Change in neurocognitive functioning in patients with treatment-resistant depression with serial intravenous ketamine infusions: The Bio-K multicenter trial.

This nonrandomized, multicenter, open-label clinical trial explored the impact of intravenous (IV) ketamine on cognitive function in adults (n = 74) with treatment-resistant depression (TRD). Patients received three IV ketamine infusions during the acute phase and, if remitted, four additional infusions in the continuation phase (Mayo site). Cognitive assessments using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were conducted at baseline, end of the acute phase, and end of the continuation phase (Mayo site). Results showed a significant 53 % (39/74) remission rate in depression symptoms after the acute phase. In adjusted models, baseline language domain score was associated with a higher odd of remission (Odds Ratio, 1.09, 95 % CI = 1.03-1.17, p = 0.004) and greater improvement in MADRS at the end of the acute phase (ß =-0.97; 95 % CI, -1.74 to -0.20; P = 0.02). The likelihood of remission was not significantly associated with baseline immediate or delayed memory, visuospatial/constructional, or attention scores. In the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. Limitations included an open-label design, potential practice effects, and ongoing psychotropic medication use. Overall, the study suggests cognitive improvement, not deterioration, associated with serial IV ketamine administrations for TRD. These findings encourage future studies with larger sample sizes and longer follow-up periods to examine any potential for deleterious effect with recurrent ketamine use for TRD. Trial Registration: ClinicalTrials.gov: NCT03156504.

Trauma and comorbid post-traumatic stress disorder in people with bipolar disorder participating in the Heinz C. Prechter Longitudinal Study.

BACKGROUND: It is estimated that up to 50 % of people with bipolar disorder (BD) also have comorbid post-traumatic stress disorder (PTSD). However, little is known about the presentation and treatment of people with this comorbidity. METHODS: Data from 577 individuals diagnosed with bipolar disorder participating in the Heinz C. Prechter Longitudinal Study of BD were explored at baseline, year two and four. Three trauma groups were created: (i) one trauma (n = 75), (ii) multiple traumas (n = 417), and comorbid PTSD (n = 85). Measures of depression, mania, sleep, number of hospitalisations, suicide attempts, and medication use were analysed using regression modelling to determine differences between the three trauma groups. RESULTS: There was an increase in depression, mania, and sleep scores and a higher number of hospitalisations in participants with comorbid PTSD compared to those experiencing one trauma. Additionally, increased mania and depression scores were reported in participants experiencing multiple traumas compared to those with one trauma. There was no difference in medication use between those who experienced one trauma compared to those with comorbid PTSD. LIMITATIONS: The trauma groups may include confounding with more participants experiencing PTSD than reported in this study due to screening processes. Additionally, the severity of trauma was not recorded, therefore number of traumas was utilised as a proxy. CONCLUSION: Comorbid BD and PTSD is associated with worse symptom scores compared to participants reporting one trauma. Clinical implications include the addition of trauma-informed care to clinical settings to identify PTSD to provide appropriate treatments.

Patterns of pharmacotherapy for bipolar disorder: A GBC survey.

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

Clinical outcomes in the biomarkers of ketamine (Bio-K) study of open-label IV ketamine for refractory depression.

OBJECTIVE: We conducted an open-label clinical trial ("Bio-K") using IV ketamine for treatment-resistant depression to identify biomarkers linked to remission. Here, we report the clinical efficacy and side effect outcomes of Bio-K. METHODS: Across 4 US sites, 75 patients ages 18-65 with treatment-refractory unipolar or bipolar depression received 3 IV ketamine infusions over an 11-day period. Key exclusion criteria were psychotic symptoms, significant substance abuse, unstable medical conditions, and any use of cannabis. Pre-existing antidepressant medication was maintained. Primary outcome was remission as measured by Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcome of 50 % reduction in Beck Suicide Scale score. Safety monitoring and varying durations of infusions were also key parameters. RESULTS: Using remission as MADRS score <10, after 3 infusions 52 % achieved remission, with 67 % achieving response. Of those achieving response after a single infusion, 66 % (22 of 33) reached remission after 3 infusions, while 40 % (16 of 40) non-responders after the first infusion went on to achieve remission after 3 infusions. Only 20 % of non-responders after 2 infusions achieved remission. Most (81 %) participants had significant suicidal ideation at baseline; of these, two-thirds (67 %) experienced at least a 50 % reduction in suicidality. Side effects were minimal. Uniquely, we had three different types of infusion categories, with individuals receiving: (1) slow (100-min) infusions only or (2) regular (40-min) infusions only or (3) a mix of infusion durations. These three infusion groups showed comparable safety and efficacy. Exploration of clinical factors revealed no link between BMI, age, or gender to remission. CONCLUSIONS: The consistency of outcomes across 4 clinical sites and across multiple instruments, suggests high acute efficacy and safety of IV ketamine for serious depressive episodes. Duration of infusion did not alter outcomes. Meaningfully, 40 % of non-responders after a single infusion did reach remission subsequently, while only 20 % of non-responders after 2 infusions achieved remission, suggesting early response is suggestive for eventual remission. Our data on varying ketamine infusion duration adds novel insights into the clinical administration of this new treatment for refractory and severe patients. Our limitations included a lack of a control group, necessitating caution about conclusions of efficacy, balanced by the utility of reporting "real-world" outcomes across multiple clinical sites. We could also not separately analyze results for bipolar disorder due to small numbers. Together, the Bio-K clinical results are promising and provide significant sample sizes for forthcoming biological markers analyses.

Comparative mortality risks in two independent bipolar cohorts.

OBJECTIVES: To compare mortality rates in bipolar disorder with common causes of mortality. METHODS: Observational data from the Prechter Longitudinal Study of Bipolar Disorder (PLS-BD) of 1128 participants including 281 controls was analyzed using logistical regression to quantify mortality rates in comparison with common comorbidities and causes of death. Outcome and treatment measures, including ASRM, GAD-7, PHQ-9 and medication use were used to stratify those with bipolar disorder (BD) that are alive or deceased. A larger cohort of 10,735 existing BD patients with 7,826 controls (no psychiatric diagnosis) from the University of Michigan Health (U-M Health) clinics was used as replication, observational secondary data analysis. RESULTS: The mortality rates are significantly different between those with BD and controls in both PLS-BD and U-M Health. Those with BD and are deceased have a higher percentage of elevated depression measures but show no difference in mania or anxiety measures nor medication use patterns. In both cohorts, a diagnosis of BD increases the odds of mortality greater than history of smoking or being older than ≥ 60-years of age. CONCLUSION: BD was found to increase odds of mortality significantly and beyond that of a history of smoking. This finding was replicated in an independent sample.

Circadian rhythm disruptions associated with opioid use disorder in synaptic proteomes of human dorsolateral prefrontal cortex and nucleus accumbens.

Opioid craving and relapse vulnerability is associated with severe and persistent sleep and circadian rhythm disruptions. Understanding the neurobiological underpinnings of circadian rhythms and opioid use disorder (OUD) may prove valuable for developing new treatments for opioid addiction. Previous work indicated molecular rhythm disruptions in the human brain associated with OUD, highlighting synaptic alterations in the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc)-key brain regions involved in cognition and reward, and heavily implicated in the pathophysiology of OUD. To provide further insights into the synaptic alterations in OUD, we used mass-spectrometry based proteomics to deeply profile protein expression alterations in bulk tissue and synaptosome preparations from DLPFC and NAc of unaffected and OUD subjects. We identified 55 differentially expressed (DE) proteins in DLPFC homogenates, and 44 DE proteins in NAc homogenates, between unaffected and OUD subjects. In synaptosomes, we identified 161 and 56 DE proteins in DLPFC and NAc, respectively, of OUD subjects. By comparing homogenate and synaptosome protein expression, we identified proteins enriched specifically in synapses that were significantly altered in both DLPFC and NAc of OUD subjects. Across brain regions, synaptic protein alterations in OUD subjects were primarily identified in glutamate, GABA, and circadian rhythm signaling. Using time-of-death (TOD) analyses, where the TOD of each subject is used as a time-point across a 24-h cycle, we were able to map circadian-related changes associated with OUD in synaptic proteomes associated with vesicle-mediated transport and membrane trafficking in the NAc and platelet-derived growth factor receptor beta signaling in DLPFC. Collectively, our findings lend further support for molecular rhythm disruptions in synaptic signaling in the human brain as a key factor in opioid addiction.

Circadian rhythm disruptions associated with opioid use disorder in the synaptic proteomes of the human dorsolateral prefrontal cortex and nucleus accumbens.

Opioid craving and relapse vulnerability is associated with severe and persistent sleep and circadian rhythm disruptions. Understanding the neurobiological underpinnings of circadian rhythms and opioid use disorder (OUD) may prove valuable for developing new treatments for opioid addiction. Previous work indicated molecular rhythm disruptions in the human brain associated with OUD, highlighting synaptic alterations in the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc)-key brain regions involved in cognition and reward, and heavily implicated in the pathophysiology of OUD. To provide further insights into the synaptic alterations in OUD, we used mass-spectrometry based proteomics to deeply profile protein expression alterations in bulk tissue and synaptosome preparations from DLPFC and NAc of unaffected and OUD subjects. We identified 55 differentially expressed (DE) proteins in DLPFC homogenates, and 44 DE proteins in NAc homogenates, between unaffected and OUD subjects. In synaptosomes, we identified 161 and 56 DE proteins in DLPFC and NAc, respectively, of OUD subjects. By comparing homogenate and synaptosome protein expression, we identified proteins enriched specifically in synapses that were significantly altered in both DLPFC and NAc of OUD subjects. Across brain regions, synaptic protein alterations in OUD subjects were primarily identified in glutamate, GABA, and circadian rhythm signaling. Using time-of-death (TOD) analyses, where the TOD of each subject is used as a time-point across a 24- hour cycle, we were able to map circadian-related changes associated with OUD in synaptic proteomes related to vesicle-mediated transport and membrane trafficking in the NAc and platelet derived growth factor receptor beta signaling in DLPFC. Collectively, our findings lend further support for molecular rhythm disruptions in synaptic signaling in the human brain as a key factor in opioid addiction.

Interpersonal Trauma and Depression Severity Among Individuals With Bipolar Disorder: Findings From the Prechter Longitudinal Study of Bipolar Disorder.

Background: Experiences of interpersonal trauma, both in childhood and in adulthood, can affect the trajectory of bipolar disorder (BD). However, the degree to which childhood and/or adult trauma impacts the longitudinal trajectory of depression severity among individuals with BD actively receiving treatment remains unclear.Methods: The effects of childhood trauma (Childhood Trauma Questionnaire) and adult trauma (Life Events Checklist) on depression severity (Hamilton Depression Rating Scale) were investigated in a treatment-receiving subsample with BD (DSM-IV) of the Prechter Longitudinal Study of Bipolar Disorder (2005-present). A mixed-effects linear regression model was used to assess the trajectory of depression severity over 4 years.Results: Depression severity was evaluated in 360 participants, of whom 267 (74.8%) reported a history of interpersonal trauma. A history of childhood trauma alone (n = 110) and childhood and adult trauma combined (n = 108)-but not adult trauma alone (n = 49) -were associated with greater depression severity at the 2-year and 6-year follow-up assessments. However, the trajectory of depression severity (ie, change over time) was similar between participants with a history of childhood trauma, those with a history of adult trauma, and those with no history of interpersonal trauma. Interestingly, participants with a history of both types of trauma showed more improvement in depression severity (ie, from year 2 to year 4: ß = 1.67, P = .019).Conclusions: Despite actively receiving treatment for BD, participants with a history of interpersonal trauma-particularly childhood trauma-presented with more severe depressive symptoms at several follow-up assessments. Hence, interpersonal trauma may represent an essential treatment target.

Heightened inflammation in bipolar disorder occurs independent of symptom severity and is explained by body mass index.

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)-1ß, 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 < .001) and differences in cytokines between the two groups was no longer significant after controlling for BMI. No differences in CRP were evident between BP and HC. These results suggest that cytokine concentrations are elevated in BP and this difference from HC is associated with obesity. Interventions targeting immune modulators in BP must carefully consider the complex relationships within the BP-inflammation-obesity triangle.

Childhood trauma relates to worse memory functioning in bipolar disorder.

BACKGROUND: Childhood trauma is commonly experienced by individuals diagnosed with bipolar disorder (BP). In BP, childhood trauma is related to a more severe clinical course, but its association with cognition remains unclear. METHODS: This study evaluated 405 adult participants diagnosed with BP and 136 controls. Participants completed the Childhood Trauma Questionnaire and a comprehensive neuropsychological battery. High versus low childhood trauma was defined with one standard deviation above the control participant's mean Childhood Trauma Questionnaire score. Neuropsychological data was transformed into eight cognitive factors, including four executive functioning, auditory and visual memory, fine motor, and emotion processing. Multivariate analysis of covariance evaluated group differences in cognition, while adjusting for covariates. RESULTS: There were significant differences among the three groups, F(16, 968) = 4.05, p < .001, Wilks' Λ = 0.88, partial η2 = 0.06. Comparing the high and low trauma BP groups, high trauma was related to lower auditory and visual memory factor scores (p < .05). As compared to controls, the BP high trauma group had lower scores on six of eight factors (all p < .01), while the BP low trauma group had lower scores on four of eight factors (all p < .01). LIMITATIONS: Analyses of factor score do not address which aspect of the memory process is affected and biomarkers may help guide interventions addressing underlying biological process. CONCLUSIONS: Adults diagnosed with BP with higher childhood trauma have worse memory functioning, beyond the lower childhood trauma BP group, highlighting the importance of understanding the long-term cognitive outcomes of childhood trauma.

Childhood trauma and depressive symptoms in bipolar disorder: A network analysis.

BACKGROUND: Childhood trauma is related to an increased number of depressive episodes and more severe depressive symptoms in bipolar disorder. The evaluation of the networks of depressive symptoms-or the patterns of relationships between individual symptoms-among people with bipolar disorder with and without a history of childhood trauma may assist in further clarifying this complex relationship. METHODS: Data from over 500 participants from the Heinz C. Prechter Longitudinal Study of Bipolar Disorder were used to construct a series of regularised Gaussian Graphical Models. The networks of individual depressive symptoms-self-reported (Patient Health Questionnaire-9; n = 543) and clinician-rated (Hamilton Depression Rating Scale-17; n = 529)-among participants with bipolar disorder with and without a history of childhood trauma (Childhood Trauma Questionnaire) were characterised and compared. RESULTS: Across the sets of networks, depressed mood consistently emerged as a central symptom (as indicated by strength centrality and expected influence); regardless of participants' history of childhood trauma. Additionally, feelings of worthlessness emerged as a key symptom in the network of self-reported depressive symptoms among participants with-but not without-a history of childhood trauma. CONCLUSION: The present analyses-although exploratory-provide nuanced insights into the impact of childhood trauma on the presentation of depressive symptoms in bipolar disorder, which have the potential to aid detection and inform targeted intervention development.

Personality traits as mediators of the relationship between childhood trauma and depression severity in bipolar disorder: A structural equation model.

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 ß = 0.32, 95% bootstrap confidence interval [CI] = 0.20-0.45, p < 0.001) and the indirect effect via neuroticism (standardised ß = 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 ß = 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.

Predictors of Functional Impairment in Bipolar Disorder: Results From 13 Cohorts From Seven Countries by the Global Bipolar Cohort Collaborative.

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 = 5882 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 to 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, the 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.Reprinted from Bipolar Disord 2022; 24:709-719, with permission from John Wiley and Sons. Copyright © 2022.

Case Reports: Exposure to SARS-CoV-2, Acute Kidney Injury, and Lithium Toxicity.

PURPOSES: 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. METHODS: 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. FINDINGS: 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. IMPLICATIONS: 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.

Lithium use associated with symptom severity in comorbid bipolar disorder I and migraine.

INTRODUCTION: Bipolar disorder (BD) and migraine headaches are frequently comorbid. The common etiological features are unknown, however cortical hyperexcitability (EEG) of migraines, and the report of hyperexcitability in pluripotent stem cell-derived neurons from lithium responsive BD subjects offers a physiological hypothesis of excitable neurons linking these disorders. However, clinical studies suggest that a history of migraine is associated with higher rates of relapse in those with BD taking lithium. Lithium use and history of migraine in this prospective longitudinal study of BD find that lithium use is associated with a greater symptom severity in BD. METHODS: Data on longitudinal outcome from 538 patients with BD I were categorized according to treatment with lithium and comorbidity with migraine. Clinical outcome measures on depression, mania, and quality of life over the most recent 2-year period compared the BD and BD/migraine cohort according to lithium treatment status. RESULTS: A history of migraines was associated with worse clinical outcomes of depression (p = .002), mania (p = .005), and mental and physical quality of life (p = .004 and p = .005, respectively), independent of lithium use. The BD/migraine cohort treated with lithium was associated with worse symptoms of mania, whereas those without migraine and lithium use were associated with milder manic symptoms (p = .026). CONCLUSIONS: Herein, we replicate the relatively worse outcome in BD with comorbid migraine. We find evidence to suggest that lithium use is associated with more severe symptoms of mania among those with BD and a history of migraine and conclude that lithium is contraindicated in BD comorbid with migraine.

Predictors of functional impairment in bipolar disorder: Results from 13 cohorts from seven countries by the global bipolar cohort collaborative.

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 = 5882 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 to 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, the 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.