteristics and medication. Results Three latent class trajectories best described inattentive symptoms, and 4 classes best described hyperactive/impulsive symptoms. Inattentive trajectories maintained their relative position over time. Hyperactive/impulsive symptoms had 2 consistent trajectories (least and most severe). A third trajectory (4.5%) started mild, then escalated; and a fourth (14%) started severe but improved dramatically. The improving trajectory was associated with the highest rate of ADHD and lowest rate of bipolar diagnoses. Three-fourths of the mildest inattention class were also in the mildest hyperactive/impulsive class; 72% of the severest inattentive class were in the severest hyperactive/impulsive class, but the severest inattention class also included 62% of the improving hyperactive-impulsive class. Conclusion An ADHD rather than bipolar diagnosis prognosticates a better course of hyperactive/impulsive, but not inattentive, symptoms. High overlap of relative severity between inattention and hyperactivity/impulsivity confirms the link between these symptom clusters. Hyperactive/impulsive symptoms wane more over time. Group means are insufficient to understand individual ADHD prognosis. A small subgroup deteriorates over time in hyperactivity/impulsivity and needs better treatments than currently provided.

The study compared use of specialty outpatient mental services among children ages six and seven and children ages eight through 12 and investigated predictors of differences in the patterns of service use by age.Eligible children were first-time patients of clinics participating in the Longitudinal Assessment of Manic Symptoms who were between ages six and 12 and who were English speaking. Children who screened positive for symptoms of mania (N=1,124) were invited to participate, and families of 621 (55%) children consented. A matched sample of 86 children without a positive screen for mania also participated. Baseline interviews assessed sociodemographic characteristics of the child and family and the child's functioning, diagnoses, and use of services.Of the 707 children, 30% were younger, and 50% used multiple types of specialty outpatient services. Younger children were more likely to be male, have Medicaid insurance, and have two parents with mental health problems. Use of multiple types of services was related to study site, high depression scores, fewer minor health issues, and fewer stressful life events among younger children and with parental stress, primary diagnosis, poor functioning, and not living with both parents among older children. Younger children were much more likely than older children to have used services before age six.Younger children showed very early use of multiple types of services for mental health problems and a pattern of persistent impairment despite long-standing use of services. These data argue strongly for focusing on emotional and behavioral issues among young children.

IMPORTANCE: Pediatric disorders characterized by behavioral and emotional dysregulation pose diagnostic and treatment challenges because of high comorbidity, suggesting that they may be better conceptualized dimensionally rather than categorically. Identifying neuroimaging measures associated with behavioral and emotional dysregulation in youth may inform understanding of underlying dimensional vs disorder-specific pathophysiologic features. OBJECTIVE: To identify, in a large cohort of behaviorally and emotionally dysregulated youth, neuroimaging measures that (1) are associated with behavioral and emotional dysregulation pathologic dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory 10-Item Mania Scale [PGBI-10M], mania, depression, and anxiety) or (2) differentiate diagnostic categories (bipolar spectrum disorders, attention-deficit/hyperactivity disorder, anxiety, and disruptive behavior disorders). DESIGN, SETTING, AND PARTICIPANTS: A multisite neuroimaging study was conducted from February 1, 2011, to April 15, 2012, at 3 academic medical centers: University Hospitals Case Medical Center, Cincinnati Children's Hospital Medical Center, and University of Pittsburgh Medical Center. Participants included a referred sample of behaviorally and emotionally dysregulated youth from the Longitudinal Assessment of Manic Symptoms (LAMS) study (n = 85) and healthy youth (n = 20). MAIN OUTCOMES AND MEASURES: Region-of-interest analyses examined relationships among prefrontal-ventral striatal reward circuitry during a reward paradigm (win, loss, and control conditions), symptom dimensions, and diagnostic categories. RESULTS: Regardless of diagnosis, higher PGBI-10M scores were associated with greater left middle prefrontal cortical activity (r = 0.28) and anxiety with greater right dorsal anterior cingulate cortical (r = 0.27) activity to win. The 20 highest (t = 2.75) and 20 lowest (t = 2.42) PGBI-10M-scoring youth showed significantly greater left middle prefrontal cortical activity to win compared with 20 healthy youth. Disruptive behavior disorders were associated with lower left ventrolateral prefrontal cortex activity to win (t = 2.68) (all P

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

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.

Transgenerational association of bipolar spectrum disorder (BPSD) and attention deficit/hyperactivity disorder (ADHD) has been reported, but inconclusively.Children ages 6-12 were systematically recruited at first outpatient visit at 9 clinics at four universities and reliably diagnosed; 621 had elevated symptoms of mania (12 on the Parent General Behavior Inventory 10-Item Mania Scale); 86 had scores below 12. We analyzed baseline data to test a familial association hypothesis: compared to children with neither BPSD nor ADHD, those with either BPSD or ADHD would have parents with higher rates of both bipolar and ADHD symptoms, and parents of comorbid children would have even higher rates of both.Of 707 children, 421 had ADHD without BPSD, 45 BPSD without ADHD, 117 comorbid ADHD+BPSD, and 124 neither. The rate of parental manic symptoms was similar for the comorbid and BPSD-alone groups, significantly greater than for ADHD alone and "neither" groups, which had similar rates. ADHD symptoms in parents of children with BPSD alone were significantly less frequent than in parents of children with ADHD (alone or comorbid), and no greater than for children with neither diagnosis. Family history of manic symptoms, but not ADHD symptoms, was associated with parent-rated child manic-symptom severity over and above child diagnosis.The sample was not epidemiologic, parent symptoms were based on family history questions, and alpha was 0.05 despite multiple tests.These results do not support familial linkage of BPSD and ADHD; they are compatible with heritability of each disorder separately with coincidental overlap.

The authors examined the association of demographic and clinical characteristics, family history, and type of treatment among children receiving outpatient mental health services and parents' perception of treatment benefit. They also examined whether perceived benefit was related to continued use of services at six-month follow-up.Parents of children age six to 12 years who were first-time patients at one of nine clinics participating in the Longitudinal Assessment of Manic Symptoms (LAMS) study completed the Parent General Behavior Inventory Ten-Item Mania Scale. Parents of children with scores of 12 or higher (N=1,124) were invited to participate in a follow-up study, and 621 agreed. During baseline assessment after the first outpatient visit and at six-month follow-up, the parents were asked about children's sociodemographic and diagnostic characteristics and use of services and asked to rate how much their children had benefited from the most recent outpatient treatment.Data were available for 573 children. At baseline, parents of 167 (29%) children reported that the treatment provided a lot of benefit, and perceived benefit was related to receiving medication (with or without therapy) versus just therapy, higher scores on functioning, LAMS site, no history of comorbid diagnoses, living with both biological parents, and having no parents or siblings with a prior hospitalization for a psychiatric illness. At six-month follow-up, perceived benefit was related to continued use of services (p.001).Medication with or without therapy was perceived as more beneficial than therapy alone. Perceived benefit was strongly related to continued use of treatment.

Bipolar Spectrum Disorders (BPSDs; Bipolar I and II, Cyclothymic Disorder, and Bipolar not otherwise specified (NOS)) are chronic, debilitating illnesses with considerable controversy surrounding their pediatric presentation.1 Over half (60%) of adults with bipolar disorder experience their first symptoms during adolescence.2,3 Nearly one-third (30%) experience symptoms prior to age 13.2,3 In clinical settings, children are increasingly likely to be given a bipolar diagnosis.4–7 Although controversy remains about the nature of bipolar spectrum presentations in youth,8 both “classic” and other spectrum presentations (BP-II, BP-NOS, cyclothymic disorder) are often associated with substantial suffering.9 Increased prevalence in clinical settings,10 combined with poor long-term outcomes, make accurate and early diagnosis of BPSD an important challenge with considerable public health significance. The few available studies examining prodromal symptoms for BPSD suggest that symptoms of mania may be indicative of early stages of illness,11–14 although many studies examining early symptoms concentrate on children of parents with BPSD,15–18 and few have used prospective designs.19–21 Growing evidence indicates a large number of children receiving psychiatric care present with elevated symptoms of mania (ESM).22–24 A substantial proportion of youth with ESM suffer from considerable dysfunction, although many do not meet strict DSM criteria for BPSD.24–27 Previous papers have described the participant characteristics28 and study design29 of the NIMH-funded Longitudinal Assessment of Manic Symptoms (LAMS) study. This article extends previous studies by describing diagnostic differences between youth with parent-reported manic symptoms that persist over two assessment points (Persistent ESM+) versus youth with manic symptoms that remit (Remitted ESM+) or are consistently low across two time points (Persistent ESM−). It was hypothesized that individuals with Persistent ESM+ would have higher rates of BPSD diagnoses than other youth. In this study, ESM is conceptualized as a phenotype that when positive and persistent (Persistent ESM+), is related to and potentially predictive of current or future BPSD diagnosis, but is not redundant with BPSD. This study’s secondary aim was to evaluate clinical utility of tracking manic symptoms over two time points in determining the presence of pediatric BPSD. Parent reports on brief rating scales have been particularly powerful at reducing the tendency to over-diagnose bipolar disorder.10,30 We expected that including information from two assessment time points would further increase the accuracy of predicting BPSD.

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.

Arnold LE, Demeter C, Mount K, Frazier TW, Youngstrom EA, Fristad M, Birmaher B, Findling RL, Horwitz SM, Kowatch R, Axelson DA. Pediatric bipolar spectrum disorder and ADHD: comparison and comorbidity in the LAMS clinical sample. Bipolar Disord 2011: 13: 509–521. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objective: To compare attention-deficit hyperactivity disorder (ADHD), bipolar spectrum disorders (BPSDs), and comorbidity in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Methods: Children ages 6–12 were recruited at first visit to clinics associated with four universities. A BPSD diagnosis required that the patient exhibit episodes. Four hypotheses were tested: (i) children with BPSD + ADHD would have a younger age of mood symptom onset than those with BPSD but no ADHD; (ii) children with BPSD + ADHD would have more severe ADHD and BPSD symptoms than those with only one disorder; (iii) global functioning would be more impaired in children with ADHD + BPSD than in children with either diagnosis alone; and (iv) the ADHD + BPSD group would have more additional diagnoses. Results: Of 707 children, 421 had ADHD alone, 45 had BPSD alone, 117 had both ADHD and BPSD, and 124 had neither. Comorbidity (16.5%) was slightly less than expected by chance (17.5%). Age of mood symptom onset was not different between the BPSD + ADHD group and the BPSD-alone group. Symptom severity increased and global functioning decreased with comorbidity. Comorbidity with other disorders was highest for the ADHD + BPSD group, but higher for the ADHD-alone than the BPSD-alone group. Children with BPSD were four times as likely to be hospitalized (22%) as children with ADHD alone. Conclusions: The high rate of BPSD in ADHD reported by some authors may be better explained as a high rate of both disorders in child outpatient settings rather than ADHD being a risk factor for BPSD. Co-occurrence of the two disorders is associated with poorer global functioning, greater symptom severity, and more additional comorbidity than for either single disorder.

To describe the design of a longitudinal study of youth with elevated symptoms of mania (ESM), as well as the prevalence and correlates of manic symptoms. Bipolar disorder in youth is serious and is surrounded by controversy about its phenomenology, course, and treatment. Yet, there are no longitudinal studies of youth selected only for ESM, the phenomenological hallmark. The study's objective is to document the rate and sociodemographic correlates of ESM in children attending outpatient psychiatric clinics.Parents of 3,329 children aged 6-12 years visiting 10 outpatient clinics were asked to complete the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M). Children with PGBI-10M scores ≥ 12 (ESM positive-screen [ESM+]) and a matched sample of ESM screen-negative (ESM-) children were invited to enroll in the longitudinal study. The sample was accrued from November 14, 2005, to November 28, 2008.Most of the children whose parents filled out the PGBI-10M (N = 2,622, 78.8%) participated in the study. Nonparticipants were slightly younger (mean age = 9.1 years [SD = 2.0 years] versus 9.4 years [SD = 2.0 years] for participants; t3327 = 4.42, P.001). Nearly half of the participants (43%) were ESM+; these were more likely to be Latino (4.2% versus 2.5% for ESM-; χ(2)1 = 5.45, P = .02), younger (mean age = 9.3 years [SD = 2.0 years] versus 9.6 years [SD = 1.9 years] for ESM-; t2620 = 3.8, P.001), and insured by Medicaid (48.4% versus 35.4% for ESM-; χ(2)1 = 45.00, P.001). There were no sociodemographic differences between those who did versus did not agree to enroll in the longitudinal portion (yes to enrollment: n = 621, 55.2%; no to enrollment: n = 503, 44.8%). Four items best discriminated ESM+ children from ESM- children. Three of the 4 items were not the most commonly endorsed items, but all were indicative of behavioral extremes.Data suggest that ESM+ is not rare in 6- to 12-year-olds. Children who are ESM+ show behavioral extremes, including rapid mood shifts, compared to ESM- children.

Background The objective of this study was to examine whether fluoxetine was superior to placebo in the acute amelioration of depressive symptomatology in adolescents with depressive illness and a comorbid substance use disorder. Methods Eligible subjects ages 12–17 years with either a current major depressive disorder (MDD) or a depressive disorder that were also suffering from a comorbid substance-related disorder were randomized to receive either fluoxetine or placebo in this single site, 8-week double-blind, placebo-controlled study. The primary outcome analysis was a random effects mixed model for repeated measurements of Children's Depression Rating Scale-Revised (CDRS-R) scores compared between treatment groups across time. Results An interim analysis was performed after 34 patients were randomized. Based on the results of a futility analysis, study enrollment was halted. Twenty-nine males and 5 females were randomized to receive fluoxetine (n = 18) or placebo (n = 16). Their mean age was 16.5 (1.1) years. Overall, patients who received fluoxetine and placebo had a reduction in CDRS-R scores. However, there was no significant difference in mean change in CDRS-R total score in those subjects treated with fluoxetine and those who received placebo (treatment difference = 0.19, S.E. = 0.58, F = 0.14, p = .74). Furthermore, there was not a significant difference in rates of positive urine drug toxicology results between treatment groups at any post-randomization visit (F = 0.22, df = 1, p = 0.65). The main limitation of this study is its modest sample size and resulting low statistical power. Other significant limitations to this study include, but are not limited to, the brevity of the trial, high placebo response rate, limited dose range of fluoxetine, and the inclusion of youth who met criteria for depressive disorders other than MDD. Conclusion Fluoxetine was not superior to placebo in alleviating depressive symptoms or in decreasing rates of positive drug screens in the acute treatment of adolescents with depression and a concomitant substance use disorder.

Since the mid 1990s, early-onset bipolar spectrum disorders (BPSDs) have received increased attention in both the popular press and scholarly press. Rates of diagnosis of BPSD in children and adolescents have increased in inpatient, outpatient, and primary care settings. BPSDs remain difficult to diagnose, particularly in youth. The current diagnostic system makes few modifications to accommodate children and adolescents. Researchers in this area have developed specific BPSD definitions that affect the generalizability of their findings to all youth with BPSD. Despite knowledge gains from the research, BPSDs are still difficult to diagnose because clinicians must: (1) consider the impact of the child’s developmental level on symptom presentation (e.g., normative behavior prevalence, environmental limitations on youth behavior, pubertal status, irritability, symptom duration); (2) weigh associated impairment and course of illness (e.g., neurocognitive functioning, failing to meet full DSM criteria, future impairment); and (3) make decisions about appropriate assessment (differentiating BPSD from medical illnesses, medications, drug use, or other psychiatric diagnoses that might better account for symptoms; comorbid disorders; informant characteristics and assessment measures to use). Research findings concerning these challenges and relevant recommendations are offered. Areas for further research to guide clinicians’ assessment of children with early-onset BPSD are highlighted.

To examine the effectiveness and cognitive effects of aripiprazole (APZ) in children with a primary diagnosis of attention-deficit/hyperactivity disorder (ADHD).Youths, ages 8-12 years, with a diagnosis of ADHD combined-type or ADHD predominately inattentive-type were enrolled into a 6-week, open-label pilot trial. Outcome measures included the ADHD Rating Scale-IV (ARS-IV), Clinical Global Impressions Scale (CGI), and Children's Global Assessment Scale (CGAS). The Conners' Continuous Performance Test II, Reading and Math Fluency subscales of the Woodcock-Johnson III Tests of Achievement, and the Stroop Color and Word Test were administered at baseline and end of study.Fourteen (9 males and 5 females) youths were diagnosed with ADHD-combined type, while 9 (5 males and 4 females) were diagnosed with ADHD-inattentive type. At a mean dose of 6.7 mg/day, end of study results showed overall significant improvement from baseline on ADHD and functional outcome measures. No significant differences in baseline performance at end of study were found on the cognitive measures. The most frequently reported adverse events were sedation (n = 18; 78.3%) and headache (n = 11; 47.8%).Although this was a brief pilot study with a small sample size, in this cohort, APZ led to clinical benefit in reducing ADHD symptoms and improving overall functioning. Of note, cognitive functioning did not appear to be negatively impacted by APZ treatment.

Background Lithium is a benchmark treatment for bipolar illness in adults. However, there has been relatively little methodologically stringent research regarding the use of lithium in youth suffering from bipolarity. Methods Under the auspices of the Best Pharmaceuticals for Children Act (BPCA), a Written Request (WR) pertaining to the study of lithium in pediatric mania was issued by the United States Food and Drug Administration (FDA) to the National Institute of Child Health and Human Development (NICHD) in 2004. Accordingly, the NICHD issued a Request for Proposals (RFP) soliciting submissions to pursue this research. Subsequently, the NICHD awarded a contract to a group of investigators in order to conduct these studies. Results The Collaborative Lithium Trials (CoLT) investigators, the BPCA-Coordinating Center, and the NICHD developed protocols to provide data that will: (1) establish evidence-based dosing strategies for lithium; (2) characterize the pharmacokinetics and biodisposition of lithium; (3) examine the acute efficacy of lithium in pediatric bipolarity; (4) investigate the long-term effectiveness of lithium treatment; and (5) characterize the short- and long-term safety of lithium. By undertaking two multi-phase trials rather than multiple single-phase studies (as was described in the WR), the feasibility of the research to be undertaken was enhanced while ensuring all the data outlined in the WR would be obtained. The first study consists of: (1) an 8-week open-label, randomized, escalating dose Pharmacokinetic Phase; (2) a 16-week Long-Term Effectiveness Phase; (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. The second study consists of: (1) an 8-week, double-blind, parallel-group, placebo-controlled Efficacy Phase; (2) an open-label Long-Term Effectiveness lasting either 16 or 24 weeks (depending upon blinded treatment assignment during the Efficacy Phase); (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. In December of 2006, enrollment into the first of these studies began across seven sites. Conclusion These innovative studies will not only provide data to inform the labeling of lithium in children and adolescents with bipolar disorder, but will also enhance clinical decision-making regarding the use of lithium treatment in pediatric bipolar illness. Trial Registration NCT00442039

Objective—Bipolar disorder is being diagnosed and treated in children and adolescents at a rapidly increasing rate, despite the lack of validated instruments to help screen for the condition or differentiate it from more common disorders. The goal of the present study was to develop and validate a brief (10 item) instrument in a large sample of outpatients presenting with a variety of different DSM-IV diagnoses, including frequent comorbid conditions. Methods—Parents completed the Parent General Behavior Inventory (P-GBI), a 73 item mood inventory, as part of a screening assessment that included a semi-structured psychiatric interview of both the parent and the child to determine the child’s diagnoses. Results—637 youths completed the diagnostic assessment and the mood inventory. A 10 item form derived from this 73 item inventory had good reliability (.92), correlated .95 with the original scale, and showed significantly better discrimination of bipolar disorders (Area Under ROC Curve [AUROC] of .856 versus .832 for full scale, p < .005), with good precision for estimation of individual scores for cases up to two standard deviations elevated on the latent trait. The 10-item scale also did well discriminating bipolar from unipolar (AUROC = .86) and bipolar from ADHD cases (AUROC = .82). Conclusions—Findings suggest that parents most notice elated mood, high energy, irritability, and rapid changes in mood and energy as the prominent features of juvenile bipolar disorder. The diagnosis of bipolar disorder in children and adolescents remains a contentious diagnostic issue. 1–3 Untreated bipolar disorder is likely to follow a progressive course, with each mood episode making it more likely that there will be future recurrences that may be more severe and resistant to treatment. 4–6 There also is concern that bipolar disorder may frequently be misdiagnosed in youths as ADHD, conduct disorder, oppositional defiant disorder, or unipolar depression. 7–9

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.

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 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. J. Am. Acad. Child Adolesc. Psychiatry , 2007;46(11):1445-1453.

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).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.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 (p0.05). 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 (p0.05). 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.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.

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 restabilization 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 restabilized with the reinitiation of Li + /DVPX combination treatment. J. Am. Acad. Child Adolesc. Psychiatry , 2006;45(2):142-148.

Objectives: To compare six promising mania measures, the Parent Mood Disorder Questionnaire (P-MDQ), the Adolescent self-report MDQ, the 10-item short form of the Parent General Behavior Inventory (PGBI-SF10), the 28-item Adolescent General Behavior Inventory (AGBI), the Parent Young Mania Rating Scale (P-YMRS), and the adolescent YMRS, in a demographically diverse outpatient sample. Methods: Participants were 262 outpatients (including 164 males and 131 African-Americans) presenting to either an academic medical center (n = 153) or a community mental health center (n = 109). Diagnoses were based on semi-structured interviews with the parent and then youth sequentially. Results: Ninety youths (34%) met criteria for a bipolar spectrum disorder. Parent measures yielded Areas Under the Receiver Operating Curve (AUROC) values of 0.81 for the PGBI-SF10 to 0.66 for the P-YMRS. Adolescent report measures performed significantly less well, with AUROCs ranging from 0.65 to 0.50. There were no significant differences in the diagnostic performance of the measures across the sites or by racial groups, although the reliability of measures tended to be lower in the urban community mental health site. The PGBI-SF10 made a significant contribution to logistic regression models examining all combinations of the instruments. The P-MDQ added information in the younger age group, and no measure improved classification of bipolar cases after controlling for the PGBI-SF10 in the older age group. Discussion: Results replicate previous findings that, in decreasing order of efficiency, the PGBI-SF10, P-MDQ, and P-YMRS significantly discriminate bipolar from non-bipolar cases in youths aged 5–18; and they appear robust in a demographically diverse community setting. Adolescent self-report measures are significantly less efficient, sometimes performing no better than chance at detecting bipolar cases.

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.