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Understanding how Bipolar Disorder (BD) affects employment is limited by cross-sectional or short-term longitudinal designs. The aims for this study are to examine condition-related and other clinical predictors of longitudinal employment status and stability in those with BD compared to healthy controls (HC).Participants were 358 individuals with BD and HC who were enrolled in the Heinz C. Prechter Longitudinal Study of BD. Participants completed self-report measurements of employment, symptoms, health, personality, life events, and neuropsychological tests at study enrollment, yearly and/or every two months. Repeated measures logistic regression was used to predict employment status and stability.Those with BD were less likely to be employed than HC. Significant predictors of unemployment in BD include having BD type I, younger age, less years with BD, higher depression, worse processing speed, and worse mental and physical health. Of those with BD, 64 % demonstrated greater employment instability compared to 37 % of HC. History of psychosis, worse memory, physical health, and greater disruption of negative life events significantly predicted employment instability.The limitations of this study include the generalizability of this sample, a large reliance of self-report measures, and a lack of employment-related factors such as job-type, functioning, performance, and satisfaction. Lastly, the effects of medication, treatment adherence, and treatment optimization were not assessed in this study.These findings highlight that different aspects of BD are important for being employed versus maintaining stable employment. These findings indicate the need for more effective treatment strategies beyond symptom management.

Objectives: Individuals with bipolar I disorder (BD) have difficulty inhibiting context-inappropriate responses. However, the neural mechanisms contributing to these difficulties, especially in emotional contexts, are little understood. This study aimed to inform mechanisms of impaired impulsivity control in response to emotion in individuals with BD, and whether response inhibition indices are altered to a similar degree in schizophrenia spectrum disorders (SZ). We examined alterations to behavioral performance and event-related potentials (ERPs) during inhibition to affective stimuli in BD, relative to healthy control participants (HC) and participants with SZ. Methods: Sixty-six participants with BD, 32 participants with SZ, and 48 HC completed a Go/No-Go task with emotional face stimuli while electroencephalography was recorded. Behavioral signal detection metrics (perceptual sensitivity, response bias) and ERPs (N200, P300) were measured and compared across groups. Results: Relative to HC, participants with BD showed reduced (1) discrimination of Go vs. No-Go stimuli (i.e. emotional vs. neutral faces); and (2) P300 amplitudes elicited by emotional faces. These results similarly extended to participants with SZ, in that BD and SZ groups did not differ on behavioral performance nor ERP amplitudes. Exploratory correlational findings showed associations between ERP amplitudes and behavioral indices as well as mood symptoms. Conclusion: Findings suggest the difficulty participants with BD and SZ experienced on the current affective response inhibition task lied largely in discriminating between facial expressions. Difficulties with discriminating emotional from neutral expressions may contribute to difficulties with appropriate behavioral responding in social-affective contexts for individuals with BD and SZ.

Objectives: Although comorbid bipolar disorder (BD) and alcohol use disorder (AUD) is extremely common and may worsen prognosis, neither research nor clinical practice sufficiently acknowledge their interplay. In this pre-registered study, we characterized longitudinal patterns of alcohol use in BD and delineated the temporal dynamics between alcohol use, mood, and life functioning over an average of ten years.Methods: Participants (n = 663) with a bipolar spectrum disorder (I, II, NOS, schizoaffective bipolar type) who had completed at least 5 years of longitudinal follow-up (range = 5-16) were selected from the Prechter Longitudinal Study of Bipolar Disorder (n = 1,357). Alcohol use was measured every 6 months alongside measures of life functioning, depression, mania, and anxiety. Dynamic Structural Equation Modeling (DSEM) was used to analyze the within-person effects of alcohol use on both mood and life functioning.Results: Participants exhibited significant variability in alcohol use over time, regardless of baseline levels of alcohol use or AUD diagnosis. Higher levels of problematic drinking predicted increased severity of depression and anxiety over the next 6 months, but not vice versa. Greater problematic alcohol use predicted reduced future life functioning related to duties at work, school, and/or activity center.Conclusions: Alcohol use, regardless of diagnostic status, predicts mood instability and functioning in BD. Given its prevalence and repercussions, alcohol use may be important to monitor and manage in the standard treatment of BD. Recommendations for assessment and future directions for research are discussed.

Inflammation is hypothesized to be a key component of bipolar disorder (BP) development and progression. However, findings linking BP prevalence and symptomology to immune functioning have been mixed, with some work suggesting that obesity may play an important role in BP-relevant inflammation. Here we investigate differences in biomarkers of inflammation [C-reactive protein (CRP), interleukin (IL)-1β, IL-6, IL-8, IL-10] between healthy controls (HC) and individuals with BP or other mental illness (MI). Adults with BP, MI, or HC (n = 545, 70% BP, 21% HC, 9% MI) self-reported depressive and manic symptoms close to a blood draw and physical exam that included measurement of height and weight. A composite score was calculated from the four cytokines measured in plasma; follow-up analyses explored a pro-inflammatory composite and IL-10, individually. BP individuals had elevated cytokine concentrations compared to HC (B = 0.197, [0.062, 0.333], t (542) = 2.855, p = .004); this difference was also evident for the pro-inflammatory composite and for IL-10. Cytokine concentrations were not associated with BP mood states. Body mass index (BMI), an indicator of obesity, was significantly higher in BP compared to HC (B = 3.780, [2.118, 5.443], t (479) = 4.457, p

Objective:Assessing performance validity is imperative in both clinical and research contexts as data interpretation presupposes adequate participation from examinees. Performance validity tests (PVTs) are utilized to identify instances in which results cannot be interpreted at face value. This study explored the hit rates for two frequently used PVTs in a research sample of individuals with and without histories of bipolar disorder (BD).Method:As part of an ongoing longitudinal study of individuals with BD, we examined the performance of 736 individuals with BD and 255 individuals with no history of mental health disorder on the Test of Memory Malingering (TOMM) and the California Verbal Learning Test forced choice trial (CVLT-FC) at three time points.Results:Undiagnosed individuals demonstrated 100% pass rate on PVTs and individuals with BD passed over 98% of the time. A mixed effects model adjusting for relevant demographic variables revealed no significant difference in TOMM scores between the groups, a = .07, SE = .07, p = .31. On the CVLT-FC, no clinically significant differences were observed (ps < .001).Conclusions:Perfect PVT scores were obtained by the majority of individuals, with no differences in failure rates between groups. The tests have approximately >98% specificity in BD and 100% specificity among non-diagnosed individuals. Further, nearly 90% of individuals with BD obtained perfect scores on both measures, a trend observed at each time point.

Background: Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied. Methods: The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool). Results: A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment. Conclusion: This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings.

Childhood trauma is associated with greater depression severity among individuals with bipolar disorder. However, the mechanisms that explain the link between childhood trauma and depression severity in bipolar disorder remain poorly understood. The mediational role of attachment insecurity in childhood and adulthood was assessed in the current study.Participants with bipolar disorder (N = 143) completed measures of childhood trauma (Childhood Trauma Questionnaire), attachment insecurity (Experiences in Close Relationships Scale) and depression severity (Hamilton Depression Rating Scale) as part of the Prechter Longitudinal Study of Bipolar Disorder. A sequential mediation model was tested using path analysis: the direct and indirect effects of childhood trauma on depression severity with attachment insecurity (attachment anxiety and avoidance) in childhood (mother and father) and adulthood (partner) as mediators were estimated.The final path model demonstrated an excellent fit to the data (comparative fit index = 0.996; root mean square error of approximation = 0.021 [90% confidence interval = 0.000-0.073]). Supporting the hypothesised sequential mediation model, maternal attachment anxiety in childhood and romantic attachment avoidance in adulthood partially mediated the relationship between childhood trauma and depression severity; this effect accounted for 12% of the total effect of childhood trauma on depression severity.Attachment insecurity in childhood and adulthood form part of the complex mechanism informing why people with bipolar disorder who have a history of childhood trauma experience greater depression severity. Addressing attachment insecurity represents a valuable psychotherapeutic treatment target for bipolar disorder.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E–09 and 4.10E–18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Lithium has been a drug for bipolar disorders (BD) for over 70 years; however, its usage has been limited by its narrow therapeutic window (between 0.6 and 1.2 mM). Understanding the cellular distribution of lithium ions (Li+) in patient cells will offer deep insight into this limitation, but selective imaging of Li+ in living cells under biomedically relevant concentration ranges has not been achieved. Herein, we report in vitro selection and development of a Li+-specific DNAzyme fluorescent sensor with >100-fold selectivity over other biorelevant metal ions. This sensor allows comparative Li+ visualization in HeLa cells, human neuronal progenitor cells (NPCs), and neurons derived from BD patients and healthy controls. Strikingly, we detected enhanced accumulation of Li+ in cells derived from BD patients compared with healthy controls in differentiated neurons but not NPCs. These results establish the DNAzyme-based sensor as a novel platform for biomedical research into BD and related areas using lithium drugs., A highly Li+ selective DNAzyme sensor for live imaging of Li+ at a biomedical relevant concentration range reveals bipolar disorder patient-derived neurons can accumulate more Li+ than healthy neurons can.

Automatic speech emotion recognition provides computers with critical context to enable user understanding. While methods trained and tested within the same dataset have been shown successful, they often fail when applied to unseen datasets. To address this, recent work has focused on adversarial methods to find more generalized representations of emotional speech. However, many of these methods have issues converging, and only involve datasets collected in laboratory conditions. In this paper, we introduce Adversarial Discriminative Domain Generalization (ADDoG), which follows an easier to train “meet in the middle” approach. The model iteratively moves representations learned for each dataset closer to one another, improving cross-dataset generalization. We also introduce Multiclass ADDoG, or MADDoG, which is able to extend the proposed method to more than two datasets, simultaneously. Our results show consistent convergence for the introduced methods, with significantly improved results when not using labels from the target dataset. We also show how, in most cases, ADDoG and MADDoG can be used to improve upon baseline state-of-the-art methods when target dataset labels are added and in-the-wild data are considered. Even though our experiments focus on cross-corpus speech emotion, these methods could be used to remove unwanted factors of variation in other settings.

BACKGROUND Mobile interventions promise to fill in gaps in care with their broad reach and flexible delivery. OBJECTIVE Our goal was to investigate delivery of a mobile version of acceptance and commitment therapy (ACT) for individuals with bipolar disorder (BP). METHODS Individuals with BP (n=30) participated in a 6-week microrandomized trial. Twice daily, participants logged symptoms in the app and were repeatedly randomized (or not) to receive an ACT intervention. Self-reported behavior and mood were measured as the energy devoted to moving toward valued domains or away from difficult emotions and with depressive d and manic m scores from the digital survey of mood in BP survey (digiBP). RESULTS Participants completed an average of 66% of in-app assessments. Interventions did not significantly impact the average toward energy or away energy but did significantly increase the average manic score m (P=.008) and depressive score d (P=.02). This was driven by increased fidgeting and irritability and interventions focused on increasing awareness of internal experiences. CONCLUSIONS The findings of the study do not support a larger study on the mobile ACT in BP but have significant implications for future studies seeking mobile therapy for individuals with BP. CLINICALTRIAL ClinicalTrials.gov NCT04098497; https://clinicaltrials.gov/ct2/show/NCT04098497

Objectives: Impaired social cognition in bipolar disorder (BD) is related to functional outcomes. A critical determinant of social cognition is the ability to discriminate the eye gaze direction of others, and its alteration may play a role in functional impairment in BD. However, the neural mechanisms underlying gaze processing in BD are unclear. Because neural oscillations and their communications through inter-region synchronization are crucial neurobiological mechanisms that support cognition, this study aimed to understand their role in gaze processing in BD.Methods: Electroencephalography (EEG) was recorded during a gaze discrimination task for 38 participants with BD and 34 healthy controls (HC). Time-frequency decomposition of EEG data was used to examine: 1) neural oscillatory power at bilateral parietal and midline frontal locations associated with face processing and higher-level cognition, and 2) feedforward and feedback connectivity between sites via theta-gamma phase-amplitude coupling (PAC).Results: Compared to HC, BD showed reduced theta power at the left parietal and midline frontal sites. BD also showed reduced PAC between bilateral parietal and midline frontal sites. Reduced theta power and PAC were related to poorer gaze discrimination task performance across participants.Conclusions: Altered theta power and feedforward/feedback connectivity between face-processing and midline frontal brain areas may underlie abnormal gaze processing in BD.

Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder.

Background: Childhood trauma is negatively associated with depression severity in bipolar disorder; however, the underlying mechanisms remain unclear. We investigated whether personality traits (neuroticism, extraversion, openness, agreeableness, conscientiousness) mediate the relationship between childhood trauma and the severity of bipolar depression. Methods: Data from 209 individuals with bipolar disorder recruited for the Prechter Longitudinal Study of Bipolar Disorder were analysed. Using structural equation modelling, we examined the direct and indirect associations between childhood trauma (Childhood Trauma Questionnaire) and depression severity (Hamilton Depression Rating Scale) – with the personality traits (NEO Personality Inventory–Revised) as mediators. Results: The direct effect of childhood trauma on depression severity (standardised β = 0.32, 95% bootstrap confidence interval [CI] = 0.20–0.45, p < 0.001) and the indirect effect via neuroticism (standardised β = 0.03, 95% bootstrap CI [0.002, 0.07], p = 0.039) were significant; supporting a partial mediation model. The indirect effect accounted for 9% of the total effect of childhood trauma on depression severity (standardised β = 0.09, 95% bootstrap CI [0.002, 0.19], p = 0.046). The final model had a good fit with the data (comparative fit index = 0.96; root mean square error of approximation = 0.05, 90% CI = [0.02, 0.07]). Conclusion: Personality traits may be relevant psychological mediators that link childhood trauma to a more severe clinical presentation of bipolar depression. Consequently, a person’s personality structure may be a crucial operative factor to incorporate in therapeutic plans when treating individuals with bipolar disorder who report a history of childhood trauma.

The aims of the study were to review 3 cases of lithium toxicity among individuals with bipolar disorder who were diagnosed with COVID-19 and to review the literature discussing the implications of COVID-19 and exposure to SARS-CoV-2 relative to medical use of lithium in management of bipolar disorder.This is a case review of medical and psychiatric notes of 3 individuals with bipolar disorder, managed with lithium, who developed COVID-19. This study discussed these cases in context of previous case reports and relevant literature pertaining to lithium and exposure to SARS-CoV-2.Infection with SARS-CoV-2 along with symptoms of COVID-19 and mental state changes in three individuals were temporally associated with lithium levels in the toxic range.Exposure to SARS-CoV-2 or symptoms suggestive of COVID-19 should result in increased clinical monitoring of individuals taking lithium. Those taking lithium and providers are advised to have a low clinical threshold for requesting lithium levels and kidney function estimates for the duration of the COVD-19 pandemic.

Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peripheral blood-derived DNA was assayed using Illumina PsychArray, and Methylation-450K or -EPIC BeadChips. Polygenic risk scores (PRS) were calculated using summary statistics from recent genome-wide association studies for BD, major depressive disorder (MDD) and cross-disorder (meta-analysis of eight psychiatric disorders). Unrelated HR participants of European ancestry (n = 103) were stratified based on their BD-PRS score within the HR-population distribution, and the top two quintiles (High-BD-PRS;n = 41) compared against the bottom two quintiles (Low-BD-PRS;n = 41). The High-BD-PRS stratum also had higher mean cross-disorder-PRS and MDD-PRS (ANCOVAp = 0.035 andp = 0.024, respectively). We evaluated DNA methylation differences between High-BD-PRS and Low-BD-PRS strata using linear models. One differentially methylated probe (DMP) (cg00933603;p = 3.54 × 10−7) inVARS2, a mitochondrial aminoacyl-tRNA synthetase, remained significantly hypomethylated after multiple-testing correction. Overall, BD-PRS appeared to broadly impact epigenetic processes, with 1,183 genes mapped to nominal DMPs (p n = 54 andn = 82, respectively), and conducted an exploratory evaluation of the effects of family environment, indexing cohesion and flexibility. This study highlights an important interplay between heritable risk and epigenetic factors, which warrant further exploration.

Background: Individuals with bipolar I disorder (BD) have difficulty inhibiting context-inappropriate responses. However, neural mechanisms of impaired cognitive control over impulsive behaviors, especially in response to emotion, are unclear. Theta-band neural oscillatory activity over midfrontal areas is thought to reflect cognitive control. The current study examined behavioral performance and theta-band activity during inhibition to affective stimuli in BD, relative to healthy control participants (HC). Methods: Sixty-seven participants with BD and 48 HC completed a Go/No-Go task with emotional face stimuli during electroencephalography (EEG) recording. Behavior was measured with reaction time, discriminability (d’) and response bias (β). Time-frequency decomposition of EEG data was used to extract event-related theta-band (4-7 Hz) neural oscillatory power and inter-trial phase consistency (ITPC) over midline fronto-central areas. Behavior and theta-band activity were compared between groups, while covarying for age. Results: Participants with BD exhibited slower response execution times on correct Go trials and reduced behavioral discrimination of emotional versus neutral faces, compared to HC. Theta-band power and ITPC were reduced in BD relative to HC. Theta-band power was higher on No-Go trials than Go trials. The magnitude of differences in theta-band activity between Go/No-Go trial types did not differ between groups. Increased theta-band power was associated with faster response execution times, greater discrimination of differing facial expressions, and stronger tendency to respond both across the full sample and within the BD group. Conclusions: Attenuated midline fronto-central theta-band activity may contribute to reduced cognitive control and maladaptive behavioral responding to emotional cues in individuals with BD.

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

Background Individuals with bipolar disorder (BD) show different personality profiles compared to non-psychiatric populations, but little is known about the temporal stability of personality traits over time, and if changes in mood state drive changes in personality. Methods Participants were 533 BD and 185 healthy controls (HC) who completed the NEO-Personality Inventory-Revised (NEO-PI-R) and clinician-administered measures of mood at baseline. One-hundred-eighty BD and 79 HC completed the measures at 5-year follow-up and 60 BD and 16 HC completed the measures at 10-year follow-up. The above measures and demographic information, but not other clinical status indicators the BD illness, were used in analyses. Results The BD group has higher Neuroticism (N)/N facets and lower Extraversion (E)/E facets and Consciousness (C)/C facets compared to HC. Significant mean-level changes existed within groups but were small in magnitude, and groups showed similar moderate-to-high rank-order stability. Change in (N)/N facets shows an association with change in depression, but changes in all other NEO-PI-R scores are not associated with changes in mood. Personality traits are clinically stable in part of our bipolar sample using clinically relevant interpretation of changes in T scores; however, some BD subjects did show more reliable changes in personality traits than the healthy controls. Limitations Reliance on self-report measurement and not all our participants completed the 5- and 10-year follow-up personality assessment who were eligible to do so. Conclusions Mean-level and rank-order personality scores show only modest changes, so most personality changes over time are not systematic. Observed changes in personality traits are not explained by changes in mood with the exception of Neuroticism, suggesting other factors influence changes in personality.

Bipolar disorder (BD) is characterized by manic and depressive mood episodes and loss of brain gray matter. Lithium has antimanic and neuroprotective properties, but only 30% BD patients respond to lithium pharmacotherapy. Dopamine signaling has been implicated in BD and may contribute to lithium response. Methamphetamine (METH) stimulates dopamine release and models the clinical features of mania but has never been used to study cell death in BD patient neurons. We used BD patient derived neuronal progenitor cells (NPCs) to determine whether the vulnerability to cell death differed in samples from lithium responder (Li-R) and non-responder (Li-NR) BD patients and healthy controls following METH exposure in vitro. We hypothesized that NPCs from Li-R and Li-NR would differ in vulnerability to METH, dopamine signaling and neuroprotection from lithium. Following METH, NPCs from controls and Li-NR showed significantly greater cell loss compared to Li-R. Pre-treatment of NPCs with the D1 dopamine receptor antagonist SCH 23390 reversed the neurotoxic effects of METH. In Li-R NPCs, expression of phosho-ERK1/2 was significantly increased. In Li-NR NPCs, phospho-AKT, D1 and D2 dopamine receptor proteins were significantly increased. Pre-treatment of NPCs with lithium before METH reversed the neurotoxic effects of METH in control NPCs, whereas Li-NR showed less protective benefit. Li-R cells showed decreased levels of cell death after METH and comparatively high viability, and lithium treatment did not increase viability any further. This novel NPC model of mania reveals differences in cell death that could help identify mechanisms of lithium response in BD.

OBJECTIVES Bipolar disorder (BP) is commonly researched in digital settings. As a result, standardized digital tools are needed to measure mood. We sought to validate a new survey that is brief, validated in digital form, and able to separately measure manic and depressive severity. METHODS We introduce a 6-item digital survey, called digiBP, for measuring mood in BP. It has three depressive items (depressed mood, fidgeting, fatigue), two manic items (increased energy, rapid speech), and one mixed item (irritability); and recovers two scores (m and d) to measure manic and depressive severity. In a secondary analysis of individuals with BP who monitored their symptoms over 6 weeks (n = 43), we perform a series of analyses to validate the digiBP survey internally, externally, and as a longitudinal measure. RESULTS We first verify a conceptual model for the survey in which items load onto two factors ("manic" and "depressive"). We then show weekly averages of m and d scores from digiBP can explain significant variation in weekly scores from the Young Mania Rating Scale (R2 = 0.47) and SIGH-D (R2 = 0.58). Lastly, we examine the utility of the survey as a longitudinal measure by predicting an individual's future m and d scores from their past m and d scores. CONCLUSIONS While further validation is warranted in larger, diverse populations, these validation analyses should encourage researchers to consider digiBP for their next digital study of BP.

Sociotropy and autonomy are cognitive-personality styles that have been hypothesized to confer vulnerability to different presentations of major depressive disorder (MDD), which may respond differentially to treatment. Specifically, the profile of low sociotropy and high autonomy is hypothesized to indicate a positive response to antidepressant medication. The current study examines sociotropy and autonomy in relation to sertraline treatment response in individuals with MDD. As part of an ancillary study to the larger Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) project, individuals with MDD participated in an 8-week trial of sertraline and completed a self-report questionnaire of sociotropy and autonomy. Discriminant function analyses were used to examine whether sociotropy and autonomy scores could distinguish antidepressant treatment responders (determined by a 50% or greater reduction in depressive symptoms) from non-responders. The sociotropy scale successfully discriminated sertraline treatment responders from non-responders. Further, lower sociotropy was associated with greater improvements in depressive symptomology following sertraline treatment. The current findings suggest individuals with MDD characterized by low sociotropy are more likely to benefit from sertraline. Given the promising results of the Sociotropy-Autonomy Scale in discriminating treatment responders from non-responders, the low resources necessary for administration, and the ease of translation into routine clinical care, the scale warrants further research attention.

BackgroundMobile transdiagnostic therapies offer a solution to the challenges of limited access to psychological care. However, it is unclear if individuals can actively synthesize and adopt concepts and skills via an app without clinician support.AimsThe present study measured comprehension of and engagement with a mobile acceptance and commitment therapy (ACT) intervention in two independent cohorts. Authors hypothesized that participants would recognize that behaviors can be flexible in form and function and respond in an ACT process-aligned manner.MethodsMixed-methods analyses were performed on open-ended responses collected from initial participants (n = 49) in two parallel micro-randomized trials with: 1) first-generation college students (FGCSs) (n = 25) from a four-year public research university and 2) individuals diagnosed with bipolar disorder (BP) (n = 24). Twice each day over six weeks, participants responded to questions about mood and behavior, after which they had a 50-50 chance of receiving an ACT-based intervention. Participants identified current behavior and categorized behavior as values-based or avoidant. Interventions were selected randomly from 84 possible prompts, each targeting one ACT process: engagement with values, openness to internal experiences, or self-awareness. Participants were randomly assigned to either exploratory (10 FGCS, 9 BP) or confirmatory (15 FGCS, 15 BP) groups for analyses. Responses from the exploratory group were used to inductively derive a qualitative coding system. This system was used to code responses in the confirmatory group. Coded confirmatory data were used for final analyses.ResultsOver 50% of participants in both cohorts submitted a non-blank response 100% of the time. For over 50% of participants, intervention responses aligned with the target ACT process for at least 96% of the time (FGCS) and 91% of the time (BP), and current behavior was labeled as values-based 70% (FGCS) and 85% (BP) of the time. Participants labeled similar behaviors flexibly as either values-based or avoidant in different contexts. Dominant themes were needs-based behaviors, interpersonal and family relationships, education, and time as a cost.ConclusionsBoth cohorts were engaged with the app, as demonstrated by responses that aligned with ACT processes. This suggests that participants had some level of understanding that behavior can be flexible in form and function.

Cognitive functioning in bipolar disorder is heterogeneous with evidence for multiple subgroups. However, cognitive subgroup change patterns over time remains unknown. While prior work suggests minimal differences in cognitive functioning patterns over time between those with bipolar disorder and controls, group-based analyses may obscure unique subgroup-based changes.Participants diagnosed with bipolar disorder (I, II, NOS; n = 568) and unaffected controls (n = 234) completed baseline, one- and five-year neuropsychological assessments. Data reduction techniques were used to limit the number of neuropsychological variables. Bipolar disorder participant baseline neuropsychological data were entered into hierarchical cluster analyses and resultant clusters were entered in multilevel models, which tested for differences in baseline and longitudinal cognitive changes in cognition among the cluster groups and with controls.Results were consistent with bipolar disorder participants forming three subgroups with high (n = 209), mid (n = 259), and low (n = 100) cognition. These groups were associated with unique clinical characteristics. Multilevel models demonstrated that over a five-year period, the low group improved, relative to the high and mid groups, and with controls, in auditory memory. Over the five-year period, the mid group, in comparison with the high group, improved in visual memory; additionally, the high group remained stable, in comparison with a slight decline in the control group, in inhibitory control.These results demonstrate that cognition-based subgroups of bipolar disorder participants have minimal differences in their longitudinal course in relation to each other and with unaffected controls.

The methods and technologies behind the analyses of genetic data and information have advanced considerably since the identification and expansion of DNA sequence-based markers, genotypes, that map the human genome. The capacity for generating large numbers of genotypes have provided a base for developing innovative methods of analysis. The approach has shifted from family-based linkage analyses to population-based association analyses and emerging results have opened new directions for inquiry. In disorders with non-Mendelian inheritance, tens to hundreds of susceptibility loci have been identified, and methods adapted to assess a polygenic risk score are being tested. Methods for estimating epigenetic influences on gene expression are actively being developed and tested. The mitochondria are an exciting frontier in the search for causality. As current methods and technologies are considered, there is momentum and innovation driving the process. Emerging data and results demand new approaches, which create new data and results.

International audience; Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD.Methods: Thirteen cohorts from 7 countries included n=5,882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors.Results: We found high rates of functional impairment, ranging from 41-75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning.Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.