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.

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.

Liraglutide in Obese or Overweight Individuals With Stable Bipolar Disorder.

BACKGROUND: Obesity is common among persons with bipolar disorder (BD). Liraglutide 3.0 mg/d subcutaneous injection is indicated for chronic weight management and associated with minimal adverse neuropsychiatric effects. This study evaluated whether liraglutide 3 mg/d reduced body weight, improved metabolic factors and eating psychopathology, and was safe and well tolerated in persons with stable BD who were obese (body mass index [BMI] >30 kg/m 2 ) or overweight (BMI ≥27 kg/m 2 ) with at least one weight-related comorbidity. METHODS: This was a 40-week, randomized (1:1 ratio), placebo-controlled, double-blind, parallel-group, 2-arm clinical trial of liraglutide targeted to 3.0 mg/d (in combination with a reduced-calorie diet and increased physical activity) in 60 participants with stable BD who were obese or overweight. Primary outcome was percent change in body weight from baseline to study end. Secondary outcomes included percentage of patients who lost ≥5% of baseline body weight, and changes in metabolic variables and measures of eating psychopathology. RESULTS: There were no significant baseline differences between the 29 liraglutide recipients and the 31 placebo recipients, except that liraglutide recipients had higher levels of binge eating and lower levels of high-density lipoprotein cholesterol. Compared with placebo, liraglutide was associated with significantly greater reductions in percent change in body weight, percentage of participants who lost at least 5% of body weight, and reductions in weight, BMI, hemoglobin A 1c levels, binge eating, and hunger. Liraglutide was well tolerated. CONCLUSIONS: Liraglutide 3 mg/d may be efficacious and safe for weight loss in individuals with stable BD and obesity or overweight. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03158805).

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.

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.

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 .

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.

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.

Effects of short-term quetiapine and lithium therapy for acute manic or mixed episodes on the limbic system and emotion regulation circuitry in youth with bipolar disorder.

Disruptions in the limbic system, and in emotion regulation circuitry that supports affect modulation, have been reported during acute manic episodes of bipolar disorder (BD). The impact of pharmacological treatment on these deficits, especially in youth, remains poorly characterized. 107 youths with acute manic or mixed episodes of bipolar I disorder and 60 group-matched healthy controls were recruited. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. Task-based fMRI studies were performed using an identical pairs continuous performance task (CPT-IP) at pre-treatment baseline and post-treatment weeks one and six. Region of interest analyses focused on the limbic system and ventral PFC - basal ganglia - thalamocortical loop structures known to be involved in emotion regulation. Changes in regional activation were compared between the two treatment groups, and pretreatment regional activation was used to predict treatment outcome. Mania treatment scores improved more rapidly in the quetiapine than lithium treated group, as did significant normalization of neural activation toward that of healthy individuals in left amygdala (p = 0.007), right putamen (p < 0.001), and right globus pallidus (p = 0.003). Activation changes in the right putamen were correlated with reduction of mania symptoms. The limbic and emotion regulation system activation at baseline and week one predicted treatment outcome in youth with bipolar disorder with significant accuracy (up to 87.5%). Our findings document more rapid functional brain changes associated with quetiapine than lithium treatment in youth with bipolar disorder, with most notable changes in the limbic system and emotion regulation circuitry. Pretreatment alterations in these regions predicted treatment response. These findings advance understanding of regional brain alterations in youth with bipolar disorder, and show that fMRI data can predict treatment outcome before it can be determined clinically, highlighting the potential utility of fMRI biomarkers for early prediction of treatment outcomes in bipolar disorder.Clinical Trials Registration: Name: Multimodal Neuroimaging of Treatment Effects in Adolescent Mania. URL: https://clinicaltrials.gov/ . Registration number: NCT00893581.

Family environment of youth with first episode Mania.

BACKGROUND: The purpose is to compare youth- and caregiver-reported characteristics of family environment, within and between families with a child experiencing a first manic episode of bipolar disorder (BPD), and families without a child with BPD or familial history of psychiatric disorders (HF). METHODS: Family environment of 61 families with a child with BPD and 44 HF were assessed with Family Environment Scale (FES). We compared FES subscale scores between families with BPD and HF, and caregiver- and youth-rated scores. RESULTS: Families with BPD differed significantly from HF on 8/10 FES subscales scores. Youth differed significantly from their caregivers on 7/10 subscales. An interaction effect was observed such that youth with BPD reported lower cohesion and organization, and higher conflict than their caregivers; however, HF did not differ significantly on these domains. CONCLUSIONS: Our results suggest that families with BPD have higher conflict and lower cohesion and organization compared to HF. Results also indicate differences between youth and caregiver perspectives in both groups, which may contribute to family discord. Interventions targeting areas of cohesion, organization, and conflict may be beneficial for youth with BPD and their families, specifically those that identify and bridge perceptual divides.

A Double-Blind Randomized Trial to Investigate Mechanisms of Antidepressant-Related Dysfunctional Arousal in Depressed or Anxious Youth at Familial Risk for Bipolar Disorder.

Antidepressants are standardly used to treat moderate to severe symptoms of depression and/or anxiety in youth but may also be associated with rare but serious psychiatric adverse events such as irritability, agitation, aggression, or suicidal ideation. Adverse events are especially common in youth with a family history of bipolar disorder (BD) who are at heightened risk for dysfunction in neurobiological systems that regulate emotion and arousal. To further understand this phenomenon, this study will examine (a) baseline risk factors associated with dysfunctional arousal in a sample of youth at high-risk for BD treated with or without an antidepressant, (b) whether antidepressant-related changes in arousal are mediated by changes in prefrontal-limbic circuitry, and (c) whether pharmacogenetic factors influence antidepressant-related changes in arousal. High-risk youth (aged 12-17 years with moderate to severe depressive and/or anxiety symptoms and at least one first-degree relative with bipolar I disorder) will be randomized to receive psychotherapy plus escitalopram or psychotherapy plus placebo. Neuroimaging and behavioral measures of arousal will be collected prior to randomization and at 4 weeks. Samples for pharmacogenetic analysis (serum escitalopram concentration, CYP2C19 metabolizer phenotype, and HTR2A and SLC6A4 genotypes) will be collected at 8 weeks. Youth will be followed for up to 16 weeks to assess change in arousal measures.

Symptom Profiles, But Not Prefrontal Neurochemistry, Differentiate ADHD Youth With and Without a Family History of Bipolar I Disorder.

Objective: To identify clinical and central features that differentiate ADHD youth with and without familial risk for bipolar I disorder (BD). Methods: Psychostimulant-free ADHD youth (10-18 years) with and without a first-degree relative with BD and healthy controls were enrolled. Bilateral ventrolateral prefrontal cortex (VLPFC) proton magnetic resonance spectroscopy (1H MRS) scans and a range of symptom ratings were performed. Results: A total of n = 145 youth were enrolled. ADHD youth with a family history of BD exhibited greater manic and depressive symptom severity, ADHD hyperactivity/impulsive symptom severity, and higher parent-reported ratings of dysregulation compared with ADHD youth without a BD family history. Although VLPFC metabolite levels did not differ across groups, choline levels in the left VLPFC correlated with different symptom ratings. Conclusion: Symptom profiles including more severe mood and externalizing symptoms, but not VLPFC neurochemistry, differentiate psychostimulant-free ADHD youth with and without a family history of BD.

Familial risk for bipolar I disorder is associated with erythrocyte omega-3 polyunsaturated fatty acid deficits in youth with attention-deficit hyperactivity disorder.

Although attention-deficit/hyperactivity disorder (ADHD) and a family history of bipolar I disorder (BD) increase the risk for developing BD, associated pathoetiological mechanisms remain poorly understood. One candidate risk factor is a neurodevelopmental deficiency in omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This study investigated erythrocyte EPA+DHA biostatus in psychostimulant-free ADHD youth with ('high-risk', HR) and without ('low-risk', LR) a first-degree relative with BD, and healthy controls (HC). Erythrocyte EPA+DHA composition was determined by gas chromatography, and symptom ratings were performed. A total of n = 123 (HR, n = 41; LR, n = 42; HC, n = 40) youth (mean age: 14.4 ± 2.5 years) were included in the analysis. Compared with HC, erythrocyte EPA+DHA composition was significantly lower in HR (-13%) but not LR (-3%), and there was a trend for HR to be lower than LR (-11%). Both HR and LR differed significantly from HC on all symptom ratings. HR had greater ADHD hyperactivity/impulsive symptom severity, manic symptom severity, and higher parent-reported ratings of internalization, externalization, and dysregulation, compared with LR. ADHD youth with a BD family history exhibit erythrocyte EPA+DHA deficits and a more severe clinical profile, including greater manic and dysregulation symptoms, compared with ADHD youth without a BD family history.

Pretreatment Alterations and Acute Medication Treatment Effects on Brain Task-Related Functional Connectivity in Youth With Bipolar Disorder: A Neuroimaging Randomized Clinical Trial.

OBJECTIVE: Disruptions in cognition are a clinically significant feature of bipolar disorder (BD). The effects of different treatments on these deficits and the brain systems that support them remain to be established. METHOD: A continuous performance test was administered to 55 healthy controls and 71 acutely ill youths with mixed/manic BD to assess vigilance and working memory during task-based functional magnetic resonance imaging studies. Patients, who were untreated for at least 7 days at baseline, and controls were scanned at pretreatment baseline and at weeks 1 and 6. After baseline testing, patients (n = 71) were randomly assigned to 6-week double-blind treatment with lithium (n = 26; 1.0-1.2 mEq/L) or quetiapine (n = 45; 400-600 mg). Weighted seed-based connectivity (wSBC) was used to assess regional brain interactions during the attention task compared with the control condition. RESULTS: At baseline, youths with BD showed reduced connectivity between bilateral anterior cingulate cortex and both left ventral lateral prefrontal cortex and left insula and increased connectivity between left ventral lateral prefrontal cortex and left temporal pole, left orbital frontal cortex and right postcentral gyrus, and right amygdala and right occipital pole compared with controls. At 1-week follow-up, quetiapine, but not lithium, treatment led to a significant shift of connectivity patterns toward those of the controls. At week 6, compared with baseline, there was no difference between treatment conditions, at which time both patient groups showed significant normalization of brain connectivity toward that of controls. CONCLUSION: Functional alterations in several brain regions associated with cognitive processing and the integration of cognitive and affective processing were demonstrated in untreated youths with BD before treatment. Treatment reduced several of these alterations, with significant effects at week 1 only in the quetiapine treatment group. Normalization of functional connectivity might represent a promising biomarker for early target engagement in youth with BD. CLINICAL TRIAL REGISTRATION INFORMATION: Multimodal Neuroimaging of Treatment Effects in Adolescent Mania; https://clinicaltrials.gov/; NCT00893581.

N-acetylcysteine for depression and glutamate changes in the left prefrontal cortex in adolescents and young adults at risk for bipolar disorder: A pilot study.

AIMS: To investigate the mechanism of action of N-acetylcysteine (NAC) in depressive symptoms in young individuals at familial risk for bipolar disorder. METHODS: We conducted an 8-week open label clinical trial of NAC 2400 mg/days in 15-24 years old depressed offspring of a bipolar I disorder parent, with baseline and endpoint proton magnetic resonance spectroscopy acquired within the left ventrolateral prefrontal cortex (VLPFC). RESULTS: Nine participants were enrolled and finished the study. NAC significantly improved depressive and anxiety symptom scores, and clinical global impression (all p < .001). There was a non-significant reduction in glutamate levels in the left VLPFC. Reduction in depressive symptom scores was positively associated with reduction in glutamate levels in the left VLPFC (p = .007). CONCLUSIONS: This pilot study suggests that NAC might be efficacious for depressive symptoms in at-risk youth, and that its mechanism of action involves the modulation of glutamate in the left VLPFC.

A preliminary study of the effects of mindfulness-based cognitive therapy on structural brain networks in mood-dysregulated youth with a familial risk for bipolar disorder.

BACKGROUND: Mindfulness-based cognitive therapy for children (MBCT-C), as a psychotherapeutic intervention, has been shown to be effective for treating mood dysregulation (MD). While previous neuroimaging studies of MD have reported both pre-treatment structural and functional alterations, the effects of MBCT-C on brain morphological network organisation has not been investigated. METHODS: We investigated brain morphological network organisation in 10 mood-dysregulated youth with familial risk for bipolar disorder and 15 matched healthy comparison youth (HC). Effects of 12 weeks of MBCT-C were examined in the mood-dysregulated youth. Topological properties of brain networks used for analyses were constructed based on morphological similarities in regional grey matter using a graph-theory approach using MRI data. RESULTS: At baseline, compared with the HC group, the mood-dysregulated group exhibited increased global efficiency (Eglob ), decreased path length (Lp ), and abnormal nodal properties, mainly in the limbic system. Right temporal pole alterations at baseline predicted change in Child and Adolescent Mindfulness Measure scores after treatment. The mood-dysregulated group showed significant decreases in both the Eglob and Lp metrics after MBCT-C, suggesting an improved capacity for optimal information processing. Changes in Lp were correlated with changes in Emotion Regulation Checklist scores. Our results show significant topological alterations in the mood-dysregulated group as compared to controls at baseline. After MBCT-C, disrupted topological properties in the mood-dysregulated group were significantly reduced. CONCLUSION: MBCT-C may facilitate clinically meaningful changes in the brain structural network in mood-dysregulated individuals.

Study protocol and rationale for a randomized, placebo-controlled trial of solriamfetol to treat binge eating disorder.

INTRODUCTION: Binge eating disorder (BED) is an important public health problem associated with severe psychosocial and medical consequences for which treatment options are limited. The objective of this study is to evaluate the efficacy and tolerability of the novel dopamine and norepinephrine reuptake inhibitor (DNRI) solriamfetol in the treatment of BED. METHODS: This study is a 12-week, randomized (1:1 ratio), placebo-controlled, double-blind, parallel-group, 2-arm clinical trial of solriamfetol in 64 outpatients with BED. The primary outcome is binge-eating day frequency as assessed by take-home patient-completed binge eating diaries. Secondary outcomes include binge-eating episode frequency and scores on The Yale-Brown Obsessive Compulsive Scale for Binge Eating (YBOCS-BE) and Clinical Global Severity (CGIS) scale. DISCUSSION: To our knowledge this is the first randomized, double-blind protocol investigating the safety and efficacy of solriamfetol in BED. We highlight the background and rationale for this study, including a discussion on using DNRIs in BED. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov, identifier NCT04602936, on Oct 26, 2020 https://www.clinicaltrials.gov/ct2/show/NCT04602936.

A Randomized, Double-Blind, Controlled Trial of Lithium Versus Quetiapine for the Treatment of Acute Mania in Youth with Early Course Bipolar Disorder.

Objective: To compare the efficacy and tolerability of lithium versus quetiapine for the treatment of manic or mixed episodes in youths with early course bipolar I disorder. Methods: Six-week, randomized, double-blind clinical trial of lithium versus quetiapine for the treatment of adolescents with acute manic/mixed episode. Target dose of quetiapine dose was adjusted to a target dose of 400-600 mg and target serum level for lithium was 1.0-1.2 mEq/L. Primary outcome measure was baseline-to-endpoint change in the Young Mania Rating Scale (YMRS). Secondary outcomes were treatment response (50% or more decrease from baseline in YMRS score) and remission (YMRS score ≤12, Children's Depression Rating Scale-Revised [CDRS-R] total score ≤28 and Clinical Global Impression Bipolar Severity Scale [CGI-BP-S] overall score of ≤3, respectively). Results: A total of 109 patients were randomized (quetiapine = 58 and lithium = 51). Participants in the quetiapine treatment group showed a significantly greater reduction in YMRS score than those in the lithium group (-11.0 vs. -13.2; p < 0.001; effect size 0.39). Response rate was 72% in the quetiapine group and 49% in the lithium group (p = 0.012); no differences in remission rates between groups were observed. Most frequent side effects for lithium were headaches (60.8%), nausea (39.2%), somnolence (27.5%), and tremor (27.5%); for quetiapine somnolence (63.8%), headaches (55.2%), tremor (36.2%), and dizziness (36.2%) were evidenced. Participants receiving quetiapine experienced more somnolence (p < 0.001), dizziness (p < 0.05), and weight gain (p < 0.05). Conclusions: Treatment with both lithium and quetiapine led to clinical improvement. Most study participants in this study experienced a clinical response; however, less than half of the participants in this study achieved symptomatic remission. The head-to-head comparison of both treatment groups showed quetiapine was associated with a statistically significant greater rate of response and overall symptom reduction compared with lithium. Trial registration: clinicaltrials.gov NCT00893581.

Network-level functional topological changes after mindfulness-based cognitive therapy in mood dysregulated adolescents at familial risk for bipolar disorder: a pilot study.

BACKGROUND: Given that psychopharmacological approaches routinely used to treat mood-related problems may result in adverse outcomes in mood dysregulated adolescents at familial risk for bipolar disorder (BD), Mindfulness-Based Cognitive Therapy for Children (MBCT-C) provides an alternative effective and safe option. However, little is known about the brain mechanisms of beneficial outcomes from this intervention. Herein, we aimed to investigate the network-level neurofunctional effects of MBCT-C in mood dysregulated adolescents. METHODS: Ten mood dysregulated adolescents at familial risk for BD underwent a 12-week MBCT-C intervention. Resting-state functional magnetic resonance imaging (fMRI) was performed prior to and following MBCT-C. Topological metrics of three intrinsic functional networks (default mode network (DMN), fronto-parietal network (FPN) and cingulo-opercular network (CON)) were investigated respectively using graph theory analysis. RESULTS: Following MBCT-C, mood dysregulated adolescents showed increased global efficiency and decreased characteristic path length within both CON and FPN. Enhanced functional connectivity strength of frontal and limbic areas were identified within the DMN and CON. Moreover, change in characteristic path length within the CON was suggested to be significantly related to change in the Emotion Regulation Checklist score. CONCLUSIONS: 12-week MBCT-C treatment in mood dysregulated adolescents at familial risk for BD yield network-level neurofunctional effects within the FPN and CON, suggesting enhanced functional integration of the dual-network. Decreased characteristic path length of the CON may be associated with the improvement of emotion regulation following mindfulness training. However, current findings derived from small sample size should be interpreted with caution. Future randomized controlled trials including larger samples are critical to validate our findings.

A Preliminary Study of the Effects of Treatment with Lithium Versus Quetiapine on Attention of Adolescents with Bipolar Disorder.

Objectives: Despite attentional deficits being a prominent feature of bipolar disorder, there are limited data on the effects of common treatments for bipolar disorder on attention. Thus, we sought to compare the effects of lithium versus quetiapine on attention in adolescents with bipolar disorder. Methods: Adolescents ages 10-17 with bipolar disorder, type I, who were experiencing a manic or mixed episode, were recruited from outpatient settings and the inpatient psychiatric units at Cincinnati Children's Hospital Medical Center during their first manic episode. Healthy comparison subjects were recruited from outreach programs in the community. Patients were randomized to lithium or quetiapine, administered in a double-dummy, double-blinded manner for 6 weeks. Attentional deficits were assessed in all groups using the Identical Pairs Continuous Performance Task at baseline and at week 6. Results: Patients with bipolar disorder (n = 79) had impaired attention relative to the healthy group (n = 57) at both baseline and after 6 weeks of treatment. The lithium-treated group (n = 30) had poorer attentional performance than the healthy group at week 6. There was a difference in change in performance between lithium- and quetiapine-treated (n = 49) groups. Conclusion: Youth with bipolar disorder may have impaired attention relative to their healthy peers. Conclusions are limited by the high dropout rate in the lithium-treated group.