Search

Objectives: Attention deficit has been shown to exist in adult and pediatric bipolar disorder across the life span. Given that emotion dysregulation is central to bipolar disorder, this study hypothesizes that emotional circuitry regions are altered along with anomalies in the attentional systems during cognitive deployment in bipolar disorder., Methods: An activation likelihood estimation meta-analysis of attentional activities using GingerALE software was completed for adult and pediatric bipolar disorder populations in all published studies till December 2017. The meta-analysis of all fMRI studies included a total of ten pediatric studies (comprised of pediatric bipolar disorder (PBD) and typically developing (TD) groups) and nine adult patient studies (comprised of adult bipolar disorder (ABD) and healthy control (HC) groups)., Results: While engaged in attentional tasks, increased activation was seen in inferior frontal gyrus with decreased activation in limbic regions in subjects with PBD, relative to TD. Differential patterns of underactivity were also noted in the dorsal attentional system i.e., frontostriatal circuit (dorsolateral prefrontal cortex, anterior cingulate cortex, right lentiform nucleus and right globus pallidus) in PBD patients relative to the TD. However, we did not see any significant differences between the adult groups i.e., ABD vs. HC., Conclusions: In PBD, deploying attentional system potentially improves the fronto-limbic affective circuitry function, despite impaired dorsal attentional system i.e., fronto-striatal circuitry. In contrast, these neural correlates underlying attentional engagement appeared to be not significant in adult BD., Limitations: We examined the PBD vs. TD and the ABD vs. HC separately instead of four-way contrast (dual meta-analytic study). Also, attentional tasks were not unidimensional and tend to capture selective and sustained attention along with response inhibition, thereby recruiting multiple brain circuits., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Lithium is a benchmark treatment for bipolar disorder in adults. Definitive studies of lithium in pediatric bipolar I disorder (BP-I) are lacking., Methods: This multicenter, randomized, double-blind, placebo-controlled study of pediatric participants (ages 7-17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus placebo (n = 28) for up to 8 weeks. The a priori primary efficacy measure was change from baseline to the end of study (week 8/ET) in the Young Mania Rating Scale (YMRS) score, based on last-observation-carried-forward analysis., Results: The change in YMRS score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03). Overall Clinical Global Impression-Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03). A statistically significant increase in thyrotropin concentration was seen with lithium (3.0 ± 3.1 mIU/L) compared with placebo (-0.1 ± 0.9 mIU/L; P < .001). There was no statistically significant between-group difference with respect to weight gain., Conclusions: Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder., (Copyright © 2015 by the American Academy of Pediatrics.)

Objective: Previous studies have found that family-based psychosocial treatments are effective adjuncts to pharmacotherapy among adults and adolescents with bipolar disorder (BD). The objective of this study was to compare the efficacy of adjunctive child- and family-focused cognitive-behavioral therapy (CFF-CBT) to psychotherapy as usual (control) for mood symptom severity and global functioning in children with BD., Method: Sixty-nine youth, aged 7 to 13 years (mean = 9.19, SD = 1.61) with DSM-IV-TR bipolar I, II, or not otherwise specified (NOS) disorder were randomly assigned to CFF-CBT or control groups. Both treatments consisted of 12 weekly sessions followed by 6 monthly booster sessions delivered over a total of 9 months. Independent evaluators assessed participants at baseline, week 4, week 8, week 12 (posttreatment), and week 39 (6-month follow-up)., Results: Participants in CFF-CBT attended more sessions, were less likely to drop out, and reported greater satisfaction with treatment than controls. CFF-CBT demonstrated efficacy compared to the control treatment in reducing parent-reported mania at posttreatment and depression symptoms at posttreatment and follow-up. Global functioning did not differ at posttreatment but was higher among CFF-CBT participants at follow-up., Conclusion: CFF-CBT may be efficacious in reducing acute mood symptoms and improving long-term psychosocial functioning among children with BD., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Activation changes at the interface of affective and cognitive systems are examined over a 3 year period in pediatric bipolar disorder (PBD)., Methods: Thirteen participants with PBD and 10 healthy controls (HC) matched on demographics and IQ were scanned at baseline, at 16 weeks, and after 3 years. All patients received pharmacotherapy based on a medication algorithm. A pediatric affective color matching paradigm was used to probe cognitive processing under emotional challenge., Results: At baseline, in response to emotional vs. neutral words, patients with PBD showed greater activation than HC in the right dorsal lateral prefrontal cortex (DLPFC) and amygdala, ventral lateral prefrontal cortex (VLPFC), bilateral anterior cingulate cortex (ACC), and ventral striatum. Increased activation in DLPFC in the PBD group normalized by 16 weeks. By 3 years, normalization was observed in VLPFC, ACC, amygdala, and striatum., Limitations: Small sample size renders the present findings preliminary., Conclusions: Greater activation in fronto-striatal and fronto-limbic circuits were observed in unmedicated patients with PBD. Present findings suggest the possibility that DLPFC is most malleable to pharmacological intervention with systematic pharmacotherapy leading to immediate response, which extended to amygdalostriatal and ventral cortical regions at 3 years. The seminal observation from this study is the prolonged length of recovery time in the normalization of subcortical activity along with their interfacing cortical regions. Findings from this proof of concept study need to be replicated in a larger sample., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The aim of the present study was to map the pathophysiology of resting state functional connectivity accompanying structural and functional abnormalities in children with bipolar disorder., Methods: Children with bipolar disorder and demographically matched healthy controls underwent resting-state functional magnetic resonance imaging. A model-free independent component analysis was performed to identify intrinsically interconnected networks., Results: We included 34 children with bipolar disorder and 40 controls in our analysis. Three distinct resting state networks corresponding to affective, executive and sensorimotor functions emerged as being significantly different between the pediatric bipolar disorder (PBD) and control groups. All 3 networks showed hyperconnectivity in the PBD relative to the control group. Specifically, the connectivity of the dorsal anterior cingulate cortex (ACC) differentiated the PBD from the control group in both the affective and the executive networks. Exploratory analysis suggests that greater connectivity of the right amygdala within the affective network is associated with better executive function in children with bipolar disorder, but not in controls., Limitations: Unique clinical characteristics of the study sample allowed us to evaluate the pathophysiology of resting state connectivity at an early state of PBD, which led to the lack of generalizability in terms of comorbid disorders existing in a typical PBD population., Conclusion: Abnormally engaged resting state affective, executive and sensorimotor networks observed in children with bipolar disorder may reflect a biological context in which abnormal task-based brain activity can occur. Dual engagement of the dorsal ACC in affective and executive networks supports the neuroanatomical interface of these networks, and the amygdala's engagement in moderating executive function illustrates the intricate interplay of these neural operations at rest.

Background: In response to emotional faces, patients with adolescent bipolar disorder (ABD) exhibit increased neural activity in subcortical emotional processing regions (e.g., amygdala, ventral striatum) and variable prefrontal activity. We extend previous research by identifying cortical and subcortical regions showing altered hemodynamic response shapes in ABD relative to healthy controls (HC)., Methods: ABD (N=65) and matched HC (N=79) completed a slow event-related affective hemodynamic probe task that required indicating the gender of fearful and neutral faces. An informed basis set in SPM8 evaluated shape variations of the hemodynamic responses to these faces., Results: Patients with ABD showed higher activity for fearful relative to neutral faces in the amygdala and prefrontal cortex and a delayed hemodynamic response to fearful faces in dorsolateral and ventrolateral prefrontal cortices (PFC), as well as bilateral amygdala and caudate. Furthermore, the ABD group, relative to HC, showed a prolonged response to fearful faces in right dorsolateral PFC. Clinical measures of mania and depression severity correlated with increased processing delays in the amygdala and striatum., Limitations: By design, the task contained fewer, more widely-spaced stimuli, possibly reducing its power to detect group differences. The use of fearful faces makes comparisons with prior literature in ABD somewhat more difficult., Conclusions: The ABD group engaged in enhanced neural processing of the fearful faces which was associated with increasingly severe manic/mixed mood states. These exploratory findings could help elucidate a "biosignature" of emotion-attention interactions in ABD and present a potential target for reversal with medication treatment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This study examined whether processing of emotional words impairs cognitive performance in acutely ill patients with pediatric bipolar disorder (PBD), with or without comorbid attention-deficit hyperactivity disorder (ADHD), relative to healthy controls (HC). Forty youths with PBD without ADHD, 20 youths with PBD and ADHD, and 29 HC (mean age = 12.97 ± 3.13) performed a Synonym Matching task, where they decided which of two probe words was the synonym of a target word. The three words presented on each trial all had the same emotional valence, which could be negative, positive, or neutral. Relative to HC both PBD groups exhibited worse accuracy for emotional words relative to neutral ones. This effect was greater with negative words and observed regardless of whether PBD patients had comorbid ADHD. In the PBD group without ADHD, manic symptoms correlated negatively with accuracy for negative words, and positively with reaction time (RT) for all word types. Our findings suggest a greater disruptive effect of emotional valence in both PBD groups relative to HC, reflecting the adverse effect of altered emotion processing on cognitive function in PBD. Future studies including an ADHD group will help clarify how ADHD symptoms may affect emotional interference independently of PBD.

Background: Pediatric Bipolar Disorder (PBD) is a debilitating condition associated with impairment in many domains. Social functioning is one of the disorder's most notable areas of impairment and this deficit may be in part due to difficulties recognizing affect in others., Methods: In the present study, medication naïve youth with PBD were compared to age-matched healthy controls on their ability to (a) distinguish between categorical emotions, such as happiness, anger, and sadness on the Emotion Recognition Test (ER-40) and (b) differentiate between levels of emotional intensity on an adapted version of the Penn Emotional Acuity Task (Chicago-PEAT)., Results: Results indicated that PBD youth misidentified sad, fearful, and neutral faces more often than controls, and PBD girls mislabeled 'very angry' faces more often than healthy girls. A mediation analyses indicated that these diagnostic group differences on emotion recognition were significantly mediated by irritability., Limitations: The Chicago-PEAT only examined variations in emotional intensity for the emotions happy and anger. Additionally, all results are correlational; therefore causal inferences cannot be made., Conclusions: Supporting previous literature, the present findings highlight the importance of emotion recognition deficits in PBD individuals. Additionally, the irritability associated with PBD may be an important mechanism of this deficit and may thus represent an important target for treatment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background:   Impaired profiles of neurocognitive function have been consistently demonstrated among pediatric patients with bipolar disorder (BD), and may aid in the identification of endophenotypes across subtypes of the disorder. This study aims to determine phenotypic cognitive profiles of patients with BD Type I and II., Methods:   Subjects (N = 79) consisted of BD I (n = 27) and BD II (n = 19) patients and demographic and intellectually matched healthy controls (HC; n = 33) that completed a battery of neurocognitive tasks., Results:   Bipolar disorder Type I patients performed significantly more poorly compared to HC on all domains of cognitive function including attention, executive function, working memory, visual memory, and verbal learning and memory. BD I patients also performed more poorly compared to BD II patients on all domains of cognitive functioning with the exception of working memory, whereas BD II patients did poorly relative to HC only on verbal learning and memory., Conclusions:   Findings from the current study indicate that BD I patients are characterized by more severe cognitive impairment relative to BD II patients who show an intermediate pattern of performance between BD I patients and HC. Verbal learning and memory may effectively differentiate pediatric BD patients and controls, regardless of the subtype of BD, and may serve as a cognitive endophenotype for the disorder. Additionally, these findings move us closer to developing effective cognitive interventions tailored to specific subtypes of pediatric BD patients., (© 2012 The Authors. Journal of Child Psychology and Psychiatry © 2012 Association for Child and Adolescent Mental Health.)

Objective: The current study examined the impact of risperidone and divalproex on affective and working memory circuitry in patients with pediatric bipolar disorder (PBD)., Method: This was a six-week, double-blind, randomized trial of risperidone plus placebo versus divalproex plus placebo for patients with mania (n = 21; 13.6 ± 2.5 years of age). Functional magnetic resonance imaging (fMRI) outcomes were measured using a block design, affective, N-back task with angry, happy, and neutral face stimuli at baseline and at 6-week follow-up. Matched healthy controls (HC; n = 15, 14.5 ± 2.8 years) were also scanned twice., Results: In post hoc analyses on the significant interaction in a 3×2×2 analysis of variance (ANOVA) that included patient groups and HC, the risperidone group showed greater activation after treatment in response to the angry face condition in the left subgenual anterior cingulate cortex (ACC) and striatum relative to the divalproex group. The divalproex group showed greater activation relative to the risperidone group in the left inferior frontal gyrus and right middle temporal gyrus. Over the treatment course, the risperidone group showed greater change in activation in the left ventral striatum than the divalproex group, and the divalproex group showed greater activation change in left inferior frontal gyrus and right middle temporal gyrus than the risperidone group. Furthermore, each patient group showed increased activation relative to HC in fronto-striato-temporal regions over time. The happy face condition was potentially less emotionally challenging in this study and did not elicit notable findings., Conclusions: When patients performed a working memory task under emotional duress inherent in the paradigm, divalproex enhanced activation in a fronto-temporal circuit whereas risperidone increased activation in the dopamine (D₂) receptor-rich ventral striatum. Clinical trial registration information-Risperidone and Divalproex Sodium With MRI Assessment in Pediatric Bipolar; http://www.clinicaltrials.gov; NCT00176202.

Objective: The aim of the current study was to determine the influence of implicated affective circuitry disturbance in pediatric bipolar disorder (PBD) on behavioral inhibition. The differential influence of an antipsychotic and an anti-epileptic medication on the functional connectivity across affective and cognitive neural operations in PBD was examined., Methods: This was a six-week double blind randomized fMRI trial of risperidone plus placebo vs. divalproex plus placebo for patients with mania (n=22; 13.6 ± 2.5 years). Healthy controls (HC; n=14, 14.5 ± 2.8 years) were also scanned for normative comparison. Participants performed a response inhibition fMRI task where a motor response, already 'on the way' to execution, had to be voluntarily inhibited on trials where a stop signal was presented. Independent component analysis was used to map functional connectivity across the whole brain., Results: While there were no behavioral differences between the groups at pre- or post-drug trial, there was significant improvement on manic symptoms in the patient groups. All participants engaged an evaluative affective circuit (EAC: bilateral inferior frontal gyrus, middle frontal gyrus, anterior cingulate cortex (ACC), middle temporal gyrus, insulae, caudate and putamen) and a reactive affective circuit (RAC: bilateral occipital cortex, amygdala, medial frontal gyrus and insula) during task performance. Within the EAC, post-treatment and relative to HC, greater engagement was seen in left insula in risperidone group and left subgenual ACC in divalproex group. Within the RAC, greater baseline amygdala connectivity in patients did not alter with treatment., Conclusion: EAC and RAC are two key circuits that moderate emotional influence on response inhibition in PBD. Risperidone and divalproex differentially engage the EAC. Limited change in amygdala activity with treatment in all patients indicates a likely trait deficit in PBD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

This study examined whether adolescents with pediatric bipolar disorder (PBD) have abnormal regional functional connectivity in distributed brain networks during an affective working memory task. Adolescents with PBD (n=41) and healthy controls (HC; n=16) performed a two-back functional magnetic resonance imaging working memory task with blocks of either angry or neutral faces. Independent component analysis methodology identified two temporally independent and functionally connected brain networks that showed differential functional connectivity in PBD and HC. Within a network for "affect evaluation and regulation," PBD showed decreased functional connectivity relative to HC in regions involved in emotion processing such as the right amygdala, and in emotion regulation regions such as the right ventrolateral prefrontal cortex (VLPFC), while functional connectivity was increased in emotion evaluation regions such as the bilateral medial PFC. Furthermore, in an "Affective Working Memory Network," PBD exhibited greater connectivity relative to HC in left dorsolateral PFC (DLPFC), caudate, and right VLPFC; and simultaneously reduced connectivity in emotion processing regions, such as the right amygdala, bilateral temporal regions, and the junction of DLPFC/VLPFC, which interfaces affective and cognitive processes. Dysfunction in network engagement in PBD patients illustrates that they are expending greater effort in face emotion evaluation, while being less able to engage affect regulation regions.

Objective: Co-morbid diagnoses, such as disruptive behavior disorders (DBDs) and high levels of aggression, are extremely common among youth with pediatric bipolar disorder (PBD) and may interfere with treatment response; however, they have rarely been examined as predictors of response to pharmacotherapy. The current study examines co-morbid DBD and aggression prospectively as predictors of pharmacotherapy outcome, as well as potential moderators of response to a specific medication (risperidone vs. divalproex), among children with PBD., Methods: Data are from a prospective 6-week double-blind, placebo-controlled, randomized outpatient medication treatment trial of risperidone versus divalproex for manic episodes in 65 children 8-18 with PBD. Outcome measures were administered at pretest, post-test, and weekly during the 6 weeks of treatment. Mixed-effects regression models were used to examine pharmacotherapy response., Results: Results indicated that youth with co-morbid DBD experienced greater improvement in manic symptoms in response to risperidone versus divalproex, whereas youth with non-co-morbid DBD experienced similar trajectories of symptom improvement in both medication groups. In addition, the non-DBD group experienced greater improvement in global functioning over time as compared with youth with co-morbid-DBD, and this gap increased over the course of treatment. Results also indicated that high-aggression youth experienced worse global functioning by end treatment versus low-aggression youth., Conclusions: In conclusion, a co-morbid diagnosis of DBD and/or high levels of aggressive symptoms in youth with PBD may be important clinical predictors of variation in treatment response to pharmacotherapy. These findings may help researchers and clinicians develop tailored treatment approaches that optimize symptom and functional outcomes.

Rationale: Neural deficits at the interface of affect and cognition may improve with pharmacotherapy in pediatric bipolar disorder (PBD)., Objectives: We examined lamotrigine treatment impact on the neural interface of working memory and affect in PBD., Methods: Un-medicated, acutely ill, patients with mania and hypomania (n = 17), and healthy controls (HC; n = 13; mean age = 13.36 ± 2.55) performed an affective two-back functional magnetic resonance imaging task with blocks of angry vs neutral faces (i.e., angry face condition) or happy vs neutral faces (i.e., happy face condition) before treatment and at follow-up, after 8-week treatment with second-generation antipsychotics followed by 6 weeks of lamotrigine monotherapy., Results: At baseline, for the angry face condition, PBD, relative to HC, showed reduced activation in the left ventrolateral prefrontal cortex (VLPFC) and right caudate; for the happy face condition, PBD showed increased activation in bilateral PFC and right amygdala and middle temporal gyrus. Post-treatment, PBD showed greater activation in right amygdala relative to HC for both conditions. Patients, relative to HC, exhibited greater changes over time in the right VLPFC and amygdala, left subgenual anterior cingulate cortex and left caudate for the angry face condition, and in right middle temporal gyrus for the happy face condition., Conclusions: Pharmacotherapy resulted in symptom improvement and normalization of higher cortical emotional and cognitive regions in patients relative to HC, suggesting that the VLPFC dysfunction may be state-specific in PBD. Amygdala was overactive in PBD, relative to HC, regardless of reduction in manic symptoms, and may be a trait marker of PBD.

The aim of this research was to determine the relative effects of risperidone and divalproex on brain function in pediatric mania. This is a double-blind 6-week functional magnetic resonance imaging trial with 24 unmedicated manic patients randomized to risperidone or divalproex, and 14 healthy controls (HCs) matched for IQ and demographic factors (mean age: 13.1±3.3years). A pediatric affective color matching task, in which subjects matched the color of a positive, negative or neutral word with one of two colored circles, was administered. The primary clinical measure was the Young Mania Rating Scale (YMRS). The risperidone group, relative to HC, showed an increase in activation from pre- to post-treatment in right pregenual and subgenual anterior cingulate cortex and decreased activation in bilateral middle frontal gyrus during the negative condition; and decreased activation in left inferior and medial, and right middle frontal gyri, left inferior parietal lobe, and right striatum with positive condition. In the divalproex group, relative to HC, there was an increased activation in right superior temporal gyrus in the negative condition; and in left medial frontal gyrus and right precuneus with the positive condition. Greater pre-treatment right amygdala activity with negative and positive condition in the risperidone group, and left amygdala activity with positive condition in divalproex group, predicted poor response on YMRS. Risperidone and divalproex yield differential patterns of prefrontal activity during an emotion processing task in pediatric mania. Increased amygdala activity at baseline is a potential biomarker predicting poor treatment response to both the risperidone and divalproex., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

A deeper understanding of how the relationships between impulsivity, reward systems and executive function deficits may be similar or different in attention-deficit/hyperactivity disorder (ADHD) and pediatric bipolar disorder (PBD) is fundamental for better defining phenotypy in these two developmental illnesses, and moving towards improved treatment and intervention. We focus our article on recent neurocognitive and neuroimaging data examining the behavioral and neural aspects of poor behavior regulation, response inhibition and reward systems in ADHD and PBD. In light of recent research evidence, we propose that the common behavioral manifestations of impulsivity in ADHD and PBD may indeed originate from different neural mechanisms mediated by altered reward systems. In order to define and differentiate these mechanisms, unlike previous approaches, our theoretical model examines the interface of the dorsal frontostriatal circuit, involved in behavior regulation, and the ventral frontostriatal circuit, which is involved in reward-related and affect processes. Preliminary evidence suggests that the neural systems involved in impulsivity, reward systems and executive function engage differently in the two illnesses. In PBD, 'emotional impulsivity' is predominantly 'bottom-up' and emotionally/motivationally driven, and stems from ventral frontostriatal circuitry dysfunction. By contrast, in ADHD 'cognitive impulsivity' is predominantly 'top-down' and more 'cognitively driven', and stems from dorsal frontostriatal dysfunction. We discuss this evidence in view of clinically relevant questions and implications for illness-based intervention. We conclude that the reward-related mechanisms underlying the interactions between executive function, behavior regulation and impulsivity in PBD and ADHD may be differentially compromised, and in accordance differently shape the clinical symptoms of impulsivity and goal-directed behavior.

Objectives: Cognitive and emotional deficits have been documented in youth with pediatric bipolar disorder (PBD); however, to date, a systematic evaluation of comprehension and memory for verbally presented information has not been conducted. The effect of emotion on comprehension and memory for verbally presented material also has not been examined. We examined whether youth with PBD have difficulty recalling the big picture (macrostructure) as well as the story details (microstructure)., Methods: A total of 35 youth with PBD and 25 healthy controls completed an Affective Story Task. A psychological processing model allowed for the examination of both the macrostructure and microstructure of language comprehension., Results: Youth with PBD were capable of comprehending the gist of the stories and were not impaired by emotion when comprehending and remembering macrostructure. However, negative emotional material was found to proactively interfere with the encoding and recall of microstructure. Level of depression appeared to impact recall of microstructure, but not macrostructure., Conclusions: Negatively valenced material may impair subsequent comprehension and memory for details among youth with PBD. This deficit could impact the daily functioning of these youth, as the perception of negative affect may derail aspects of successful comprehension and learning., (© 2011 John Wiley and Sons A/S.)

Background: The development of valid parent-report measures of symptom change in pediatric bipolar disorder (PBD) is imperative to evaluate the effectiveness of different treatment approaches; yet, few studies have tested the sensitivity of symptom measures. The current study evaluated the sensitivity of the Child Mania Rating Scale (CMRS-P) to detect symptom change over time in a treatment study for PBD., Methods: Data on symptom change were drawn from a prospective six-week, double-blind, placebo-controlled, randomized outpatient medication treatment trial of risperidone versus divalproex. The sample included 66 children with Bipolar type I disorder. Measures were administered every week for six weeks of treatment., Results: The CMRS-P demonstrated statistically (p ≤ .05) and clinically significant change in symptom report from pre to post-test. Growth curve modeling indicated that the CMRS-P demonstrated overall similarity to the YMRS in the magnitude and trajectory of change over time. Finally, results indicate that the CMRS-P is able to detect response rates with moderate levels of agreement with other measures., Limitations: Limitations of this study include a relatively small sample size and uncertain generalizability beyond treatment trials., Conclusions: The CMRS-P is short, easy to administer, and represents parent's report of symptoms, all strengths which make it a compelling treatment outcome tool. This preliminary evidence of its validity as a treatment outcome measure makes it applicable in other research settings and suggests its potential use in clinical settings., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The aim of this study was to determine functional connectivity among patients with pediatric bipolar disorder (PBD) who are responders to pharmacotherapy and those who are nonresponders, and learn how they differ from healthy controls (HC) while performing a task that engages affective and cognitive neural systems. PBD participants (n = 34; 13.4 ± 2.3 years) were defined as responders if there was ≥ 50% improvement in Young Mania Rating Scale (YMRS) scores (n = 22) versus nonresponders with < 50% improvement (n = 12) with one of three mood stabilizing medications (divalproex, risperidone, or lamotrigine). HC (n = 14; 14.2 ± 3.1 years) participants also were scanned at baseline and follow-up. During functional magnetic resonance imaging, participants performed a color-matching task in which they had to match the color of positive, negative, or neutral words with colored dots. Independent component analysis was used to identify functionally connected networks across the whole brain, which were subsequently interrogated using region-of-interest analyses to test for group differences. A frontolimbic network was identified that showed impaired functional integration in PBD relative to HC when participants viewed negatively valenced words. PBD medication responders showed greater connectivity of the amygdala into the network before and after treatment compared with nonresponders, with responders showing a pattern more similar to HC than to nonresponders. Regardless of medication type, the degree of amygdala functional connectivity predicted medication response as well as the improvement in YMRS scores across responders and nonresponders. These findings suggest that increased functional integration of the amygdala within the frontolimbic network might be a biomarker of general mood stabilizer medication responsivity in bipolar disorder.

Given the severity and early onset of pediatric bipolar disorder, early intervention is important to bring about recovery and alter the course of the illness. There is a new and burgeoning body of literature on the biological basis of early signs of the illness and the mechanistic understanding of treatment interventions. Biological findings based on multimodal imaging, genomic studies of cellular proteins, and performance-based findings of neurocognitive studies are beginning to assemble a cohesive and interlinked model of systems neuroscience. This offers the promise of identifying biomarkers, predictors of illness, and treatment outcomes. In complement, at the tier of clinical application is a multitude of efficacy trials, yet neither a single medication nor a combination of choices seems to suffice in reality. The current review develops a point of view bridging scientific developments to where comprehensive, multipronged treatment strategies find their clinical application-a model that is similarly applicable in adult bipolar disorder.

Objective: The aim of the current study is to determine whether pharmacotherapy normalizes cognitive circuitry function supporting voluntary behavioral inhibition in adolescent bipolar disorder., Method: Healthy controls and unmedicated patients with DSM-IV adolescent bipolar disorder in manic, mixed, or hypomanic episodes were matched on demographics and IQ (n = 13 per group; mean age = 14.4 ± 2.4 years). Functional magnetic resonance imaging studies were performed at baseline and after 14 weeks, during which time patients with adolescent bipolar disorder were treated initially with second-generation antipsychotics (SGAs) followed by lamotrigine monotherapy. The primary outcome measure was a Response Inhibition Task, which involved a planned motor response, already "on the way" to execution, that had to be voluntarily inhibited by the subjects in the trials in which a stop signal was presented. There were 6 blocks, each with a predominant rate of either "go" or "stop" trials. The study was conducted from June 2006 through July 2009., Results: All patients showed significant improvement (P < .001) in both the manic and depressive symptoms from baseline. Behavioral data showed that accuracy improved over 14 weeks in patients and healthy controls. Significant time by group interaction effects for the difference between stop versus go blocks showed greater increases of activation in prefrontal (left inferior and middle frontal gyri and medial frontal gyrus bilaterally) and temporal (left superior temporal gyrus and right middle temporal gyrus) regions and greater decreases in activation in right putamen and bilateral thalamus at follow-up in the adolescent bipolar disorder group than in healthy controls. Increased ventrolateral prefrontal cortex function was related to clinical treatment response., Conclusions: Treatment with SGAs followed by lamotrigine monotherapy enhanced prefrontal and temporal lobe activity during a Response Inhibition Task demonstrating the reversal of disorder-relevant neural circuitry dysfunction in patients with adolescent bipolar disorder. Patient performance was not slowed down with this treatment regimen., Trial Registration: clinicaltrials.gov Identifier: NCT00176228., (© Copyright 2010 Physicians Postgraduate Press, Inc.)

Objective: This functional magnetic resonance imaging (fMRI) study examined how working memory circuits are affected by face emotion processing in pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD)., Methods: A total of 23 patients with PBD, 14 patients with ADHD, and 19 healthy control (HC) subjects (mean age, 13.36 ± 2.55 years) underwent an affective, two-back fMRI task with blocks of happy, angry, and neutral faces., Results: For angry versus neutral faces PBD patients, relative to ADHD patients, exhibited increased activation in the subgenual anterior cingulate cortex (ACC) and orbitofrontal cortex, and reduced activation in the dorsolateral prefrontal cortex (DLPFC) and premotor cortex. Relative to the HC group, the PBD group showed no increased activation and reduced activation at the junction of DLPFC and ventrolateral prefrontal cortex (VLPFC). Relative to HC, the ADHD patients exhibited greater activation in the DLPFC and reduced activation in the ventral and medial PFC, pregenual ACC, striatum, and temporo-parietal regions. For happy versus neutral faces, relative to the ADHD group, the PBD group exhibited greater activation in the bilateral caudate, and relative to the HC group the ADHD group showed increased activation in the DLPFC, striatal, and parietal regions, and no reduced activation. The ADHD group, compared with the HC group, showed no reduced activation and increased activation in regions that were underactive for the angry face condition., Conclusions: Relative to the ADHD group, the PBD group exhibited greater deployment of the emotion-processing circuitry and reduced deployment of working memory circuitry. Commonalities across PBD and ADHD patients, relative to the HC individuals, entailed cortico-subcortical activity that was reduced under negative emotional challenge and increased under positive emotional challenge., (Copyright © 2010 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: This functional magnetic resonance imaging (fMRI) study investigated the effects of pharmacotherapy on brain function underlying affect dysregulation and cognitive function in pediatric bipolar disorder (PBD)., Method: Healthy controls (HC) (n=14; mean age =14.1 ± 2.4 years) and unmedicated PBD patients with manic or hypomanic episodes (n=17; mean age =14.3 ± 1.1 years) were matched on intelligence quotient (IQ) and demographic factors. The fMRI studies were performed at baseline and after 14 weeks, during which PBD patients were treated initially with second-generation antipsychotics (SGAs) followed by lamotrigine monotherapy. The pediatric affective color-matching task was used where subjects matched the color of a positive, negative, or neutral word with one of the two colored circles below in each of the trials. There were five blocks of each emotional word type, with 10 trials per block., Results: Behavioral data showed that the PBD group was modestly slower and less accurate than the HC, regardless of condition or treatment status. The blood oxygen level-dependent (BOLD) signal activity was reduced with treatment in the PBD group relative to the HC group during the negative versus neutral condition in bilateral dorsolateral prefrontal cortex (DLPFC), right posterior cingulate gyrus, parahippocampal gyrus, and inferior parietal lobule, but increased in left ventromedial prefrontal cortex (VMPFC). Similarly, during the positive versus neutral condition, the PBD group, relative to HC, showed reduced activity in right DLPFC, precuneus, and inferior parietal lobule and increased activity in the right VMPFC. However, within the PBD group, there was treatment related decrease in VMPFC and DLPFC. Improvement on Young Mania Rating Scale (YMRS) score significantly correlated with the decreased activity in VMPFC within the patient group., Conclusions: Pharmacotherapy in PBD patients led to differential effort with persistently increased activity in the affective regions and decreased activity in the cognitive regions relative to HC, demonstrating altered mechanisms of affective and cognitive systems of brain function, regardless of symptom response.

Objective: To determine the relative effects of risperidone and divalproex in pediatric mania., Methods: This is a double-blind, randomized, outpatient clinical trial with 66 children and adolescents (mean age= 10.9 ± 3.3 years; age range= 8-18 years) with mania who were randomly assigned to either risperidone (0.5-2 mg/day, n= 33) or divalproex (60-120 μg/mL, n= 33) for a six-week period. Measures included the Young Mania Rating Scale (YMRS) and Child Depression Rating Scale-Revised (CDRS-R)., Results: Mixed-effects regression models, with interaction between time and the active drug as predictors, found that the risperidone group had more rapid improvement than the divalproex group (p < 0.05), although final scores did not differ significantly between groups. Mixed models using only those subjects who completed the six-week study found similar results. The response rate on YMRS was 78.1% for risperidone and 45.5% for divalproex (p < 0.01). The remission rate for risperidone was 62.5%, compared with 33.3% for divalproex (p < 0.05). Improvement on the CDRS-R was significantly higher for the risperidone group relative to the divalproex group (p < 0.05). There were no significant differences between groups in safety, but subject retention was significantly higher at study endpoint in the risperidone group (p < 0.01). Dropout rate was 24% in the risperidone group and 48% in the divalproex group, with increased irritability being the most common reason for dropout in the latter. There was no significant weight gain in either group., Conclusion: Results suggest that risperidone was associated with more rapid improvement and greater reduction in manic symptoms compared to divalproex. Although the results suggest that both drugs are safe, risperidone's lower attrition rate and lower rate of adverse events may suggest better toleration. Clinical trials with larger samples are required to confirm these preliminary findings., (© 2010 John Wiley and Sons A/S.)

Background: Brain-derived neurotrophic factor (BDNF) is a member of a neurotrophin family and is involved in many physiological functions, including cell proliferation, migration, and differentiation, and neuron survival in the human nervous system. Abnormalities of BDNF have been implicated in the pathophysiology of depression based on observations that antidepressant drugs cause increases in the levels of BDNF in rat brains and its abnormalities have appeared in the serum of depressed patients and in postmortem brains of suicide victims., Methods: We examined the gene expression of BDNF in the lymphocytes and protein expression in the platelets of adult and pediatric depressed patients during a drug-free period. We determined BDNF gene expression using a quantitative RT-PCR method and protein expression using the ELISA method., Results: We observed that the gene expression of BDNF was significantly decreased in the lymphocytes of adult and pediatric depressed patients compared with normal control subjects. Similarly, the protein expression of BDNF was significantly decreased in the platelets of adult and pediatric depressed patients compared with normal control subjects., Conclusions: To our knowledge, this is the first study that reports a decrease in BDNF gene expression in the peripheral cells of depressed patients. Because of the bidirectional movement of BDNF between the periphery and the CNS, the reduced gene expression in the lymphocytes and the protein expression in the platelets may be an index of similar abnormalities in the brain and could be a target for antidepressant drugs., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: To examine the treatment impact of lamotrigine on the neurocognitive profile of patients with pediatric bipolar disorder (PBD)., Method: Healthy controls (HC) (n = 24; mean age = 12.4 +/- 3.3 years) and unmedicated PBD patients with manic, mixed, or hypomanic episodes (n = 34; mean age = 13 +/- 3.1 years) were matched for IQ, age, sex, race, and socioeconomic status. A neurocognitive battery was administered at baseline and again after 14 weeks, during which PBD patients were treated with lamotrigine., Results: Clinical symptoms improved with treatment in the patient group with significant change from baseline to follow-up on the Young Mania Rating Scale (p < 0.001) and the Children's Depression Rating Scale-Revised (p < 0.001). Global neurocognitive function improved with lamotrigine in PBD patients over time relative to that in HC, although overall performance remained impaired. Working memory and verbal memory significantly improved with treatment in patients, and deficits in these domains were no longer significantly impaired relative to HC at follow-up. Executive function significantly improved with treatment in the patient group but still lagged behind HC at follow-up. Performance on attention tests did not improve with treatment., Conclusions: There appears to be significant improvement in cognitive abilities in PBD patients treated with lamotrigine that is most prominent in the areas of working memory and verbal memory and that occurs along with mood stabilization.

Impulsivity, inattention and poor behavioral inhibition are common deficits in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD). This study aimed to identify similarities and differences in the neural substrate of response inhibition deficits that are associated with these disorders. A functional magnetic resonance imaging (fMRI) study was conducted on 15 unmedicated PBD patients (Type I, manic/mixed), 11 unmedicated ADHD patients, and 15 healthy controls (HC) (mean age = 13.5 years; S.D. = 3.5). A response inhibition task examined the ability to inhibit a motor response to a target when a stop cue appeared shortly after. The PBD and ADHD groups did not differ on behavioral performance, although both groups were less accurate than the HC group. fMRI findings showed that for trials requiring response inhibition, the ADHD group, relative to the PBD and HC groups, demonstrated reduced activation in both ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and increased bilateral caudate activation compared with HC. The PBD group, relative to HC, showed decreased activation in the left VLPFC, at the junction of the inferior and middle frontal gyri, and in the right anterior cingulate cortex (ACC). Prefrontal dysfunction was observed in both the ADHD and PBD groups relative to HC, although it was more extensive and accompanied by subcortical overactivity in ADHD.

This fMRI study investigates the neural bases of cognitive control of emotion processing in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD). Seventeen un-medicated PBD patients, 15 un-medicated ADHD patients, and 14 healthy controls (HC) (mean age = 13.78 +/- 2.47) performed an emotional valence Stroop Task, requiring them to match the color of an emotionally valenced word to the color of either of two adjacent circles. Both patient groups responded significantly slower than HC, but there were no group differences in accuracy. A voxel-wise analysis of variance on brain activation revealed a significant interaction of group by word valence [F(2,41) = 4.44; p = .02]. Similar group differences were found for negative and positive words. For negative versus neutral words, both patient groups exhibited greater activation in dorsolateral prefrontal cortex (DLPFC) and parietal cortex relative to HC. The PBD group exhibited greater activation in ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) relative to HC. The ADHD group exhibited decreased VLPFC activation relative to HC and the PBD group. During cognitive control of emotion processing, PBD patients deployed the VLPFC to a greater extent than HC. The ADHD patients showed decreased VLPFC engagement relative to both HC and PBD patients.

Adjunctive psychosocial interventions are increasingly recognized as an important aspect of comprehensive treatment for bipolar disorder (BPD) in childhood and adolescence. Research in this area is relatively new, but psychosocial interventions being developed and tested include: multi-family psychoeducation groups for school-aged children with either BPD or depressive disorders; family-focused treatment, dialectical behavior therapy, and interpersonal and social rhythm therapy for adolescents with BPD; and child and family-focused cognitive-behavioral therapy for school-aged children with BPD. Preliminary evidence, where available, indicates that these interventions are feasible, well-received by families, and associated with positive outcomes. The continued study of adjunctive psychosocial interventions will help identify critical treatment ingredients that target specific areas of functioning and enhance overall treatment effectiveness for children and adolescents with BPD and their families.

Background: To investigate microstructure of white matter fiber tracts in pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD)., Methods: A diffusion tensor imaging (DTI) study was conducted at 3 Tesla on age- and IQ-matched children and adolescents with PBD (n = 13), ADHD (n = 13), and healthy control subjects (HC) (n = 15). Three DTI parameters, fractional anisotropy (FA), apparent diffusion coefficient (ADC), and regional fiber coherence index (r-FCI), were examined in eight fiber tracts: anterior corona radiata (ACR), anterior limb of the internal capsule (ALIC), superior region of the internal capsule (SRI), posterior limb of the internal capsule (PLIC), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), cingulum (CG), and splenium (SP)., Results: Significantly lower FA was observed in ACR in both PBD and ADHD relative to HC. In addition, FA and r-FCI values were significantly lower in ADHD relative to PBD and HC in both the ALIC and the SRI. Further, ADC was significantly greater in ADHD relative to both the PBD and HC in ACR, ALIC, PLIC, SRI, CG, ILF, and SLF., Conclusions: Decreased FA in ACR implies an impaired fiber density or reduced myelination in both PBD and ADHD in this prefrontal tract. These abnormalities, together with the reduced fiber coherence, extended to corticobulbar tracts in ADHD. Increased ADC across multiple white matter tracts in ADHD indicates extensive cellular abnormalities with less diffusion restriction in ADHD relative to PBD.

Objective: To use functional neuroimaging to probe the affective circuitry dysfunctions underlying disturbances in emotion processing and emotional reactivity in pediatric bipolar disorder (PBD)., Method: Equal numbers of controls (HC) and unmedicated patients with euthymia and PBD were matched for age, sex, race, socioeconomic status, and IQ (n = 10 per group; mean age 14.2 years [SD 2.0 years]). The task consisted of a "directed" emotion processing condition where subjects judged whether emotion in facial expression was positive or negative and an "incidental" condition where subjects judged whether faces expressing similar affect were older or younger than 35 years., Results: Relative to the directed condition, the incidental condition elicited greater activation in the right amygdala and the right insula, the left middle frontal gyrus, and the left posterior cingulate cortex in patients with PBD, in contrast to the HC that showed greater activation in the right superior frontal gyrus. In both incidental and directed conditions, relative to visual fixation, patients with PBD showed less activation in the right prefrontal cortex (superior, middle, and inferior frontal gyri) and the pregenual anterior cingulate cortex and greater activation in the posterior visual and face-processing regions (i.e., right precuneus/cuneus, fusiform gyrus)., Conclusions: Increased amygdala activation observed in patients with PBD elicited by incidental emotional processing relative to directed emotional processing may indicate more intense automatic emotional reactivity. Furthermore, the right prefrontal systems that are believed to modulate affect seem to be less engaged in patients with PBD regardless of whether the emotion processing is incidental or directed, which may signify reduced top-down control of emotional reactivity in PBD.

Objective: Longitudinal follow-up of neurocognitive functioning in people with pediatric bipolar disorder (PBD) was conducted to characterize the developmental trajectory of cognitive disabilities in this disorder., Method: Patients with PBD (n = 26) and controls (HC; n = 17; mean age 11.66 +/- 2.70 years) completed cognitive testing at baseline and then again at a 3-year follow-up. Groups were matched at baseline on age, sex, race, parental socioeconomic status, general intelligence, and single-word reading ability. The PBD group received treatment guided by a standardized medication algorithm during the 3-year period. A battery of neuropsychological tests was administered to assess attention, executive function, working memory, verbal memory, visual memory, and visuospatial perception at baseline and follow-up., Results: At baseline and follow-up, the patients showed deficits in all of the examined domains. At 3-year follow-up, developmental progress in executive functions and verbal memory was significantly less in the patients with PBD than in the HC. Improvement on attention, working memory, visual memory, and visuospatial perception tasks in the patients with PBD was comparable to that of the HC, but the patients with PBD remained impaired in all domains relative to the HC., Conclusions: The developmental delay in some neurocognitive functioning in PBD suggests that the illness disrupts cognitive development with potential lifelong implications for reduced functional ability. Treating bipolar symptoms does not seem to prevent the lag in cognitive development. This dysmaturation may be a direct effect of the illness on brain function, or it may represent indirect consequences of psychopathology or medications on cognitive development.

Objective: The aim of this study was to test the effectiveness and safety of lamotrigine in maintenance of manic and depressive symptom control in pediatric bipolar disorder (PBD)., Methods: A 14-week open trial was conducted with 46 subjects presenting with mania or hypomania. Lamotrigine was slowly titrated to a therapeutic dose over an 8-week period, during which acute symptoms were stabilized using second-generation antipsychotics (SGA), followed by a 6-week lamotrigine monotherapy phase., Results: The response rate on manic symptoms (Young Mania Rating Score [YMRS] <12) was 72%, on depressive symptoms was 82% (Children's Depression Rating Scale-Revised [CDRS-R] <40), and the remission rate was 56% at the 14-week end point, on an average end-point lamotrigine dose of 1.8 mg/lb. There was further reduction in depressive symptoms during the lamotrigine maintenance phase. Benign rash was noted in 6.4% of patients. Out of half of the subjects who were in remission at 8 week, 3 subjects (23%) relapsed by week 14., Conclusion: Lamotrigine monotherapy appears to be effective in maintaining symptom control of manic and depressive symptoms in PBD and shows minimal adverse effects, although a future double-blind controlled trial is needed to confirm this finding. Portal of entry for lamotrigine treatment can be during acute illness and can sustain symptom control after establishing mood stabilization.

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

Objective: To provide an overview of clinical research aiming to develop a mechanistic understanding of brain dysfunction in child psychiatric disorders., Method: Technological, conceptual, and translational approaches relevant to the investigation of brain function in pediatric psychiatric illnesses are explored. Research in the area of pediatric bipolar disorder is used as a prototypic model illustrating the use of complementary techniques of functional magnetic neuroimaging and neurocognitive studies to identify abnormalities in neural circuitry function., Results: Studies of bipolar youths indicate impairment in cognitive and affective neural systems and in the interface of these two circuits. This evolving field paves a future pathway for identifying diagnostic biomarkers for the disorder, providing tools for monitoring response to pharmacotherapy, examining illness-associated alterations in developmental trajectory, and facilitating the use of animal research for guiding the development of novel treatment strategies., Conclusions: Studies of brain function in child psychiatry are establishing a platform of knowledge and methods that offer promise for revolutionizing both models of illness pathophysiology and future diagnostic and therapeutic practice.

Unlabelled: Pediatric bipolar disorder (PBD) presents with severe affect dysregulation characterized by elated mood, irritability and depressive symptoms, often in the form of a mixed episode. Early recognition of the external clinical features and the underlying emotional processing circuitry will help us understand the neurobiological underpinnings of this disorder and offer innovative ideas for early intervention., Methods: A 5-year review was conducted in structural and functional imaging studies in PBD that are potentially relevant to the emotional processing in PBD., Results: The ventral frontolimbic circuitry and the dorsal frontostriatal circuitry appear to be involved in affect regulation, with the ventral circuitry being more directly involved in emotion processing. The associated and interlinked circuits include the facial emotion-processing circuit and the association circuit between the occipital and the limbic regions responsible for automatic processing of emotions., Conclusion: While we are at a preliminary stage in understanding the neural circuitry behind emotional processing, there appears to be a top-down regulation of affect with prefrontal systems modulating subcortical structures such as the amygdala and the ventral striatum. Structural and connectivity studies support the functional studies findings, providing a cogent model for understanding emotion-processing circuits involving corticosubcortical neural systems. Functional studies with PBD patients are beginning to demonstrate the dysfunction in the affective and cognitive circuits that work in concert.

Objective: Pediatric bipolar disorder (PBD) is a major public health concern; however, little is known about the cellular and genetic factors that are involved in the pathophysiology of this illness. The observed structural abnormality in the brains of patients with mood disorders has been related to abnormal brain-derived neurotrophic factor (BDNF) function, suggesting an important role for BDNF in these disorders., Method: We determined the gene expression of BDNF in lymphocytes obtained from 26 PBD subjects during a drug-free baseline period and during the eighth week of treatment (n = 19) and from 21 medication-free normal control subjects. We also determined the protein levels of BDNF in platelets of patients with PBD and normal control subjects. Subjects were diagnosed according to DSM-IV diagnostic criteria using the Washington University at St. Louis Schedule for Affective Disorders and Schizophrenia., Results: The mRNA levels of BDNF in lymphocytes of PBD subjects were significantly decreased compared with those of normal control subjects and were significantly higher in 19 subjects after 8 weeks of treatment than the pretreatment drug-free baseline levels and similar to those of normal controls. Similarly, protein levels of BDNF were decreased in platelets of patients with PBD., Conclusions: These studies suggest that BDNF levels may be a potential biomarker for PBD. BDNF levels may also serve as a potential treatment predictor and prognostic indicator in PBD.

The pathophysiology of pediatric bipolar disorder (PBD) impacts both affective and cognitive brain systems. Understanding disturbances in the neural circuits subserving these abilities is critical for characterizing developmental aberrations associated with the disorder and developing improved treatments. Our objective is to use functional neuroimaging with pediatric bipolar disorder patients employing a task that probes the functional integrity of attentional control and affect processing. Ten euthymic unmedicated pediatric bipolar patients and healthy controls matched for age, sex, race, socioeconomic status, and IQ were scanned using functional magnetic resonance imaging. In a pediatric color word matching paradigm, subjects were asked to match the color of a word with one of two colored circles below. Words had a positive, negative or neutral emotional valence, and were presented in 30-s blocks. In the negative affect condition, relative to the neutral condition, patients with bipolar disorder demonstrated greater activation of bilateral pregenual anterior cingulate cortex and left amygdala, and less activation in right rostral ventrolateral prefrontal cortex (PFC) and dorsolateral PFC at the junction of the middle frontal and inferior frontal gyri. In the positive affect condition, there was no reduced activation of PFC or increased amygdala activation. The pattern of reduced activation of ventrolateral PFC and greater amygdala activation in bipolar children in response to negative stimuli suggests both disinhibition of emotional reactivity in the limbic system and reduced function in PFC systems that regulate those responses. Higher cortical cognitive areas such as the dorsolateral PFC may also be adversely affected by exaggerated emotional responsivity to negative emotions. This pattern of functional alteration in affective and cognitive circuitry may contribute to the reduced capacity for affect regulation and behavioral self-control in pediatric bipolar disorder.

Recent theories suggest that children with pediatric bipolar disorder (PBD) may exhibit more difficult temperaments premorbidly, including traits such as behavioral disinhibition and difficulty with emotion regulation. We investigated temperament characteristics retrospectively during infancy and toddlerhood in subjects with PBD (n=25), attention-deficit/hyperactivity disorder (ADHD; n=25), and healthy controls (n=25). Children with PBD were reported to experience increased difficult temperament in both infancy and toddlerhood compared to children with ADHD. Several characteristics of difficult temperament were associated with residual symptoms of mania and depression. Difficult premorbid temperament characteristics may be a specific indicator of a bipolar diathesis, or might signal underlying dysfunction in affective processes that significantly increase risk for a mood disorder.

Parent-child relationships may have a significant effect on illness characteristics of children with pediatric bipolar disorder (PBD), and these relationships may, in turn, be affected by the child's illness. We characterized maternal reports of parent-child relationships using the five-factor Parent-Child Relationship Questionnaire (PCRQ) in 60 families (30 PBD youth and 30 matched controls). Data on child proband and parental psychopathology were also obtained. Compared to controls, parent-child relationships in the PBD group were characterized by significantly less warmth, affection, and intimacy, and more quarreling and forceful punishment. Among PBD participants, elevated symptoms of mania, comorbid ADHD, an earlier age of illness onset, living in a single parent home, and the presence of a parental mood disorder were associated with greater parent-child relationship difficulties. These findings have implications for the development of interventions that focus on the quality of parent-child relationships, in addition to symptom management, in the treatment of PBD.

This study assesses the sensitivity of full and brief forms of a parent-rated mania scale to variations in diagnoses. Parents of a sample of 150 subjects either diagnosed with bipolar disorder (BD) or attention deficit hyperactivity disorder (ADHD), or healthy controls (HC), completed the full Child Mania Rating Scale and other measures. We used single-parameter item-response theory models to produce a brief parent mania rating scale from the full version. The 10-item, brief Child Mania Rating Scale -- Parent (CMRS-P) version correlated .93 with 11 items from the full CMRS-P that were not used in constructing the brief version, and showed accuracy comparable to the full scale in differentiating BD from ADHD, and in discriminating among bipolar subtypes.

Pediatric bipolar disorder (PBD) is a major public health concern, however, its neurobiology is poorly understood. We, therefore, studied the role of protein kinase C (PKC) in the pathophysiology of bipolar illness. We determined PKC activity and immunolabeling of various PKC isozymes (i.e., PKC alpha, PKC betaI, PKC betaII, and PKC delta) in the cytosol and membrane fractions of platelets obtained from PBD patients and normal control subjects. PKC activity and PKC isozymes were also determined after 8 weeks of pharmacotherapy of PBD patients (n=16) with mood stabilizers. PKC activity and the protein expression of PKC betaI and betaII, but not PKC alpha or PKC delta, were significantly decreased in both membrane as well as cytosol fractions of platelets obtained from medication-free PBD patients compared with normal control subjects. Eight weeks of pharmacotherapy resulted in significantly increased PKC activity but no significant changes in any of the PKC isozymes in PBD patients. These results indicate that decreases of specific PKC isozymes and decreased PKC activity may be associated with the pathophysiology of PBD and that pharmacotherapy with mood stabilizing drugs results in an increase and normalization of PKC activity along with improvement in clinical symptoms.

Objective: Past investigations indicate facial emotion-processing abnormalities in pediatric bipolar disorder (PBD) subjects. However, the extent to which these deficits represent state- and trait-related factors is unclear. We investigated facial affect processing in acutely ill and clinically stabilized children with PBD and matched healthy subjects., Method: Subjects (N = 86) consisted of unmedicated/acutely ill (n = 29) and medicated/clinically stabilized (n = 29) PBD youths and matched healthy subjects (n = 28) who completed tasks of facial affect identification and differentiation., Results: Subjects with PBD, regardless of clinical and treatment status, showed marked impairments in the ability to correctly identify emotionally intense happy and sad facial expressions, with both groups tending to misjudge extreme facial expressions as being moderate to mild in intensity. However, when differentiating subtle variations of happy or sad expressions, only unmedicated/acutely ill PBD patients performed more poorly than healthy subjects. Younger age at onset was associated with more impaired emotion processing only in the PBD sample. PBD subjects with comorbid attention-deficit/hyperactivity disorder (ADHD) performed more poorly than subjects without ADHD when processing sad facial expressions, but not happy ones., Conclusions: This study found evidence of both state-of-illness and trait-related deficits in emotion processing in PBD. Treatments are needed to better reduce this impairment and to reduce its developmental impact on interpersonal functioning.

Background: Facial emotions are central to human interaction. Identifying pathophysiology in affect processing circuitry that supports the ability to assess facial emotions might facilitate understanding of affect regulation in pediatric bipolar disorder., Methods: Ten euthymic, unmedicated pediatric bipolar patients and 10 healthy control subjects matched for age, gender, race, socioeconomic status, and IQ were scanned with functional magnetic resonance imaging. Angry, happy, and neutral faces were presented in 30-sec blocks, with a 20-sec rest period between blocks. Subjects were asked to press a button when each face appeared, to ensure that attention was maintained on-task., Results: In bipolar patients, in response to both angry and happy faces relative to neutral faces, we observed reduced activation of right rostral ventrolateral prefrontal cortex together with increased activity in right pregenual anterior cingulate, amygdala, and paralimbic cortex. Bipolar patients also showed reduced activation of visual areas in occipital cortex together with greater activation in higher-order visual perceptual areas, including superior temporal sulcus and fusiform gyrus with angry faces and posterior parietal cortex with happy faces., Conclusions: Findings document a disturbance in affective neurocircuitry in pediatric bipolar disorder. Reduced activation in ventrolateral prefrontal cortex might reflect diminished top-down control that leads to the observed exaggerated activation in amygdala and paralimbic areas. Changes in occipital areas might represent an effort to gate sensory input when affective responses to the faces could not be successfully modulated. Disturbances in affect processing circuitry could contribute to emotional dysregulation and social cognitive difficulties in bipolar youth.

Objective: The chronic and refractory course of pediatric bipolar disorder merits the study of adjunctive psychosocial interventions designed to facilitate long-term improvements. The objective of this study is to conduct a pilot study of a maintenance model of the child- and family-focused cognitive-behavioral therapy program (CFF-CBT), which comprises psychosocial booster sessions and optimized pharmacotherapy, and to assess whether positive effects seen after the acute phase of treatment could be sustained over time with the use of this model., Method: The study design was an open trial with the goal of assessing feasibility of such a maintenance model over time. Thirty-four patients 5 to 17 years of age who underwent CFF-CBT were delivered the maintenance model of treatment over a 3-year period and assessed for symptom changes (Children's Global Impressions Scale-Bipolar) and global functioning (Children's Global Assessment Scale)., Results: Results indicated that participation in the maintenance model of CFF-CBT treatment was associated with positive effects in symptoms and functioning over the 3-year follow-up period. There were no statistically significant differences in postacute-phase treatment scores and scores at years 1, 2, or 3 on any study measures, indicating the maintenance of clinically significant improvements., Conclusions: These findings suggest that maintenance treatment models are feasible and may help facilitate the long-term management of symptoms. Controlled clinical trials that build on this model will help advance treatments for pediatric bipolar disorder toward addressing the low recovery and high relapse rates associated with the disorder.

Background: The current study attempted to determine whether neurodevelopmental and acquired brain abnormalities are more common in pediatric bipolar disorder (PBD)., Methods: The study sample consisted of 98 subjects with a mean age of 11.5 +/- 3.3 years comprising three demographically matched groups: healthy controls (HC, n = 28), subjects with bipolar disorder - Type I (PBD, n = 37), and bipolar disorder - Type I combined with attention deficit hyperactivity disorder (PBD+ADHD, n = 33). Family history of PBD was determined using the Family History Screen. Additional measures were administered to assess the history on perinatal risk, development milestones, serious physical illnesses, and head injury., Results: Logistic regression showed that that family history and perinatal risk factors predicted the diagnosis of PBD. PBD diagnosis was 15 times higher among those with a family history of BD. Second, for every additional perinatal risk factor such as prenatal exposure to drugs or birth complications, the risk of having a PBD diagnosis increased more than six-fold., Conclusions: Having a positive familial history of BD in a first degree relative and perinatal insults may elevate the risk for developing PBD. Presence of these risk factors, especially in the context of clinical signs of affect dysregulation, should alert clinicians to screen for PBD.

Background: Previous research has demonstrated that academic and neuropsychological functions are compromised in pediatric bipolar disorder (PBD). Investigation of the degree to which neuropsychological deficits might contribute to those academic problems is needed to aid in the recognition and intervention for school achievement difficulties in PBD., Methods: A sample of 55 children and adolescents with PBD with and without attention-deficit/hyperactivity disorder (ADHD) (PBD group, n = 28; PBD+ADHD group, n = 27) were tested with a computerized neurocognitive battery and standardized neuropsychological tests. Age range of subjects was 7-17 years, with the mean age of 11.97 (3.18) years. Parents completed a structured questionnaire on school and academic functioning., Results: Logistic regression analyses indicated that executive function, attention, working memory, and verbal memory scores were poorer in those with a history of reading/writing difficulties. A separate logistic regression analysis found that attentional dysfunction predicted math difficulties. These relationships between neuropsychological function and academic difficulties were not different in those with PBD+ADHD than in those with PBD alone., Conclusions: In PBD neuropsychological deficits in the areas of attention, working memory, and organization/problem solving skills all contribute to academic difficulties. Early identification and intervention for these difficulties might help prevent lower academic achievement in PBD.

Objective: The aim of this study was to assess the safety and efficacy of risperidone augmentation of lithium in preschool-onset bipolar disorder (BD) among youth who insufficiently respond to lithium monotherapy., Method: Thirty-eight subjects between the ages of 4 and 17 years (mean age = 11.37 +/- 3.8 years) with onset of BD in preschool years (manic or mixed episode) entered this 12-month trial. All subjects received lithium monotherapy. Patients who failed to adequately respond to lithium monotherapy after 8 weeks and those who relapsed after an initial response were given risperidone augmentation for up to 11 months. The Young Mania Rating Scale (YMRS) was the primary outcome measure. Response was defined as a > or =50% decrease from baseline. Additional data were collected on diagnostic comorbidity, family history, number of hospitalizations, perinatal risk factors, history of physical or sexual abuse, Child Depression Rating Scale-Revised (CDRS-R), Clinical Global Impression (CGI) scale for BD (CGI-BP), Children's Global Assessment Scale (C-GAS), and adverse medication effects., Results: Of the 38 subjects treated with lithium monotherapy, 17 responded, whereas 21 required augmentation with risperidone. Response rate in the youths treated with lithium + risperidone was 85.7% (n = 18/21). Significant predictors of inadequate response to lithium monotherapy requiring augmentation were: (1) attention-deficit/hyperactivity disorder (ADHD), (2) severity at baseline, (3) history of sexual or physical abuse, and (4) preschool age. Combination treatment of lithium and risperidone was found to be safe and well tolerated., Conclusions: A substantial proportion of youth with a history of preschool-onset BD treated with lithium were either nonresponders or partial responders. Subsequent augmentation of lithium with risperidone in these cases was well tolerated and efficacious. Potential predictors of lithium nonresponse identified in this study may guide the choice of medications earlier in the treatment process.