Showing papers by "Benjamin I. Goldstein published in 2021"

Peripheral inflammatory biomarkers define biotypes of bipolar depression.

Abstract: We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith–Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab’s hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) and TNF receptor-1 (TNFR1) comprised factor “NEV1,” whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted “NEV2”. Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2 = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

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

Abstract: 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 (β = -0.29 p = 0.001), and TC (β = -0.21 p = 0.016), with hippocampal volume, and triglycerides with ACC volume (β = -0.25 p = 0.01) and area (β = -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 (β = -0.27 p = 0.007) and reduced HDL-C (β = 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.

Correspondence between patterns of cerebral blood flow and structure in adolescents with and without bipolar disorder.

Abstract: Adolescence is a period of rapid development of the brain’s inherent functional and structural networks; however, little is known about the region-to-region organization of adolescent cerebral bloo...

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

Abstract: 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 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.

A Longitudinal Study of Psychiatric Disorders in Offspring of Parents With Bipolar Disorder From Preschool to Adolescence.

Abstract: Objective To compare the prevalence of psychopathology, particularly bipolar disorder (BD), between preschool offspring of parents with BD and community controls Method A total of 116 offspring of BD-I/II parents and 98 controls (53 parents with non-BD psychopathology and 45 healthy parents) were recruited at ages 2 to 5 years and followed on average 96 years (on average: 2−5: 16 times; after age 5: 4 times) (average ages at intake/last follow-up: 38/134, retention: 98%) Participants were evaluated with standardized instruments blinded to parental diagnoses Results After adjusting for confounders, offspring of BD parents only showed more attention-deficit/hyperactivity disorder (ADHD) during ages 2 to 5 years than the other 2 groups After age 5, offspring of BD parents did not differ from offspring of parents with non-BD psychopathology, but they had more anxiety, ADHD, and behavior problems than offspring of healthy parents Only offspring of BD parents developed BD-I/II: 34% (n = 4) and BD−not-otherwise-specified (BD-NOS): 112% (n = 13), with mean onset ages 114 and 74, respectively About 70% of offspring with BD had non-BD disorders before BD Only ADHD, diagnosed before age 6 years, and early-onset parental BD were significantly associated with BD risk Conclusion Most offspring of BD parents did not develop BD, but they were at specific high risk for developing BD, particularly those with preschool ADHD and early-onset parental BD BD symptoms were scarce during the preschool years and increased throughout the school age, mainly in the form of BD-NOS, a disorder that conveys poor prognosis and high risk to develop BD-I/II Developing early interventions to delay or, ideally, to prevent its onset are warranted

Novel therapeutic targets in mood disorders: Pentoxifylline (PTX) as a candidate treatment.

Abstract: Numerous pharmacological treatments for mood disorders are currently available; however, rates of treatment resistance, relapse and recurrence remain high. Therefore, novel treatments acting outside of the conventionally targeted monoamine system are urgently needed to improve patient outcomes. Emerging and converging evidence suggests that immune dysfunction, oxidative stress, impaired cerebral blood flow (CBF) and decreased neurotrophic factors all contribute to mood disorder pathophysiology and are therefore treatment targets of interest. Pentoxifylline (PTX) is a phosphodiesterase inhibitor with potent anti-inflammatory and antioxidant effects, with additional pleiotropic effects that lead to improved CBF and increases in brain derived neurotrophic factor (BDNF) levels. The direct effect of non-specific phosphodiesterase inhibition may also improve alertness and cognitive function through enhancing second messenger systems. Replicated preclinical studies have demonstrated antidepressant-like effects in animal models. Small preliminary clinical trials have demonstrated promising results for antidepressant and procognitive effects, however, have yet to be replicated in larger mood disorder samples. Only one randomized clinical trial (RCT) specifically assessed the effects of adjunctive PTX in major depressive disorder (MDD), showing clinically and statistically significant antidepressant effects compared to placebo. No studies have assessed PTX in bipolar disorder (BD), where inflammation and altered CBF have also been strongly implicated. Taken together, PTX presents as a promising pleiotropic agent with several potential novel mechanisms of action meriting further evaluation in clinical trials to evaluate target engagement, antidepressant, procognitive and mood stabilizing effects.

Clinical staging for youth at‐risk for serious mental illness: A longitudinal perspective

Abstract: Objective The objective of this study was to identify a sample of youth in distinct stages of risk for the development of a serious mental illness (SMI) according to a published clinical staging model and to follow this sample longitudinally to determine clinical changes over time. This article reports the 6- and 12-month follow-up of the cohort. Methods This study recruited 243 youth, ages 12 to 25. The sample included (a) 42 healthy controls, (b) 41 nonhelpseeking individuals with no mental illness but some risk of SMI, for example, having a first-degree relative with an SMI (stage 0), (c) 53 youth experiencing distress and mild symptoms of anxiety or depression (stage 1a), and (d) 107 youth with attenuated symptoms of SMIs such as bipolar disorder or psychosis (stage 1b). Participants completed a range of measures assessing depression, anxiety, mania, suicide ideation, attenuated psychotic symptoms, negative symptoms, anhedonia and beliefs about oneself at baseline, 6- and 12-months. Results There were few changes for healthy controls and stage 0 participants, although approximately 7% did move to a symptomatic stage within 12-months. Of stage 1a participants, 50% remained symptomatic, with 7.5% moving to stage 1b or developing a SMI. Approximately 9% of stage 1byouth developed a SMI within 12-months and approximately one-third had remission of symptoms during the follow-up. Conclusions Results suggest that the implementation of a transdiagnostic staging model may be useful in youth mental health and support consideration of clinical stage-based treatment for youth with early features of risk.

Neurostructural phenotypes of CACNA1C rs1006737 in adolescents with bipolar disorder and healthy controls.

Abstract: Objective Investigate the effects of CACNA1C rs1006737 on cortical and subcortical neurostructural phenotypes in Caucasian bipolar disorder (BD) and healthy control (HC) adolescents. Methods Seventy-one adolescents (14–20 years; 38BD, 33HC) underwent 3-Tesla Magnetic Resonance Imaging (MRI). Region of interest (ROI) and vertex-wise analyses examined cortical volume, surface area (SA), and thickness, as well as subcortical volume. ROIs included the ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), putamen, and amygdala. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and total intracranial volume. Results Vertex-wise analysis found significant BD-by-rs1006737 interactions for prefrontal and occipital regions such that BD A-carriers were found to have greater SA relative to BD non-carriers, while HC A-carriers had reduced SA relative to HC non-carriers. ROI analysis found an interaction in the ACC such that BD A-carriers were found to have greater SA relative to BD non-carriers, while no significant difference was found in HCs. Main effects of rs1006737 were also found on ACC SA from ROI analysis, and occipital SA from vertex-wise analysis, such that A-carriers had larger SA relative to non-carriers in both of these regions. Conclusions The current study identified neurostructural intermediate phenotypes relevant to the impact of CACNA1C rs1006737 on adolescent BD. Further investigation is warranted into the neurofunctional and neurocognitive relevance of rs1006737 associations with BD-specific elevations in regional SA.

Functional imaging in youth at risk for transdiagnostic serious mental illness: Initial results from the PROCAN study.

Abstract: Background In their early stages, serious mental illnesses (SMIs) are often indistinguishable from one another, suggesting that studying alterations in brain activity in a transdiagnostic fashion could help to understand the neurophysiological origins of different SMI. The purpose of this study was to examine brain activity in youth at varying stages of risk for SMI using functional magnetic resonance imaging tasks (fMRI) that engage brain systems believed to be affected. Methods Two hundred and forty three participants at different stages of risk for SMI were recruited to the Canadian Psychiatric Risk and Outcome (PROCAN) study, however only 179 were scanned. Stages included asymptomatic participants at no elevated risk, asymptomatic participants at elevated risk due to family history, participants with undifferentiated general symptoms of mental illness, and those experiencing attenuated versions of diagnosable psychiatric illnesses. The fMRI tasks included: (1) a monetary incentive delay task; (2) an emotional Go-NoGo and (3) an n-back working memory task. Results Strong main effects with each of the tasks were found in brain regions previously described in the literature. However, there were no significant differences in brain activity between any of the stages of risk for SMI for any of the task contrasts, after accounting for site, sex and age. Furthermore, results indicated no significant differences even when participants were dichotomized as asymptomatic or symptomatic. Conclusions These results suggest that univariate BOLD responses during typical fMRI tasks are not sensitive markers of SMI risk and that further study, particularly longitudinal designs, will be necessary to understand brain changes underlying the early stages of SMI.

Prospectively ascertained mania and hypomania among young adults with child- and adolescent-onset bipolar disorder.

Abstract: OBJECTIVES While adults with bipolar disorder (BD) often report symptoms starting in childhood, continuity of mania and/or hypomania (mania/hypomania) from childhood to adulthood has been questioned. Using longitudinal data from the Course and Outcome of Bipolar Youth (COBY) study, we assessed threshold mania/hypomania in young adults who manifested BD as youth. METHODS COBY is a naturalistic, longitudinal study of 446 youth with BD (84% recruited from outpatient clinics), 7-17 years old at intake, and over 11 years of follow-up. Focusing on youth with BD-I/II (n = 297), we examined adult mania/hypomania risk (>18 years old; mean 7.9 years of follow-up) according to child (<13 years old) versus adolescent (13-17 years old) onset. We next used penalized regression to test demographic and clinical predictors of young adult mania/hypomania. RESULTS Most participants (64%) had child-onset mania/hypomania, 57% of whom also experienced mania/hypomania in adolescence. Among those who experienced an episode in adolescence, over 40% also had mania/hypomania during adulthood; the risk did not differ according to child versus adolescent onset. In contrast, 7% with mania/hypomania in childhood, but not adolescence, experienced mania/hypomania in adulthood. Family history (of mania and suicide attempts) predicted mania/hypomania in young adulthood (p-values <0.05); age of onset was not a significant predictor. Among participants with no mania/hypomania during adulthood, 53% (105/198) still experienced subthreshold manic episodes. DISCUSSION We find substantial continuity across developmental stage indicating that, in this carefully characterized sample, children who experience mania/hypomania-particularly those who also experience mania/hypomania in adolescence-are likely to experience mania/hypomania in young adulthood.

Personality and risk for serious mental illness.

Abstract: Aim Certain personality traits may be related to an increased risk of developing a severe mental illness (SMI). This study examined differences in personality characteristics in a sample of youth at-risk of SMI across different clinical stages compared to healthy controls (HCs). Method Personality characteristics were assessed with the NEO-Five-Factor Inventory-3 for 41 non-help seeking asymptomatic youth with risk factors for SMI (Stage 0), 52 youth with early mood and anxiety symptoms and distress (Stage 1a), 108 youth with an attenuated psychiatric syndrome (Stage 1b), and 42 HCs. Results Symptomatic participants scored significantly higher in neuroticism, and lower in extraversion, and conscientiousness compared to non-symptomatic participants. Compared to published norms, symptomatic participants had ratings of extraversion and conscientiousness in the low range and those with attenuated psychiatric syndromes scored high on neuroticism. Conclusion The observed personality profiles of the symptomatic stages were similar to reported profiles for discrete disorders. Early identification of this profile could aid identification of those at risk of SMI.

A Bayesian multilevel analysis of the longitudinal associations between relationship quality and suicidal ideation and attempts among youth with bipolar disorder

Abstract: Background Youth with bipolar disorder (BD) are at high risk for suicidal thoughts and behaviors and frequently experience interpersonal impairment, which is a risk factor for suicide. Yet, no study to date has examined the longitudinal associations between relationship quality in family/peer domains and suicidal thoughts and behaviors among youth with BD. Thus, we investigated how between-person differences - reflecting the average relationship quality across time - and within-person changes, reflecting recent fluctuations in relationship quality, act as distal and/or proximal risk factors for suicidal ideation (SI) and suicide attempts. Methods We used longitudinal data from the Course and Outcome of Bipolar Youth Study (N = 413). Relationship quality variables were decomposed into stable (i.e., average) and varying (i.e., recent) components and entered, along with major clinical covariates, into separate Bayesian multilevel models predicting SI and suicide attempt. We also examined how the relationship quality effects interacted with age and sex. Results Poorer average relationship quality with parents (β = -.33, 95% Bayesian highest density interval (HDI) [-0.54, -0.11]) or friends (β = -.33, 95% HDI [-0.55, -0.11]) was longitudinally associated with increased risk of SI but not suicide attempt. Worsening recent relationship quality with parents (β = -.10, 95% HDI [-0.19, -0.03]) and, to a lesser extent, friends (β = -.06, 95% HDI [-0.15, 0.03]) was longitudinally associated with increased risk of SI, but only worsening recent relationship quality with parents was also associated with increased risk of suicide attempt (β = -.15, 95% HDI [-0.31, 0.01]). The effects of certain relationship quality variables were moderated by gender but not age. Conclusions Among youth with BD, having poorer average relationship quality with peers and/or parents represents a distal risk factor for SI but not suicide attempts. Additionally, worsening recent relationship quality with parents may be a time-sensitive indicator of increased risk for SI or suicide attempt.

Markedly increased prevalence of migraine headaches in adolescents with bipolar disorder.

Abstract: OBJECTIVE There is substantial evidence of increased prevalence of migraines, and negative psychiatric correlates of migraines, in adults with bipolar disorder (BD). Given the paucity of data on this topic in youth, we investigated the prevalence and correlates of migraine in a large sample of adolescents with BD. METHOD The study included 165 adolescents with BD-I, -II, or -not otherwise specified (NOS), diagnosed via the KSADS-PL semi-structured interview, and 89 healthy controls (HCs). Non-migraine headache and migraine headache was evaluated using the validated ID-Migraine 3-item screener. RESULTS Although the prevalence of non-migraine headaches did not differ between adolescents with BD (24.2%) and HCs (32.6%; P = .15), migraine was significantly more prevalent among adolescents with BD (38.2%) compared to HCs (3.4%; adjusted odds ratio 14.76, 95% confidence interval 4.39-49.57; P < .001). Within BD, migraine was associated with female sex, BD-II/-NOS subtype, less severe worst past functioning, higher past depression severity, higher self-reported affective lability, higher body mass index, and less use of lithium and second-generation antipsychotics. DISCUSSION Migraine is much more prevalent among adolescents with BD compared to HCs; the magnitude of this association exceeds what has been reported in adult samples. Correlates of migraine in youth BD are similar to those found for adults, including the link with the depressive polarity of BD. Future prospective studies are warranted to evaluate temporal associations between migraine and mood symptoms, and to evaluate neurobiological and cardiovascular underpinnings of these associations.

Antioxidative Defense Genes and Brain Structure in Youth Bipolar Disorder.

Abstract: Background Oxidative stress is implicated in the neuropathology of bipolar disorder (BD). We investigated the association of single-nucleotide polymorphisms (SNPs) in the antioxidative genes superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3) with structural neuroimaging phenotypes in youth BD. Methods SOD2 rs4880 and GPX3 rs3792797 SNP genotypes, along with structural magnetic resonance imaging, were obtained from 147 youth (BD=75; healthy controls (HC)=72). Images were processed using FreeSurfer, yielding surface area, volume, and thickness values for regions of interest (ROI; prefrontal cortex (PFC), caudal anterior cingulate cortex (cACC), hippocampus) and for vertex-wise whole brain analysis. Analyses controlled for age, sex, race, and intracranial volume for volume area, and thickness analyses. Result ROI analyses revealed diagnosis-by-SOD2 rs4880 interaction effects for cACC volume and surface area, and PFC volume; in each case, there was lower volume/area in the BD GG genotype group vs. the HC GG genotype group. There was a significant BD diagnosis x GPX3 rs3793797 interaction effect for PFC surface area, where area was lower in the BD A-allele carrier group vs. the other genotype groups. Vertex-wise analyses revealed significant interaction effects in frontal, temporal, and parietal regions, related to smaller brain structure in the BD SOD2 rs4880 GG group and BD GPX3 rs3793797 A-allele carrier group. Conclusion We found preliminary evidence that SOD2 rs4880 and GPX3 rs3792797 are differentially associated with brain structure in youth with BD, in regions that are relevant to BD. Further studies incorporating additional neuroimaging phenotypes and blood levels of oxidative stress markers are warranted.

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

Abstract: 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.

A commentary on youth onset bipolar disorder.

Abstract: 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.

White matter microstructure in youth at risk for serious mental illness: A comparative analysis.

Abstract: Identifying biomarkers of serious mental illness, such as altered white matter microstructure, can aid in early diagnosis and treatment. White matter microstructure was assessed using constrained spherical deconvolution of diffusion imaging data in a sample of 219 youth (age 12–25 years, 64.84% female) across 8 sites. Participants were classified as healthy controls (HC; n = 47), familial risk for serious mental illness (n = 31), mild-symptoms (n = 37), attenuated syndromes (n = 66), or discrete disorder (n = 38) based on clinical assessments. Fractional anisotropy (FA) and mean diffusivity (MD) values were derived for the whole brain white matter, forceps minor, anterior cingulate, anterior thalamic radiations (ATR), inferior fronto-occipital fasciculus, superior longitudinal fasciculus (SLF), and uncinate fasciculus (UF). Linear mixed effects models showed a significant effect of age on MD of the left ATR, left SLF, and left UF, and a significant effect of group on FA for all tracts examined. For most tracts, the discrete disorder group had significantly lower FA than other groups, and the attenuated syndromes group had higher FA compared to HC, with few differences between the remaining groups. White matter differences in MDD are most evident in individuals following illness onset, as few significant differences were observed in the risk phase.

Substance use in youth at-risk for serious mental illness.

Abstract: Aim The aim of this paper is to describe the substance use of participants who are at-risk for serious mental illness (SMI). Method The Canadian Psychiatric Risk and Outcome study (PROCAN) is a two-site study of 243 youth and young adults aged 13 to 25 years, categorized into four groups: healthy controls (n = 42), stage 0 (asymptomatic individuals with risk of SMI typically family high risk; n = 41), stage 1a (distress disorder or mild symptoms of anxiety or depression; n = 53) and stage 1b (attenuated syndromes, including bipolar disorder or psychosis; n = 107). Substance use measures were administered at baseline, 6- and 12-months. Results At baseline, the most commonly reported substance used in the past month was alcohol (43.6%), followed by cannabis (14.4%) and tobacco (12.4%). There were no significant group differences in use. 42.4% of all participants reported ever using cannabis in their lifetime, whereas 21.4% reported currently using cannabis. There were no group differences in ever having used cannabis. Regarding lifetime substance abuse disorders, cannabis use disorder (5.7%) and alcohol use disorder (4.5%) were the most common and more often reported in stage 1b participants relative to other groups. Furthermore, alcohol, cannabis and tobacco use remained relatively consistent at 6- and 12-month follow-ups when compared to baseline use. Conclusion Alcohol was the most commonly used substance followed by cannabis and tobacco. Although substance use did not differ between those at different stages of risk, overall prevention strategies are still warranted for youth at-risk for SMI, especially those who are more symptomatic and potentially at greater risk of developing an SMI.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations.

Abstract: Objectives The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided- a critical gap which the current update aims to address. Method Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. Results No agents met threshold for first line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first line, and lithium and olanzapine identified as second line options. Conclusion The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.

Neurostructural correlates of BDNF rs6265 genotype in youth bipolar disorder.

Abstract: Objective Brain-derived neurotrophic factor (BDNF) rs6265 single-nucleotide polymorphism has been associated with bipolar disorder (BD), and with brain structure among adults with BD. We set out to investigate the association of the BDNF rs6265 Met allele with neurostructural phenotypes in youth BD. Methods Caucasian youth (N = 99; 13-20 years; n = 56 BD, n = 43 age and sex-matched healthy controls) underwent 3-Tesla Magnetic Resonance Imaging and genotyping for BDNF rs6265. Region of interest (ROI) analyses of the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and hippocampus were complemented by vertex-wise analyses examining cortical thickness, surface area (SA) and volume. Multivariable models included the main effects of diagnosis and gene, and a diagnosis-by-genotype interaction term, controlling for age, sex, and intracranial volume. Results There were no significant gene main effects or diagnosis-by-gene interaction effects in ROI analyses. The vertex-wise analysis yielded a significant gene main effect whereby Met allele carriers had greater middle temporal gyrus SA (p = 0.001) and supramarginal gyrus volume (p = 0.03) than Val/Val individuals. Significant interaction effects were found on lateral occipital lobe SA (p = 0.03), whereby the Met allele was associated with increased SA in BD only. Interaction effects were also found on postcentral gyrus SA (p = 0.049) and supramarginal gyrus SA (p = 0.04), with smaller SA in BD Met carriers versus healthy control Met carriers. Conclusion These findings suggest that BDNF rs6265 is differentially associated with regional SA in youth BD. Further investigation is warranted to evaluate whether BDNF protein levels mediate the observed effects, and to evaluate rs6265-related developmental changes.

Bipolar disorder and cardiovascular dysfunction: Mechanisms and implications

Abstract: Premature cardiovascular disease, occurring over a decade earlier in bipolar disorder as compared with the general population, contributes significantly to early mortality. This association cannot be explained by medication use, lifestyle, or traditional cardiovascular risk factors alone. Negative clinical outcomes, including amount of time spent symptomatic, suicide risk, and number of psychiatric comorbidities, are all notably elevated in patients at higher cardiovascular risk. In spite of robust data that support significantly elevated risk and burden within bipolar disorder, clinical training still does not underscore this link, and little focus has been placed on intentionally targeting the vascular system to ameliorate psychiatric symptoms. Numerous emerging cardiovascular biomarkers may help to better explain this vascular-bipolar link and uncover underlying pathophysiology and new treatment targets.