Sex differences in cerebral blood flow among adolescents with bipolar disorder.

BACKGROUND: Abnormalities in cerebral blood flow (CBF) are common in bipolar disorder (BD). Despite known differences in CBF between healthy adolescent males and females, sex differences in CBF among adolescents with BD have never been studied. OBJECTIVE: To examine sex differences in CBF among adolescents with BD versus healthy controls (HC). METHODS: CBF images were acquired using arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) in 123 adolescents (72 BD: 30M, 42F; 51 HC: 22M, 29F) matched for age (13-20 years). Whole brain voxel-wise analysis was performed in a general linear model with sex and diagnosis as fixed factors, sex-diagnosis interaction effect, and age as a covariate. We tested for main effects of sex, diagnosis, and their interaction. Results were thresholded at cluster forming p = 0.0125, with posthoc Bonferroni correction (p = 0.05/4 groups). RESULTS: A main effect of diagnosis (BD > HC) was observed in the superior longitudinal fasciculus (SLF), underlying the left precentral gyrus (F =10.24 (3), p < 0.0001). A main effect of sex (F > M) on CBF was detected in the precuneus/posterior cingulate cortex (PCC), left frontal and occipital poles, left thalamus, left SLF, and right inferior longitudinal fasciculus (ILF). No regions demonstrated a significant sex-by-diagnosis interaction. Exploratory pairwise testing in regions with a main effect of sex revealed greater CBF in females with BD versus HC in the precuneus/PCC (F = 7.1 (3), p < 0.01). CONCLUSION: Greater CBF in female adolescents with BD versus HC in the precuneus/PCC may reflect the role of this region in the neurobiological sex differences of adolescent-onset BD. Larger studies targeting underlying mechanisms, such as mitochondrial dysfunction or oxidative stress, are warranted.

Self-harm among youth during the first 28 months of the COVID-19 pandemic in Ontario, Canada: a population-based study.

BACKGROUND: Youth have reported worsening mental health during the COVID-19 pandemic. We sought to evaluate rates of pediatric acute care visits for self-harm during the pandemic according to age, sex and mental health service use. METHODS: We conducted a population-based, repeated cross-sectional study using linked health administrative data sets to measure monthly rates of emergency department visits and hospital admissions for self-harm among youth aged 10-17 years between Jan. 1, 2017, and June 30, 2022, in Ontario, Canada. We modelled expected rates of acute care visits for self-harm after the pandemic onset based on prepandemic rates. We reported relative differences between observed and expected monthly rates overall and by age group (10-13 yr and 14-17 yr), sex and mental health service use (new and continuing). RESULTS: In this population of about 1.3 million children and adolescents, rates of acute care visits for self-harm during the pandemic were higher than expected for emergency department visits (0.27/1000 population v. 0.21/1000 population; adjusted rate ratio [RR] 1.29, 95% confidence interval [CI] 1.19-1.39) and hospital admissions (0.74/10 000 population v. 0.43/10 000 population, adjusted RR 1.72, 95% CI 1.46-2.03). This increase was primarily observed among females. Rates of emergency department visits and hospital admissions for self-harm were higher than expected for both those aged 10-13 years and those aged 14-17 years, as well as for both those new to the mental health system and those already engaged in care. INTERPRETATION: Rates of acute care visits for self-harm among children and adolescents were higher than expected during the first 2 and a half years of the COVID-19 pandemic, particularly among females. These findings support the need for accessible and intensive prevention efforts and mental health supports in this population.

Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

Resting-state functional connectivity indicators of risk and resilience for self-harm in adolescent bipolar disorder.

BACKGROUND: Suicide is the second leading cause of death in all youth and among adults with bipolar disorder (BD). The risk of suicide in BD is among the highest of all psychiatric conditions. Self-harm, including suicide attempts and non-suicidal self-injury, is a leading risk factor for suicide. Neuroimaging studies suggest reward circuits are implicated in both BD and self-harm; however, studies have yet to examine self-harm related resting-state functional connectivity (rsFC) phenotypes within adolescent BD. METHODS: Resting-state fMRI data were analyzed for 141 adolescents, ages 13-20 years, including 38 with BD and lifetime self-harm (BDSH+), 33 with BD and no self-harm (BDSH-), and 70 healthy controls (HC). The dorsolateral prefrontal cortex (dlPFC), orbitofrontal cortex (OFC) and amygdala were examined as regions of interest in seed-to-voxel analyses. A general linear model was used to explore the bivariate correlations for each seed. RESULTS: BDSH- had increased positive rsFC between the left amygdala and left lateral occipital cortex, and between the right dlPFC and right frontal pole, and increased negative rsFC between the left amygdala and left superior frontal gyrus compared to BDSH+ and HC. BDSH+ had increased positive rsFC of the right OFC with the precuneus and left paracingulate gyrus compared to BDSH- and HC. CONCLUSIONS: This study provides preliminary evidence of altered reward-related rsFC in relation to self-harm in adolescents with BD. Between-group differences conveyed a combination of putative risk and resilience connectivity patterns. Future studies are warranted to evaluate changes in rsFC in response to treatment and related changes in self-harm.

Clinical correlates of suicidality and self-injurious behaviour among Canadian adolescents with bipolar disorder.

There is high risk of suicidality in bipolar disorder (BD), particularly in early onset cases. The literature regarding correlates and putative predictors of suicide attempts (SA), non-suicidal self-injury (NSSI) and suicidal ideation (SI) among youth with BD remains sparse. Participants included 197 adolescents with BD, divided into 4 groups: SA (with or without NSSI), NSSI (with or without SI), SI only, and comparison group (CG; no SA/NSSI/SI). Diagnoses, treatment, and suicidality measures were determined via semi-structured interviews, conducted between 2009 and 2017. Univariate analyses were followed by multinomial regression. Overall, 73.6% of participants had history of SA, NSSI, and/or SI. In comparison to CG, SA and NSSI were each associated with BD-II/-NOS (odds ratio [OR] = 15.99, p = 0.002; OR = 16.76, p = 0.003), female sex (OR = 6.89, p = 0.006; OR = 3.76, p = 0.02), and emotion dysregulation (OR = 1.10, p < 0.001; OR = 1.07, p = 0.004). NSSI and SI were each associated with most severe lifetime depression (OR = 1.10, p = 0.01; OR = 1.10, p = 0.01). SA and SI were associated with psychiatric hospitalization (OR = 19.45, p = 0.001; OR = 6.09, p = 0.03). SA was associated with poorer global functioning at most severe episode (OR = 0.88, p = 0.008). NSSI was associated with not living with both natural parents (OR = 0.22, p = 0.009). Study limitations include cross-sectional and retrospective design, stringent cut-offs for SA and NSSI, and recruitment from a tertiary clinical setting. Three quarters of adolescents with BD have had suicidality and/or self-injury. SA and NSSI were most similar to one another, and most different from CG, supporting the broader construct of self-harm. Future research should address the gap in knowledge regarding how sex differences and neurobiology are associated with the observed clinical differences.

Prevalence and correlates of childhood-onset bipolar disorder among adolescents.

AIM: Early-onset bipolar disorder (BD) is associated with a more severe illness as well as a number of clinical factors among adults. Early-onset can be categorized as childhood- (age < 13) or adolescent- (age ≥ 13) onset, with the two displaying different clinical profiles. We set out to examine differences in clinical, and familial characteristics among adolescents with childhood- versus adolescent-onset BD. METHODS: The study included 195 adolescents with BD, ages 14-18 years. Age of onset was determined retrospectively by self-report. Participants completed the semi-structured K-SADS-PL diagnostic interviews along with self-reported dimensional scales. Analyses examined between-group differences for clinical and familial variables. Variables associated with age of onset at p < 0.1 in univariate analyses were evaluated in a logistic regression model. RESULTS: Approximately one-fifth of participants had childhood-onset BD (n = 35; 17.9%). A number of clinical and familial factors were significantly associated with childhood-onset BD. However, there were no significant differences in depressive and manic symptom severity. In multivariate analyses, the variables most strongly associated with childhood-onset were police contact, and family history of suicidal ideation. Smoking and psychiatric hospitalization were associated with adolescent-onset. CONCLUSIONS: In this large clinical sample of adolescents with BD, one-fifth reported childhood-onset BD. Correlates of childhood-onset generally aligned with those observed in the literature. Future research is warranted to better understand the genetic and environmental implications of high familial loading of psychopathology associated with childhood-onset, and to integrate age-related treatment and prevention strategies.

Suicide Assessment and Prevention in Bipolar Disorder: How Current Evidence Can Inform Clinical Practice.

Bipolar disorder is associated with a considerable risk of suicide, and this fact must be incorporated into management of all patients with the condition. This article highlights the importance of a more nuanced understanding of the factors associated with the increased risk of suicidal behavior in people diagnosed as having bipolar disorder and interventions that could mitigate it. Several sociodemographic, clinical, environmental, and other variables have been associated with suicide attempts or deaths in bipolar disorder. Youths with bipolar disorder are a particularly vulnerable group, and their trajectory of illness could be modified by early interventions. Several medications have been studied regarding their relationship to suicide risk in bipolar disorder, and interventional psychiatry is a newer area of research focus. Finally, community-based approaches can be incorporated into a comprehensive approach to suicide prevention. This article summarizes the current understanding of key variables that can help inform a clinical risk assessment of individuals and interventions that can be employed in suicide prevention in bipolar disorder.

Factors Associated With Sleep Disturbance Amongst Youth With Bipolar Disorder.

Background: While sleep disturbances and their impact on functioning are well-established in adults with bipolar disorder (BD), little is known about this topic in youth. Objective: This study investigates the prevalence and correlates of sleep disturbance among youth with BD. Methods: The study included 103 youth (72 BD, 31 healthy controls [HC]), ages 14-20 years. Study measures included a semi-structured diagnostic interview and the Pittsburgh Sleep Quality Index (PSQI). PSQI yields a global score and 7 subscale scores. Analyses examined between group differences in PSQI scores, and correlates of PSQI within BD. Results: BD youth had significantly higher (worse) global sleep scores, and higher scores on 5/7 subscales (quality, latency, disturbance, sleep medication use, daytime dysfunction). In univariate analyses, poorer sleep quality was associated with higher lifetime and current depression severity, mixed mood state, self-reported affective lability, and borderline personality traits. Lifetime lithium treatment and euthymic mood state were associated with better sleep scores. In multivariate analyses, greater current depression severity and self-reported affective lability were most robustly associated with poor sleep quality. Conclusions: Converging with data from adults, present findings indicate greater sleep disturbance among youth with BD versus HC. Also convergent with adults with BD, mood disturbance, whether depression severity or emotional lability, comprised the predominant correlates of sleep disturbance among youth with BD. Future research is warranted to better understand the temporal association between sleep disturbance and its correlates in youth with BD. Relatedly, interventions that address both mood and sleep disturbances may help improve overall functioning.

Contexte: Bien que les perturbations du sommeil et leur effet sur le fonctionnement soient bien établies chez les adultes souffrant du trouble bipolaire (TB). Nous en savons peu à ce sujet chez les jeunes. Objectif: La présente étude investigue la prévalence et les corrélats de la perturbation du sommeil chez les jeunes souffrant du TB. Méthodes: L'étude comprenait 103 jeunes (72 TB, 31 témoins en santé [TS]), âgés de 14 à 20 ans. Les mesures de l'étude étaient notamment une entrevue diagnostique semi-structurée et l'Index de Qualité du Sommeil de Pittsburgh (IQSP). L'IQSP donne un score global et 7 scores de sous-échelles. Les analyses ont examiné entre les différences de groupes dans les scores IQSP, et les corrélats d'IQSP dans le TB. Résultats: Les jeunes souffrant de TB avaient des scores de sommeil globaux significativement plus élevés (pires), et des scores plus élevés à 5/7 sous-échelles (qualité, latence, perturbation, utilisation de médicament pour dormir, dysfonction diurne). Dans les analyses univariées, la mauvaise qualité du sommeil était associée à la gravité de la dépression de durée de vie et actuelle, à l'état de l'humeur mixte, à la labilité affective auto-déclarée, et aux traits de la personnalité limite. Le traitement au lithium de durée de vie et l'état de l'humeur euthymique étaient associés avec de meilleurs scores de sommeil. Dans les analyses multivariées, une plus grande gravité de la dépression actuelle et de la labilité affective auto-déclarée étaient très robustement associées à une mauvaise qualité du sommeil. Conclusions: Convergeant avec les données des adultes, les résultats actuels indiquent une plus grande perturbation du sommeil chez les jeunes souffrant du TB contre les TS. Convergeant également avec les adultes souffrant de TB, la perturbation de l'humeur, que ce soit par la gravité de la dépression ou la labilité émotionnelle, comprenait les corrélats prédominants de la perturbation du sommeil chez les jeunes souffrant de TB. La future recherche est justifiée pour mieux comprendre l'association temporelle entre la perturbation du sommeil et ses corrélats chez les jeunes souffrant du TB. Étant liées, les interventions qui abordent l'humeur et les perturbations du sommeil peuvent aider à améliorer le fonctionnement général.

Comorbid Eating Disorders in a Sample of Youth With Bipolar Disorder: Elevated Burden of Dimensional and Categorical Psychopathology.

Objective: There is growing recognition of the importance of comorbid eating disorders (ED) among individuals with bipolar disorder (BD). However, most studies on this topic have focused on adult samples, and little is known regarding comorbid ED among youth with BD.Methods: The sample included 197 youth with DSM-IV BD (BD-I, BD-II, or BD-NOS [not otherwise specified]), aged 13-20 years and recruited from a subspecialized clinic within a tertiary academic health sciences center from 2009 to 2017. Univariate analyses examined demographic and clinical variables among participants with versus without lifetime DSM-IV ED. Variables significant at P < .10 were entered into a backward stepwise regression.Results: Fifty-six participants (28.4%) had lifetime DSM-IV ED (3.6% anorexia nervosa, 8.1% bulimia nervosa, 16.8% ED not otherwise specified). Significant correlates of lifetime ED were female sex (P < .001), BD-II subtype (P = .03), suicidal ideation (P = .006), suicide attempts (P = .004), non-suicidal self-injury (P < .001), sexual abuse (P = .02), cigarette smoking (P = .001), anxiety disorders (P = .004), posttraumatic stress disorder (P = .004), substance use disorders (P = .006), history of individual therapy (P = .01), and family history of anxiety (P = .01). Significant correlates of no lifetime ED were BD-I subtype (P < .001) and lifetime lithium use (P = .01). The ED group had significantly more severe lifetime depression (P < .001) and significantly more self-reported affective lability (P < .001) and borderline personality traits (P < .001). In multivariate analysis, the most robust predictors of lifetime ED were female sex (odds ratio [OR] = 4.61, P = .004), BD-I subtype (OR = 0.21, P = .03), cigarette smoking (OR = 2.78, P = .02), individual therapy (OR = 3.92, P = .03), family history of anxiety (OR = 2.86, P = .02), and borderline personality traits (OR = 1.01, P = .009).Conclusions: ED are common among youth with BD and associated with adverse clinical characteristics, many of which converge with prior adult literature. Future studies evaluating specific ED subtypes are warranted, as are treatment studies targeting comorbid ED in youth with BD.

Neurostructural differences associated with self-harm in youth bipolar disorder.

BACKGROUND: Youth with bipolar disorder (BD) are at greatly elevated risk for suicide. Self-harm, encompassing all self-injurious behaviors regardless of suicidal intent, is among one of the greatest risk factors for death by suicide. This study aims to extend the sparse literature regarding the neurostructural correlates of self-harm in youth with BD. METHODS: Participants included 156 youth (17.14 ± 1.61 years): 38 BD with lifetime history of self-harm (BDSH+ ), 43 BD without history of self-harm (BDSH- ), and 75 healthy controls (HC). Measures of cortical thickness, surface area (SA), and volume were obtained using 3 T magnetic resonance imaging. Orbitofrontal and ventrolateral prefrontal cortices were examined in region-of-interest (ROI) analyses, complemented by exploratory vertex-wise analyses using a general linear model controlling for age, sex, and intracranial volume. RESULTS: In ROI analyses, there were no between-group differences after correction for multiple comparisons. Vertex-wise analysis revealed three significant clusters in precentral gyrus SA, inferior temporal gyrus SA, and caudal middle frontal gyrus volume. Post-hoc vertex-wise analyses showed BDSH+ had lower cortical SA and volume compared with both BDSH- and HC for all clusters. CONCLUSIONS: Significant vertex-wise findings were observed in frontotemporal regions relevant to BD and self-harm, with smaller neurostructural measures among BDSH+ compared with both BDSH- and HC. Future studies are needed to evaluate the temporal nature of the relationship of these neurostructural differences (i.e., potential risk indicators) to self-harm and to identify mechanisms underlying these findings.

Association of blood pressure with brain structure in youth with and without bipolar disorder.

BACKGROUND: We previously found that blood pressure (BP) is elevated, and associated with poorer neurocognition, in youth with bipolar disorder (BD). While higher BP is associated with smaller brain structure in adults, studies have not examined this topic in BD or youth. METHODS: Participants were 154 youth, ages 13-20 (n = 81 BD, n = 73 HC). Structural magnetic resonance imaging and diastolic (DBP), and systolic (SBP) pressure were obtained. Region of interest (ROI; anterior cingulate cortex [ACC], insular cortex, hippocampus) and vertex-wise analyses controlling for age, sex, body-mass-index, and intracranial volume investigated BP-neurostructural associations; a group-by-BP interaction was also assessed. RESULTS: In ROI analyses, higher DBP in the overall sample was associated with smaller insular cortex area (ß=-0.18 p = 0.007) and was associated with smaller ACC area to a significantly greater extent in HC vs. BD (ß=-0.14 p = 0.015). In vertex-wise analyses, higher DBP and SBP were associated with smaller area and volume in the insular cortex, frontal, parietal, and temporal regions in the overall sample. Additionally, higher SBP was associated with greater thickness in temporal and parietal regions. Finally, higher SBP was associated with smaller area and volume in frontal, parietal, and temporal regions to a significantly greater extent in BD vs. HC. LIMITATIONS: Cross-sectional design, single assessment of BP. CONCLUSION: BP is associated with brain structure in youth, with variability related to structural phenotype (volume vs. thickness) and psychiatric diagnosis (BD vs. HC). Future studies evaluating temporality of these findings, and the association of BP changes on brain structure in youth, are warranted.

Prevalence and correlates of police contact amongst youth with bipolar disorder.

OBJECTIVES: While multiple studies have examined prevalence and correlates of police contact in adults with bipolar disorder (BD), literature on this topic in youth is sparse. We therefore examined the prevalence and correlates of police contact amongst youth with BD. METHODS: The study included 197 youth with BD and 127 healthy controls, ages 14-20 years. Semi-structured interviews were used to determine diagnoses, treatment and police contact. The Life Problems Inventory examined self-reported trait impulsivity and emotional dysregulation. Analyses examined demographic and clinical variables among youth with versus without lifetime police contact. Variables that were associated with police contact at p<0.1 in univariate analyses were evaluated in a logistic regression model. Specific reasons for police contact, determined based on chart review, are reported descriptively. RESULTS: Lifetime prevalence of police contact was significantly higher amongst youth with BD versus healthy controls (36% versus. 3%; χ 2 = 47.58, p =<0.001). In multivariate analyses, age of BD onset, living with both natural parents, comorbid substance use disorder and conduct disorder, and psychiatric hospitalization were associated with police contact. Common reasons for police contact included shoplifting/theft and suicidality/self-harm . LIMITATIONS: The cross-sectional and retrospective study design precludes conclusions regarding directionality of the observed associations and/or causal inferences. CONCLUSIONS: One third of youth with BD experienced police contact. Correlates generally aligned with those observed with adults. Future longitudinal research is warranted to understand distal and proximal antecedents of police contact, with the goal of developing strategies to prevent police contact, incarceration, and related consequences.

Elevated lipids are associated with reduced regional brain structure in youth with bipolar disorder.

OBJECTIVE: Abnormal blood lipid levels are common in bipolar disorder (BD) and correlate with mood symptoms and neurocognition. However, studies have not examined the lipid-brain structure association in BD or youth. METHODS: This study examined low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), triglycerides, and total cholesterol (TC) levels in relation to brain structure utilizing T1-weighted images, among participants ages 13-20 with BD (n = 55) and healthy controls (HC; n = 47). General linear models investigated group differences in the association of lipids with anterior cingulate cortex (ACC), hippocampus, and inferior parietal lobe structure, controlling for age, sex, body mass index, and intracranial volume. For significant associations, post hoc within-group analyses were undertaken. Exploratory vertex-wise analyses further investigated group differences in the lipid-brain structure association. RESULTS: There were significant group differences in the association of LDL-C (ß = -0.29 p = 0.001), and TC (ß = -0.21 p = 0.016), with hippocampal volume, and triglycerides with ACC volume (ß = -0.25 p = 0.01) and area (ß = -0.26 p = 0.004). Elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC. Post hoc analyses revealed that elevated LDL-C (ß = -0.27 p = 0.007) and reduced HDL-C (ß = 0.24 p = 0.01) were associated with smaller hippocampal volume in the BD group. Exclusion of BD second-generation antipsychotic users did not alter these results. Vertex-wise analyses further showed that elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC, across the cortex. CONCLUSION: Elevated lipids are associated with smaller brain structure in BD. Research evaluating lipid-brain structure associations prospectively and whether lipid optimization has salutary effects on brain structure is necessary.

Severe anhedonia among adolescents with bipolar disorder is common and associated with increased psychiatric symptom burden.

BACKGROUND: Anhedonia, a deficit in the ability to experience pleasure, is a cardinal symptom of major depressive episodes. In contrast to adolescent major depressive disorder, there is limited research examining anhedonia in the context of depression among adolescents with bipolar disorder (BD). We therefore examined clinical characteristics of anhedonia in a large sample of adolescents with BD. METHODS: Participants were 197 adolescents, aged 13-20 years old, with BD type I, II or not otherwise specified. Diagnoses were determined using a semi-structured interview. Anhedonia severity was rated from one to six on the Depression Rating Scale (DRS). Adolescents were divided into "severe" and "non-severe" anhedonia groups based on the DRS item scoring. The association of anhedonia with clinical and demographic variables was evaluated in univariate analyses followed by logistic regression analyses for variables with p ≤ 0.1. RESULTS: Threshold anhedonia was evident among 90.9% during their most severe depressive episode. Significant factors associated with severe most severe lifetime anhedonia ("lifetime anhedonia") included: female sex, lifetime history of self-injurious behavior, physical abuse, affective lability, higher lifetime depression severity, comorbid anxiety disorders, family history of ADHD, and second-generation antipsychotic use. In regression analyses, severe lifetime anhedonia was independently associated with female sex, comorbid anxiety disorders, most severe lifetime mania severity, and lifetime second-generation antipsychotic use. CONCLUSION: The vast majority of adolescents with BD experience anhedonia. More severe anhedonia is associated with indicators of greater illness severity. Future research is warranted to evaluate the neurobiological underpinnings of anhedonia among adolescents with BD.

Clinical and neuroimaging correlates of cardiorespiratory fitness in adolescents with bipolar disorder.

INTRODUCTION: Cardiovascular disease (CVD) is exceedingly prevalent, and occurs prematurely in individuals with bipolar disorder (BD). Cardiorespiratory fitness (CRF), arguably the most important modifiable CVD risk factor, is also associated with brain structure and function. There is a gap in knowledge regarding CRF in BD, particularly in relation to brain structure. METHODS: Adolescents with BD (n = 54) and healthy controls (HC; n = 53) completed semi-structured diagnostic interviews, self-report questionnaires, and 20 minutes of cardiorespiratory exercise at 60-80% of estimated maximum heart rate (HR) on a bicycle ergometer. Average power (watts/kg) within this HR range served as a previously validated proxy for CRF. Brain magnetic resonance imaging (MRI) structural analysis was done using FreeSurfer. Analyses controlled for age and sex. RESULTS: CRF was significantly lower in BD vs HC (0.91 ± 0.32 vs 1.01 ± 0.30, p = 0.03, F = 4.66, df=1, η2 =0.04). Within BD, greater depression symptoms were associated with lower CRF (P = .02), and greater physical activity (PA) was associated with greater CRF (P < .001). In multivariable analyses, there were significant main effects of diagnosis (HC>BD; P = .03) and sex (M > F; P < .001) on power. Significant predictors of power within BD included male sex (P = .02) and PA (P = .002) but not depression symptoms (P = .29). Significant diagnosis by CRF interaction effects was found in frontal, parietal, and occipital cortical regions. CONCLUSION: CRF was reduced among adolescents with BD, particularly women, related in part to depression symptoms and inactivity and was differentially associated with regional brain structure. Studies seeking to improve CRF as a means of reducing psychiatric symptoms of BD are warranted.