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MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness.

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Introduction Disturbances to sleep-wake patterns are associated with bipolar disorder (BD) and borderline personality disorder (BPD). Objective assessment typically involves actigraphy monitoring, although it may be possible to derive sleep-wake metrics from other digital data, such as smartphone battery degradation. Objectives To assess whether common actigraphy-derived phase markers of the sleep-wake pattern (L5 and M10 onset) are in agreement with measures derived from smartphone battery data and explore if battery metrics differ between people with BD, BPD , and a healthy control group (HC). Methods High frequency smartphone battery data was collected from 30 BD, 19 BPD and 33 HC participants enrolled in the Automated Monitoring of Symptom Severity (AMoSS) study, over 28 days. Participants also wore an actigraph during this period. L5 and M10 values were calculated separately based on the rate of smartphone battery degradation and conventional actigraphy methods. Bland-Altman analyses were performed to assess agreement between battery-derived and actigraphy-derived values, and Kruskal-Wallis tests used to compare diagnostic groups. Results For L5, battery-derived and actigraphy-derived values had a bias of 0.46 [-0.10, 1.02], upper limit of agreement (LOA): 5.45 [4.49, 6.41], and lower LOA: -4.53 [-3.56, -5.49]. For M10, the bias was 0 [-0.92, 0.92], upper LOA: 8.19 [6.61, 9.76], and lower LOA: -8.19 [-6.61, -9.76]. Between diagnostic groups, there was no difference for battery-derived M10 (p=0.652), or L5 (p=0.122). Conclusions Our results suggest battery-derived and actigraphy-derived M10 and L5 show good overall equivalence. However, battery-derived methods exhibit large variability, which limits the clinical utility of smartphone battery data to infer sleep-wake metrics. Disclosure No significant relationships.

Abstract Background Bipolar disorder (BD) is associated with excess and premature cardiovascular mortality. Elevated blood pressure (BP) is a leading contributor to cardiovascular risk. However, few studies have examined BP in BD in comparison to other psychiatric disorders. Furthermore, the association between BP and mood instability is not presently clear despite increasing interest in repurposing existing antihypertensive medications as possible novel BD treatments. Thus we examined BP differences between BD and borderline personality disorder (BPD), a disorder with a similar symptom profile through chronic mood instability. Methods A total of 106 adults (38 BD, 25 BPD, and 43 healthy controls), evaluated in the Automated Monitoring of Symptom Severity (AMoSS) study, completed a week-long home blood pressure monitoring assessment and ecological momentary assessment of mood. We examined group-wise differences in mean BP and BP variability and their association with mood instability. Results BD individuals had a significantly wider resting pulse pressure (40.8 ± 7.4, mmHg) compared to BPD (35.7 ± 5.3, mmHg, P = 0.03) and control participants (37.3 ± 6.3, mmHg, P = 0.036). Systolic BP was negatively associated with sad mood instability, and all measures of mean BP (systolic, diastolic, and mean arterial pressure) were negatively associated with positive mood instability. Conclusions This study demonstrates BP differences between BD and healthy and clinical controls that are within a normotensive range. Early pulse pressure widening may be a modifiable pathophysiological feature of BD that confers later cardiovascular risk. BP may be an important transdiagnostic predictor of mood instability and a potential explicit treatment target.

Background Social functioning is often impaired in schizophrenia (SZ) and Alzheimer’s disease (AD). However, commonalities and differences in social dysfunction among these patient groups remain elusive. Materials and methods Using data from the PRISM study, behavioral (all subscales and total score of the Social Functioning Scale) and affective (perceived social disability and loneliness) indicators of social functioning were measured in patients with SZ (N = 56), probable AD (N = 50) and age-matched healthy controls groups (HC, N = 29 and N = 28). We examined to what extent social functioning differed between disease and age-matched HC groups, as well as between patient groups. Furthermore, we examined how severity of disease and mood were correlated with social functioning, irrespective of diagnosis. Results As compared to HC, both behavioral and affective social functioning seemed impaired in SZ patients (Cohen’s d’s 0.81–1.69), whereas AD patients mainly showed impaired behavioral social function (Cohen’s d’s 0.65–1.14). While behavioral indices of social functioning were similar across patient groups, SZ patients reported more perceived social disability than AD patients (Cohen’s d’s 0.65). Across patient groups, positive mood, lower depression and anxiety levels were strong determinants of better social functioning (p’s Conclusions AD and SZ patients both exhibit poor social functioning in comparison to age- and sex matched HC participants. Social dysfunction in SZ patients may be more severe than in AD patients, though this may be due to underreporting by AD patients. Across patients, social functioning appeared as more influenced by mood states than by severity of disease.

Introduction Differences in the relationship between mood and digital communication metrics have been shown to act as a diagnostic marker in Bipolar Disorder (BD) and Borderline Personality Disorder (BPD). Anxiety has been associated with mobile-phone use in non-clinical populations, although a potential association between anxiety and digital communications in BD or BPD populations hasn’t been studied. Objectives To explore the association between self-reported anxiety symptoms and objective, naturalistic digital communications metrics in BD and BPD participants. Methods BD (n= 17) and BPD (n=17) cohorts were provided with a smartphone application which monitored phone call and SMS frequency and duration, alongside weekly self-reported anxiety (Generalised Anxiety Disorder 7-item scale). Linear mixed-effects regression models assessed the association between digital communications, anxiety state and interaction effects between anxiety and diagnosis. Results Self-reported anxiety state was negatively associated with decreased total call frequency (B=-5.150, p=0.002), cumulative total call duration (seconds; B=-1456.779, p

Background: Remote monitoring and digital phenotyping harbor potential to aid clinical diagnosis, predict episode course and recognize early signs of mental health crises. Digital communication metrics, such as phone call and short message service (SMS) use may represent novel biomarkers of mood and diagnosis in Bipolar Disorder (BD) and Borderline Personality Disorder (BPD).Materials and Methods: BD (n = 17), BPD (n = 17) and Healthy Control (HC, n = 21) participants used a smartphone application which monitored phone calls and SMS messaging, alongside self-reported mood. Linear mixed-effects regression models were used to assess the association between digital communications and mood symptoms, mood state, trait-impulsivity, diagnosis and the interaction effect between mood and diagnosis.Results: Transdiagnostically, self-rated manic symptoms and manic state were positively associated with total and outgoing call frequency and cumulative total, incoming and outgoing call duration. Manic symptoms were also associated with total and outgoing SMS frequency. Transdiagnostic depressive symptoms were associated with increased mean incoming call duration. For the different diagnostic groups, BD was associated with increased total call frequency and BPD with increased total and outgoing SMS frequency and length compared to HC. Depression in BD, but not BPD, was associated with decreased total and outgoing call frequency, mean total and outgoing call duration and total and outgoing SMS frequency. Finally, trait-impulsivity was positively associated with total call frequency, total and outgoing SMS frequency and cumulative total and outgoing SMS length.Conclusion: These results identify a general increase in phone call and SMS communications associated with self-reported manic symptoms and a diagnosis-moderated decrease in communications associated with depression in BD, but not BPD, participants. These findings may inform the development of clinical tools to aid diagnosis and remote symptom monitoring, as well as informing understanding of differential psychopathologies in BD and BPD.

Background: Behavioral tasks focusing on different subdomains of reward processing may provide more objective and quantifiable measures of anhedonia and impaired motivation compared with clinical scales. Typically, single tasks are used in relatively small studies to compare cases and controls in one indication, but they are rarely included in larger multisite trials. This is due to limited systematic standardization as well as the challenges of deployment in international studies and stringent adherence to the high regulatory requirements for data integrity. The Reward Task Optimization Consortium (RTOC) was formed to facilitate operational implementation of reward processing tasks, making them suitable for use in future large-scale, international, multisite drug development studies across multiple indications. The RTOC clinical study aims to conduct initial optimization of a set of tasks in patients with major depressive disorder (MDD) or schizophrenia (SZ).Methods: We will conduct a multicenter study across four EU countries. Participants (MDD = 37, SZ = 37, with ≤80 age- and gender-matched healthy volunteers) will attend a study visit comprising screening, self-report and clinically rated assessments of anhedonia and symptom severity, and three reward processing tasks; specifically, the Grip Strength Effort task, the Doors task, and the Reinforcement Learning Working Memory task. The Grip Strength Effort and Doors tasks include simultaneous electroencephalography/event-related potential recordings. Outcomes will be compared using a two-way group design of MDD and SZ with matched controls, respectively. Further analyses will include anhedonia assessment scores as covariates. Planned analyses will assess whether our findings replicate previously published data, and multisite deployment will be evaluated through assessments of quality and conduct. A subset of participants will complete a second visit, to assess test–retest reliability of the task battery.Discussion: This study will evaluate the operational deployment of three reward processing tasks to the regulatory standards required for use in drug development trials. We will explore the potential of these tasks to differentiate patients from controls and to provide a quantitative marker of anhedonia and/or impaired motivation, establishing their usefulness as endpoints in multisite clinical trials. This study should demonstrate where multifaceted reward deficits are similar or divergent across patient populations.Registration: ClinicalTrials.gov (NCT04024371).

Abstract Background The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. Methods A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. Results Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. Conclusions Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

Abstract Variable mood is an important feature of psychiatric disorders. However, its measurement and relationship to objective measureas of physiology and behaviour have rarely been studied. Smart-phones facilitate continuous personalized prospective monitoring of subjective experience and behavioural and physiological signals can be measured through wearable devices. Such passive data streams allow novel estimates of diurnal variability. Phase and amplitude of diurnal rhythms were quantified using new techniques that fitted sinusoids to heart rate (HR) and acceleration signals. We investigated mood and diurnal variation for four days in 20 outpatients with bipolar disorder (BD), 14 with borderline personality disorder (BPD) and 20 healthy controls (HC) using a smart-phone app, portable electrocardiogram (ECG), and actigraphy. Variability in negative affect, positive affect, and irritability was elevated in patient groups compared with HC. The study demonstrated convincing associations between variability in subjective mood and objective variability in diurnal physiology. For BPD there was a pattern of positive correlations between mood variability and variation in activity, sleep and HR. The findings suggest BPD is linked more than currently believed with a disorder of diurnal rhythm; in both BPD and BD reducing the variability of sleep phase may be a way to reduce variability of subjective mood.

Close and intimate relationships are important promoters of health. Oxytocin and its association with social cognition have been investigated in a large number of studies, especially highlighting the neuropeptide’s involvement in attachment behavior and intimate relationships. However, mixed findings on exogenous oxytocin application have led to the focus on moderators and mediators, suggesting that the effects are depended on specific factors – namely context and salience. The objective of the current study was to assess the effect of intranasal oxytocin on social appraisal of own and others’ close intimate relationship characteristics. Different characteristics of relationships, including trust or closeness, between romantic couples (unknown and own) were assessed using the Couple Appraisal Task. In a randomized controlled double-blind cross-over within subject design, N = 71 healthy men and women were investigated after receiving first intranasal oxytocin and 2 weeks later placebo, or vice versa. We found an oxytocin-induced increase in the positive appraisal of one’s own overall relationship characteristics but not in the evaluation of the relationship of others. The present study – one of the first of its kind administrating oxytocin in a repeated measures cross-over design – adds further evidence to the mediating role of oxytocin in social cognition, specifically with regard to romantic relationship characteristics.