Adherence Rates and Barriers to Second-Generation Antipsychotic Medication Use in Youth with Bipolar Spectrum Disorders Who Have Overweight/Obesity.

Objective: Youth with bipolar spectrum disorders (BSD) are frequently prescribed second-generation antipsychotics (SGAs). Nonadherence to treatment often results in increased mood symptoms and diminished quality of life. We examined SGA adherence rates and adherence barriers among youth who have overweight/obesity and are diagnosed with BSD enrolled in a multisite pragmatic clinical trial. Methods: SGA adherence and adherence barriers at baseline via patient- and caregiver report was assessed. Adherence was defined as taking ≥70% of prescribed SGA doses in the past week. The weighted Kappa statistic was used to measure child-caregiver agreement about adherence rates, barriers, and caregiver assistance. Regression analyses were used to examine associations of caregiver assistance, age, sex, race, insurance status, dosing frequency, and number of concomitant medications with adherence. Barriers to adherence were analyzed separately for youth and their caregivers, using logistic regression to assess associations between informant-reported barriers and informant-reported adherence. Results: Participants included 1485 patients and/or caregivers. At baseline, 88.6% of patients self-reported as adherent; 92.0% of caregivers reported their child was adherent. Concordance between patients and caregivers was moderate (k = 0.42). Approximately, 50% of the sample reported no adherence barriers. Frequently endorsed barriers included forgetting, side effects, being embarrassed to take medications, and preferring to do something else. Concordance between informants regarding adherence barriers was weak (k = 0.05-0.36). Patients and caregivers who did not endorse adherence barriers reported higher adherence than those who endorsed barriers. Male sex and having once daily dosing of medications were associated with lower adherence. Discussion: One-week patient- and caregiver-reported adherence was high in this sample. Half of the sample reported adherence barriers. Most commonly endorsed barriers were forgetting, side effects, being embarrassed, and preferring to do something else. Caregivers and patients have unique perspectives regarding adherence barriers. Understanding and addressing treatment barriers in clinical practice may facilitate adherence.

Prevalence and Correlates of Eating Disorder Symptoms in Adolescents with Bipolar I Disorder.

Objective: To investigate the prevalence and correlates of eating disorder symptoms in adolescents with bipolar I disorder (BP I). Methods: We retrospectively collected a DSM-IV-TR-based diagnostic assessment of 179 adolescents with BP I and evaluated clinical variables in those with and without eating disorder symptoms. For comparison, we retrospectively evaluated eating disorder symptoms in adolescents with generalized anxiety disorder (GAD). Results: Thirty-six percent of adolescents with BP I experienced lifetime eating disorder symptoms; among comorbid adolescents, 74% reported eating disorder cognitions and 40% reported symptoms related to bingeing, 25% purging, and 17% restricting. BP I adolescents with (vs. without) eating disorder symptoms had higher Children's Depression Rating Scale-Revised scores (40.5 vs. 34.5; p < 0.001; effect size = 0.59) and were more likely to be female (75% vs. 45%; p < 0.001; odds ratio = 3.8). There were no differences in Young Mania Rating Scale scores (p = 0.70); lifetime presence of attention-deficit/hyperactivity disorder (p = 0.86) and alcohol (p = 0.59) or substance (p = 0.89) abuse/dependence symptoms; age of BP I onset (p = 0.14); inpatient hospitalization status at baseline (p = 0.53); presence of lifetime inpatient hospitalization (p = 0.64) or suicide attempt (p = 0.35); seriousness of suicidality (p = 0.86); body mass index (p = 0.48); and second-generation antipsychotic (SGA; p = 0.32) or non-SGA mood stabilizer (p = 0.09) use. Eating disorder cognitions (rather than behaviors) were higher in the GAD group (58%) compared with the BP I group (27%; p = 0.004). Limitations: A retrospective study is subject to recall bias and limits our understanding of the temporal relationship between eating disorder and mood symptoms. Conclusions: Eating disorder symptoms are frequently comorbid in adolescents with BP I. The comorbidity is associated with more severe depression but does not confer a more severe illness course.

Common and distinct cortical thickness alterations in youth with autism spectrum disorder and attention-deficit/hyperactivity disorder.

BACKGROUND: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders with overlapping behavioral features and genetic etiology. While brain cortical thickness (CTh) alterations have been reported in ASD and ADHD separately, the degree to which ASD and ADHD are associated with common and distinct patterns of CTh changes is unclear. METHODS: We searched PubMed, Web of Science, Embase, and Science Direct from inception to 8 December 2023 and included studies of cortical thickness comparing youth (age less than 18) with ASD or ADHD with typically developing controls (TDC). We conducted a comparative meta-analysis of vertex-based studies to identify common and distinct CTh alterations in ASD and ADHD. RESULTS: Twelve ASD datasets involving 458 individuals with ASD and 10 ADHD datasets involving 383 individuals with ADHD were included in the analysis. Compared to TDC, ASD showed increased CTh in bilateral superior frontal gyrus, left middle temporal gyrus, and right superior parietal lobule (SPL) and decreased CTh in right temporoparietal junction (TPJ). ADHD showed decreased CTh in bilateral precentral gyri, right postcentral gyrus, and right TPJ relative to TDC. Conjunction analysis showed both disorders shared reduced TPJ CTh located in default mode network (DMN). Comparative analyses indicated ASD had greater CTh in right SPL and TPJ located in dorsal attention network and thinner CTh in right TPJ located in ventral attention network than ADHD. CONCLUSIONS: These results suggest shared thinner TPJ located in DMN is an overlapping neurobiological feature of ASD and ADHD. This alteration together with SPL alterations might be related to altered biological motion processing in ASD, while abnormalities in sensorimotor systems may contribute to behavioral control problems in ADHD. The disorder-specific thinner TPJ located in disparate attention networks provides novel insight into distinct symptoms of attentional deficits associated with the two neurodevelopmental disorders. TRIAL REGISTRATION: PROSPERO CRD42022370620. Registered on November 9, 2022.

Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study.

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes (CYP2C19 or CYP2D6), the serotonin transporter (SLC6A4), and the serotonin receptor 2A subtype (HTR2A). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC0-24; p = 0.025), trough concentrations (Ctrough; p = 0.013), and elimination half-lives (t1/2; p < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia (p = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores (p = 0.017). Escitalopram maximum concentration, AUC0-24, CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.

Aberrant brain network topology in youth with a familial risk for bipolar disorder: a task-based fMRI connectome study.

BACKGROUND: Youth with a family history of bipolar disorder (BD) may be at increased risk for mood disorders and for developing side effects after antidepressant exposure. The neurobiological basis of these risks remains poorly understood. We aimed to identify biomarkers underlying risk by characterizing abnormalities in the brain connectome of symptomatic youth at familial risk for BD. METHODS: Depressed and/or anxious youth (n = 119, age = 14.9 ± 1.6 years) with a family history of BD but no prior antidepressant exposure and typically developing controls (n = 57, age = 14.8 ± 1.7 years) received functional magnetic resonance imaging (fMRI) during an emotional continuous performance task. A generalized psychophysiological interaction (gPPI) analysis was performed to compare their brain connectome patterns, followed by machine learning of topological metrics. RESULTS: High-risk youth showed weaker connectivity patterns that were mainly located in the default mode network (DMN) (network weight = 50.1%) relative to controls, and connectivity patterns derived from the visual network (VN) constituted the largest proportion of aberrant stronger pairs (network weight = 54.9%). Global local efficiency (Elocal , p = .022) and clustering coefficient (Cp , p = .029) and nodal metrics of the right superior frontal gyrus (SFG) (Elocal : p < .001; Cp : p = .001) in the high-risk group were significantly higher than those in healthy subjects, and similar patterns were also found in the left insula (degree: p = .004; betweenness: p = .005; age-by-group interaction, p = .038) and right hippocampus (degree: p = .003; betweenness: p = .003). The case-control classifier achieved a cross-validation accuracy of 78.4%. CONCLUSIONS: Our findings of abnormal connectome organization in the DMN and VN may advance mechanistic understanding of risk for BD. Neuroimaging biomarkers of increased network segregation in the SFG and altered topological centrality in the insula and hippocampus in broader limbic systems may be used to target interventions tailored to mitigate the underlying risk of brain abnormalities in these at-risk youth.

Common and distinct neural correlates of emotional processing in individuals at familial risk for major depressive disorder and bipolar disorder: A comparative meta-analysis.

Individuals at familial risk for mood disorders exhibit deficits in emotional processing and associated brain dysfunction prior to illness onset. However, such brain-behavior abnormalities related to familial predisposition remain poorly understood. To investigate robust abnormal functional activation patterns during emotional processing in unaffected at-risk relatives of patients with major depressive disorder (UAR-MDD) and bipolar disorder (UAR-BD), we performed a meta-analysis of task-based functional magnetic resonance imaging studies using Seed-based d Mapping (SDM) toolbox. Common and distinct patterns of abnormal functional activation between UAR-MDD and UAR-BD were detected via conjunction and differential analyses. A total of 17 studies comparing 481 UAR and 670 healthy controls (HC) were included. Compared with HC, UAR-MDD exhibited hyperactivation in the parahippocampal gyrus, amygdala and cerebellum, while UAR-BD exhibited parahippocampal hyperactivation and hypoactivation in the striatum and middle occipital gyrus (MOG). Conjunction analysis revealed shared hyperactivated PHG in both groups. Differential analysis indicated that the activation patterns of amygdala and MOG significantly differed between UAR-MDD and UAR-BD. These findings provide novel insights into common and distinct neural phenotypes for familial risk and associated risk mechanisms in MDD and BD, which may have implications in guiding precise prevention strategies tailored to the family context.

Effect of non-invasive spinal cord stimulation in unmedicated adults with major depressive disorder: a pilot randomized controlled trial and induced current flow pattern.

Converging theoretical frameworks suggest a role and a therapeutic potential for spinal interoceptive pathways in major depressive disorder (MDD). Here, we aimed to evaluate the antidepressant effects and tolerability of transcutaneous spinal direct current stimulation (tsDCS) in MDD. This was a double-blind, randomized, sham-controlled, parallel group, pilot clinical trial in unmedicated adults with moderate MDD. Twenty participants were randomly allocated (1:1 ratio) to receive "active" 2.5 mA or "sham" anodal tsDCS sessions with a thoracic (anode; T10)/right shoulder (cathode) electrode montage 3 times/week for 8 weeks. Change in depression severity (MADRS) scores (prespecified primary outcome) and secondary clinical outcomes were analyzed with ANOVA models. An E-Field model was generated using the active tsDCS parameters. Compared to sham (n = 9), the active tsDCS group (n = 10) showed a greater baseline to endpoint decrease in MADRS score with a large effect size (-14.6 ± 2.5 vs. -21.7 ± 2.3, p = 0.040, d = 0.86). Additionally, compared to sham, active tsDCS induced a greater decrease in MADRS "reported sadness" item (-1.8 ± 0.4 vs. -3.2 ± 0.4, p = 0.012), and a greater cumulative decrease in pre/post tsDCS session diastolic blood pressure change from baseline to endpoint (group difference: 7.9 ± 3.7 mmHg, p = 0.039). Statistical trends in the same direction were observed for MADRS "pessimistic thoughts" item and week-8 CGI-I scores. No group differences were observed in adverse events (AEs) and no serious AEs occurred. The current flow simulation showed electric field at strength within the neuromodulation range (max. ~0.45 V/m) reaching the thoracic spinal gray matter. The results from this pilot study suggest that tsDCS is feasible, well-tolerated, and shows therapeutic potential in MDD. This work also provides the initial framework for the cautious exploration of non-invasive spinal cord neuromodulation in the context of mental health research and therapeutics. The underlying mechanisms warrant further investigation. Clinicaltrials.gov registration: NCT03433339 URL: https://clinicaltrials.gov/ct2/show/NCT03433339 .

Editors' Best of 2023.

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, modifying version after version into shape. Acknowledging these biases, here are the 2023 articles that we think deserve your attention or at least a second read.

Aberrant Neurofunctional Responses During Emotional and Attentional Processing Differentiate ADHD Youth With and Without a Family History of Bipolar I Disorder.

OBJECTIVE: To compare neurofunctional responses in emotional and attentional networks of psychostimulant-free ADHD youth with and without familial risk for bipolar I disorder (BD). METHODS: ADHD youth with (high-risk, HR, n = 48) and without (low-risk, LR, n = 50) a first-degree relative with BD and healthy controls (n = 46) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional distracters. Region-of-interest analyses were performed for bilateral amygdala (AMY), ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and anterior (ACC) and posterior cingulate cortex (PCC). RESULTS: Compared with HC, HR, but not LR, exhibited predominantly left-lateralized AMY, VLPFC, DLPFC, PCC, and rostral ACC hyperactivation to emotional distractors, whereas LR exhibited right VLPFC and bilateral dorsal ACC hypoactivation to attentional targets. Regional responses correlated with emotional and attention symptoms. CONCLUSION: Aberrant neurofunctional responses during emotional and attentional processing differentiate ADHD youth with and without a family history of BD and correlate with relevant symptoms ratings.

Shared and Distinct Neurobiological Bases of Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Comparative Meta-analysis of Structural Abnormalities.

OBJECTIVE: Pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur and share dysfunctions in affective and cognitive domains. As the neural substrates underlying their overlapping and dissociable symptomatology have not been well delineated, a meta-analysis of whole-brain voxel-based morphometry studies in PBD and ADHD was conducted. METHOD: A systematic literature search was performed in PubMed, Web of Science, and Embase. The seed-based d mapping toolbox was used to identify altered clusters of PBD or ADHD and obtain their conjunctive and comparative abnormalities. Suprathreshold patterns were subjected to large-scale network analysis to identify affected brain networks. RESULTS: The search revealed 10 PBD studies (268 patients) and 32 ADHD studies (1,333 patients). Decreased gray matter volumes in the right insula and anterior cingulate cortex relative to typically developing individuals were conjunctive in PBD and ADHD. Reduced volumes in the right inferior frontal gyrus, left orbitofrontal cortex, and hippocampus were more substantial in PBD, while decreased volumes in the left precentral gyrus, left inferior frontal gyrus, and right superior frontal gyrus were more pronounced in ADHD. Neurodevelopmental effects modulated patterns of the left hippocampus in PBD and those of the left inferior frontal gyrus in ADHD. CONCLUSION: These findings suggest that PBD and ADHD are characterized by both common and distinct patterns of gray matter volume alterations. Their overlapping abnormalities may represent a transdiagnostic problem of attention and emotion regulation shared by PBD and ADHD, whereas the disorder-differentiating substrates may contribute to the relative differences in cognitive and affective features that define the 2 disorders. STUDY PREREGISTRATION INFORMATION: Structural Brain Abnormalities of Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder in Children/Adolescents: An Overlapping Meta-analysis; https://osf.io/trg4m.

Modification of an Intervention to Improve Adherence in Adolescents and Young Adults With Bipolar Disorder.

Objective: Managing bipolar disorder (BD) is particularly challenging for adolescents and young adults (AYAs) ages 16 to 21. Few interventions exist that address self-management in AYAs with BD. Thus, this study aimed to modify the customized adherence enhancement behavioral intervention for AYAs through an iterative, patient-centered process. Method: The Obesity-Related Behavioral Intervention Trials (ORBIT) model was used for intervention development. In phase 1a, adherence barriers and facilitators were identified to refine intervention content. Phase 1b occurred following curriculum modification to ensure that the modified intervention was relevant and usable by the target population. Data were collected via focus groups and interviews with AYAs with BD, parents, and providers. Transcripts were analyzed using directed content analysis. Results: Phase 1a included focus groups/interviews with AYAs (n = 10), parents (n = 4), and providers (n = 9) who described the difficulties and successes in managing BD symptoms, improving adherence, and transitioning care from caregivers. Phase 1b included an advisory board composed of 8 phase 1a participants who provided feedback on modified session activities, module delivery, and curriculum. Phase 1b involved usability testing with new participants (n = 8), revealing the need for modifiable language based on developmental level, more engaging visual images, and confirmation that topics were salient to AYAs with BD. Conclusion: Though sample sizes were small and not representative of the population of AYAs with BD, the ORBIT methodology informed the adaptation of the customized adherence enhancement intervention to improve adherence in AYAs with BD. Important next steps are to conduct a pilot randomized clinical trial of customized adherence enhancement for AYAs.

Editors' Note: Third Annual Report Regarding JAACAP's Antiracist Journey.

In 2020, we wrote to you of our dedication and vision for JAACAP "to be antiracist at every level."1 Over the last 3 years, we have pursued initiatives "to reshape the Journal to pursue this vision."2,3 In this article, we provide an update on these goals and initiatives (Figure 1). With the launching of our new open access journal, JAACAP Open,4 in late 2022, we now extend these initiatives to both scientific journals in the JAACAP family and aspire to be a leader among mental health journals in our intentional pursuit of antiracist policies and practices.

Cortical and subcortical structural differences in psychostimulant-free ADHD youth with and without a family history of bipolar I disorder: a cross-sectional morphometric comparison.

Although attention-deficit/hyperactivity disorder (ADHD) and a family history of bipolar I disorder (BD) are associated with increased risk for developing BD, their neuroanatomical substrates remain poorly understood. This study compared cortical and subcortical gray matter morphology in psychostimulant-free ADHD youth with and without a first-degree relative with BD and typically developing healthy controls. ADHD youth (ages 10-18 years) with ('high-risk', HR) or without ('low-risk', LR) a first-degree relative with BD and healthy comparison youth (HC) were enrolled. High-resolution 3D T1-weighted images were acquired using a Philips 3.0 T MR scanner. The FreeSurfer image analysis suite was used to measure cortical thickness, surface area, and subcortical volumes. A general linear model evaluated group differences in MRI features with age and sex as covariates, and exploratory correlational analyses evaluated associations with symptom ratings. A total of n = 142 youth (mean age: 14.16 ± 2.54 years, 35.9% female) were included in the analysis (HC, n = 48; LR, n = 49; HR, n = 45). The HR group exhibited a more severe symptom profile, including higher mania and dysregulation scores, compared to the LR group. For subcortical volumes, the HR group exhibited smaller bilateral thalamic, hippocampal, and left caudate nucleus volumes compared to both LR and HC, and smaller right caudate nucleus compared with LR. No differences were found between LR and HC groups. For cortical surface area, the HR group exhibited lower parietal and temporal surface area compared with HC and LR, and lower orbitofrontal and superior frontal surface area compared to LR. The HR group exhibited lower left anterior cingulate surface area compared with HC. LR participants exhibited greater right pars opercularis surface area compared with the HC. Some cortical alterations correlated with symptom severity ratings. These findings suggest that ADHD in youth with a BD family history is associated with a more a severe symptom profile and a neuroanatomical phenotype that distinguishes it from ADHD without a BD family history.

Brain network structural connectome abnormalities among youth with attention-deficit/hyperactivity disorder at varying risk for bipolar I disorder: a cross-sectional graph-based magnetic resonance imaging study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is highly prevalent among youth with or at familial risk for bipolar-I disorder (BD-I), and ADHD symptoms commonly precede and may increase the risk for BD-I; however, associated neuropathophysiological mechanisms are not known. In this cross-sectional study, we sought to investigate brain structural network topology among youth with ADHD, with and without familial risk of BD-I. METHODS: We recruited 3 groups of psychostimulant-free youth (aged 10-18 yr), namely youth with ADHD and at least 1 biological parent or sibling with BD-I (high-risk group), youth with ADHD who did not have a first- or second-degree relative with a mood or psychotic disorder (low-risk group) and healthy controls. We used graph-based network analysis of structural magnetic resonance imaging data to investigate topological properties of brain networks. We also evaluated relationships between topological metrics and mood and ADHD symptom ratings. RESULTS: A total of 149 youth were included in the analysis (49 healthy controls, 50 low-risk youth, 50 high-risk youth). Low-risk and high-risk ADHD groups exhibited similar differences from healthy controls, mainly in the default mode network and central executive network. We found topological alterations in the salience network of the high-risk group, relative to both low-risk and control groups. We found significant abnormalities in global network properties in the high-risk group only, compared with healthy controls. Among both low-risk and high-risk ADHD groups, nodal metrics in the right triangular inferior frontal gyrus correlated positively with ADHD total and hyperactivity/impulsivity subscale scores. LIMITATIONS: The cross-sectional design of this study could not determine the relevance of these findings to BD-I risk progression. CONCLUSION: Youth with ADHD, with and without familial risk for BD-I, exhibit common regional abnormalities in the brain connectome compared with healthy youth, whereas alterations in the salience network distinguish these groups and may represent a prodromal feature relevant to BD-I risk.

Cognitive, Family, and Quality-of-Life Characteristics of Youth with Depression Associated with Bipolar Disorder.

Background: Depression associated with bipolar disorder (BD) is more common compared to mania. Cognitive, family, and quality-of-life (QOL) factors associated with pediatric bipolar depression are understudied. The goal of this study was to evaluate cognitive, family environmental, and QOL characteristics of youth with bipolar depression. Methods: Thirty-two youth (12-18 years of age) with BD type I currently depressed were recruited from inpatient and outpatient setting. Subjects were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), the Family Environment Scale (FES), and the Child Health Questionnaire-Parental-Form 50 (CHQ-PF50). Results were compared with population norms and the relationship between these domains was calculated. Results: Youth with depression associated with BD did not show significant impairment in executive functions. They displayed impaired family environment in the domains of cohesion, independence, achievement orientation, and organization. Youth also displayed impairments in the psychosocial health domains compared with the population normative data. The CHQ-Psychosocial health significantly negatively correlated with the BRIEF-Global Executive Control score (r = -0.76, p < 0.0001). Conclusion: Depression in youth with BD is associated with impairments in family functioning and QOL. Impairments in psychosocial QOL are associated with cognitive functioning. Further intervention studies examining executive functioning and family environment as treatment targets are needed. ClinicalTrials.gov identifier:NCT00232414.

Deficits in sustained attention in adolescents with bipolar disorder during their first manic episode.

OBJECTIVES: Evaluate differences in sustained attention (SAT) and associated neurofunctional profiles between bipolar disorder type I (BD), attention-deficit/hyperactivity disorder (ADHD), and healthy comparison (HC) youth. METHODS: Adolescent participants, aged 12-17 years, with BD (n = 30) and ADHD (n = 28) and HC adolescents (n = 26) underwent structural and functional magnetic resonance imaging (fMRI) while completing a modified Continuous Performance Task-Identical Pairs task. Attentional load was modifying in this task using three levels of image distortion (0 %, 25 % and 50 % image distortion). Task related fMRI activation and performance measures: perceptual sensitivity index (PSI); response bias (RB) and response time (RT); were calculated and compared between groups. RESULTS: BD participants displayed lower perceptual sensitivity index (0 % p = 0.012; 25 % p = 0.015; 50 % p = 0.036) and higher values of response bias across levels of distortion (0 % p = 0.002, 25 % p = 0.001, and 50 % p = 0.008) as compared to HC. No statistically significant differences were observed for PSI and RB between BD and ADHD groups. No difference in RT were detected. Between-group and within-group differences in task related fMRI measures were detected in several clusters. In a region of interest (ROI) analysis of these clusters comparing BD and ADHD confirmed differences between these two groups. CONCLUSIONS: Compared with HC, BD participants displayed SAT deficits. Increased attentional load revealed that BD participants had lower activation in brain regions associated with performance and integration of neural processes in SAT. ROI analysis between BD and ADHD participants shows that the differences were likely not attributable to ADHD comorbidity, suggesting SAT deficits were distinct to the BD group.

Different brain functional network abnormalities between attention-deficit/hyperactivity disorder youth with and without familial risk for bipolar disorder.

Attention-deficit/hyperactivity disorder (ADHD) commonly precedes the initial onset of mania in youth with familial risk for bipolar disorder (BD). Although ADHD youth with and without BD familial risk exhibit different clinical features, associated neuropathophysiological mechanisms remain poorly understood. This study aimed to identify brain functional network abnormalities associated with ADHD in youth with and without familial risk for BD. Resting-state functional magnetic resonance imaging scans were acquired from 37 ADHD youth with a family history of BD (high-risk), 45 ADHD youth without a family history of BD (low-risk), and 32 healthy controls (HC). Individual whole-brain functional networks were constructed, and graph theory analysis was applied to estimate network topological metrics. Topological metrics, including network efficiency, small-worldness and nodal centrality, were compared across groups, and associations between topological metrics and clinical ratings were evaluated. Compared to HC, low-risk ADHD youth exhibited weaker global integration (i.e., decreased global efficiency and increased characteristic path length), while high-risk ADHD youth showed a disruption of localized network components with decreased frontoparietal and frontolimbic connectivity. Common topological deficits were observed in the medial superior frontal gyrus between low- and high-risk ADHD. Distinct network deficits were found in the inferior parietal lobule and corticostriatal circuitry. Associations between global topological metrics and externalizing symptoms differed significantly between the two ADHD groups. Different patterns of functional network topological abnormalities were found in high- as compared to low-risk ADHD, suggesting that ADHD in youth with BD familial risk may represent a phenotype that is different from ADHD alone.

Morphological abnormalities in youth with bipolar disorder and their relationship to clinical characteristics.

OBJECTIVES: To characterize the neuroanatomy of BD in youth and its correlation to clinical characteristics. METHODS: The current study includes a sample of 105 unmedicated youth with first-episode BD, aged between 10.1 and 17.9 years, and 61 healthy comparison adolescents, aged between 10.1 and 17.7 years, who were matched for age, race, sex, socioeconomic status, intelligence quotient (IQ), and education level. T1-weighted magnetic resonance imaging (MRI) images were obtained using a 4 T MRI scanner. Freesurfer (V6.0) was used to preprocess and parcellate the structural data, and 68 cortical and 12 subcortical regions were considered for statistical comparisons. The relationship between morphological deficits and clinical and demographic characteristics were evaluated using linear models. RESULTS: Compared with healthy youth, youth with BD had decreased cortical thickness in frontal, parietal, and anterior cingulate regions. These youth also showed decreased gray matter volumes in 6 of the 12 subcortical regions examined including thalamus, putamen, amygdala and caudate. In further subgroup analyses, we found that youth with BD with comorbid attention-deficit hyperactivity disorder (ADHD) or with psychotic symptoms had more significant deficits in subcortical gray matter volume. LIMITATIONS: We cannot provide information about the course of structural changes and impact of treatment and illness progression. CONCLUSIONS: Our findings indicate that youth with BD have significant neurostructural deficits in both cortical and subcortical regions mainly located in the regions related to emotion processing and regulation. Variability in clinical characteristics and comorbidities may contribute to the severity of anatomic alterations in this disorder.

A Double-Blind Placebo-Controlled Pilot Study of Topiramate in Manic Adolescents Treated with Olanzapine.

Objective: To conduct a pilot study to examine topiramate for the treatment of weight gain associated with olanzapine in manic adolescents with bipolar disorder. Methods: We conducted a 12-week double-blind randomized placebo-controlled pilot study of topiramate (300-400 mg/day) versus placebo in manic youth (ages 10-18 years) with bipolar disorder who were treated with olanzapine (10-20 mg/day). The primary outcome measure was gender- and weight-normed change in body mass index (BMI z-score). Results: Thirty manic adolescents were treated with olanzapine and were randomized to either topiramate (n = 16) or placebo (n = 14). There was a significantly greater increase in BMI z-scores in the placebo group (0.28 standard deviations [SDs]) compared with the topiramate group (0.10 SDs) when analyzed by longitudinal regression (p = 0.049). The placebo group had greater increases in raw BMI and weight (2.25 kg/m2 and 6.9 kg, respectively) compared with the topiramate (0.99 kg/m2 and 2.9 kg) group (p = 0.011 for BMI, p = 0.016 for weight). The most common adverse events in the topiramate group were headache (n = 7, 44%), gastrointestinal upset (n = 3, 19%), and muscle stiffness (n = 3, 19%). Conclusions: Topiramate may minimize the weight gain associated with olanzapine treatment in adolescents with bipolar disorder. Moreover, topiramate in combination with olanzapine was well tolerated. Larger studies that are adequately powered are necessary to determine the efficacy of topiramate for second-generation antipsychotic-related weight gain. Trial Registration: ClinicalTrials.gov Identifier number NCT00394095.

Regional microstructural differences in ADHD youth with and without a family history of bipolar I disorder.

BACKGROUND: Having a first-degree relative with bipolar I disorder (BD) in conjunction with prodromal attention deficit/hyperactivity disorder (ADHD) may represent a unique phenotype that confers greater risk for developing BD than ADHD alone. However, underlying neuropathoetiological mechanisms remain poorly understood. This cross-sectional study compared regional microstructure in psychostimulant-free ADHD youth with ('high-risk', HR) and without ('low-risk', LR) a first-degree relative with BD, and healthy controls (HC). METHODS: A total of 140 (high-risk, n = 44; low-risk, n = 49; and HC, n = 47) youth (mean age: 14.1 ± 2.5 years, 65 % male) were included in the analysis. Diffusion tensor images were collected and fractional anisotropy (FA) and mean diffusivity (MD) maps were calculated. Both tract-based and voxel-based analyses were performed. Correlations between clinical ratings and microstructural metrics that differed among groups were examined. RESULTS: No significant group differences in major long-distance fiber tracts were observed. The high-risk ADHD group exhibited predominantly higher FA and lower MD in frontal, limbic, and striatal subregions compared with the low-risk ADHD group. Both low-risk and high-risk ADHD groups exhibited higher FA in unique and overlapping regions compared with HC subjects. Significant correlations between regional microstructural metrics and clinical ratings were observed in ADHD groups. LIMITATIONS: Prospective longitudinal studies will be required to determine the relevance of these findings to BD risk progression. CONCLUSIONS: Psychostimulant-free ADHD youth with a BD family history exhibit different microstructure alterations in frontal, limbic, and striatal regions compared with ADHD youth without a BD family history, and may therefore represent a unique phenotype relevant to BD risk progression.