Bipolar Disorder Subgroups Research Articles

A meta-analysis of data-driven cognitive subgroups in bipolar disorder

The delineation of cognitive subgroups of bipolar disorder (BD) might be helpful for identifying biologically valid subtypes of this disorder. This meta-analysis identified peer-reviewed literature on studies investigating cognitive subgroups of BD with data-driven clustering methods. Relevant studies were searched in PubMed, Scopus, and Web of Science. Random-effects meta-analysis was performed using R software. A total of 14 cross-sectional studies including euthymic or mildly symptomatic patients with BD were included in the current meta-analysis. The available studies have consistently supported a 3-cluster solution. The pooled prevalence of the severe-impairment, moderate-impairment, and major good-functioning groups were 23.1 % (95%CI, 18.5 %–27.7 %), 42.5 % (95%CI, 36.3 %–48.8 %), and 33.5 % (95%CI, 25.9 %–41.1 %) respectively. Compared to healthy controls, both the severe-impairment (g=−1.40 to −1.73) and moderate-impairment groups (g=−0.59 to −0.96) had significant deficits in all six cognitive domains (verbal memory, visual memory, executive functions, working memory, attention and processing speed). The good-performance subgroup had a small increase in the performance of executive functions (g=0.23) and normal functioning in all other domains. Compared to the good-performance subgroup, the severe-impairment subgroup was characterized by more severe functional impairment, more hospital admissions, a higher percentage of type I BD and antipsychotic use. The characteristics of the moderate-impairment subgroup were lying between the other two subgroups for most of the measures. The current findings support the existence of 3 cognitive subgroups in BD including severe-impairment and moderate-impairment groups which are associated with a more severe course of illness.

White matter microstructural and inflammation-based subgroups in bipolar disorder II depression differentiate in depressive and psychotic symptoms

BackgroundElevated inflammation and impaired white matter (WM) microstructure have been observed in bipolar disorder (BD). The link between inflammation, WM integrity, and psychiatric symptoms in BD-II depression (BDII-D) remains unknown. We aimed to define BDII-D subgroups through the interplay of inflammation and WM microstructure, and to explore differences in psychiatric symptoms between subgroups, thus offering insight into elucidating the explanatory measures linked to BDII-D. MethodsWM differences were compared between 146 BDII-D individuals and 151 health controls (HCs) by Tract-Based Spatial Statistics. Partial correlation with multiple comparison corrections was used to explore associations between WM, inflammation, and psychiatric symptoms. The canonical correlation analysis metrics of WM and inflammation followed by k-means clustering were used to define WM microstructural-inflammation subgroups of BDII-D. The differences in clinical profiles were compared between the subgroups. ResultsCompared with HCs, BDII-D showed significant WM alterations in the anterior thalamic radiation (ATR), cingulum, forceps, and inferior fronto-occipital fasciculus. In BDII-D, lower fraction anisotropy (FA) within the right ATR and cingulum were significantly associated with higher interleukin-6, while lower FA in the cingulum and lower axial diffusivity in the forceps major exhibited significant links with higher C-reactive protein. Among the subgroups identified, subgroup II characterized by elevated inflammation and impaired WM integrity displayed greater psychiatric symptoms. ConclusionsWM alterations are concentrated in emotional neurocircuits and are linked to inflammation in BDII-D. WM-inflammation subgroups exhibit distinct variations in psychiatric symptoms. Thus, WM alterations and inflammation might be an explanatory process in the pathophysiology of BDII-D.

Prevalence of insulin resistance and its associated factors in drug-naïve patients with bipolar disorder among Han Chinese population

BackgroundMetabolic syndrome (Mets) is commonly seen in bipolar disorder (BD). As the key component and early biological index of Mets, insulin resistance (IR) among BD has received more and more attention. However, little is known about the prevalence of IR and its associated factors in drug-naïve patients with (BD), especially among Han Chinese population.MethodsA cross-sectional study was conducted on 125 drug-naïve patients with bipolar disorder (BD) and 85 healthy controls (HC). The Homeostatic Model Assessment of insulin resistance (HOMA-IR) was calculated, and IR was defined as HOMA-IR greater than the 75th percentile value for health controls (2.35). Clinical characteristics of BD were collected through semi-structural interview performed by a trained interviewer with background of psychiatric education.ResultsAmong the measured anthropocentric variables including BMI, waist circumference, abdomen circumference, hipline, and hip-waist ratio, waist circumference was found to be the most closely related to IR (0R = 1.070, 95%CI = 1.031–1.110, P < 0.001). Male was another factor that was associated with IR (OR = 2.281, 95%CI = 1.107–4.702, P = 0.025). After adjusted for gender and waist circumference, the risk of IR was significantly higher in bipolar disorder than in healthy controls (OR = 2.66, 95%CI = 1.364–5.214, P = 0.004). No significant association was found between IR and any of the observed physical and mental comorbidities, any characteristic of illness course including age onset, number of mixed episodes, types of current state, duration of current episode, duration of illness course, rapid cycling, number of mood episodes, and subgroup of BD. Hypersomnia was the only symptomatic feature that was significantly associated with IR (OR = 0.316, 95%CI = 0.124–0.803, P = 0.016).ConclusionsBipolar disorder increases two-to-three-fold risk of IR, both circumference and male are the risk factors of IR but hypersomnia act as a protective factor.

Supra-second interval timing in bipolar disorder: examining the role of disorder sub-type, mood, and medication status

BackgroundWidely reported by bipolar disorder (BD) patients, cognitive symptoms, including deficits in executive function, memory, attention, and timing are under-studied. Work suggests that individuals with BD show impairments in interval timing tasks, including supra-second, sub-second, and implicit motor timing compared to the neuronormative population. However, how time perception differs within individuals with BD based on disorder sub-type (BDI vs II), depressed mood, or antipsychotic medication-use has not been thoroughly investigated. The present work administered a supra-second interval timing task concurrent with electroencephalography (EEG) to patients with BD and a neuronormative comparison group. As this task is known to elicit frontal theta oscillations, signal from the frontal (Fz) lead was analyzed at rest and during the task.ResultsResults suggest that individuals with BD show impairments in supra-second interval timing and reduced frontal theta power during the task compared to neuronormative controls. However, within BD sub-groups, neither time perception nor frontal theta differed in accordance with BD sub-type, depressed mood, or antipsychotic medication use.ConclusionsThis work suggests that BD sub-type, depressed mood status or antipsychotic medication use does not alter timing profile or frontal theta activity. Together with previous work, these findings point to timing impairments in BD patients across a wide range of modalities and durations indicating that an altered ability to assess the passage of time may be a fundamental cognitive abnormality in BD.

Euthymic and depressed bipolar patients are characterized by different RNA editing patterns in blood

Bipolar disorder (BD) is a worldwide leading cause of disability. Inflammation roles in this disease is well established. ADAR1-mediated RNA editing is one of the key mechanisms regulating the inflammatory response. We have identified a panel of RNA editing-based blood biomarkers which allowed to discriminate unipolar from BD depression with high accuracy. We confirmed here the diagnostic value of this panel in a new cohort of BD patients recruited in Brazil. We also identified new combinations which allow a clear discrimination of BD from healthy controls and among BD subgroups, confirming that RNA editing is a key mechanism in BD.

The longitudinal trajectory of emotional cognition in subgroups of recently diagnosed patients with bipolar disorder

Although cross-sectional studies show heterogeneity in emotional cognition in bipolar disorder (BD), the temporal course within subgroups is unclear. In this prospective, longitudinal study we assessed the trajectories of emotional cognition subgroups within a 16-month follow-up period in recently diagnosed BD patients compared to healthy controls (HC). Recently diagnosed BD patients and HC underwent comprehensive emotional and non-emotional testing at baseline and again at follow-up. We employed hierarchical cluster analysis at baseline to identify homogenous emotional cognition subgroups of patients, and changes across the subgroups of BD and HC were assessed with linear mixed-model analyses. We found two emotional cognition subgroups: subgroup 1 (65%, n = 179), showing heightened negative emotional reactivity in neutral and negative social scenarios and faster recognition of emotional facial expressions than HC (ps<0.001, n = 190), and subgroup 2 (35%, n = 96) showing blunted reactivity in positive social scenarios, impaired emotion regulation, poorer recognition of positive and slower recognition of all facial expressions than HC (ps≤.03). Subgroup 1 exhibited normalization of the initial emotional cognition abnormalities in follow-up. In contrast, subgroup 2 showed a lack of improvement in reactivity positively-valenced emotional information. Patients in subgroup 2 presented more and longer mixed episodes during the follow-up time and were more often prescribed lithium. One third of patients display blunted emotional reactivity, impaired emotion regulation abilities and facial expression recognition difficulties also show persistent impairments and poorer course of illness. This subgroup may indicate a need for earlier and more targeted therapeutic interventions.

Definition of early age at onset in bipolar disorder according to distinctive neurodevelopmental pathways: insights from the FACE-BD study.

Converging evidence suggests that a subgroup of bipolar disorder (BD) with an early age at onset (AAO) may develop from aberrant neurodevelopment. However, the definition of early AAO remains unprecise. We thus tested which age cut-off for early AAO best corresponds to distinguishable neurodevelopmental pathways. We analyzed data from the FondaMental Advanced Center of Expertise-Bipolar Disorder cohort, a naturalistic sample of 4421 patients. First, a supervised learning framework was applied in binary classification experiments using neurodevelopmental history to predict early AAO, defined either with Gaussian mixture models (GMM) clustering or with each of the different cut-offs in the range 14 to 25 years. Second, an unsupervised learning approach was used to find clusters based on neurodevelopmental factors and to examine the overlap between such data-driven groups and definitions of early AAO used for supervised learning. A young cut-off, i.e. 14 up to 16 years, induced higher separability [mean nested cross-validation test AUROC = 0.7327 (± 0.0169) for ⩽16 years]. Predictive performance deteriorated increasing the cut-off or setting early AAO with GMM. Similarly, defining early AAO below 17 years was associated with a higher degree of overlap with data-driven clusters (Normalized Mutual Information = 0.41 for ⩽17 years) relatively to other definitions. Early AAO best captures distinctive neurodevelopmental patterns when defined as ⩽17 years. GMM-based definition of early AAO falls short of mapping to highly distinguishable neurodevelopmental pathways. These results should be used to improve patients' stratification in future studies of BD pathophysiology and biomarkers.

Predominant polarity as a neurobiological specifier in bipolar disorder: Evidence from a multimodal neuroimaging study

BackgroundWhile predominant (PP) and onset polarity (OP) have considerable clinical and treatment implications in bipolar disorder (BD), the neurobiological underpinnings of PP and OP from a radiological perspective remain largely unknown. The main objective of this study is to investigate the neuroanatomical profile of polarity subphenotypes (PP and OP) in euthymic BD patients, using a standardized multimodal neuroimaging protocol to evaluate regional gray matter (GM) volumes, cortical thickness, as well as white matter (WM) integrity of major projection, commissural and association tracts. MethodsForty-two euthymic BD patients stratified for PP and OP and 42 healthy controls (HC) were included in this computational neuroimaging study to comprehensively characterize gray and white matter alterations. Univariate analyses of covariance (ANCOVAs) were conducted with Bonferroni corrections for each MRI modality and Cohen's d effect sizes were calculated for group comparisons. ResultsPhenotype-associated cortical thickness abnormalities and volumetric alterations were identified, but no WM changes ascertained. Specifically, we found a main effect of OP on GM volume of left middle frontal gyrus and of OP and PP (either or both) on cortical thickness of various regions previously implicated in BD, i.e. inferior frontal gyrus-pars opercularis (left) and pars orbitalis (bilateral), left lateral orbitofrontal gyrus, bilateral medial segment of the superior frontal gyrus, left planum polare, right anterior cingulate gyrus, left anterior and posterior insula, bilateral frontal operculum (both OP and PP); left anterior and posterior orbitofrontal gyrus, left transverse temporal gyrus, right posterior insula (only OP); and right medial frontal cortex (only PP). Based on the magnitude of differences on pairwise comparisons, we found a large effect of OP on cortical thickness in a single region (left anterior orbitofrontal gyrus) (OP-M > OP-D), while PP subgroups showed large or medium effect size differences in cortical thickness (PP-M > PP-D) in a wider array of regions (right medial frontal cortex, left frontal operculum, left inferior frontal gyrus-pars opercularis, bilateral medial segment of the superior frontal gyrus). For most regions, PP-D patients showed the greatest decreases in cortical thickness compared to HC while PP-M showed the smallest, with PP-U showing an “unspecified” pattern mostly lying in-between PP-D and PP-M. ConclusionsOur multimodal imaging findings suggest specific polarity BD subgroups with compromised cortical thickness; we recorded a greater impact of PP on brain structure compared to OP, which provides additional evidence that PP can be considered as a neurobiological specifier in BD.

Differential genetic associations and expression of PAPST1/SLC35B2 in bipolar disorder and schizophrenia

Lithium's inhibitory effect on enzymes involved in sulfation process, such as inhibition of 3'(2')-phosphoadenosine 5'-phosphate (PAP) phosphatase, is a possible mechanism of its therapeutic effect for bipolar disorder (BD). 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is translocated from cytosol to Golgi lumen by PAPS transporter 1 (PAPST1/SLC35B2), where it acts as a sulfa donor. Since SLC35B2 was previously recognized as a molecule that facilitates the release of D-serine, a co-agonist of N-methyl-D-aspartate type glutamate receptor, altered function of SLC35B2 might be associated with the pathophysiology of BD and schizophrenia (SCZ). We performed genetic association analyses of the SLC35B2 gene using Japanese cohorts with 366 BD cases and 370 controls and 2012 SCZ cases and 2170 controls. We then investigated expression of SLC35B2 mRNA in postmortem brains by QPCR using a Caucasian cohort with 33 BD and 34 SCZ cases and 34 controls and by in situ hybridization using a Caucasian cohort with 37 SCZ and 29 controls. We found significant associations between three SNPs (rs575034, rs1875324, and rs3832441) and BD, and significantly reduced SLC35B2 mRNA expression in postmortem dorsolateral prefrontal cortex (DLPFC) of BD. Moreover, we observed normalized SLC35B2 mRNA expression in BD subgroups who were medicated with lithium. While there was a significant association of SLC35B2 with SCZ (SNP rs2233437), its expression was not changed in SCZ. These findings indicate that SLC35B2 might be differentially involved in the pathophysiology of BD and SCZ by influencing the sulfation process and/or glutamate system in the central nervous system.

Characterization of clinical features and comorbidities between bipolar affective disorder with and without depressive episodes.

A proportion of patients with bipolar disorder (BD) manifests with only unipolar mania (UM). This study examined relevant clinical features and psychosocial characteristics in UM compared with depressive-manic (D-M) subgroups. Moreover, comorbidity patterns of physical conditions and psychiatric disorders were evaluated between the UM and D-M groups. This clinical retrospective study (N = 1015) analyzed cases with an average of 10 years of illness duration and a nationwide population-based cohort (N = 8343) followed up for 10 years in the Taiwanese population. UM was defined as patients who did not experience depressive episodes and were not prescribed adequate antidepressant treatment during the disease course of BD. Logistic regression models adjusted for relevant covariates were used to evaluate the characteristics and lifetime comorbidities in the two groups. The proportion of UM ranged from 12.91% to 14.87% in the two datasets. Compared with the D-M group, the UM group had more psychotic symptoms, fewer suicidal behaviors, a higher proportion of morningness chronotype, better sleep quality, higher extraversion, lower neuroticism, and less harm avoidance personality traits. Substantially different lifetime comorbidity patterns were observed between the two groups. Patients with UM exhibited distinct clinical and psychosocial features compared with patients with the D-M subtype. In particular, a higher risk of comorbid cardiovascular diseases and anxiety disorders is apparent in patients with D-M. Further studies are warranted to investigate the underlying mechanisms for diverse presentations in subgroups of BDs.

Temperament and character dimensions as psychological markers of mood disorders in Polish adolescents and young adults-A prospective study.

An increasing incidence of mood disorders in adolescents and young adults is being observed. The assessment of personality traits seems to be an interesting tool in identifying early markers of major depression (MD) or bipolar disorder (BD) as well as predictors of the course of the disease. The aim of this study was to compare the personality profiles in young patients with MD and BD in acute and remitted mood states. Seventy-nine adolescents and young adults with mood disorder diagnoses (MD or BD) were included in the study. The participants were assessed based on structured diagnostic interviews and completed the Temperament and Character Inventory (TCI). The clinical evaluation was conducted during the acute episodes and after reaching the stabilized mood in the course of follow-up visits in a 2-year study observation. At baseline, MD patients had higher scores on the harm avoidance (HA) with more pronounced anticipatory worry and fatigability subscale than BD patients. Conversely, BD patients reached higher scores in the total self-directedness (SD) character dimension and its sub-dimensions. MD patients with acute depressive symptoms had higher scores in the HA dimension and its subscale: anticipatory worry, shyness, and fatigability compared with their euthymic states. No significant differences in TCI dimensions between baseline and euthymia in the BD subgroup were found, and no differences between euthymic MD and BD patients. Higher ST and SD sub-dimensions may constitute a personality profile specific to BD, while high HA seems to be related to major depression in both acute and remitted states in young patients.

The Correlation of Reduced Fractional Anisotropy in the Cingulum With Suicide Risk in Bipolar Disorder.

Objective: This study aims to investigate the significant alterations in brain white matter integrity in individuals with bipolar disorder (BD) who had attempted suicide by applying a tract-based spatial statistics (TBSS) approach with tensor-based spatial normalization.Methods: A TBSS approach with novel tensor-based registration was used to compare the white matter fractional anisotropy (FA) between 51 individuals with BD, of whom 19 had attempted suicide, and 43 healthy controls (HC). The suicide attempt was assessed with the Columbia-Suicide Severity Rating Scale (C-SSRS). In addition, we also investigated the correlations of FA values with clinical measures in BD, including illness duration, and the severity of depression and anxiety measured by the Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA), respectively.Results: A significant reduction of FA value in the hippocampal cingulum was observed in BD individuals who had attempted suicide compared with those who had not. For the genu/body of the corpus callosum, inferior fronto-occipital fasciculus, uncinate fasciculus, and anterior thalamic radiation, the reductions in FA values were significantly greater in both BD subgroups who attempted suicide and who did not, compared to HC. The correlation analysis showed that the illness duration of attempters was correlated to the FA value of the genu of the corpus callosum, while the HAMD and HAMA scores of non-attempters were relevant to the FA of the superior longitudinal fasciculus.Conclusion: The observation that white matter integrity was altered in the hippocampal cingulum in BD individuals who attempted suicide suggested that this brain area may be the neurobiological basis of suicide attempts. Our findings also support the involvement of white matter (WM) microstructure of frontal–subcortical circuits in the neurobiological mechanism of BD. In addition, the illness duration of patients with attempted suicide may have an effect on the altered integrity of the corpus callosum.

Validation of the youth mood recurrences risk calculator in an adult sample with bipolar disorder

BackgroundThe ability to predict an individual's risk of mood episode recurrence can facilitate personalized medicine in bipolar disorder (BD). We sought to externally validate, in an adult sample, a risk calculator of mood episode recurrence developed in youth/young adults with BD from the Course and Outcome of Bipolar Youth (COBY) study. MethodsAdult participants from the National Institute of Mental Health Collaborative Depression Study (CDS; N=258; mean(SD) age=35.5(12.0) years; mean follow-up=24.9 years) were utilized as a sample to validate the youth COBY risk calculator for onset of depressive, manic, or any mood episodes. ResultsIn this older validation sample, the risk calculator predicted recurrence of any episode over 1, 2, 3, or 5-year follow-up intervals, with Area Under the Curves (AUCs) approximating 0.77. The AUC for prediction of depressive episodes was about 0.81 for each of the time windows, which was higher than for manic or hypomanic episodes (AUC=0.72). While the risk calculator was well-calibrated across the range of risk scores, it systematically underestimated risk in the CDS sample by about 20%. The length of current remission was a highly significant predictor of recurrence risk in the CDS sample. LimitationsPredominantly self-reported White samples may limit generalizability; the risk calculator does not assess more proximal risk (e.g., 1 month). ConclusionsRisk of mood episode recurrence can be predicted with good accuracy in youth and adults with BD in remission. The risk calculators may help identify higher risk BD subgroups for treatment and research.

Significant Shortening of Leukocyte Telomere Length in Korean Patients with Bipolar Disorder 1

ObjectiveTelomere shortening has been seen in major psychiatric disorders, including major depressive disorder. However, only a few small studies have examined this in bipolar disorder (BD). We compared the telomere length in patients with BD1 or BD2 with that in matched healthy controls.MethodsWe included 215 patients with BD (128 BD1, 87 BD2) and 204 age- and sex-matched healthy controls. Relative telomere length was determined by quantitative polymerase chain reaction. The patients and controls were compared separately for age groups, sex, and BD subgroups (BD1 and BD2).ResultsWe found significant telomere shortening in patients with BD1 (p < 0.001), but not in patients with BD2. In male patients with BD1, the 30−39 year age group had significant shortening of telomere length than controls (p = 0.01). Female patients with BD1 in the 19−29-year age group had significantly shortened telomeres compared to the controls (p < 0.01).ConclusionOur results suggest a significant reduction in telomere length in BD1. Telomere shortening would be a potential biomarker for BD.

The functional impairment of different subtypes and occupational states in euthymic patients with bipolar disorder

BackgroundThe aim was to explore the associations between clinical symptoms, demographic variables, social and neurocognitive functioning in euthymic patients with bipolar disorder (BD) stratified by subgroups of DSM-IV BD (type I (BD-I) and type II (BD-II)) and occupational status (employed/unemployed), and to highlight the significance of occupational status when assessing social and neurocognitive functioning in euthymic BD patients.MethodsA total of 81 euthymic BD patients were participated in the study. The severity of the depressive and manic/hypomanic symptoms was measured using the 17-item Hamilton Depression Rating Scale (HDRS-17) and the Young Mania Rating Scale (YMRS), respectively. Social functioning and neurocognitive functioning were evaluated by the Functioning Assessment Short Test (FAST) and neurocognitive measures, respectively.ResultsEmployed BD patients displayed greater social functioning (autonomy, occupational functioning, interpersonal relationship domain) and better verbal learning performance and speed of processing than unemployed BD patients. The correlation between neurocognitive functioning and social functioning was stronger in the employed group than in the unemployed group. There were no significant differences in neurocognitive and social functioning between the BD-I and BD-II groups, and the correlation between neurocognitive functioning and social functioning was similar between the BD-I and BD-II groups.ConclusionEmployed BD patients may present greater occupational functioning and interpersonal relationships, as well as better verbal learning performance and speed of processing.

A unified model of the pathophysiology of bipolar disorder.

This work provides an overview of the most consistent alterations in bipolar disorder (BD), attempting to unify them in an internally coherent working model of the pathophysiology of BD. Data on immune-inflammatory changes, structural brain abnormalities (in gray and white matter), and functional brain alterations (from neurotransmitter signaling to intrinsic brain activity) in BD were reviewed. Based on the reported data, (1) we hypothesized that the core pathological alteration in BD is a damage of the limbic network that results in alterations of neurotransmitter signaling. Although heterogeneous conditions can lead to such damage, we supposed that the main pathophysiological mechanism is traceable to an immune/inflammatory-mediated alteration of white matter involving the limbic network connections, which destabilizes the neurotransmitter signaling, such as dopamine and serotonin signaling. Then, (2) we suggested that changes in such neurotransmitter signaling (potentially triggered by heterogeneous stressors onto a structurally-damaged limbic network) lead to phasic (and often recurrent) reconfigurations of intrinsic brain activity, from abnormal subcortical-cortical coupling to changes in network activity. We suggested that the resulting dysbalance between networks, such as sensorimotor networks, salience network, and default-mode network, clinically manifest in combined alterations of psychomotricity, affectivity, and thought during the manic and depressive phases of BD. Finally, (3) we supposed that an additional contribution of gray matter alterations and related cognitive deterioration characterize a clinical-biological subgroup of BD. This model may provide a general framework for integrating the current data on BD and suggests novel specific hypotheses, prompting for a better understanding of the pathophysiology of BD.

Age-Related Brain Structure Differences, by Age of Onset, in Older Adults with Bipolar Disorder

<h3>Introduction</h3> While brain structure during adolescence and early adulthood has been relatively well characterized in bipolar disorder (BD), it is still unclear how the brain's structure is affected by the illness in later life, and whether age of onset may influence age-related changes. <h3>Methods</h3> High resolution structural magnetic resonance images were acquired at 3 Tesla in 103 individuals with BD and 98 healthy controls (HC), ages 40 to 79 years. Categorical group comparisons (BD vs. HC), and analyses for group differences in age-related patterns, were performed for cortical thickness and grey matter volume. The BD group was also subdivided by age of first mood symptom onset, being either age 25 years and over (adult-onset, <i>n</i>=21) or below age 25 years (adolescent-onset, <i>n</i>=82), and the BD subgroups were compared to controls in a three-way analysis. <h3>Results</h3> Compared to the HC group, the overall BD group was characterized by lower cortical thickness within the insula and parahippocampus regions (<i>pcorrected</i>= 0.0054), and lower grey matter volume within the hippocampus, thalamus and putamen (<i>pcorrected</i> = 0.001). Significant age-related differences were not detected between the overall BD group and HC group. However, when individuals with BD were divided by those with adolescent or adult onset of the illness, the adult-onset BD subgroup showed significant age-related declines in insula and parahippocampal thickness, and hippocampal, thalamic and striatal grey matter volume, compared to the early-onset BD subgroup and HC group (<i>p</i> = 0.021). <h3>Conclusions</h3> The findings support structural abnormalities within the insula, parahippocampus, hippocampus, thalamus and striatum in adults with BD ages 40-79 years. Age-related decreases within the insula, parahippocampus and hippocampus may occur particularly in individuals with BD with onset after the age of 25 years. The results suggest that individuals with later onset of BD may be at a greater risk for age-related abnormalities in brain structure in brain systems that subserve emotional and cognitive processes. <h3>Funding</h3> Funding for the project was awarded by the National Institute of Mental Health.

Early identification of bipolar disorder among young adults - a 22-year community birth cohort.

We set forth to build a prediction model of individuals who would develop bipolar disorder (BD) using machine learning techniques in a large birth cohort. A total of 3748 subjects were studied at birth, 11, 15, 18, and 22years of age in a community birth cohort. We used the elastic net algorithm with 10-fold cross-validation to predict which individuals would develop BD at endpoint (22years) at each follow-up visit before diagnosis (from birth up to 18years). Afterward, we used the best model to calculate the subgroups of subjects at higher and lower risk of developing BD and analyzed the clinical differences among them. A total of 107 (2.8%) individuals within the cohort presented with BD type I, 26 (0.6%) with BD type II, and 87 (2.3%) with BD not otherwise specified. Frequency of female individuals was 58.82% (n=150) in the BD sample and 53.02% (n=1868) among the unaffected population. The model with variables assessed at the 18-year follow-up visit achieved the best performance: AUC 0.82 (CI 0.75-0.88), balanced accuracy 0.75, sensitivity 0.72, and specificity 0.77. The most important variables to detect BD at the 18-year follow-up visit were suicide risk, generalized anxiety disorder, parental physical abuse, and financial problems. Additionally, the high-risk subgroup of BD showed a high frequency of drug use and depressive symptoms. We developed a risk calculator for BD incorporating both demographic and clinical variables from a 22-year birth cohort. Our findings support previous studies in high-risk samples showing the significance of suicide risk and generalized anxiety disorder prior to the onset of BD, and highlight the role of social factors and adverse life events.

Cerebro-cerebellar white matter connectivity in bipolar disorder and associated polarity subphenotypes

BackgroundThe cerebellum has a crucial role in mood regulation. While cerebellar grey matter (GM) alterations have been previously reported in bipolar disorder (BD), cerebro-cerebellar white matter (WM) connectivity alterations and cerebellar GM profiles have not been characterised in the context of predominant polarity (PP) and onset polarity (OP) subphenotypes of BD patients which is the aim of the present study. MethodsForty-two euthymic BD patients stratified for PP and OP and 42 healthy controls (HC) were included in this quantitative neuroimaging study to evaluate cerebellar GM patterns and cerebro-cerebellar WM connections. Diffusion tensor tractography was used to characterise afferent and efferent cerebro-cerebellar tract integrity. False discovery rate corrections were applied in post-hoc comparisons. ResultsBD patients exhibited higher fractional anisotropy (FA) in fronto-ponto-cerebellar tracts bilaterally compared to HC. Subphenotype-specific FA profiles were identified within the BD cohort. Regarding PP subgroups, we found FA changes in a) left contralateral fronto-ponto-cerebellar tract (depressive-PP > HC) and b) contralateral/ipsilateral fronto-ponto-cerebellar tracts bilaterally (manic-PP > HC). Regarding OP subgroups, we observed FA changes in a) left/right contralateral fronto-ponto-cerebellar tracts (depressive-OP > HC) and b) all fronto-ponto-cerebellar, most parieto-ponto-cerebellar and right contralateral occipito-ponto-cerebellar tracts (manic-OP>HC). In general, greater and more widespread cerebro-cerebellar changes were observed in manic-OP patients than in depressive-OP patients compared to HC. Manic-OP showed higher FA compared to depressive-OP patients in several afferent WM tracts. No GM differences were identified between BD and HC and across BD subgroups. ConclusionsOur findings highlight fronto-ponto-cerebellar connectivity alterations in euthymic BD. Polarity-related subphenotypes have distinctive cerebro-cerebellar WM signatures with potential clinical and pathobiological implications.

Conceptualizing the later stage of bipolar disorder: Descriptive analyses from the ORBIT trial.

This study aimed to investigate the features of later stage bipolar disorder (BD) and specifically, factors underlying later stage BD and potential subgroups within this stage, to understand more about the later stage group and contribute to the measurement of stage. An exploratory factor analysis was conducted using variables relating to current phenomenological aspects of illness, followed by cluster analyses based on the identified factors. Finally, the resultant clusters were compared based on course of illness variables. Fourteen extracted factors explained 57 percent of the variance. Latent structures aligned with current depressive symptoms, energy and interest, independence, occupational functioning, symptoms of anxiety, pain, elevated symptoms, interpersonal functioning, anger, perceptions of social connections, and perceptions of current medication effectiveness, cognitive issues, sleep issues, and sense of isolation. Two clusters were identified which differed significantly on each of these factors, and on a range of course of illness features including lifetime number of episodes, duration of illness and number of depressive hospitalizations. Latent phenomenological features relevant to individuals in the later stage of BD were identified. Two clusters of individuals in later stage BD differ based on these features as well as course of illness, suggesting that there are distinct subgroups of individuals in the later stage of BD, distinguishable based on current phenomenology and illness history. However, findings are exploratory and therefore require confirmation before they can be applied clinically.