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Bipolar disorder is a chronic and typically recurring illness with significant psychosocial morbidity. Although the aetiological factors that contribute to the onset of mania, and by definition bipolar I disorder, are poorly understood, it most commonly occurs during the adolescent period. Putative risk factors for developing bipolar disorder include having a first-degree relative with a mood disorder, physical/sexual abuse and other psychosocial stressors, substance use disorders, psychostimulant and antidepressant medication exposure and omega-3 fatty acid deficiency. Prominent prodromal clinical features include episodic symptoms of depression, anxiety, hypomania, anger/irritability and disturbances in sleep and attention. Because prodromal mood symptoms precede the onset of mania by an average of 10 years, and there is low specificity of risk factors and prodromal features for mania, interventions initiated prior to onset of the disorder (primary prevention) or early in the course of the disorder (early or secondary prevention) must be safe and well tolerated upon long-term exposure. Indeed, antidepressant and psychostimulant medications may precipitate the onset of mania. Although mood stabilizers and atypical antipsychotic medications exhibit efficacy in youth with bipolar I disorder, their efficacy for the treatment of prodromal mood symptoms is largely unknown. Moreover, mood stabilizers and atypical antipsychotics are associated with prohibitive treatment-emergent adverse effects. In contrast, omega-3 fatty acids have neurotrophic and neuroprotective properties and have been found to be efficacious, safe and well tolerated in the treatment of manic and depressive symptoms in children and adolescents. Together, extant evidence endorses a clinical staging model in which subjects at elevated risk for developing mania are treated with safer interventions (i.e. omega-3 fatty acids, family-focused therapy) in the prodromal phase, followed by pharmacological agents with potential adverse effects for nonresponsive cases and secondary prevention. This approach warrants evaluation in prospective longitudinal trials in youth determined to be at ultra-high risk for bipolar I disorder. [ABSTRACT FROM AUTHOR]

Child and adolescent bipolar disorder (BPD) is a serious psychiatric disorder that often causes significant impairment in functioning. Pharmacological intervention is the cornerstone of treatment for bipolar youth, although psychotherapeutic interventions may be beneficial as adjunctive treatment. Medications used for the treatment of BPD in adults are still commonly used for bipolar children and adolescents. With the recent US FDA indication of risperidone, aripiprazole, quetiapine and olanzapine for the treatment of bipolar youth, the atypical antipsychotics are rapidly becoming a first-line treatment option. However, these agents are associated with adverse effects such as increased appetite, weight gain and type II diabetes mellitus. Although several evidence-based medications are now available for the treatment of BPD in younger populations, additional studies to evaluate the short- and long-term efficacy and potential for adverse events of these and other medications are needed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate changes in brain activation patterns detected by functional magnetic resonance imaging (FMRI), and the relationship between FMRI activation patterns and results of formal neuropsychological testing, in patients with childhood-onset systemic lupus erythematosus (SLE). METHODS: Ten patients with childhood-onset SLE underwent formal neuropsychological testing and FMRI using 3 paradigms: a continuous performance task (CPT) to evaluate attention, an N-Back task to assess working memory, and verb generation to evaluate language processing. Composite Z maps were generated to summarize the brain activation patterns for each FMRI paradigm in patients with childhood-onset SLE and to compare these patterns with those observed in healthy controls. Between-group comparison Z maps showing differences in activation between childhood-onset SLE patients and controls were generated, using a significance level of P < 0.05 in a general linear model. RESULTS: Compared with the control group, the childhood-onset SLE group showed statistically significant increased activation of brain areas involved in the CPT, N-Back, and verb generation tasks. In contrast, in the absence of active stimulus, e.g., during times of the paradigm control tasks, childhood-onset SLE patients consistently undersuppressed activity in the expected brain areas. Activation in selected cortical areas was found to correlate negatively with results of a subset of individual neuropsychological test scores. CONCLUSION: FMRI abnormalities are present in childhood-onset SLE, manifesting as an imbalance between active and inhibitory responses to an array of stimuli. Differences in brain activation patterns compared with those observed in controls suggest that childhood-onset SLE may be associated with abnormalities in white matter connectivity resulting in neuronal network dysfunction, rather than injury of specific gray matter areas. [ABSTRACT FROM AUTHOR]

Background: Response to pharmacotherapy varies considerably among youths with bipolar disorder (BD) and is poorly predicted by clinical or demographic features. It can take several weeks to determine whether medication for BD is clinically effective. Although neuroimaging biomarkers are promising predictors, few studies examined the predictive value of the brain connectomic topology., Methods: BD-I youth (N = 121) with no prior psychopharmacotherapy were randomized to 6-weeks of double-blind quetiapine or lithium. Structural magnetic resonance imaging (MRI) was performed before medication and at one week after medication initiation. Brain structural connectome was established from the MRI scans, and topological metrics were calculated for each patient. Deep learning-based prediction model was built using baseline and one-week connectome topology to predict medication response at week 6., Results: Both baseline topological metrics and one-week topological changes could predict treatment response with significant accuracy (73.8 % - 86.8 %). A longitudinally joint model combining baseline and one-week topology provided the highest accuracy (91.3 %). The transferability between models for quetiapine and lithium was relatively poor. In addition, predictions for the two drugs were driven by similar baseline but distinct one-week salient topological patterns., Limitations: Independent replication is needed to validate our preliminary findings., Conclusion: Brain structural connectomic topology at baseline and its acute changes within the first week enable accurate BD medication response prediction. The most contributive brain regions differed between prediction models for quetiapine and lithium after one week. These findings provide preliminary evidence for the development of neuroimaging-based biomarkers for guiding therapeutic interventions in youth with BD., Competing Interests: Declaration of competing interest Dr. Strawn has received research support from the National Institutes of Health (NIMH/NIEHS/NICHD) as well as Allergan, Neuronetics, and Otsuka. He has received material support from and provided consultation to Myriad Genetics and receives royalties from the publication of two texts (Springer) and serves as an author for UpToDate and an Associate Editor for Current Psychiatry. He has spoken in CME presentations for Neuroscience Education Institute and CMEology. Finally, Dr. Strawn also has provided consultation to the FDA and Intracellular Therapeutics. Dr. Sweeney consults to VeriSci. Drs. DelBello and Adler are on the lecture bureau for Otsuka, and Dr. Adler is on the lecture bureau for Janssen. Dr. Patino and Dr. DelBello have received research support from Acadia, Allergan, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sunovion and Supernus and Dr. DelBello has provided consultation or advisory board services for Alkermes, Allergan, Assurex, CMEology, Janssen, Johnson and Johnson, Lundbeck, Neuronetics, Otsuka, Pfizer, Sunovion and Supernus. Dr. Adler has received research support from Merck, Forest, and Alkermes, and provided consultation for Janssen. All other authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Little is known about rates of COVID-19 vaccine uptake among youth with bipolar spectrum disorders (BSD). As such, the aim of this study is to assess rates and predictors of COVID-19 vaccine uptake among youth with BSD and their caregivers in the United States., Methods: Youth and their main caregiver were recruited from a large pragmatic study cohort. Youth who were aged 8-22 at the time of this data collection, had a bipolar-spectrum disorder diagnosis, had overweight or obesity, and were treated with a second-generation antipsychotic were invited to participate in an online survey and interview assessing the impact of the COVID-19 pandemic., Results: A total of 453 surveys and 341 interviews were completed 07/2021-05/2022 by youth and their caregivers. Sixty-seven percent of caregivers and 63 % of youth reported receiving the COVID-19 vaccine. Vaccine uptake rates among youth and caregivers were highly correlated. Predictors of vaccine uptake among youth were older age and living in the Northeast Region of the United States. Predictors of caregiver vaccine uptake were male sex, higher annual household income and not having to quarantine due to COVID-19., Limitations: The sample was small and not a full representation of a population with bipolar-spectrum disorders therefore, the results may not be generalizable. The study design and statistical method do not allow for causal inferences to be made., Conclusions: These findings may aid in targeting interventions to maximize COVID-19 and other vaccine uptake in youth with bipolar disorders and their families., Competing Interests: Declaration of competing interest Author Disclosures: Dr. DelBello has received research support from Allergan, Alkermes, Janssen, Johnson and Johnson, Lundbeck, Myriad, NIMH, Otsuka, PCORI, Pfizer, Shire, and Sunovion. She has received consulting/advisory/board/honoraria support from Alkermes, CMEology, Johnson and Johnson, Medscape, Myriad, and Sage. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Car dio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen,Takeda and PCORI. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. Dr. Patino has received research support from NIMH, PCORI, Acadia, Alkermes, Allergan, Janssen, Johnson and Johnson, Lundbeck, Myriad, Otsuka, Pfizer, Sunovion, and Shire. Drs. Klein, Welge, Fornari, and Higdon and Mr. Blom received salary support from PCORI. Ms. Keller and Ms. Wingler declare they have no financial interests. This study was funded by: PCORI Award Number: PCS-1406-19276., (Published by Elsevier B.V.)

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.

Children and adolescents with severe or relapsing major depressive disorder (MDD) may require long-term antidepressant use, but safety and tolerability data on long-term treatment are limited. In a randomized, placebo-controlled trial in children and another in adolescents, vortioxetine and placebo groups showed improvement in MDD symptoms without statistically significant differences between groups. To gain insights on long-term safety and tolerability of vortioxetine in pediatric patients, participants from these two studies were enrolled in two long-term extension studies: 6 months (NCT02871297) followed by another 18 months (NCT03108625). Key safety measures included adverse events (AEs) and Columbia-Suicide Severity Rating Scale (C-SSRS); effectiveness measures included depression symptom severity, cognitive function, and overall functioning. Among the 662 patients in the 6-month extension, 61% experienced a treatment-emergent AE (TEAE), with the most common being nausea (20.8%); 2.1% had a serious AE (SAE), and 6% withdrew because of TEAEs. In the following 18-month extension (n = 94), 51% of patients experienced a TEAE, with the most common being headache (13.8%); no SAEs were reported. Based on the C-SSRS, 94% and 96% of patients reported no suicidal ideation or behavior in the 6- and 18-month studies, respectively. During the extension studies, patients continued to show improvement in depressive symptoms and cognitive and overall functioning, with > 50% of patients in remission at the end of each study, regardless of study treatment in the lead-in trial. Overall, vortioxetine remained well tolerated in pediatric patients with MDD who continued in the long-term extension studies with no observed increased risk in suicidal ideation., (© 2024. The Author(s).)

Recent studies have provided promising evidence that neuroimaging data can predict treatment outcomes for patients with major depressive disorder (MDD). As most of these studies had small sample sizes, a meta-analysis is warranted to identify the most robust findings and imaging modalities, and to compare predictive outcomes obtained in magnetic resonance imaging (MRI) and studies using clinical and demographic features. We conducted a literature search from database inception to July 22, 2023, to identify studies using pretreatment clinical or brain MRI features to predict treatment outcomes in patients with MDD. Two meta-analyses were conducted on clinical and MRI studies, respectively. The meta-regression was employed to explore the effects of covariates and compare the predictive performance between clinical and MRI groups, as well as across MRI modalities and intervention subgroups. Meta-analysis of 13 clinical studies yielded an area under the curve (AUC) of 0.73, while in 44 MRI studies, the AUC was 0.89. MRI studies showed a higher sensitivity than clinical studies (0.78 vs. 0.62, Z = 3.42, P = 0.001). In MRI studies, resting-state functional MRI (rsfMRI) exhibited a higher specificity than task-based fMRI (tbfMRI) (0.79 vs. 0.69, Z = -2.86, P = 0.004). No significant differences in predictive performance were found between structural and functional MRI, nor between different interventions. Of note, predictive MRI features for treatment outcomes in studies using antidepressants were predominantly located in the limbic and default mode networks, while studies of electroconvulsive therapy (ECT) were restricted mainly to the limbic network. Our findings suggest a promise for pretreatment brain MRI features to predict MDD treatment outcomes, outperforming clinical features. While tasks in tbfMRI studies differed, those studies overall had less predictive utility than rsfMRI data. Overlapping but distinct network-level measures predicted antidepressants and ECT outcomes. Future studies are needed to predict outcomes using multiple MRI features, and to clarify whether imaging features predict outcomes generally or differ depending on treatments., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To compare second-generation antipsychotics (SGAs) and mood stabilizers (MSs) in youth with a bipolar disorder type I (BD-I) manic/mixed episode., Method: A systematic PubMed/Embase/PsycInfo literature search until December 31, 2023, for randomized trials of SGAs or MSs in patients ≤18 years of age with BD-I manic/mixed episode was conducted. The study included a network meta-analysis comparing treatments regarding mania symptoms and mania response (co-primary outcomes), and secondary efficacy and tolerability outcomes., Results: Eighteen studies (n = 2844, mean age = 11.74, female participants = 48.0%, mean study duration = 5.4 weeks) comparing 6 SGAs (aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and ziprasidone) and 4 MSs (lithium, oxcarbazepine, topiramate, and valproate) were meta-analyzed. All 6 SGAs outperformed placebo in reducing manic symptomatology, including risperidone (standardized mean difference [SMD] = -1.18, 95% CI = -0.92, -1.45, Confidence in Network Meta-Analysis [CINeMA] = moderate confidence), olanzapine (SMD = -0.77, 95% CI = -0.36, -1.18, low confidence), aripiprazole (SMD = -0.67, 95% CI = -0.33, -1.01, moderate confidence), quetiapine (SMD = -0.60, 95% CI = -0.32, -0.87, high confidence), asenapine (SMD = -0.54, 95% CI = -0.19, -0.89, moderate confidence), and ziprasidone (SMD = -0.43, 95% CI = -0.17, 0.70, low confidence), whereas no mood stabilizer outperformed placebo. Concerning mania response, risperidone (Risk ratio [RR] = 2.58, 95% CI = 1.88, 3.54, low confidence), olanzapine (RR = 2.42, 95% CI = 1.33, 3.54, very low confidence), aripiprazole (RR = 2.05, 95% CI = 1.44, 2.92, low confidence), quetiapine (RR = 1.89, 95% CI = 1.45n 2.47, moderate confidence), asenapine (RR = 1.81, 95% CI = 1.28, 2.55, very low confidence) and lithium (RR = 1.35, 95% CI = 1.00, 1.83, p = .049, very low confidence) outperformed placebo, without superiority of other MSs vs placebo. Individually, risperidone was more efficacious in reducing manic symptomatology than all other comparators, except olanzapine and topiramate, yet with low/very low confidence, and was associated with increased prolactin and glucose. Pooled together, SGAs outperformed both placebo and MSs for mania symptom reduction (SMD = -0.68, 95% CI = -0.86, -0.51 and SMD = -0.61, 95% CI = -0.82, -0.40, moderate confidence), and mania response (RR = 1.85, 95% CI = 1.53, 2.24 and RR = 1.65, 95% CI = 1.33, 2.04, moderate confidence) without differences between MSs and placebo. There were no significant treatment-placebo differences for all-cause discontinuation, whereas lithium, ziprasidone, and oxcarbazepine were associated with more adverse event-related drop-outs than placebo. Most SGAs were associated with more sedation, weight gain, and metabolic issues vs placebo and MSs., Conclusion: SGAs were more efficacious than placebo and MSs in treating acute mania symptoms, however, their use must be carefully weighed against important side effects., (Copyright © 2024 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 (E local , p = .022) and clustering coefficient (C p , p = .029) and nodal metrics of the right superior frontal gyrus (SFG) (E local : p < .001; C p : 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., (© 2024 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

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., Plain Language Summary: Pediatric bipolar disorder (BD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur, with overlapping changes in emotional and cognitive functioning. This meta-analysis summarizes findings from 10 articles on BD and 32 articles on ADHD to identify similarities and differences in brain structure between youth with BD and youth with ADHD. The authors found that both disorders share decreased gray matter volumes in the right insula and anterior cingulate cortex, which play important roles in emotion processing and attention, respectively. Youth with BD had decreased gray matter volume in the right inferior frontal gyrus, left orbitofrontal gyrus, and left hippocampus, while youth with ADHD had decreased volumes in the left precentral gyrus, left inferior frontal gyrus, and right superior frontal gyrus., 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., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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., (© 2024. The Author(s).)

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.R.P receives research funding from NIH, PCORI, Abbvie, Allergan, Janssen, Johnson and Johnson, Lundbeck, Lilly, Otsuka, Pfizer, and Sunovion. M.P.D. receives research support from NIH, PCORI, Acadia, Alkermes, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sage, Sunovion, and Vanda. She is also a consultant or on the advisory board for Alkermes, Allergan, Janssen, Johnson and Johnson, Lundbeck, Merck, Myriad, and Sage, R.K.M. has received research support from Martek Biosciences Inc, Royal DSM Nutritional Products, LLC, Inflammation Research Foundation, Ortho-McNeil Janssen, AstraZeneca, Eli Lilly, NARSAD, and NIH, and previously served on the scientific advisory board of the Inflammation Research Foundation. The remaining authors do not have disclosures.

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 ., (© 2023. The Author(s).)

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., Competing Interests: Declaration of competing interest Dr. DelBello have received research support from NIMH, PCORI, Acadia, Alkermes, Allergan, Janssen, Johnson and Johnson, Lundbeck, Myriad, Otsuka, Pfizer, Sunovion and Shire. Dr. DelBello has provided consultation or advisory board services for Alkermes, Allergan, CMEology, Janssen, Johnson and Johnson, Lundbeck, Medscape, Myriad, Pfizer, Sage, Sunovion. Dr. Sweeney consults to VeraSci. Other authors report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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 (AUC 0-24 ; p  = 0.025), trough concentrations (C trough ; p  = 0.013), and elimination half-lives (t 1/2 ; 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, AUC 0-24 , 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.

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., (© 2023. The Author(s).)

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., Competing Interests: Declaration of competing interest Luis R. Patino has received research support from Eli Lilly, Pfizer, Otsuka, Novartis, Lundbeck, Sunovion, AbbVie, Martek and Shire. Caleb M. Adler has received research support from National Institute of Mental Health, Johnson and Johnson, Merck, Forest, Otsuka, Purdue, Takeda, Pfizer, Shire, Sunovion, and SyneuRx; has received consulting/honoraria from Sunovion. Jeffry A. Welge has received research support from National Institute of Mental Health. Melissa P DelBello has received research support from National Institute of Mental Health, National Institute of Child Health and Human Development, Amylin, Eli Lilly, Pfizer, Otsuka, GlaxoSmithKline, Merck, Martek, Novartis, Lundbeck, Pfizer, Sunovion, and Shire; has received consulting/advisory board/honoraria/travel support from Pfizer, Lundbeck, Sunovian, Supernus, and Otsuka. The other authors have no disclosures. The authors declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

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., Competing Interests: Declaration of competing interest Dr. Strawn has received research support from the National Institutes of Health (NIMH/NIEHS/NICHD) as well as Allergan, Neuronetics and Otsuka. He has received material support from and provided consultation to Myriad Genetics and receives royalties from the publication of two texts (Springer) and serves as an author for UpToDate and an Associate Editor for Current Psychiatry. He has spoken in CME presentations for Neuroscience Education Institute and CMEology. Dr. Strawn also has provided consultation to the FDA and Intracellular Therapeutics. Dr. Sweeney consults to VeriSci. Dr. Patino and Dr. DelBello have received research support from NIMH, PCORI, Acadia, Alkermes, Allergan, Janssen, Johnson and Johnson, Lundbeck, Myriad, Otsuka, Pfizer, Sunovion and Shire. Dr. DelBello has provided consultation or advisory board services for Alkermes, Allergan, CMEology, Janssen, Johnson and Johnson, Lundbeck, Medscape, Myriad, Pfizer, Sage, and Sunovion. All other authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

Competing Interests: Dr DelBello has received research support from NIMH, PCORI, Acadia, Alkermes, Allergan, Janssen, Johnson and Johnson, Lundbeck, Myriad, Otsuka, Pfizer, Sunovion, and Shire, and has provided consultation or advisory board services for Alkermes, Allergan, CMEology, Janssen, Johnson and Johnson, Lundbeck, Medscape, Myriad, Pfizer, Sage, and Sunovion. All other authors declare that they have no competing interests.

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.

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., Competing Interests: Competing interests: Rodrigo Patino receives research funding from the National Institutes of Health (NIH), the Patient-Centered Outcomes Research Institute (PCORI), Abbvie, Allergan, Janssen, Johnson & Johnson, Lundbeck, Lilly, Otsuka, Pfizer and Sunovion. Melissa DelBello receives research support from the NIH, PCORI, Acadia, Alkermes, Allergan, Janssen, Johnson & Johnson, Lundbeck, Otsuka, Pfizer, Sage, Sunovion and Vanda. She is also a consultant, on the advisory board or has received honoraria for speaking for Alkermes, Allergan, Assurex, CMEology, Janssen, Johnson & Johnson, Lundbeck, Myriad, Neuronetics, Otsuka, Pfizer, Sage, Sunovion and Supernus. She has received travel support from the American Academy of Child and Adolescent Psychiatry. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

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.

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., Competing Interests: Declaration of competing interest Dr. Sweeney consults to VeriSci. Dr. McNamara has received research support from Martek Biosciences Inc., Royal DSM Nutritional Products, LLC, Inflammation Research Foundation, Ortho-McNeil Janssen, AstraZeneca, Eli Lilly, NARSAD, and national institutes of health (NIH), and previously served on the scientific advisory board of the Inflammation Research Foundation. Dr. Patino and Dr. DelBello have received research support from NIMH, PCORI, Acadia, Alkermes, Allergan, Janssen, Johnson and Johnson, Lundbeck, Myriad, Otsuka, Pfizer, Sunovion and Shire and Dr. DelBello has provided consultation or advisory board services for Alkermes, Allergan, CMEology, Janssen, Johnson and Johnson, Lundbeck, Medscape, Myriad, Pfizer, Sage, Sunovion. All other authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Identification of treatment-specific predictors of drug therapies for bipolar disorder (BD) is important because only about half of individuals respond to any specific medication. However, medication response in pediatric BD is variable and not well predicted by clinical characteristics., Methods: A total of 121 youth with early course BD (acute manic/mixed episode) were prospectively recruited and randomized to 6 weeks of double-blind treatment with quetiapine ( n = 71) or lithium ( n = 50). Participants completed structural magnetic resonance imaging (MRI) at baseline before treatment and 1 week after treatment initiation, and brain morphometric features were extracted for each individual based on MRI scans. Positive antimanic treatment response at week 6 was defined as an over 50% reduction of Young Mania Rating Scale scores from baseline. Two-stage deep learning prediction model was established to distinguish responders and non-responders based on different feature sets., Results: Pre-treatment morphometry and morphometric changes occurring during the first week can both independently predict treatment outcome of quetiapine and lithium with balanced accuracy over 75% (all p < 0.05). Combining brain morphometry at baseline and week 1 allows prediction with the highest balanced accuracy (quetiapine: 83.2% and lithium: 83.5%). Predictions in the quetiapine and lithium group were found to be driven by different morphometric patterns., Conclusions: These findings demonstrate that pre-treatment morphometric measures and acute brain morphometric changes can serve as medication response predictors in pediatric BD. Brain morphometric features may provide promising biomarkers for developing biologically-informed treatment outcome prediction and patient stratification tools for BD treatment development.

Background: In order to identify biomarkers of prodromal mood disorders, we examined functional brain activation in children and adolescent at familial risk for bipolar disorder., Methods: Offspring of parents with bipolar I disorder (at-risk youth; N = 115, mean ± SD age: 13.6 ± 2.7; 54 % girls) and group-matched offspring of healthy parents (healthy controls; N = 58, mean ± SD age: 14.2 ± 3.0; 53 % girls) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional and neutral distracters. At baseline, at-risk youth had no history of mood episodes or psychotic disorders. Subjects were followed longitudinally until developing their first mood episode or being lost to follow-up. Standard event-related region-of-interest (ROI) analyses were performed to compare brain activation at baseline between groups and in survival analyses., Results: At baseline, at-risk youth exhibited reduced activation to emotional distracters in the right ventrolateral prefrontal cortex (VLPFC) (p = 0.04). Activation was not significantly altered in additional ROIs, including left VLPFC, bilateral amygdala, caudate, or putamen. In those at-risk youth who developed their first mood episode during follow-up (n = 17), baseline increased activation in right VLPFC, right caudate, and right putamen activation predicted the development of a mood episode., Limitations: Sample size of converters, loss to follow-up, and number of statistical comparisons., Conclusions: We found preliminary evidence that a reduced activation in right VLPFC might be a marker of risk for or resilience to mood disorders in at-risk youth. Conversely, an increased activation in the right VLPFC, caudate, and putamen might indicate an increased risk for the later development of their first mood episode., Competing Interests: Conflict of interest Dr. Nery's spouse is an employee of Eli Lilly & Co. Dr. Patino has received research support from Acadia, Allergan, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sunovion and Supernus. Dr. Strawn has received research support from Edgemont, Shire, AbbVie, Otsuka, the Yung Family Foundation and the National Institutes of Health (NICHD, NIMH and NIEHS). He receives royalties from Springer Publishing for two texts and has received material support from Myriad genetics and honoraria from CMEology and Neuroscience Educational Institute. He provided consultation to the U.S. Food and Drug Administration as a Special Government Employee and consulted to Intracellular Therapeutics. Dr. Adler has spoken for Otsuka and Janssen. He has received research support from Merck, Forest, and Alkermes, and provided consultation for Janssen. Dr. Strakowski chairs Data Safety and Monitoring Boards for Sunovion and has grant funding (through the University of Texas) from Janssen. Dr. DelBello is on the lecture bureau for Otsuka; has received research support from Acadia, Allergan, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sunovion and Supernus; and has provided consultation or advisory board services for Alkermes, Allergan, Assurex, CMEology, Janssen, Johnson and Johnson, Lundbeck, Neuronetics, Otsuka, Pfizer, Sunovion and Supernus. The remaining authors reported no conflicts of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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/m 2 and 6.9 kg, respectively) compared with the topiramate (0.99 kg/m 2 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.

Objective: Youth with bipolar spectrum disorders may experience improved mood stability when treated with second generation antipsychotics (SGAs); however, SGAs are associated with unhealthy weight gain and adverse metabolic effects. Metformin may mitigate this weight gain but is rarely prescribed by community mental health practitioners. Its long-term efficacy, safety, and acceptability in usual care, and factors that might moderate these effects, are unknown. The Metformin for Overweight and Obese Children and Adolescents with Bipolar Spectrum Disorders Treated with Second Generation Antipsychotics (MOBILITY) trial aims to fill these gaps. We present the design and analytic plan of this multi-site, open-label, randomized trial., Method: Patients will be randomized to either metformin plus brief healthy diet and exercise education (MET+LIFE) or to LIFE alone. Up to 1637 patients will be followed for up to 2 years at 64 community and academic mental health treatment facilities. Patients may switch between treatment arms during follow-up., Discussion: Pragmatic trials place few burdens and constraints on participating patients, families, and clinicians. This flexibility will allow MOBILITY to obtain long-term follow-up in a large, diverse sample, but produces analytic challenges. MOBILITY's flexible design has the potential to generate several novel methodological issues that we address. Some patients randomized to LIFE will fail to lose weight, and therefore metformin initiation contrary to the randomization may result from weight gain. Adherence to medications, SGAs, and lifestyle recommendations as well as satiety are potential time-varying mediators, moderators, or confounders of the effect of metformin. Adherence to metformin and SGAs may be positively correlated; therefore, a beneficial effect of metformin on weight could be obscured by the known SGA adverse effect on body weight. However, such correlation could facilitate causal inference by providing indirect information about unknown metformin adherence among patients who did not receive it. A perceived protective effect of metformin could potentially lead to risk compensation, with poorer diet and activity among those receiving metformin. We discuss limitations of traditional statistical approaches and summarize an advanced methodology ("Targeted Learning") that addresses some of these limitations., Clinical Trial Registration Information: Metformin for Overweight & OBese ChILdren and Adolescents With BDS Treated With SGAs (MOBILITY); https://clinicaltrials.gov/; NCT02515773., (© 2023 The Authors.)

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., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Bipolar disorder (BD) is a familial disorder with high heritability. Genetic factors have been linked to the pathogenesis of BD. Relatives of probands with BD who are at familial risk can exhibit brain abnormalities prior to illness onset. Given its involvement in prefrontal cognitive control and in frontolimbic circuitry that regulates emotional reactivity, the inferior frontal gyrus (IFG) has been a focus of research in studies of BD-related pathology and BD-risk mechanism. In this review, we discuss multimodal neuroimaging findings of the IFG based on studies comparing at-risk relatives and low-risk controls. Review of these studies in at-risk cases suggests the presence of both risk and resilience markers related to the IFG. At-risk individuals exhibited larger gray matter volume and increased functional activities in IFG compared with low-risk controls, which might result from an adaptive brain compensation to support emotion regulation as an aspect of psychological resilience. Functional connectivity between IFG and downstream limbic or striatal areas was typically decreased in at-risk individuals relative to controls, which could contribute to risk-related problems of cognitive and emotional control. Large-scale and longitudinal investigations on at-risk individuals will further elucidate the role of IFG and other brain regions in relation to familial risk for BD, and together guide identification of at-risk individuals for primary prevention., Competing Interests: Dr. Sweeney consults to VeriSci. Dr. Sweeney, being an associate editor of Psychoradiology, was not involved in the review and the decision on the manuscript. Dr. DelBello have received research support from NIMH, PCORI, Acadia, Alkermes, Allergan, Janssen, Johnson and Johnson, Lundbeck, Myriad, Otsuka, Pfizer, Sunovion and Shire and Dr. DelBello has provided consultation or advisory board services for Alkermes, Allergan, CMEology, Janssen, Johnson and Johnson, Lundbeck, Medscape, Myriad, Pfizer, Sage, Sunovion. All other authors declare that they have no competing interests., (© The Author(s) 2022. Published by Oxford University Press on behalf of West China School of Medicine/West China Hospital (WCSM/WCH) of Sichuan University.)

Psychiatry, as a field, lacks objective markers for diagnosis, progression, treatment planning, and prognosis, in part due to difficulties studying the brain in vivo , and diagnoses are based on self-reported symptoms and observation of patient behavior and cognition. Rapid advances in brain imaging techniques allow clinical investigators to noninvasively quantify brain features at the structural, functional, and molecular levels. Psychoradiology is an emerging discipline at the intersection of psychiatry and radiology. Psychoradiology applies medical imaging technologies to psychiatry and promises not only to improve insight into structural and functional brain abnormalities in patients with psychiatric disorders but also to have potential clinical utility. We searched for representative studies related to recent advances in psychoradiology through May 1, 2022, and conducted a selective review of 165 references, including 75 research articles. We summarize the novel dynamic imaging processing methods to model brain networks and present imaging genetics studies that reveal the relationship between various neuroimaging endophenotypes and genetic markers in psychiatric disorders. Furthermore, we survey recent advances in psychoradiology, with a focus on future psychiatric diagnostic approaches with dimensional analysis and a shift from group-level to individualized analysis. Finally, we examine the application of machine learning in psychoradiology studies and the potential of a novel option for brain stimulation treatment based on psychoradiological findings in precision medicine. Here, we provide a summary of recent advances in psychoradiology research, and we hope this review will help guide the practice of psychoradiology in the scientific and clinical fields., (Creative Commons Attribution license.)

Bipolar disorder presents on a spectrum, with bipolar depression on one end and bipolar I on the other and a host of other presentations in between. In addition to its many permutations and the difficulty of differentiating between diagnoses, comorbidities, incorrect treatment, and low self-report contribute to delayed diagnoses and inappropriate or delayed treatment. Once a diagnosis is reached, the latest evidence of the safety and efficacy profiles of existing and emerging treatments adds to the complexity when developing treatment strategies for patients with bipolar disorder. As guidelines are updated and new treatments become available, developing individualized treatment regimens is key and collaboration between clinician and patient and family is critical in optimizing patient outcomes. New treatment options can reduce some of the side effect burdens associated with treating bipolar disorder, and clinicians should use measurement-based care to assess whether treatment changes are necessary, which requires engaging with the patient to monitor efficacy and manage side effects. It is important to ensure that the patient and family understand the information to foster informed decision making and create a better therapeutic alliance. Involving patients in designing their own treatment strategies according to their tolerability criteria can help combat the 90% nonadherence rate, and ultimately lead to better patient care., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

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 ( 1 H 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.

Disrupted topological organization of brain functional networks has been widely reported in bipolar disorder. However, the potential clinical implications of structural connectome abnormalities have not been systematically investigated. The present study included 109 unmedicated subjects with acute mania who were assigned to 8 weeks of treatment with quetiapine or lithium and 60 healthy controls. High resolution 3D-T1 weighted magnetic resonance images (MRI) were collected from both groups at baseline, week 1 and week 8. Brain networks were constructed based on the similarity of morphological features across brain regions and analyzed using graph theory approaches. At baseline, individuals with bipolar disorder illness showed significantly lower clustering coefficient (C p ) (p = 0.012) and normalized characteristic path length (λ) (p = 0.004) compared to healthy individuals, as well as differences in nodal centralities across multiple brain regions. No baseline or post-treatment differences were identified between drug treatment conditions, so change after treatment were considered in the combined treatment groups. Relative to healthy individuals, differences in C p , λ and cingulate gyrus nodal centrality were significantly reduced with treatment; changes in these parameters correlated with changes in Young Mania Rating Scale scores. Baseline structural connectome matrices significantly differentiated responder and non-responder groups at 8 weeks with 74% accuracy. Global and nodal network alterations evident at baseline were normalized with treatment and these changes associated with symptomatic improvement. Further, baseline structural connectome matrices predicted treatment response. These findings suggest that structural connectome abnormalities are clinically significant and may be useful for predicting clinical outcome of treatment and tracking drug effects on brain anatomy in bipolar disorder., Clinical Trials Registration: Name: Functional and Neurochemical Brain Changes in First-episode Bipolar Mania Following Successful Treatment with Lithium or Quetiapine. URL: https://clinicaltrials.gov/ ., Registration Number: NCT00609193. Name: Neurofunctional and Neurochemical Markers of Treatment Response in Bipolar Disorder. URL: https://clinicaltrials.gov/ ., Registration Number: NCT00608075., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Objective: To evaluate the efficacy and safety of vortioxetine in adolescents with major depressive disorder (MDD)., Method: After 4 weeks of single-blind lead-in treatment with a Brief Psychosocial Intervention (BPI) plus placebo, patients (aged 12-17 years) with MDD (DSM-5) who did not meet response criteria (Children's Depression Rating Scale-Revised [CDRS-R]; total score ≥40 plus <40% reduction and a Parent Global Assessment score >2) were randomized 1:1:1:1 to 8 weeks of BPI plus double-blind treatment with vortioxetine 10 mg, vortioxetine 20 mg, fluoxetine 20 mg, or placebo. The primary endpoint was change from randomization in CDRS-R total score at week 8; the primary comparison was the average effect of 2 vortioxetine doses vs placebo., Results: Of 784 patients enrolled in the lead-in, 616 were randomized. At week 8, the mean change in CDRS-R total score averaged for vortioxetine doses was -18.01 (SE = 0.98) and the mean difference vs placebo was 0.21 (P = .878; not significant). For fluoxetine, the mean change in CDRS-R total score was -21.95 and the mean difference vs placebo was -3.73 (P = .015). Treatment-emergent adverse events occurring in ≥5% of patients in either vortioxetine arm and at least twice more frequently than placebo were nausea, headache, vomiting, and dizziness., Conclusion: Patients in all groups showed reduction in CDRS-R scores by the end of the study, with no difference between combined doses of vortioxetine and placebo. The primary endpoint was not met, thereby rendering the study negative. The overall favorable safety profile of vortioxetine in an adolescent patient population was consistent with that seen in adults., Clinical Trial Registration Information: Active Reference (Fluoxetine) Fixed-Dose Study of Vortioxetine in Paediatric Patients Aged 12 to 17 Years With Major Depressive Disorder (MDD); http://clinicaltrials.gov; NCT02709746., (Copyright © 2022 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)