Effects of ebselen addition on emotional processing and brain neurochemistry in depressed patients unresponsive to antidepressant medication.

Lithium is an effective augmenting agent for depressed patients with inadequate response to standard antidepressant therapy, but numerous adverse effects limit its use. We previously reported that a lithium-mimetic agent, ebselen, promoted a positive emotional bias-an indicator of potential antidepressant activity in healthy participants. We therefore aimed to investigate the effects of short-term ebselen treatment on emotional processing and brain neurochemistry in depressed patients with inadequate response to standard antidepressants. We conducted a double-blind, placebo-controlled 7-day experimental medicine study in 51 patients with major depressive disorder who were currently taking antidepressants but had an inadequate response to treatment. Participants received either ebselen 600 mg twice daily for seven days or identical matching placebo. An emotional testing battery, magnetic resonance spectroscopy and depression and anxiety rating scales were conducted at baseline and after seven days of treatment. Ebselen did not increase the recognition of positive facial expressions in the depressed patient group. However, ebselen increased the response bias towards fear emotion in the signal detection measurement. In the anterior cingulate cortex, ebselen significantly reduced the concentrations of inositol and Glx (glutamate+glutamine). We found no significant differences in depression and anxiety rating scales between visits. Our study did not find any positive shift in emotional bias in depressed patients with an inadequate response to antidepressant medication. We confirmed the ability of ebselen to lower inositol and Glx in the anterior cingulate cortex. These latter effects are probably mediated through inhibition of inositol monophosphatase and glutaminase respectively.

Predicting depressed and elevated mood symptomatology in bipolar disorder using brain functional connectomes.

BACKGROUND: The study is aimed to identify brain functional connectomes predictive of depressed and elevated mood symptomatology in individuals with bipolar disorder (BD) using the machine learning approach Connectome-based Predictive Modeling (CPM). METHODS: Functional magnetic resonance imaging data were obtained from 81 adults with BD while they performed an emotion processing task. CPM with 5000 permutations of leave-one-out cross-validation was applied to identify functional connectomes predictive of depressed and elevated mood symptom scores on the Hamilton Depression and Young Mania rating scales. The predictive ability of the identified connectomes was tested in an independent sample of 43 adults with BD. RESULTS: CPM predicted the severity of depressed [concordance between actual and predicted values (r = 0.23, pperm (permutation test) = 0.031) and elevated (r = 0.27, pperm = 0.01) mood. Functional connectivity of left dorsolateral prefrontal cortex and supplementary motor area nodes, with inter- and intra-hemispheric connections to other anterior and posterior cortical, limbic, motor, and cerebellar regions, predicted depressed mood severity. Connectivity of left fusiform and right visual association area nodes with inter- and intra-hemispheric connections to the motor, insular, limbic, and posterior cortices predicted elevated mood severity. These networks were predictive of mood symptomatology in the independent sample (r ⩾ 0.45, p = 0.002). CONCLUSIONS: This study identified distributed functional connectomes predictive of depressed and elevated mood severity in BD. Connectomes subserving emotional, cognitive, and psychomotor control predicted depressed mood severity, while those subserving emotional and social perceptual functions predicted elevated mood severity. Identification of these connectome networks may help inform the development of targeted treatments for mood symptoms.

Essential data dimensions for prospective international data collection in older age bipolar disorder (OABD): Recommendations from the GAGE-BD group.

BACKGROUND: By 2030, over 50% of individuals living with bipolar disorder (BD) are expected to be aged ≥50 years. However, older age bipolar disorder (OABD) remains understudied. There are limited large-scale prospectively collected data organized in key dimensions capable of addressing several fundamental questions about BD affecting this subgroup of patients. METHODS: We developed initial recommendations for the essential dimensions for OABD data collection, based on (1) a systematic review of measures used in OABD studies, (2) a Delphi consensus of international OABD experts, (3) experience with harmonizing OABD data in the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD, n ≥ 4500 participants), and (4) critical feedback from 34 global experts in geriatric mental health. RESULTS: We identified 15 key dimensions and variables within each that are relevant for the investigation of OABD: (1) demographics, (2) core symptoms of depression and (3) mania, (4) cognition screening and subjective cognitive function, (5) elements for BD diagnosis, (6) descriptors of course of illness, (7) treatment, (8) suicidality, (9) current medication, (10) psychiatric comorbidity, (11) psychotic symptoms, (12) general medical comorbidities, (13) functioning, (14) family history, and (15) other. We also recommend particular instruments for capturing some of the dimensions and variables. CONCLUSION: The essential data dimensions we present should be of use to guide future international data collection in OABD and clinical practice. In the longer term, we aim to establish a prospective consortium using this core set of dimensions and associated variables to answer research questions relevant to OABD.

Aging of the brain in bipolar disorder: Illness- and onset-related effects in cortical thickness and subcortical gray matter volume.

BACKGROUND: Older adults with bipolar disorder (BD) have received little study, although they often have severe symptoms, treatment resistance and high suicide risk. Furthermore, a subset develops cognitive dysfunction for unknown reasons. METHODS: Here, cortical thickness and subcortical gray matter volume were compared across individuals ages 40-79y: 103 with BD ("later-onset" at ages ≥25y, n = 21; "early-onset" < 25y, n = 82) and healthy controls (HCs, n = 98). RESULTS: Overall, those with BD showed lower prefrontal, cingulate, sensorimotor, parahippocampal, insula, temporal, parietal, and occipital cortical thickness (Cohen's d: 0.4 to 0.8) and hippocampal, amygdalar, thalamic, and striatal gray matter volume (d: 0.6 to 0.8). Later-onset BD showed negative relationships between age and parahippocampal, insular, temporal, parietal, and occipital cortical thickness, and hippocampal, thalamic and striatal volume (r: -0.7 to -0.4). Suicide attempt history was associated with lower dorsolateral prefrontal cortical thickness (d = 0.5). LIMITATIONS: The study used a cross-sectional design and the sample of those with a later-onset of BD was relatively modest. CONCLUSIONS: Results support widespread gray matter decreases in older adults with BD, and also suggest a separable later-onset phenotype characterized by age-related gray matter reductions in regions subserving cognitive, emotional and perceptual processes. Moreover, the results are the first to demonstrate structural brain differences associated with a history of suicide attempts in older adults with BD.

Bipolar I and bipolar II subtypes in older age: Results from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) project.

OBJECTIVES: The distinction between bipolar I disorder (BD-I) and bipolar II disorder (BD-II) has been a topic of long-lasting debate. This study examined differences between BD-I and BD-II in a large, global sample of OABD, focusing on general functioning, cognition and somatic burden as these domains are often affected in OABD. METHODS: Cross-sectional analyses were conducted with data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database. The sample included 963 participants aged ≥50 years (714 BD-I, 249 BD-II). Sociodemographic and clinical factors were compared between BD subtypes including adjustment for study cohort. Multivariable analyses were conducted with generalized linear mixed models (GLMMs) and estimated associations between BD subtype and (1) general functioning (GAF), (2) cognitive performance (g-score) and (3) somatic burden, with study cohort as random intercept. RESULTS: After adjustment for study cohort, BD-II patients more often had a late onset ≥50 years (p = 0.008) and more current severe depression (p = 0.041). BD-I patients were more likely to have a history of psychiatric hospitalization (p < 0.001) and current use of anti-psychotics (p = 0.003). Multivariable analyses showed that BD subtype was not related to GAF, cognitive g-score or somatic burden. CONCLUSION: BD-I and BD-II patients did not differ in terms of general functioning, cognitive impairment or somatic burden. Some clinical differences were observed between the groups, which could be the consequence of diagnostic definitions. The distinction between BD-I and BD-II is not the best way to subtype OABD patients. Future research should investigate other disease specifiers in this population.

Neuroimaging Studies of Brain Structure in Older Adults with Bipolar Disorder: A Review.

Bipolar disorder (BD) is a common mood disorder that can have severe consequences during later life, including suffering and impairment due to mood and cognitive symptoms, elevated risk for dementia and an especially high risk for suicide. Greater understanding of the brain circuitry differences involved in older adults with BD (OABD) in later life and their relationship to aging processes is required to improve outcomes of OABD. The current literature on gray and white matter findings, from high resolution structural and diffusion-weighted magnetic resonance imaging (MRI) studies, has shown that BD in younger age groups is associated with gray matter reductions within cortical and subcortical brain regions that subserve emotion processing and regulation, as well as reduced structural integrity of white matter tracts connecting these brain regions. While fewer neuroimaging studies have focused on OABD, it does appear that many of the structural brain differences found in younger samples are present in OABD. There is also initial suggestion that there are additional brain differences, for at least a subset of OABD, that may result from more pronounced gray and white matter declines with age that may contribute to adverse outcomes. Preclinical and clinical data supporting neuro-plastic and -protective effects of mood-stabilizing medications, suggest that treatments may reverse and/or prevent the progression of brain changes thereby reducing symptoms. Future neuroimaging research implementing longitudinal designs, and large-scale, multi-site initiatives with detailed clinical and treatment data, holds promise for reducing suffering, cognitive dysfunction and suicide in OABD.

Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium.

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.

Gender-related association among childhood maltreatment, brain structure and clinical features in bipolar disorder.

Bipolar disorder (BD) and exposure to childhood maltreatment (CM), which is present at high rates in BD, are both associated with hippocampus and prefrontal cortex structural alterations thought to contribute to clinical features. Gender-related differences are implicated in BD for CM exposure, brain structure and clinical features. However, relationships among these factors in BD are understudied. This study aimed to investigate associations among gender, CM, hippocampus and prefrontal gray matter structure and clinical features in BD. Childhood trauma questionnaire, structured clinical assessments and 3 Tesla structural magnetic resonance imaging were obtained for 236 adults (18-63 years, 32.0 ± 12.6): 119 with BD (58.8% women) and 117 healthy controls (HCs, 50.4% women). Women with BD reported higher CM severity than men with BD and HCs (B=-14.34, 95% confidence intervals (CI)[-22.71,-5.97], p<.001). CM and gender showed a significant interaction for left hippocampus (B=-7.41, 95% CI[-14.10,-0.71], p<.05); CM severity was negatively associated with left hippocampus only in women with BD. In women with BD, CM was associated with post-traumatic stress disorder comorbidity (B = 25.68, 95% CI[15.11,36.25], p<.001). In men with BD, CM severity was associated with lower left frontal pole (B=-0.71, 95% CI[-1.14,-0.28], p<.05) and right superior frontal (B=-17.78, 95% CI[-30.66,-4.90], p<.05) surface area; the latter related to earlier age of first mood symptoms (B = 33.97, 95% CI[7.61, 60.33], p<.05). Findings support gender-related effects of CM on frontotemporal structure and clinical features of BD. The findings bring novel perspectives for gendered pathophysiological models of effects of CM in BD.

Comparing continuous and harmonized measures of depression severity in older adults with bipolar disorder: Relationship to functioning.

OBJECTIVE: Harmonizing different depression severity scales often requires creation of categorical variables that may decrease the sensitivity of the measure. Our aim was to compare the associations between categorical and continuous and harmonized measures of depression and global functioning in a large dataset of older age patients with bipolar disorder (OABD). METHOD: In the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) the 17-item Hamilton Depression scale (HAM-D), Montgomery Asberg Depression Rating Scale (MADRS) or the Center for Epidemiological Studies Depression scales (CES-D) was used to assess current depressive symptoms, while the Global Assessment of Functioning (GAF) assessed functional status. Data were harmonized from 8 OABD studies (n = 582). In each subsample, the relationship of depression severity as a continuous and categorical measure was compared to GAF. In the total sample, harmonized ordinal depression categories were compared to GAF. RESULTS: Effect size and variance explained by the model for the categorical measure in the total sample was higher than both the categorical and continuous measure in the CES-D subsample, higher than the categorical but lower than the continuous measure in the HAM-D subsample, and lower than both the categorical and continuous measures in the MADRS subsample. LIMITATIONS: All included studies have different inclusion and exclusion criteria, study designs, and differ in aspects of sociodemographic variables. CONCLUSIONS: Associations were only slightly larger for the continuous vs categorical measures of depression scales. Harmonizing different depression scales into ordinal categories for analyses is feasible without losing statistical power.

Demographic and Clinical Characteristics of Antipsychotic Drug-Treated Older Adults with Bipolar Disorder from the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD).

Objectives: Antipsychotic drugs (APS) are widely used to treat patients with bipolar disorder (BD), but there is limited information in older-age bipolar disorder (OABD). This analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) investigated characteristics of OABD patients prescribed APS vs. those not prescribed APS. Experimental Design: The observational analysis used baseline, cross-sectional data from 16 international studies for adults aged ≥ 50 years with BD comprising 1,007 individuals with mean age 63.2 years (SD = 9.0), 57.4% women, and mean age of onset 31.6 years (SD = 15.0). The dependent variable was current APS treatment status. The independent variables included demographic and clinical variables, and a random effect for study, that were included in generalized mixed models. Principal Observations: 46.6% of individuals (n = 469) were using APS. The multivariate model results suggest that those treated with APS were younger (p = 0.01), less likely to be employed (p < 0.001), had more psychiatric hospitalizations (p = 0.009) and were less likely to be on lithium (p < 0.001). Of individuals on APS, only 6.6% of those (n = 27) were on first-generation antipsychotics (FGAs) and experienced a greater burden of psychiatric hospitalizations (p = 0.012). Conclusions: APS are widely prescribed in OABD, observed in nearly half of this sample with great variation across sites. Individuals with OABD on APS have more severe illness, more frequent hospitalizations and are more often unemployed vs. those not on APS. Future studies need to examine longitudinal outcomes in OABD prescribed APS to characterize underlying causal relationships.

Rethinking "aggression" and impulsivity in bipolar disorder: Risk, clinical and brain circuitry features.

BACKGROUND: Elevated aggression and impulsivity are implicated in Bipolar Disorder (BD); however, relationships between these behavioral constructs have not been clarified, which can lead to misconceptions with negative consequences including stigma and adverse outcomes including suicide. The study aimed to clarify brain-based distinctions between the two constructs and their associations to risk factors, symptoms and suicide thoughts and behaviors. METHODS: Self-rated Brown-Goodwin Aggression (BGA) and Barratt Impulsiveness Scale (BIS) scores were compared between adults with BD (n = 38, 74% female) and healthy controls (HC, n = 29, 64% female). Relationships were examined between BGA and BIS with childhood trauma questionnaire (CTQ), mood, comorbidities, and magnetic resonance imaging gray matter volume (GMV) assessments. RESULTS: In BD, BGA and BIS total scores were both elevated and associated with childhood maltreatment (CM), particularly emotional CM, depression, substance use disorders (SUDs) and suicide attempts (SAs). BGA scores were increased by items corresponding to dysregulation of emotional and social behavior and associated with elevated mood states and suicide ideation and GMV decreases in bilateral orbitofrontal cortex and left posterior insula brain regions, previously associated with these behaviors and clinical features. BIS motor impulsiveness scores were associated with GMV decreases in anterior cingulate cortex implicated in mood and behavioral dyscontrol. LIMITATIONS: modest sample size, self-reports CONCLUSIONS: The findings suggest separable brain-based domains of dysfunction in BD of motor impulsiveness versus emotionally dysregulated feelings that are primarily self-directed. Both domains are associated with suicide behavior and modifiable risk factors of CM, depression and SUDs that could be targeted for prevention.

Graph theory analysis of whole brain functional connectivity to assess disturbances associated with suicide attempts in bipolar disorder.

Brain targets to lower the high risk of suicide in Bipolar Disorder (BD) are needed. Neuroimaging studies employing analyses dependent on regional assumptions could miss hubs of dysfunction critical to the pathophysiology of suicide behaviors and their prevention. This study applied intrinsic connectivity distribution (ICD), a whole brain graph-theoretical approach, to identify hubs of functional connectivity (FC) disturbances associated with suicide attempts in BD. ICD, from functional magnetic resonance imaging data acquired while performing a task involving implicit emotion regulation processes important in BD and suicide behaviors, was compared across 40 adults with BD with prior suicide attempts (SAs), 49 with BD with no prior attempts (NSAs) and 51 healthy volunteers (HVs). Areas of significant group differences were used as seeds to identify regional FC differences and explore associations with suicide risk-related measures. ICD was significantly lower in SAs than in NSAs and HVs in bilateral ventromedial prefrontal cortex (vmPFC) and right anterior insula (RaIns). Seed connectivity revealed altered FC from vmPFC to bilateral anteromedial orbitofrontal cortex, left ventrolateral PFC (vlPFC) and cerebellum, and from RaIns to right vlPFC and temporopolar cortices. VmPFC and RaIns ICD were negatively associated with suicidal ideation severity, and vmPFC ICD with hopelessness and attempt lethality severity. The findings suggest that SAs with BD have vmPFC and RaIns hubs of dysfunction associated with altered FC to other ventral frontal, temporopolar and cerebellar cortices, and with suicidal ideation, hopelessness, and attempt lethality. These hubs may be targets for novel therapeutics to reduce suicide risk in BD.

Brain grey and white matter structural associations with future suicidal ideation and behaviors in adolescent and young adult females with mood disorders.

Background: To reduce suicide in females with mood disorders, it is critical to understand brain substrates underlying their vulnerability to future suicidal ideation and behaviors (SIBs) in adolescence and young adulthood. In an international collaboration, grey and white matter structure was investigated in adolescent and young adult females with future suicidal behaviors (fSB) and ideation (fSI), and without SIBs (fnonSIB). Methods: Structural (n = 91) and diffusion-weighted (n = 88) magnetic resonance imaging scans at baseline and SIB measures at follow-up on average two years later (standard deviation, SD = 1 year) were assessed in 92 females [age(SD) = 16.1(2.6) years] with bipolar disorder (BD, 28.3%) or major depressive disorder (MDD, 71.7%). One-way analyses of covariance comparing baseline regional grey matter cortical surface area, thickness, subcortical grey volumes, or white matter tensor-based fractional anisotropy across fSB (n = 40, 43.5%), fSI (n = 33, 35.9%) and fnonSIB (n = 19, 20.6%) groups were followed by pairwise comparisons in significant regions (p < 0.05). Results: Compared to fnonSIBs, fSIs and fSBs showed significant decreases in cortical thickness of right inferior frontal gyrus pars orbitalis and middle temporal gyrus, fSIs of left inferior frontal gyrus, pars orbitalis. FSIs and fSBs showed lower fractional anisotropy in left uncinate fasciculus and corona radiata, and fSBs in right uncinate and superior fronto-occipital fasciculi. Conclusions: The study provides preliminary evidence of grey and white matter alterations in brain regions subserving emotional and behavioral regulation and perceptual processing in adolescent and young adult females with mood disorders with, versus without, future SIBs. Findings suggest potential targets to prevent SIBs in female adolescents and young adults.

Telehealth Social Rhythm Therapy to Reduce Mood Symptoms and Suicide Risk Among Adolescents and Young Adults With Bipolar Disorder.

OBJECTIVE: Social rhythm irregularities are associated with increased bipolar disorder symptoms and suicide risk. This study was the first to examine the feasibility and acceptability of a 12-week social rhythm therapy (SRT) delivered predominantly via telehealth (three in-person sessions, nine via video teleconferencing) to adolescents and young adults with bipolar disorder. The primary aim was to determine the feasibility and acceptability of SRT delivered predominantly via telehealth. Secondary aims were to explore the intervention's impacts on social rhythm regularity, mood symptoms, and suicide propensity. METHODS: Thirteen adolescents and young adults with bipolar disorder received a modified SRT called Brain Emotion circuitry-targeted Self-Monitoring And Regulation Therapy for Daily Rhythms (BE-SMART-DR) administered mostly remotely, adjunctive to treatment as usual. Retention rates, client satisfaction, therapeutic alliance, and pre- to postintervention changes in social rhythm regularity, mood symptoms, and suicide propensity were assessed. RESULTS: BE-SMART-DR was associated with high retention rates (77%), high mean±SD scores on the Client Satisfaction Questionnaire (29.4±2.7), and high participant global scores on the Working Alliance Inventory (231.3±8.1), indicative of strong therapeutic alliance. Secondary outcome measures on social rhythm irregularities, mood symptoms, and suicide propensity decreased from pre- to posttherapy. Increased social rhythm regularity was associated with reduced suicide propensity after analyses were controlled for reductions in mood symptoms. CONCLUSIONS: These preliminary results indicate that SRT delivered largely by telemedicine is feasible and acceptable. The intervention appeared to reduce mood symptoms, and suicide propensity independent of mood symptoms, among adolescents and young adults with bipolar disorder.