Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

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.

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.

Low rate of performance validity failures among individuals with bipolar disorder.

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.

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.

Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes.

OBJECTIVE: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. METHODS: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4-0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. RESULTS: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. CONCLUSION: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

Exploration of baseline and early changes in neurocognitive characteristics as predictors of treatment response to bupropion, sertraline, and placebo in the EMBARC clinical trial.

BACKGROUND: Treatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner. METHODS: In the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin reuptake inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/dopamine reuptake inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16. RESULTS: Greater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline. CONCLUSION: These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.

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.

Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies.

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.

Strategies and foundations for scientific discovery in longitudinal studies of bipolar disorder.

Bipolar disorder (BD) is a complex and dynamic condition with a typical onset in late adolescence or early adulthood followed by an episodic course with intervening periods of subthreshold symptoms or euthymia. It is complicated by the accumulation of comorbid medical and psychiatric disorders. The etiology of BD remains unknown and no reliable biological markers have yet been identified. This is likely due to lack of comprehensive ontological framework and, most importantly, the fact that most studies have been based on small nonrepresentative clinical samples with cross-sectional designs. We propose to establish large, global longitudinal cohorts of BD studied consistently in a multidimensional and multidisciplinary manner to determine etiology and help improve treatment. Herein we propose collection of a broad range of data that reflect the heterogenic phenotypic manifestations of BD that include dimensional and categorical measures of mood, neurocognitive, personality, behavior, sleep and circadian, life-story, and outcomes domains. In combination with genetic and biological information such an approach promotes the integrating and harmonizing of data within and across current ontology systems while supporting a paradigm shift that will facilitate discovery and become the basis for novel hypotheses.

Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY: NCT0127253.

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.

Limited time-specific and longitudinal effects of depressive and manic symptoms on cognition in bipolar spectrum disorders.

OBJECTIVES: Previous research suggests that cognitive performance worsens during manic and depressed states in bipolar disorder (BD). However, studies have often relied upon between-subject, cross-sectional analyses and smaller sample sizes. The current study examined the relationship between mood symptoms and cognition in a within-subject, longitudinal study with a large sample. METHODS: Seven hundred and seventy-three individuals with BD completed a neuropsychological battery and mood assessments at baseline and 1-year follow-up. The battery captured eight domains of cognition: fine motor dexterity, visual memory, auditory memory, emotion processing, and four aspects of executive functioning: verbal fluency and processing speed; conceptual reasoning and set shifting; processing speed with influence resolution; and inhibitory control. Structural equation modeling was conducted to examine the cross-sectional and longitudinal relationships between depressive symptoms, manic symptoms, and cognitive performance. Age and education were included as covariates. Eight models were run with the respective cognitive domains. RESULTS: Baseline mood positively predicted 1-year mood, and baseline cognition positively predicted 1-year cognition. Mood and cognition were generally not related for the eight cognitive domains. Baseline mania was predictive in one of eight baseline domains (conceptual reasoning and set shifting); baseline cognition predicted 1-year symptoms (inhibitory control-depression symptoms, visual memory-manic symptoms). CONCLUSIONS: In a large community sample of patients with bipolar spectrum disorder, cognitive performance appears to be largely unrelated to depressive and manic symptoms, suggesting that cognitive dysfunction is stable in BD and is not dependent on mood state in BD. Future work could examine how treatment affects relationship between cognition and mood. SIGNIFICANT OUTCOMES: Cognitive dysfunction appears to be largely independent of mood symptoms in bipolar disorder. LIMITATIONS: The sample was generally highly educated (M = 15.22), the majority of the subsample with elevated manic symptoms generally presented with concurrent depressive elevated symptoms, and the study did not stratify recruitment based on mood state.

Cognitive subgroups and their longitudinal trajectories in bipolar disorder.

INTRODUCTION: 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. MATERIAL AND METHODS: 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: 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. CONCLUSION: 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.

Attachment insecurity partially mediates the relationship between childhood trauma and depression severity in bipolar disorder.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Childhood trauma and treatment outcomes during mood-stabilising treatment with lithium or quetiapine among outpatients with bipolar disorder.

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 history is linked to abnormal brain connectivity in major depression.

Patients with major depressive disorder (MDD) present with heterogeneous symptom profiles, while neurobiological mechanisms are still largely unknown. Brain network studies consistently report disruptions of resting-state networks (RSNs) in patients with MDD, including hypoconnectivity in the frontoparietal network (FPN), hyperconnectivity in the default mode network (DMN), and increased connection between the DMN and FPN. Using a large, multisite fMRI dataset (n = 189 patients with MDD, n = 39 controls), we investigated network connectivity differences within and between RSNs in patients with MDD and healthy controls. We found that MDD could be characterized by a network model with the following abnormalities relative to controls: (i) lower within-network connectivity in three task-positive RSNs [FPN, dorsal attention network (DAN), and cingulo-opercular network (CON)], (ii) higher within-network connectivity in two intrinsic networks [DMN and salience network (SAN)], and (iii) higher within-network connectivity in two sensory networks [sensorimotor network (SMN) and visual network (VIS)]. Furthermore, we found significant alterations in connectivity between a number of these networks. Among patients with MDD, a history of childhood trauma and current symptoms quantified by clinical assessments were associated with a multivariate pattern of seven different within- and between-network connectivities involving the DAN, FPN, CON, subcortical regions, ventral attention network (VAN), auditory network (AUD), VIS, and SMN. Overall, our study showed that traumatic childhood experiences and dimensional symptoms are linked to abnormal network architecture in MDD. Our results suggest that RSN connectivity may explain underlying neurobiological mechanisms of MDD symptoms and has the potential to serve as an effective diagnostic biomarker.

Discovery and replication of cerebral blood flow differences in major depressive disorder.

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.

Reward related ventral striatal activity and differential response to sertraline versus placebo in depressed individuals.

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. A total of 222 unmedicated adults with MDD randomized to receive sertraline (n = 110) or placebo (n = 112) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study completed demographic and clinical assessments, and pretreatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression (HSRD) over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on week-8 depression levels (Fs ≥ 9.67, ps ≤ 0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pretreatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pretreatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment.

A digital self-report survey of mood for bipolar disorder.

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.