Brain morphometric features predict medication response in youth with bipolar disorder: a prospective randomized clinical trial.

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.

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

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

Individual prediction of symptomatic converters in youth offspring of bipolar parents using proton magnetic resonance spectroscopy.

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.

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

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

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

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

Brain functional activation and first mood episode in youth at risk for bipolar disorder.

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.

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

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

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

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

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

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

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

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

Emotion-Related Network Reorganization Following Fish Oil Supplementation in Depressed Bipolar Offspring: An fMRI Graph-Based Connectome Analysis.

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<0.05). Compared with placebo, 12-week fish oil supplementation increased erythrocyte EPA+DHA levels (p<0.001), network clustering coefficient (p = 0.005), global (p = 0.047) and local (p = 0.023) efficiency, and node centralities mainly in temporal regions (p<0.05). LIMITATIONS: The duration of fish oil supplementation was relatively short and the sample size was relatively small. CONCLUSIONS: These findings provide preliminary evidence that abnormalities in emotion-related network organization observed in depressed high-risk youth may be amenable to modification through fish oil supplementation.

Changes in the brain structural connectome after a prospective randomized clinical trial of lithium and quetiapine treatment in youth with bipolar disorder.

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.

Effects of Fish Oil Monotherapy on Depression and Prefrontal Neurochemistry in Adolescents at High Risk for Bipolar I Disorder: A 12-Week Placebo-Controlled Proton Magnetic Resonance Spectroscopy Trial.

Objectives: To evaluate the clinical and neurochemical effects of 12-week fish oil, a source of omega-3 polyunsaturated fatty acids (n-3 PUFAs), in depressed adolescents with a family history of bipolar I disorder. Methods: Adolescents with a current Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision diagnosis of Major Depressive Disorder or Depressive Disorder not otherwise specified, a Childhood Depression Rating Scale-Revised (CDRS-R) Version raw score of ≥40, and at least one biological parent with bipolar I disorder were randomized to double-blind treatment with fish oil (2100 mg/day) or placebo for 12 weeks. The primary outcome measure was change in CDRS-R total score, and secondary outcomes measures were change in manic symptoms (Young Mania Rating Scale), global symptom and functioning measures (Clinical Global Impression-Severity [CGI-S] /CGI Improvement [CGI-I], Children's Global Assessment Scale, and Child Behavior Checklist), safety and laboratory measures, and anterior cingulate cortex (ACC) and bilateral ventrolateral prefrontal cortex neurometabolite concentrations using proton magnetic resonance spectroscopy at 4 T. Results: Fifty-six patients were randomized, and 42 completed the 12-week trial (placebo: n = 21; fish oil, n = 21). Subjects randomized to fish oil, but not placebo, exhibited a significant baseline to endpoint increase in erythrocyte n-3 PUFAs. Reductions in CDRS-R scores did not differ between treatment groups (p = 0.15), and similar remission (p = 0.58) and response (p = 0.77) rates were observed. Fish oil produced a significantly greater decrease in CGI-S (p = 0.0042) and CGI-I (p = 0.036) scores compared with placebo. Baseline to endpoint change in ACC creatine (p = 0.004) and ACC choline (Cho) (p = 0.024) differed significantly between groups. Baseline ACC Cho levels were inversely correlated with baseline and baseline to endpoint change in CDRS-R scores, and baseline to endpoint change in ACC Cho correlated with baseline-endpoint change in CDRS-R scores and n-3 PUFA. There were no group differences in safety and tolerability ratings or laboratory measures. Conclusions: Fish oil monotherapy was not superior to placebo for reducing depressive symptoms in high-risk youth as assessed by the CDRS-R, but was safe and well tolerated and superior to placebo on clinician ratings of global symptom improvement. Associations among ACC Cho levels, depression symptom severity, and n-3 PUFA warrant additional investigation.

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

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

Discrete patterns of cortical thickness in youth with bipolar disorder differentially predict treatment response to quetiapine but not lithium.

The need for treatment response predictive biomarkers is being increasingly recognized in children and adolescents with psychiatric disorders. Structural gray matter abnormalities as a predictor of treatment outcome in pediatric bipolar disorder have not been systematically investigated, especially early in the illness course. With a prospective longitudinal study design, the present study enrolled 52 bipolar adolescents with no history of treatment with mood stabilizers or a therapeutic dose of antipsychotic drugs and 31 healthy controls. Patients were randomly assigned to treatment with quetiapine or lithium after pretreatment data collection. A hierarchical cluster analysis was performed using pretreatment cortical thickness data that identified two discrete patient subgroups. Compared to healthy subjects, patients in subgroup 1 (n = 16) showed widespread greater cortical thickness mainly across heteromodal cortex but also involving some regions of unimodal cortex, while those in subgroup 2 (n = 36) showed regional cortical thinning mainly in superior temporal and superior parietal regions. Patients within subgroup 1 showed a significantly higher response rate to quetiapine than those in subgroup 2 (100% vs 53%). No statistically significant difference was found in lithium response rate between the patient subgroups (63% vs 53%). Pretreatment clinical ratings and neuropsychological data did not differ across subgroups. Our findings suggest the existence of distinct and clinically relevant subgroups of pediatric bipolar patients, as defined by pattern of cortical thickness. These groups appear to differentially respond to antipsychotic treatment-notably with greater cortical thickness relative to controls predicting better treatment response.

Neural Function Before and After Mindfulness-Based Cognitive Therapy in Anxious Adolescents at Risk for Developing Bipolar Disorder.

OBJECTIVE: We sought to evaluate the neurophysiology of mindfulness-based cognitive therapy for children (MBCT-C) in youth with generalized, social, and/or separation anxiety disorder who were at risk for developing bipolar disorder. METHODS: Nine youth (mean age: 13 ± 2 years) with a generalized, social, and/or separation anxiety disorder and a parent with bipolar disorder completed functional magnetic resonance imaging (fMRI) while performing a continuous processing task with emotional and neutral distractors (CPT-END) prior to and following 12 weeks of MBCT-C. RESULTS: MBCT-C was associated with increases in activation of the bilateral insula, lentiform nucleus, and thalamus, as well as the left anterior cingulate while viewing emotional stimuli during the CPT-END, and decreases in anxiety were correlated with change in activation in the bilateral insula and anterior cingulate during the viewing of emotional stimuli (p < 0.05, uncorrected; p < 0.005 corrected; cluster size, 37 voxels). CONCLUSIONS: MBCT-C treatment in anxious youth with a familial history of bipolar disorder is associated with increased activation of brain structures that subserve interoception and the processing of internal stimuli-functions that are ostensibly improved by this treatment.

Familial risk for bipolar disorder is not associated with impaired peroxisomal function: Dissociation from docosahexaenoic acid deficits.

Bipolar I disorder is associated with deficits in the long-chain omega-3 fatty acid docosahexaenoic acid (DHA, 22:6n-3). The final biosynthesis of DHA is mediated by peroxisomes, and some heritable peroxisomal disorders are associated with DHA deficits and progressive psychopathology. The present cross-sectional study investigated whether medication-free asymptomatic and symptomatic youth with familial risk for bipolar I disorder exhibit impaired peroxisomal function using a comprehensive diagnostic blood panel. Measures of peroxisomal impairment included plasma concentrations of very long-chain fatty acids (VLCFA), branched-chain fatty acids, bile acid intermediates, and pipecolic acid, and erythrocyte plasmalogen and DHA levels. Compared with healthy subjects, significant erythrocyte DHA deficits were observed in ultra-high risk and first-episode bipolar groups, and there was a trend for lower DHA in the high-risk group. There were no significant group differences for any other measure of peroxisomal function, and erythrocyte DHA levels were not correlated with any measure of peroxisome function. These results indicate that familial risk for bipolar I disorder is not associated with impaired peroxisomal function, and that DHA deficits associated with familial bipolar disorder are not attributed to heritable defects in peroxisomal function.

Neurofunctional Differences Among Youth With and at Varying Risk for Developing Mania.

OBJECTIVE: To examine prefrontal and amygdala activation during emotional processing in youth with or at varying risk for developing mania to identify candidate central prodromal risk biomarkers. METHOD: Four groups of medication-free adolescents (10-20 years old) participated: adolescents with first-episode bipolar I disorder (BP-I; n = 32), adolescents with a parent with bipolar disorder and a depressive disorder (at-risk depressed [ARD]; n = 32), healthy adolescents with a parent with bipolar disorder (at-risk healthy [ARH]; n = 32), and healthy adolescents with no personal or family history of psychiatric illness (healthy comparison [HC]; n = 32). Participants underwent functional magnetic resonance imaging while performing a continuous performance task with emotional and neutral distracters. Region-of-interest analyses were performed for the bilateral amygdala and for subregions of the ventrolateral prefrontal cortex and anterior cingulate cortex. RESULTS: Overall, no group differences in bilateral amygdala and ventrolateral prefrontal cortex (Brodmann area [BA] 45/47) activation during emotional or neutral stimuli were observed. The BP-I group exhibited lower right pregenual anterior cingulate cortex activation compared with the HC group, and activation in the left BA 44 was greater in the ARH and ARD groups compared with the HC group. BP-I and ARD groups exhibited blunted activation in the right BA 10 compared with the ARH group. CONCLUSION: During emotional processing, amygdala and ventrolateral prefrontal cortex (BA 45/47) activation does not differ in youth with or at increasing risk for BP-I. However, blunted pregenual anterior cingulate cortex activation in first-episode mania could represent an illness biomarker, and greater prefrontal BA 10 and BA 44 activations in at-risk youth could represent a biomarker of risk or resilience warranting additional investigation in prospective longitudinal studies.