Patterns of pharmacotherapy for bipolar disorder: A GBC survey.

OBJECTIVES: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia. METHODS: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns. RESULTS: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. CONCLUSIONS: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD.

Effects of polygenic risk for suicide attempt and risky behavior on brain structure in young people with familial risk of bipolar disorder.

Bipolar disorder (BD) is associated with a 20-30-fold increased suicide risk compared to the general population. First-degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide-related polygenic risk scores (PRSs)-a quantitative index of genomic risk-and variability in brain structures implicated in SA. Participants (n = 206; aged 12-30 years) were unrelated individuals of European ancestry and comprised three groups: 41 BD cases, 96 BD relatives ("high risk"), and 69 controls. Genotyping employed PsychArray, followed by imputation. Three PRSs were computed using genome-wide association data for SA in BD (SA-in-BD), SA in major depressive disorder (SA-in-MDD) (Mullins et al., 2019, The American Journal of Psychiatry, 176(8), 651-660), and risky behavior (Karlsson Linnér et al., 2019, Nature Genetics, 51(2), 245-257). Structural magnetic resonance imaging processing employed FreeSurfer v5.3.0. General linear models were constructed using 32 regions-of-interest identified from suicide neuroimaging literature, with false-discovery-rate correction. SA-in-MDD and SA-in-BD PRSs negatively predicted parahippocampal thickness, with the latter association modified by group membership. SA-in-BD and Risky Behavior PRSs inversely predicted rostral and caudal anterior cingulate structure, respectively, with the latter effect driven by the "high risk" group. SA-in-MDD and SA-in-BD PRSs positively predicted cuneus structure, irrespective of group. This study demonstrated associations between PRSs for suicide-related phenotypes and structural variability in brain regions implicated in SA. Future exploration of extended PRSs, in conjunction with a range of biological, phenotypic, environmental, and experiential data in high risk populations, may inform predictive models for suicidal behaviors.

Connectomics of bipolar disorder: a critical review, and evidence for dynamic instabilities within interoceptive networks.

The notion that specific cognitive and emotional processes arise from functionally distinct brain regions has lately shifted toward a connectivity-based approach that emphasizes the role of network-mediated integration across regions. The clinical neurosciences have likewise shifted from a predominantly lesion-based approach to a connectomic paradigm-framing disorders as diverse as stroke, schizophrenia (SCZ), and dementia as "dysconnection syndromes". Here we position bipolar disorder (BD) within this paradigm. We first summarise the disruptions in structural, functional and effective connectivity that have been documented in BD. Not surprisingly, these disturbances show a preferential impact on circuits that support emotional processes, cognitive control and executive functions. Those at high risk (HR) for BD also show patterns of connectivity that differ from both matched control populations and those with BD, and which may thus speak to neurobiological markers of both risk and resilience. We highlight research fields that aim to link brain network disturbances to the phenotype of BD, including the study of large-scale brain dynamics, the principles of network stability and control, and the study of interoception (the perception of physiological states). Together, these findings suggest that the affective dysregulation of BD arises from dynamic instabilities in interoceptive circuits which subsequently impact on fear circuitry and cognitive control systems. We describe the resulting disturbance as a "psychosis of interoception".

Correction: Connectomics of bipolar disorder: a critical review, and evidence for dynamic instabilities within interoceptive networks.

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Clinical predictors of conversion to bipolar disorder in a prospective longitudinal familial high-risk sample: focus on depressive features.

BACKGROUND: Identifying clinical features that predict conversion to bipolar disorder (BD) in those at high familial risk (HR) would assist in identifying a more focused population for early intervention. METHOD: In total 287 participants aged 12-30 (163 HR with a first-degree relative with BD and 124 controls (CONs)) were followed annually for a median of 5 years. We used the baseline presence of DSM-IV depressive, anxiety, behavioural and substance use disorders, as well as a constellation of specific depressive symptoms (as identified by the Probabilistic Approach to Bipolar Depression) to predict the subsequent development of hypo/manic episodes. RESULTS: At baseline, HR participants were significantly more likely to report ⩾4 Probabilistic features (40.4%) when depressed than CONs (6.7%; p < .05). Nineteen HR subjects later developed either threshold (n = 8; 4.9%) or subthreshold (n = 11; 6.7%) hypo/mania. The presence of ⩾4 Probabilistic features was associated with a seven-fold increase in the risk of 'conversion' to threshold BD (hazard ratio = 6.9, p < .05) above and beyond the fourteen-fold increase in risk related to major depressive episodes (MDEs) per se (hazard ratio = 13.9, p < .05). Individual depressive features predicting conversion were psychomotor retardation and ⩾5 MDEs. Behavioural disorders only predicted conversion to subthreshold BD (hazard ratio = 5.23, p < .01), while anxiety and substance disorders did not predict either threshold or subthreshold hypo/mania. CONCLUSIONS: This study suggests that specific depressive characteristics substantially increase the risk of young people at familial risk of BD going on to develop future hypo/manic episodes and may identify a more targeted HR population for the development of early intervention programs.

Prevalence of psychopathology in bipolar high-risk offspring and siblings: a meta-analysis.

This meta-analysis aimed to update existing data on the comparison of prevalence rates of psychopathology primarily among offspring with at least one parent with bipolar disorder (BD) and offspring of parents without psychiatric illness. Seventeen studies were derived from a systematic search of PsychInfo, Medline, Scopus and Embase. Inclusion criteria were use of a control offspring group, standardized diagnostic procedures and reporting of clear frequency data. Risk of psychopathology was estimated by aggregating frequency data from selected studies. Compared to control offspring, high-risk BD offspring are nine times more likely to have a bipolar-type disorder, almost two and a half times more likely to develop a non-BD affective disorder and over two times more likely to develop at least one anxiety disorder. High-risk offspring also showed a significant increased risk of other non-mood psychopathology such as attention deficit hyperactivity disorder (ADHD), any type of behavioral disorder and substance use disorder (SUDs). Risk of developing a broad range of affective and non-affective psychopathology is significantly higher in high-risk BD offspring. Identifying clinical presentations of this genetically high-risk cohort is important in establishing appropriate preventative treatment.

Consistency-based thresholding of the human connectome.

Densely seeded probabilistic tractography yields weighted networks that are nearly fully connected, hence containing many spurious fibers. It is thus necessary to prune spurious connections from probabilistically-derived networks to obtain a more reliable overall estimate of the connectivity. A standard method is to threshold by weight, keeping only the strongest edges. Here, by measuring the consistency of edge weights across subjects, we propose a new thresholding method that aims to reduce the rate of false-positives in group-averaged connectivity matrices. Close inspection of the relationship between consistency, weight, and distance suggests that the most consistent edges are in fact those that are strong for their length, rather than simply strong overall. Hence retaining the most consistent edges preserves more long-distance connections than traditional weight-based thresholding, which penalizes long connections for being weak regardless of anatomy. By comparing our thresholded networks to mouse and macaque tracer data, we also show that consistency-based thresholding exhibits the species-invariant exponential decay of connection weights with distance, while weight-based thresholding does not. We also show that consistency-based thresholding can be used to identify highly consistent and highly inconsistent subnetworks across subjects, enabling more nuanced analyses of group-level connectivity than just the mean connectivity.

Substance use disorders in adolescent and young adult relatives of probands with bipolar disorder: What drives the increased risk?

BACKGROUND: Adults with bipolar disorder (BD) have higher rates of substance use disorders (SUDs) compared to the general population. SUD rates in young offspring/relatives of BD probands, as well as factors which drive those rates, are not as well-characterized. METHODS: We aimed to examine SUD prevalence among adolescent/young adult offspring and relatives of probands with and without BD. Data were collected from five sites in the US and Australia during 2006-2011. Youth offspring/relatives ("Relatives of BD probands;" n=267; mean age=16.8years; ±2.9S.D.), identified through a proband family member with DSM-IV BD (Type I or II), were compared to offspring/relatives of control probands ("relatives of control probands;" n=149; mean age=17.4years; ±2.9S.D.). Logistic regression with generalized estimating equations was used to compare the groups across a range of substance use and SUD variables. Odds ratios were calculated for lifetime prevalence of substance outcomes. RESULTS: Bivariate analyses showed DSM-IV SUDs were more prevalent among relatives of BD probands than among relatives of control probands (29% vs. 18%; p=0.01). Generalized estimating equation models showed BD mood and childhood-onset externalizing disorders in adolescent and young adult relatives to each significantly increase the odds (OR=2.80-3.17; p<0.02) for the development of several substance variables among all relatives, whereas the risk of SUDs in relatives was not increased when the relatives had no mood or externalizing disorders themselves. CONCLUSION: Relatives of BD probands with lifetime mood and externalizing disorders report more substance use/SUDs than relatives of control probands. In contrast, SUD outcomes in relatives of BD probands without mood or externalizing disorders were no different from control relatives without psychopathology. Early recognition and treatment of psychiatric disorders may lead to less substance use in this highly vulnerable population.

Disruptive mood dysregulation disorder, severe mood dysregulation and chronic irritability in youth at high familial risk of bipolar disorder.

OBJECTIVE: Disruptive mood dysregulation disorder is a newly proposed childhood disorder included in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition to describe children ⩽18 years of age with chronic irritability/temper outbursts. This study aimed to examine the prevalence of disruptive mood dysregulation disorder, severe mood dysregulation and chronic irritability in an Australian study of young people at increased familial risk of developing bipolar disorder ('HR' group) and controls ('CON' group). METHODS: A total of 242 12- to 30-year-old HR or CON subjects were administered the severe mood dysregulation module. Of these, 42 were aged ⩽18 years at the time of assessment, with 29 subjects in the HR group and 13 in the CON group. RESULTS: No subjects ⩽18 years - in either group - fulfilled current or lifetime criteria for disruptive mood dysregulation disorder or severe mood dysregulation, the precursor to disruptive mood dysregulation disorder. Similarly, no subjects in either group endorsed the severe mood dysregulation/disruptive mood dysregulation disorder criteria for irritable mood or marked excessive reactivity. One HR participant endorsed three severe mood dysregulation criteria (distractibility, physical restlessness and intrusiveness), while none of the comparison subjects endorsed any criteria. Exploratory studies of the broader 12- to 30-year-old sample similarly found no subjects with severe mood dysregulation/disruptive mood dysregulation disorder in either the HR or CON group and no increased rates of chronic irritability, although significantly more HR subjects reported at least one severe mood dysregulation/disruptive mood dysregulation disorder criterion (likelihood ratio = 6.17; p = 0.013); most of the reported criteria were severe mood dysregulation 'chronic hyper-arousal' symptoms. CONCLUSION: This study comprises one of the few non-US reports on the prevalence of disruptive mood dysregulation disorder and severe mood dysregulation and is the first non-US study of the prevalence of these conditions in a high-risk bipolar disorder sample. The failure to replicate the finding of higher rates of disruptive mood dysregulation disorder and chronic irritability in high-risk offspring suggests that these are not robust precursors of bipolar disorder.

Clinical characteristics of women with reproductive cycle-associated bipolar disorder symptoms.

OBJECTIVE: Although there is clear evidence that reproductive cycle events are associated with mood episodes for women with bipolar disorder, few studies have examined for relationships between these and specific clinical characteristics of the disorder. This study aimed to explore the relationship between mood symptoms associated with reproductive cycle events and features of the disorder indicative of a more severe lifetime course. METHOD: Totally, 158 women of at least 18 years of age participated in the study. Subjects were recruited through a specialist clinic at the Black Dog Institute, Sydney, Australia. RESULTS: In total, 77% of women reported increases in mood symptoms during perimenstrual, postnatal or menopausal periods. These women had an earlier age of onset for depressive and hypo/manic episodes and a greater likelihood of comorbid anxiety disorders, rapid cycling and mixed mood compared to those who did not report such reproductive cycle-associated mood changes. Women who experienced postnatal episodes were also more likely to experience worse mood symptoms perimenstrually and menopausally. CONCLUSION: First, reproductive cycle event-related worsening of mood was associated with a more severe lifetime course of bipolar disorder, and, second, it appears that some women have a greater propensity to mood worsening at each of these reproductive cycle events. If replicated, these findings provide important information for clinicians treating women with reproductive cycle event mood changes and highlight the need for improved therapeutics for such presentations.

The contribution of geometry to the human connectome.

The human connectome is a topologically complex, spatially embedded network. While its topological properties have been richly characterized, the constraints imposed by its spatial embedding are poorly understood. By applying a novel resampling method to tractography data, we show that the brain's spatial embedding makes a major, but not definitive, contribution to the topology of the human connectome. We first identify where the brain's structural hubs would likely be located if geometry was the sole determinant of brain topology. Empirical networks show a widespread shift away from this geometric center toward more peripheral interconnected skeletons in each hemisphere, with discrete clusters around the anterior insula, and the anterior and posterior midline regions of the cortex. A relatively small number of strong inter-hemispheric connections assimilate these intra-hemispheric structures into a rich club, whose connections are locally more clustered but globally longer than predicted by geometry. We also quantify the extent to which the segregation, integration, and modularity of the human brain are passively inherited from its geometry. These analyses reveal novel insights into the influence of spatial geometry on the human connectome, highlighting specific topological features that likely confer functional advantages but carry an additional metabolic cost.

Network dysfunction of emotional and cognitive processes in those at genetic risk of bipolar disorder.

The emotional and cognitive vulnerabilities that precede the development of bipolar disorder are poorly understood. The inferior frontal gyrus-a key cortical hub for the integration of cognitive and emotional processes-exhibits both structural and functional changes in bipolar disorder, and is also functionally impaired in unaffected first-degree relatives, showing diminished engagement during inhibition of threat-related emotional stimuli. We hypothesized that this functional impairment of the inferior frontal gyrus in those at genetic risk of bipolar disorder reflects the dysfunction of broader network dynamics underlying the coordination of emotion perception and cognitive control. To test this, we studied effective connectivity in functional magnetic resonance imaging data acquired from 41 first-degree relatives of patients with bipolar disorder, 45 matched healthy controls and 55 participants with established bipolar disorder. Dynamic causal modelling was used to model the neuronal interaction between key regions associated with fear perception (the anterior cingulate), inhibition (the left dorsolateral prefrontal cortex) and the region upon which these influences converge, namely the inferior frontal gyrus. Network models that embodied non-linear, hierarchical relationships were the most strongly supported by data from our healthy control and bipolar participants. We observed a marked difference in the hierarchical influence of the anterior cingulate on the effective connectivity from the dorsolateral prefrontal cortex to the inferior frontal gyrus that is unique to the at-risk cohort. Non-specific, non-hierarchical mechanisms appear to compensate for this network disturbance. We thus establish a specific network disturbance suggesting dysfunction in the processes that support hierarchical relationships between emotion and cognitive control in those at high genetic risk for bipolar disorder.

The organisation of the elderly connectome.

Investigations of the human connectome have elucidated core features of adult structural networks, particularly the crucial role of hub-regions. However, little is known regarding network organisation of the healthy elderly connectome, a crucial prelude to the systematic study of neurodegenerative disorders. Here, whole-brain probabilistic tractography was performed on high-angular diffusion-weighted images acquired from 115 healthy elderly subjects (age 76-94 years; 65 females). Structural networks were reconstructed between 512 cortical and subcortical brain regions. We sought to investigate the architectural features of hub-regions, as well as left-right asymmetries, and sexual dimorphisms. We observed that the topology of hub-regions is consistent with a young adult population, and previously published adult connectomic data. More importantly, the architectural features of hub connections reflect their ongoing vital role in network communication. We also found substantial sexual dimorphisms, with females exhibiting stronger inter-hemispheric connections between cingulate and prefrontal cortices. Lastly, we demonstrate intriguing left-lateralized subnetworks consistent with the neural circuitry specialised for language and executive functions, whilst rightward subnetworks were dominant in visual and visuospatial streams. These findings provide insights into healthy brain ageing and provide a benchmark for the study of neurodegenerative disorders such as Alzheimer's disease (AD) and frontotemporal dementia (FTD).

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At-Risk Individuals.

Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European-ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12-30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty-two disease-associated SNPs from the PGC-BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10(-5) , AUC = 0.60). In families with a high-polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at-risk youth, regardless of affected status, compared to unrelated controls (GEE-χ(2) = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease-associated variants than unrelated controls and first-degree relatives, and illustrate the potential utility of PRS assessment in a family context.

Rejection sensitivity and pain in bipolar versus unipolar depression.

OBJECTIVES: Recent neuroimaging studies support the contention that depression, pain distress, and rejection distress share the same neurobiological circuits. In two recently published studies we confirmed the hypothesis that the perception of increased pain during both treatment-refractory depression (predominantly unipolar) and difficult-to-treat bipolar depression was related to increased state rejection sensitivity (i.e., rejection sensitivity when depressed). In the present study, we aimed to compare the correlates of pain and rejection sensitivity in individuals with bipolar versus unipolar depression and test the hypothesis that bipolar disorder may be distinguished from unipolar depression both by an increased perception of pain and heightened rejection sensitivity during depression. METHODS: We analyzed data from 113 bipolar and 146 unipolar depressed patients presenting to the Black Dog Institute, Sydney, Australia. The patients all met DSM-IV criteria for bipolar disorder or unipolar depression (major depressive disorder). RESULTS: Bipolar disorder predicted a major increase in state rejection sensitivity when depressed (p = 0.001), whereas trait rejection sensitivity (i.e., a long-standing pattern of rejection sensitivity) was not predicted by polarity. A major increase in the experience of headaches (p = 0.007), chest pain (p < 0.001), and body aches and pains (p = 0.02) during depression was predicted by a major increase in state rejection sensitivity for both bipolar and unipolar depression. CONCLUSIONS: State, but not trait, rejection sensitivity is significantly predicted by bipolar depression, suggesting that this might be considered as a state marker for bipolar depression and taken into account in the clinical differentiation of bipolar and unipolar depression.

Cognitive styles and clinical correlates of childhood abuse in bipolar disorder.

OBJECTIVES: In a relatively small number of previous studies, childhood abuse has been found to be associated with more severe symptom course, earlier onset, greater comorbidity, and greater suicidality in those diagnosed with bipolar disorder. There have been no prior reports looking for any association between childhood abuse and cognitive style. This study aimed to examine the relationship between cognitive factors, such as response styles to depressed mood and dysfunctional attitudes, clinical features, and childhood physical and sexual abuse in this population. METHODS: A total of 157 adult participants diagnosed with DSM-IV bipolar disorder I or II were assessed on clinical features of this condition and measures of childhood sexual and physical abuse. Participants also completed self-report questionnaires covering areas such as symptom measures of depression, anxiety and stress, dysfunctional attitudes, and response styles to depressed mood. RESULTS: Seventy-four participants (37%) reported having experienced either sexual or physical abuse. Those who reported physical or sexual abuse were significantly more likely to report self-harm or suicidal behaviors and showed higher stress scores. Specifically, those who reported sexual abuse were more likely to have simple phobias, to have attempted suicide, and to have had more hospitalizations for depression. After controlling for current mood severity, there were no significant differences on the self-report cognitive style measures for those who reported childhood sexual or physical abuse compared to those who did not report abuse. CONCLUSIONS: Cognitive styles were not found to be associated with childhood sexual or physical abuse in participants with bipolar disorder. Stress may be important to target in psychological interventions, whilst special attention should also be paid to those with a history of sexual abuse given the greater likelihood of suicide attempt.

Family environment and polygenic risk in the bipolar high-risk context.

Background: The interaction of polygenic risk (PRS) and environmental effects on development of bipolar disorder (BD) is understudied, as are high-risk offspring perceptions of their family environment (FE). We tested the association of offspring-perceived FE in interaction with BD-PRS on liability for BD in offspring at high or low familial risk for BD. Methods: Offspring of a parent with BD (oBD; n = 266) or no psychiatric disorders (n = 174), aged 12-21 at recruitment, participated in the US and Australia. Empirically-derived profiles of FE classified offspring by their perceived levels of familial cohesion, flexibility, and conflict. Offspring BD-PRS were derived from Psychiatric Genomics Consortium BD-GWAS. Lifetime DSM-IV bipolar disorders were derived from the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. We used a novel stepwise approach for latent class modeling with predictors and distal outcomes. Results: Fifty-two offspring were diagnosed with BD. For those with well-functioning FE (two-thirds of the sample), higher BD-PRS tracked positively with liability for BD. However, for those with high-conflict FEs, the relationship between BD-PRS and liability to BD was negative, with highest risk for BD observed with lower BD-PRS. In exploratory analyses, European-ancestry offspring with BD had elevated history of suicidal ideation in high-conflict FE compared to well-functioning-FE, and of suicide attempt with low-BD-PRS and high-conflict FE. Conclusions: The data suggest that the relationship of BD-PRS and offspring liability for BD differed between well-functioning versus high-conflict FE, potentially in line with a multifactorial liability threshold model and supporting future study of and interventions improving family dynamics.

Multi-Site Statistical Mapping of Along-Tract Microstructural Abnormalities in Bipolar Disorder with Diffusion MRI Tractometry.

Investigating alterations in brain circuitry associated with bipolar disorder (BD) may offer a valuable approach to discover brain biomarkers for genetic and interventional studies of the disorder and related mental illnesses. Some diffusion MRI studies report evidence of microstructural abnormalities in white matter regions of interest, but we lack a fine-scale spatial mapping of brain microstructural differences along tracts in BD. We also lack large-scale studies that integrate tractometry data from multiple sites, as larger datasets can greatly enhance power to detect subtle effects and assess whether effects replicate across larger international datasets. In this multisite diffusion MRI study, we used BUndle ANalytics (BUAN, Chandio 2020), a recently developed analytic approach for tractography, to extract, map, and visualize profiles of microstructural abnormalities on 3D models of fiber tracts in 148 participants with BD and 259 healthy controls from 6 independent scan sites. Modeling site differences as random effects, we investigated along-tract white matter (WM) microstructural differences between diagnostic groups. QQ plots showed that group differences were gradually enhanced as more sites were added. Using the BUAN pipeline, BD was associated with lower mean fractional anisotropy (FA) in fronto-limbic, interhemispheric, and posterior pathways; higher FA was also noted in posterior bundles, relative to controls. By integrating tractography and anatomical information, BUAN effectively captures unique effects along white matter (WM) tracts, providing valuable insights into anatomical variations that may assist in the classification of diseases.

Polygenic Scores and Onset of Major Mood or Psychotic Disorders Among Offspring of Affected Parents.

OBJECTIVE: Family history is an established risk factor for mental illness. The authors sought to investigate whether polygenic scores (PGSs) can complement family history to improve identification of risk for major mood and psychotic disorders. METHODS: Eight cohorts were combined to create a sample of 1,884 participants ages 2-36 years, including 1,339 offspring of parents with mood or psychotic disorders, who were prospectively assessed with diagnostic interviews over an average of 5.1 years. PGSs were constructed for depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuroticism, subjective well-being, p factor, and height (as a negative control). Cox regression was used to test associations between PGSs, family history of major mental illness, and onsets of major mood and psychotic disorders. RESULTS: There were 435 onsets of major mood and psychotic disorders across follow-up. PGSs for neuroticism (hazard ratio=1.23, 95% CI=1.12-1.36), schizophrenia (hazard ratio=1.15, 95% CI=1.04-1.26), depression (hazard ratio=1.11, 95% CI=1.01-1.22), ADHD (hazard ratio=1.10, 95% CI=1.00-1.21), subjective well-being (hazard ratio=0.90, 95% CI=0.82-0.99), and p factor (hazard ratio=1.14, 95% CI=1.04-1.26) were associated with onsets. After controlling for family history, neuroticism PGS remained significantly positively associated (hazard ratio=1.19, 95% CI=1.08-1.31) and subjective well-being PGS remained significantly negatively associated (hazard ratio=0.89, 95% CI=0.81-0.98) with onsets. CONCLUSIONS: Neuroticism and subjective well-being PGSs capture risk of major mood and psychotic disorders that is independent of family history, whereas PGSs for psychiatric illness provide limited predictive power when family history is known. Neuroticism and subjective well-being PGSs may complement family history in the early identification of persons at elevated risk.

Longitudinal Changes in Structural Connectivity in Young People at High Genetic Risk for Bipolar Disorder.

OBJECTIVE: Recent studies of patients with bipolar disorder or at high genetic risk reveal structural dysconnections among key brain networks supporting cognitive and affective processes. Understanding the longitudinal trajectories of these networks across the peak age range of bipolar disorder onset could inform mechanisms of illness onset or resilience. METHODS: Longitudinal diffusion-weighted MRI and phenotypic data were acquired at baseline and after 2 years in 183 individuals ages 12-30 years in two cohorts: 97 unaffected individuals with a first-degree relative with bipolar disorder (the high-risk group) and 86 individuals with no family history of mental illness (the control group). Whole-brain structural networks were derived using tractography, and longitudinal changes in these networks were studied using network-based statistics and mixed linear models. RESULTS: Both groups showed widespread longitudinal changes, comprising both increases and decreases in structural connectivity, consistent with a shared neurodevelopmental process. On top of these shared changes, high-risk participants showed weakening of connectivity in a network encompassing the left inferior and middle frontal areas, left striatal and thalamic structures, the left fusiform, and right parietal and occipital regions. Connections among these regions strengthened in the control group, whereas they weakened in the high-risk group, shifting toward a cohort with established bipolar disorder. There was marginal evidence for even greater network weakening in those who had their first manic or hypomanic episode before follow-up. CONCLUSIONS: Neurodevelopment from adolescence into early adulthood is associated with a substantial reorganization of structural brain networks. Differences in these maturational processes occur in a multisystem network in individuals at high genetic risk of bipolar disorder. This may represent a novel candidate to understand resilience and predict conversion to bipolar disorder.