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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.

Adjunctive l-methylfolate is commonly prescribed for children and adolescents with treatment-resistant mood disorders; however, the relationship between l-methylfolate augmentation across methylenetetrahydrofolate reductase (MTHFR) genotypes in youths with depressive symptoms is unclear.We retrospectively examined the electronic health records of patients (N = 412) with depressive symptoms associated with unipolar depressive disorders and their MTHFR C677T genotypes from 2013 to 2019. Patients were ≤18 years of age at the time of MTHFR pharmacogenetic testing. Treatment response was assessed with Clinical Global Impression-Improvement (CGI-I) score reported in the medical record.Patients with an MTHFR C677T C/T or T/T genotype were more likely to be prescribed l-methylfolate when the clinician knew their MTHFR genotype (p 0.0001, OR: 15.1, 95 % CI: [5.1, 44.2]), but not when the clinician did not know their genotype (p = 0.4, OR: 2.1, 95 % CI: [0.4, 11.4]). Change in baseline and endpoint CGI-I scores between patients with an MTHFR C677T variant who were prescribed and not prescribed l-methylfolate did not significantly differ (p = 0.39). Response rate was not associated with l-methylfolate prescription (p = 0.17) or l-methylfolate dose (p = 0.69).This was a retrospective study, which yielded a heterogeneous patient population and limited data availability (e.g., adherence). Patients are severely ill and may have a refractory illness that limits response to adjunctive l-methylfolate.Clinicians prescribe l-methylfolate to children and adolescents with depressive symptoms associated with unipolar depressive disorders who have an MTHFR C677T variant, although augmentation may not be associated with treatment response, regardless of MTHFR genotype or dose.

Amygdala-ventrolateral prefrontal cortex (VLPFC) circuitry is disrupted in pediatric anxiety disorders, yet how selective serotonin reuptake inhibitors (SSRIs) affect this circuitry is unknown. We examined the impact of the SSRI escitalopram on functional connectivity (FC) within this circuit, and whether early FC changes predicted treatment response in adolescents with generalized anxiety disorder (GAD).Resting-state functional magnetic resonance (MR) images were acquired before and after 2 weeks of treatment in 41 adolescents with GAD (12-17 years of age) who received double-blind escitalopram or placebo for 8 weeks. Change in amygdala-based whole-brain FC and anxiety severity were analyzed.Controlling for age, sex, and pretreatment anxiety, escitalopram increased amygdala-VLPFC connectivity compared to placebo (F = 17.79, p = .002 FWE-corrected). This early FC change predicted 76.7% of the variability in improvement trajectory in patients who received escitalopram (p .001) but not placebo (p = .169); the predictive power of early amygdala-VLPFC FC change significantly differed between placebo and escitalopram (p = .013). Furthermore, this FC change predicted improvement better than baseline FC or clinical/demographic characteristics. Exploratory analyses of amygdala subfields' FC revealed connectivity of left basolateral amygdala (BLA) -VLPFC (F = 19.64, p .001 FWE-corrected) and superficial amygdala-posterior cingulate cortex (F = 22.92, p = .001 FWE-corrected) were also increased by escitalopram, but only BLA-VLPFC FC predicted improvement in anxiety over 8 weeks of treatment.In adolescents with GAD, escitalopram increased amygdala-prefrontal connectivity within the first 2 weeks of treatment, and the magnitude of this change predicted subsequent clinical improvement. Early normalization of amygdala-VLPFC circuitry might represent a useful tool for identifying future treatment responders as well as a promising biomarker for drug development.Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety; https://www.clinicaltrials.gov/; NCT02818751.

Objectives: To evaluate long-term safety and effectiveness of lurasidone in children and adolescents with bipolar depression. Methods: Participants, ages 10–17 years, with bipolar depression, who completed 6 weeks of double-blind (DB) treatment with lurasidone or placebo were enrolled in a 2-year, open-label (OL) extension study of lurasidone (20–80 mg/d). The primary effectiveness measure was the Children's Depression Rating Scale, Revised (CDRS-R). Results: A total of 306 participants entered the 2-year extension study; 195 (63.7%) completed 52 weeks, and 168 (54.9%) completed 104 weeks of treatment. For all participants entering the extension study, mean change in CDRS from OL baseline was −13.4 at week 52, and −16.4 at week 104 (−11.3 at last observation carried forward [LOCF]-endpoint). Overall, 31 participants (10.1%) discontinued due to an adverse event (AE); the three most common AEs were headache (23.9%), nausea (16.4%), and somnolence (9.8%). OL treatment with lurasidone was associated with few effects on metabolic parameters or prolactin. Mean change from DB baseline in weight was +4.25 kg at week 52 (vs. an expected weight gain of +3.76 kg), and +6.75 kg at week 104 (vs. an expected weight gain of +6.67 kg), based on the sex- and age-matched United States Center for Disease Control normative data. Conclusions: For youth with bipolar depression, up to 2 years of treatment with lurasidone was generally well tolerated, safe, and effective with relatively low rates of discontinuation due to AEs, minimal effects on weight, metabolic parameters or prolactin, and continued improvement in depressive symptoms. Clinical Trial Registration number: NCT01914393.

INTRODUCTION: Mood disorders are associated with fronto-limbic structural and functional abnormalities and deficits in omega-3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Emerging evidence also suggests that n-3 PUFA, which are enriched in fish oil, promote cortical plasticity and connectivity. The present study performed a graph-based connectome analysis to investigate the role of n-3 PUFA in emotion-related network organization in medication-free depressed adolescent bipolar offspring. METHODS: At baseline patients (n=53) were compared with healthy controls (n=53), and patients were then randomized to 12-week double-blind treatment with placebo or fish oil. At baseline and endpoint, erythrocyte EPA+DHA levels were measured and fMRI scans (4 Tesla) were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Graph-based analysis was used to characterize topological properties of large-scale brain network organization. RESULTS: Compared with healthy controls, patients exhibited lower erythrocyte EPA+DHA levels (p=0.0001), lower network clustering coefficients (p=0.029), global efficiency (p=0.042), and lower node centrality and connectivity strengths in frontal-limbic regions (p

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.

The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood.

OBJECTIVE To evaluate the effects of fish oil (FO), a source of the omega-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on emotion-generated corticolimbic functional connectivity in depressed youth at high risk for developing bipolar I disorder. METHODS Thirty-nine antidepressant-free youth with a current depressive disorder diagnosis and a biological parent with bipolar I disorder were randomized to 12-week double-blind treatment with FO or placebo. At baseline and endpoint, fMRI (4 Tesla) scans were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Seed-to-voxel functional connectivity analyses were performed using bilateral orbitofrontal cortex (OFC) and amygdala (AMY) seeds. Measures of depression, mania, global symptom severity, and erythrocyte fatty acids were obtained. RESULTS Erythrocyte EPA+DHA composition increased significantly in the FO group (+47%, p ≤ 0.0001) but not in the placebo group (-10%, p = 0.11). Significant group by time interactions were found for functional connectivity between the left OFC and the left superior temporal gyrus (STG) and between the right AMY and right inferior temporal gyrus (ITG). OFC-STG connectivity increased in the FO group (p = 0.0001) and decreased in the placebo group (p = 0.0019), and AMY-ITG connectivity decreased in the FO group (p = 0.0014) and increased in the placebo group (p

The goals of the current study were to determine whether topological organization of brain structural networks is altered in youth with bipolar disorder, whether such alterations predict treatment outcomes, and whether they are normalized by treatment. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. High-resolution MRI images were collected from children and adolescents with bipolar disorder who were experiencing a mixed or manic episode (n = 100) and healthy youth (n = 63). Brain networks were constructed based on the similarity of morphological features across regions and analyzed using graph theory approaches. We tested for pretreatment anatomical differences between bipolar and healthy youth and for changes in neuroanatomic network metrics following treatment in the youth with bipolar disorder. Youth with bipolar disorder showed significantly increased clustering coefficient (Cp) (p = 0.009) and characteristic path length (Lp) (p = 0.04) at baseline, and altered nodal centralities in insula, inferior frontal gyrus, and supplementary motor area. Cp, Lp, and nodal centrality of the insula exhibited normalization in patients following treatment. Changes in these neuroanatomic parameters were correlated with improvement in manic symptoms but did not differ between the two drug therapies. Baseline structural network matrices significantly differentiated medication responders and non-responders with 80% accuracy. These findings demonstrate that both global and nodal structural network features are altered in early course bipolar disorder, and that pretreatment alterations in neuroanatomic features predicted treatment outcome and were reduced by treatment. Similar connectome normalization with lithium and quetiapine suggests that the connectome changes are a downstream effect of both therapies that is related to their clinical efficacy.

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.

Second-generation antipsychotics (SGAs) increase risk for insulin resistance and metabolic syndrome. Less is known about the risk of nonalcoholic fatty liver disease (NAFLD) in youth treated with SGAs. MOBILITY is a large, multi-center, pragmatic study designed to assess the effect of metformin added to lifestyle instruction compared to lifestyle instruction alone on weight gain and metabolic parameters in youth with overweight and obesity (ages 8-19) and bipolar-spectrum disorders receiving SGAs. We examined baseline ALT as a marker for NAFLD in 840 youth in the study (78% with obesity; 46% female; 68% white; 17% black; 11% Hispanic) . Overall, 44% of subjects had mild ALT elevation (ALT>22 females; ALT>25 males) , and 10% had significantly elevated ALT≥ 45 (2× ULN) . Male sex (p 1 year of exposure) . There was a trend towards an association between prediabetes and significant ALT elevation (2× ULN; p=0.06) ; however, glucose was not associated with ALT elevation overall. Although we had no imaging or biopsy data in these patients, our study demonstrates that a clinically relevant percentage of youth with overweight and obesity treated with SGAs have elevated ALT suggestive of NAFLD; in fact, the prevalence of elevated ALT is higher than expected with obesity alone. Given that NAFLD is the most common liver disease now in youth and can progress to cirrhosis and liver failure, our findings suggest that pediatric psychiatrists who treat these patients must screen for NAFLD with ALT and refer patients for further evaluation and management as needed. Disclosure N.A.Crimmins: None. M.Mouzaki: None. M.P.Delbello: Board Member; Sage Pharmaceuticals, Consultant; Alkermes, Sunovion Pharmaceuticals Inc., Research Support; Alkermes, Johnson & Johnson, Lundbeck, Shire plc., Speaker's Bureau; Sunovion Pharmaceuticals Inc. C.Correll: Consultant; Alkermes, Janssen Pharmaceuticals, Inc., Lundbeck, Medscape, Mylan N.V., Neurocrine Biosciences, Inc., Otsuka America Pharmaceutical, Inc., Sunovion Pharmaceuticals Inc., Takeda Pharmaceutical Company Limited, Teva Pharmaceutical Industries Ltd. J.Welge: None. Funding Mobility: Improving Patient-Centered Outcomes Among Overweight and Obese Youth with Bipolar Spectrum Disorders Treated with Second-Generation Antipsychotics. [PICORI (Delbello) ].

Youth who have parents with bipolar I disorder appear to be most at risk for developing early-onset bipolar symptoms. The current study examined how one group counseling intervention, mindfulness-based cognitive therapy–child, may improve emotional awareness and influence the family environment over a 12-week treatment interval for a group of youth aged 11–16. Improving emotional awareness and the family environment may help slow symptom expression for youth at risk for developing bipolar I disorder. Changes in depressive symptoms for each participant were assessed using a single-case research design method to help better understand the mechanisms of change throughout treatment. While results indicate changes in emotional awareness, the majority were statistically nonsignificant. Notably, participants’ perception of control significantly changed, and participants reported significant positive changes in family environment. Some participants experienced decreases in depression over the course of the intervention.

Objectives: Placebo response is one of the most significant barriers to detecting treatment effects in pediatric (and adult) clinical trials focusing on affective and anxiety disorders. We sought to identify neurofunctional predictors of placebo response in adolescents with generalized anxiety disorder (GAD) by examining dynamic and static functional brain connectivity. Methods: Before randomization to blinded placebo, adolescents, aged 12–17 years, with GAD (N = 25) underwent resting state functional magnetic resonance imaging. Whole brain voxelwise correlation analyses were used to determine the relationship between change in anxiety symptoms from baseline to week 8 and seed-based dynamic and static functional connectivity maps of regions in the salience and ventral attention networks (amygdala, dorsal anterior cingulate cortex [dACC], and ventrolateral prefrontal cortex [VLPFC]). Results: Greater dynamic functional connectivity variability in amygdala, dACC, VLPFC, and regions within salience, default mode, and frontoparietal networks was associated with greater placebo response. Lower static functional connectivity between amygdala and dorsolateral prefrontal cortex, amygdala and medial prefrontal cortex, dACC and posterior cingulate cortex and greater static functional connectivity between VLPFC and inferior parietal lobule were associated with greater placebo response. Conclusion: Placebo response is associated with a distinct dynamic and static connectivity fingerprint characterized by “variable” dynamic but “weak” static connectivity in the salience, default mode, frontoparietal, and ventral attention networks. These data provide granular evidence of how circuit-based biotypes mechanistically relate to placebo response. Finding biosignatures that predict placebo response is critically important in clinical psychopharmacology and to improve our ability to detect medication-placebo differences in clinical trials.

OBJECTIVES: Altered activity in the ventrolateral prefrontal and anterior cingulate cortices, as well as subcortical and amygdala projection sites, were previously reported during a first manic episode in youth with bipolar disorder and observed to be associated with treatment response. To extend these findings, we investigated functional connectivity among these regions in first-episode manic participants who remitted after eight weeks of treatment compared to those that did not. METHODS: Forty-two participants with bipolar disorder (60% female) during their first manic episode were recruited and received eight weeks of treatment. Twenty-one remitted following treatment. Participants completed fMRI scans, at baseline and following eight weeks of treatment, while performing a continuous performance task with emotional and neutral distractors. A healthy comparison group (n=41) received fMRI evaluations at the same intervals. Differences in functional connectivity of the amygdala and caudate with the rostral anterior cingulate and ventrolateral prefrontal cortices at baseline (and changes in functional connectivity following treatment) were modeled between groups. RESULTS: At baseline, non-remitters showed an increase in positive connectivity between right anterior cingulate and caudate and a loss of negative connectivity between right anterior cingulate and amygdala, compared to healthy participants. Individuals who remitted following treatment showed an increase in negative connectivity between amygdala and left anterior cingulate eight weeks following treatment. CONCLUSIONS: Results provide evidence of alterations in anterior cingulate-amygdala and caudate functional connectivity in bipolar disorder non-remitters during a first manic episode and changes in anterior cingulate functional connectivity associated with remission suggesting targets to predict treatment response. Registered at ClinicalTrials.Gov; Functional and Neurochemical Brain Changes in First-episode Bipolar Mania. NCT00609193. URL: https://clinicaltrials.gov/ct2/show/NCT00609193?term=strakowski&rank=1

Objective: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). Methods: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. Results: Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). Conclusions: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

Background Despite the well-documented negative impact of untreated bipolar illness, approaches to early intervention in childhood-onset bipolar and related disorders are not well delineated. Methods We reviewed the extant treatment literature on children at high risk for bipolar disorder, with definitions based on family history, childhood adversity, and prodromal symptoms. Results A panoply of approaches have been described, but most interventions are based on an inadequate database to support their routine implementation. We classify early stage interventions as a function of their safety and tolerability with the hope that these might generate more rigorous study and a stronger database. Limitations Critics may rightly argue that identifying viable treatment methods is premature given our lack of ability to reliably predict illness trajectory in very young children. However, many of the psychosocial and pharmacological interventions we present could have nonspecific positive effects across a variety of symptoms, syndromes, and diagnoses, further enhancing the rationale for more rigorous study. Conclusions Early stage interventions have the potential to improve functioning in prodromal illness and exert long-term positive effects on the course of illness. Many of the safest interventions deserve consideration for implementation and dissemination studies.

OBJECTIVE: People with epilepsy are at increased risk for mental health comorbidities. Machine-learning methods based on spoken language can detect suicidality in adults. This study’s purpose was to use spoken words to create machine-learning classifiers that identify current or lifetime history of comorbid psychiatric conditions in teenagers and young adults with epilepsy. MATERIALS AND METHODS: Eligible participants were >12 years old with epilepsy. All participants were interviewed using the Mini International Neuropsychiatric Interview (MINI) or the MINI Kid Tracking and asked five open-ended conversational questions. N-grams and Linguistic Inquiry and Word Count (LIWC) word categories were used to construct machine learning classification models from language harvested from interviews. Data were analyzed for four individual MINI identified disorders and for three mutually exclusive groups: participants with no psychiatric disorders, participants with non-suicidal psychiatric disorders, and participants with any degree of suicidality. Performance was measured using areas under the receiver operating characteristic curve (AROCs). RESULTS: Classifiers were constructed from 227 interviews with 122 participants (7.5 ± 3.1 minutes and 454 ± 299 words). AROCs for models differentiating the nonoverlapping groups and individual disorders ranged 57%-78% (many with P < .02). DISCUSSION AND CONCLUSION: Machine-learning classifiers of spoken language can reliably identify current or lifetime history of suicidality and depression in people with epilepsy. Data suggest identification of anxiety and bipolar disorders may be achieved with larger data sets. Machine-learning analysis of spoken language can be promising as a useful screening alternative when traditional approaches are unwieldy (eg, telephone calls, primary care offices, school health clinics).

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable psychiatric disorders with partially overlapping genetic liability. Shared and disorder-specific neurobiological abnormalities associated with familial risk for developing mental illnesses are largely unknown. We performed a meta-analysis of structural brain imaging studies in relatives of patients with SCZ, BD, and MDD to identify overlapping and discrete brain structural correlates of familial risk for mental disorders. Search for voxel-based morphometry studies in relatives of patients with SCZ, BD, and MDD in PubMed and Embase identified 33 studies with 2292 relatives and 2052 healthy controls (HC). Seed-based d Mapping software was used to investigate global differences in gray matter volumes between relatives as a group versus HC, and between those of each psychiatric disorder and HC. As a group, relatives exhibited gray matter abnormalities in left supramarginal gyrus, right striatum, right inferior frontal gyrus, left thalamus, bilateral insula, right cerebellum, and right superior frontal gyrus, compared with HC. Decreased right cerebellar gray matter was the only abnormality common to relatives of all three conditions. Subgroup analyses showed disorder-specific gray matter abnormalities in left thalamus and bilateral insula associated with risk for SCZ, in left supramarginal gyrus and right frontal regions with risk for BD, and in right striatum with risk for MDD. While decreased gray matter in right cerebellum might be a common brain structural abnormality associated with shared risk for SCZ, BD, and MDD, regional gray matter abnormalities in neocortex, thalamus, and striatum appear to be disorder-specific.

Objectives: To examine metabolic monitoring rates in commercially insured children and adolescents treated with a second-generation antipsychotic (SGA) during calendar years (CYs) 2016 and 2017. Methods: In this retrospective study, data were collected from a large national commercial health plan for the period covering January 1, 2016 to December 31, 2017. Commercially insured children and adolescents, aged 8-19 years with ≥2 SGA prescription claims during the CY, were identified for the CY2016 and CY2017 cohorts. The primary outcome of interest was the percentage of subjects with any glucose or lipid metabolism parameter monitoring. Other calculated metabolic testing rates included glucose, hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), other cholesterol (including triglycerides), and combined glucose and lipid metabolism testing (≥1 test for blood glucose or HbA1c and ≥1 test for LDL-C or other cholesterol). Results: In CY2016 and CY2017, 1502 and 1239 subjects, respectively, were identified for this study. The most common psychiatric diagnoses in CY2016 and CY2017 were major depressive disorder (57.1%, 56.5%, respectively), anxiety disorders (42.9%, 47.5%), attention-deficit/hyperactivity disorder (41.6%, 45.8%), and bipolar disorder (24.1%, 25.9%). The rate of any metabolic testing was 53.5% in CY2016 and 51.3% in CY2017. Glucose testing (50.3%, 46.9%, respectively) was most common in both CYs, followed by LDL-C testing (31.2%, 28.5%). Rates of combined glucose and lipid metabolism testing were 30.7% in CY2016 and 26.9% in CY2017. Conclusions: Given the known potential for adverse cardiometabolic effects, rates of metabolic monitoring associated with SGA use in children and adolescents urgently need to be improved. There is a critical need for understanding barriers to routine monitoring, particularly of lipids, and developing interventions to enhance metabolic monitoring.

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.

BackgroundIdentification 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.MethodsA 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.ResultsPre-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% (allp< 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.ConclusionsThese 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.

Bipolar disorder is defined by the onset of the first manic episode, which typically occurs in late adolescence or early adulthood. However, it is increasingly recognized that many people with bipolar disorder experience significant premorbid symptoms, prior to an initial disorder-defining onset of mania. Combined with the heritability of bipolar disorder, it is likely that the underlying biological basis of the disorder produces premorbid and early-course neurophysiological abnormalities that might help to identify at-risk cases and herald an early onset and progression of illness course. This chapter will focus on neuroimaging in bipolar disorder in youth, as well as in at-risk individuals (unaffected and subthreshold affected children of parents with bipolar disorder), to inform models of early bipolar development. This edition’s chapter adds more emphasis on at-risk individuals and progression of neurobiological changes at illness onset, as well as the potential implications for early intervention in an effort to interrupt illness progression.

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable conditions with overlapping genetic liability. Transdiagnostic and disorder-specific brain changes associated with familial risk for developing these disorders remain poorly understood. We carried out a meta-analysis of diffusion tensor imaging (DTI) studies to investigate white matter microstructure abnormalities in relatives that might correspond to shared and discrete biomarkers of familial risk for psychotic or mood disorders. A systematic search of PubMed and Embase was performed to identify DTI studies in relatives of SCZ, BD, and MDD patients. Seed-based d Mapping software was used to investigate global differences in fractional anisotropy (FA) between overall and disorder-specific relatives and healthy controls (HC). Our search identified 25 studies that met full inclusion criteria. A total of 1,144 relatives and 1,238 HC were included in the meta-analysis. The overall relatives exhibited decreased FA in the genu and splenium of corpus callosum (CC) compared with HC. This finding was found highly replicable in jack-knife analysis and subgroup analyses. In disorder-specific analysis, compared to HC, relatives of SCZ patients exhibited the same changes while those of BD showed reduced FA in the left inferior longitudinal fasciculus (ILF). The present study showed decreased FA in the genu and splenium of CC in relatives of SCZ, BD, and MDD patients, which might represent a shared familial vulnerability marker of severe mental illness. The white matter abnormalities in the left ILF might represent a specific familial risk for bipolar disorder.

The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood.In vitro studies using cryopreserved, plated human hepatocytes (cPHHs) and pooled human liver microsomes (HLMs) were performed to more thoroughly characterise the metabolism of several ADHD medications.The use of enzyme-specific chemical inhibitors indicated a role for CYP2D6 in atomoxetine (ATX) metabolism, and roles for CYP3A4/5 in guanfacine (GUA) metabolism.The 4-hydroxy-atomoxetine and N-desmethyl-atomoxetine pathways represented 98.4% and 1.5% of ATX metabolism in cPHHs, respectively. The 3-OH-guanfacine pathway represented at least 2.6% of GUA metabolism in cPHHs, and 71% in HLMs.The major metabolising enzyme for methylphenidate (MPH) and dexmethylphenidate (dMPH) could not be identified using these methods because these compounds were too unstable. Hydrolysis of these medications was spontaneous and did not require the presence of protein to occur.Clonidine (CLD), amphetamine (AMPH), and dextroamphetamine (dAMPH) did not deplete substantially in cPHHs nor HLMs, suggesting that these compounds may not undergo considerable hepatic metabolism. The major circulating metabolites of AMPH and dAMPH (benzoic acid and hippuric acid) were not observed in either system, and therefore could not be characterised. Additionally, inhibition experiments suggested a very minimal role for CYP2D6 in CLD and AMPH metabolism. The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood. In vitro studies using cryopreserved, plated human hepatocytes (cPHHs) and pooled human liver microsomes (HLMs) were performed to more thoroughly characterise the metabolism of several ADHD medications. The use of enzyme-specific chemical inhibitors indicated a role for CYP2D6 in atomoxetine (ATX) metabolism, and roles for CYP3A4/5 in guanfacine (GUA) metabolism. The 4-hydroxy-atomoxetine and N-desmethyl-atomoxetine pathways represented 98.4% and 1.5% of ATX metabolism in cPHHs, respectively. The 3-OH-guanfacine pathway represented at least 2.6% of GUA metabolism in cPHHs, and 71% in HLMs. The major metabolising enzyme for methylphenidate (MPH) and dexmethylphenidate (dMPH) could not be identified using these methods because these compounds were too unstable. Hydrolysis of these medications was spontaneous and did not require the presence of protein to occur. Clonidine (CLD), amphetamine (AMPH), and dextroamphetamine (dAMPH) did not deplete substantially in cPHHs nor HLMs, suggesting that these compounds may not undergo considerable hepatic metabolism. The major circulating metabolites of AMPH and dAMPH (benzoic acid and hippuric acid) were not observed in either system, and therefore could not be characterised. Additionally, inhibition experiments suggested a very minimal role for CYP2D6 in CLD and AMPH metabolism.

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 (CName: Functional and Neurochemical Brain Changes in First-episode Bipolar Mania Following Successful Treatment with Lithium or Quetiapine. URL: https://clinicaltrials.gov/ .NCT00609193. Name: Neurofunctional and Neurochemical Markers of Treatment Response in Bipolar Disorder. URL: https://clinicaltrials.gov/ .NCT00608075.

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.

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.

Aim Given ongoing disagreement about the diagnosis of pediatric bipolar disorder, we sought to illuminate key empirical findings regarding the condition in children and adolescents. Methods We conducted a review of extant studies of the diagnosis, course, and treatment of bipolar disorder in children and adolescents. Results Bipolar disorder is a lifelong, familial condition with frequent onset in childhood or adolescence. Secular trends indicate that globally, the onset of puberty is occurring earlier, which may contribute to increased identification of mood disorders in younger populations. Despite opinions to the contrary, bipolar disorder has been observed in youth around the world, not just in the U.S. Discrete and episodic manic symptoms occur on a continuum/spectrum of severity and duration. Clinicians may be just as likely to miss mania (false negatives) as overcall it (false positives). As is true in adults, periodicity and heterogeneity are defining features of early onset bipolar disorder. Youth who are misdiagnosed and undiagnosed tend to do poorly over the long term. Youth with and at risk for bipolar disorder are frequently exposed to maltreatment, abuse, and bullying. Fortunately, there are now many evidence-based interventions that have been studied in thousands of youth with or at high risk for bipolar disorder, demonstrating large effect sizes for evaluated treatments versus comparative treatments. Conclusion Identifying optimal methods for the evaluation and treatment of bipolar disorder in children and adolescents represents important advances in the field. Recognizing the occurrence of mania symptoms in youth is pivotal for improving outcomes in patients living with 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

Children of individuals with bipolar disorder (bipolar offspring) are at increased risk for developing mood disorders, but strategies to predict mood episodes are unavailable. In this study, we used support vector machine (SVM) to characterize the potential of proton magnetic resonance spectroscopy (1H-MRS) in predicting the first mood episode in youth bipolar offspring. From a longitudinal neuroimaging study, 19 at-risk youth who developed their first mood episode (converters), and 19 without mood episodes during follow-up (non-converters) were selected and matched for age, sex and follow-up time. Baseline 1H-MRS data were obtained from anterior cingulate cortex (ACC) and bilateral ventrolateral prefrontal cortex (VLPFC). Glutamate (Glu), myo-inositol (mI), choline (Cho), N-acetyl aspartate (NAA), and phosphocreatine plus creatine (PCr + Cr) levels were calculated. SVM with a linear kernel was adopted to classify converters and non-converters based on their baseline metabolites. SVM allowed the significant classification of converters and non-converters across all regions for Cho (accuracy = 76.0%), but not for other metabolites. Considering all metabolites within each region, SVM allowed the significant classification of converters and non-converters for left VLPFC (accuracy = 76.5%), but not for right VLPFC or ACC. The combined mI, PCr + Cr, and Cho from left VLPFC achieved the highest accuracy differentiating converters from non-converters (79.0%). Our findings from this exploratory study suggested that 1H-MRS levels of mI, Cho, and PCr + Cr from left VLPFC might be useful to predict the development of first mood episode in youth bipolar offspring using machine learning. Future studies that prospectively examine and validate these metabolites as predictors of mood episodes in high-risk individuals are necessary.