Longitudinal Interplay Between Alcohol Use, Mood, and Functioning in Bipolar Spectrum Disorders.

Importance: Alcohol use disorder (AUD) is present in nearly half of individuals with bipolar disorder (BD) and is associated with markedly worsening outcomes. Yet, the concurrent treatment of BD and AUD remains neglected in both research and clinical care; characterizing their dynamic interplay is crucial in improving outcomes. Objective: To characterize the longitudinal alcohol use patterns in BD and examine the temporal associations among alcohol use, mood, anxiety, and functioning over time. Design, Setting, and Participants: This cohort study selected participants and analyzed data from the Prechter Longitudinal Study of Bipolar Disorder (PLS-BD), an ongoing cohort study that recruits through psychiatric clinics, mental health centers, and community outreach events across Michigan and collects repeated phenotypic data. Participants selected for the present study were those with a diagnosis of BD type I (BDI) or type II (BDII) who had been in the study for at least 5 years. Data used were extracted from February 2006 to April 2022, and follow-up ranged from 5 to 16 years. Main Outcomes and Measures: Alcohol use was measured using the Alcohol Use Disorders Identification Test. Depression, mania or hypomania, anxiety, and functioning were measured using the 9-Item Patient Health Questionnaire, the Altman Self-Rating Mania Scale, the 7-item Generalized Anxiety Disorder assessment scale, and the Life Functioning Questionnaire, respectively. Results: A total of 584 individuals (386 females (66.1%); mean [SD] age, 40 [13.6] years) were included. These participants had a BDI (445 [76.2%]) or BDII (139 [23.8%]) diagnosis, with or without a lifetime diagnosis of AUD, and a median (IQR) follow-up of 9 (0-16) years. More problematic alcohol use was associated with worse depressive (ß = 0.04; 95% credibility interval [CrI], 0.01-0.07) and manic or hypomanic symptoms (ß = 0.04; 95% CrI, 0.01-0.07) as well as lower workplace functioning (ß = 0.03; 95% CrI, 0.00-0.06) over the next 6 months, but increased depressive and manic or hypomanic symptoms were not associated with greater subsequent alcohol use. These latter 2 associations were more pronounced in BDII than BDI (mania or hypomania: ß = 0.16 [95% CrI, 0.02-0.30]; workplace functioning: ß = 0.26 [95% CrI, 0.06-0.45]). Alcohol use was not associated with anxiety over time. Conclusions and Relevance: This study found that alcohol use, regardless of diagnostic status, was associated with mood instability and poorer work functioning in BD, but increased mood symptoms were not associated with subsequent alcohol use. Given its prevalence and repercussions, dimensional and longitudinal assessment and management of alcohol use are necessary and should be integrated into research and standard treatment of BD.

Differential contributions of circadian clock genes to cell survival in bipolar disorder patient derived neuronal progenitor cells distinguishes lithium responders and non-responders.

Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium is neuroprotective and used to treat BD, but outcomes are variable. Past research identified that circadian rhythms in BD patient neurons are associated with lithium response (Li-R) or non-response (Li-NR). However, the underlying cellular mechanisms remain unknown. To study interactions among circadian clock genes and cell survival, and their role in BD and predicting lithium response, we tested selected genes (PER1, BMAL1 and REV-ERBα) and small molecule modulators of ROR/REV-ERB nuclear receptors in models of cell survival using mouse neurons and stem-cell derived neuronal progenitor cells (NPC) from BD patients and controls. In apoptosis assays using staurosporine (STS), lithium was neuroprotective. Knockdown of PER1, BMAL1 and REV-ERBα modified cell survival across models. In NPCs, reduced expression of PER1 and BMAL1 led to more extensive cell death in Li-NR vs. Li-R. Reduced REV-ERBα expression caused more extensive cell death in BD vs. control NPCs, without distinguishing Li-R and Li-NR. In IMHN, The REV-ERB agonist GSK4112 had strong effects on circadian rhythm amplitude, and was neuroprotective in mouse neurons and control NPCs, but not in BD NPCs. Expression of cell survival genes following STS and GSK4112 treatments revealed BD-associated, and Li-R associated differences in expression profiles. We conclude that the neuroprotective response to lithium is similar in NPCs from Li-R and Li-NR. However, knockdown of circadian clock genes or stimulation of REV-ERBs reveal distinct contributions to cell death in BD patient NPCs, some of which distinguish Li-R and Li-NR.

Bipolar Patient-Specific In Vitro Diagnostic Test Reveals Underlying Cardiac Arrhythmia Phenotype Caused by Calcium Channel Genetic Risk Factor.

A common genetic risk factor for bipolar disorder is CACNA1C, a gene that is also critical for cardiac rhythm. The impact of CACNA1C mutations on bipolar patient cardiac rhythm is unknown. Here, we report the cardiac electrophysiological implications of a bipolar disorder-associated genetic risk factor in CACNA1C using patient induced pluripotent stem cell-derived cardiomyocytes. Results indicate that the CACNA1C bipolar disorder-related mutation causes cardiac electrical impulse conduction slowing mediated by impaired intercellular coupling via connexin 43 gap junctions. In vitro gene therapy to restore connexin 43 expression increased cardiac electrical impulse conduction velocity and protected against thioridazine-induced QT prolongation. Patients positive for bipolar disorder CACNA1C genetic risk factors may have elevated proarrhythmic risk for adverse events in response to psychiatric medications that slow conduction or prolong the QT interval. This in vitro diagnostic tool enables cardiac testing specific to patients with psychiatric disorders to determine their sensitivity to off-target effects of psychiatric medications.

Bipolar disorder (BD) is associated with genetic risk factors that present as mutations in specific genes. One gene commonly associated with BD is the calcium channel gene CACNA1C, found in the brain and the heart. The impact of CACNA1C mutation on cardiac function in patients with BD is unclear. Here, we created a BD CACNA1C mutant patient "heart in a dish" using patient-specific stem cells. Gene editing was also used to correct the mutation to create an isogenic control cell line. We found that the BD calcium gene mutation caused slow electrical impulse propagation, reduced the function of the calcium channel, and was associated with low intercellular communication channels called connexin. Using connexin gene therapy in vitro, the the cardiac dysfunction could be corrected and cured. This new approach offers patient-specific hearts-in-a-dish that can be used to ensure that medications will not cause heart racing or arrhythmias.

An initial test of the contrast avoidance model in bipolar spectrum disorders.

The Contrast Avoidance Model suggests that individuals sensitive to negative emotional shifts use prior increases in negative affect to prevent further escalation in response to adverse situations, while the heightened negative affect amplifies positive emotional contrasts when encountering unexpected positive events. Individuals with bipolar spectrum disorders (BSDs), characterized by shifts between (hypo)manic and depressive episodes, may undergo more salient emotional contrasts. Drawing from the Contrast Avoidance Model, the shifts from depression to (hypo)mania can be conceptualized as positive emotional contrasts, potentially heightening the perceived pleasure during (hypo)manic episodes. On the other hand, the shifts from (hypo)manic to depressive episodes can be viewed as negative emotional contrasts, contributing to the challenges associated with depressive states. Despite the intriguing potential of this interplay, the link between the Contrast Avoidance Model and BSDs has never been empirically tested. Our study addressed this gap by examining group differences in contrast avoidance traits between individuals with BSDs, unipolar depression, and healthy controls in a large cohort study (N = 536). Results indicated that individuals with BSDs exhibited significantly higher scores in the total, and Discomfort with Negative Emotional Shifts and Avoidance of Negative Emotional Contrasts/Enhancement of Positive Emotional Contrasts factors, as well as separate item scores on the Contrast Avoidance Questionnaire-General Emotion (CAQ-GE), compared to those with unipolar depression and healthy controls. Although marginal, the BD II subtype demonstrated a stronger inclination to avoid negative emotional contrasts compared to BD I. These findings suggest that contrast avoidance may be a psychological mechanism implicated in BSDs.

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.

Longitudinal dynamics between anxiety and depression in bipolar spectrum disorders.

Anxiety and depression are common among individuals with bipolar spectrum disorders (BSDs), with anxiety being a risk factor for depression and vice versa. While the harmful effects of these symptoms are well recognized, their temporal dynamics have not been fully tested. To address this gap, our study investigated bidirectional relationships between anxiety and depression in individuals with BSDs using data from the Prechter Longitudinal Study of Bipolar Disorder, collected over an average of 11 years. We included 651 participants with various BSD subtypes (BD I, BD II, BD not otherwise specified, and schizoaffective bipolar type), with at least 5 years' data for adequate statistical power in detecting temporal dynamics. Bimonthly measurements of anxiety and depression were analyzed using dynamic structural equation modeling. Beyond assessing autoregressive and cross-lagged effects, this study also investigated whether temporal dynamics differed based on demographic characteristics and the use of psychiatric medication. Our findings revealed that individuals with BSDs experienced significant fluctuations in anxiety and depression over time. In addition, we found significant autoregressive and cross-lagged effects of anxiety and depression. Comparison of the cross-lagged effects demonstrated that anxiety had a greater effect on subsequent depression than vice versa. Age and marital status impacted cross-lagged and autoregressive effects. Specifically, older participants had stronger temporal associations between depression and subsequent anxiety, while widowed participants exhibited a heightened impact of depression on subsequent depression. These results underscore the importance of early identification and integrative interventions aimed at addressing both anxiety and depression to mitigate subsequent symptoms in BSDs. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

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.

Reward Behavior Disengagement, a Neuroeconomic Model-Based Objective Measure of Reward Pathology in Depression: Findings from the EMBARC Trial.

The probabilistic reward task (PRT) has identified reward learning impairments in those with major depressive disorder (MDD), as well as anhedonia-specific reward learning impairments. However, attempts to validate the anhedonia-specific impairments have produced inconsistent findings. Thus, we seek to determine whether the Reward Behavior Disengagement (RBD), our proposed economic augmentation of PRT, differs between MDD participants and controls, and whether there is a level at which RBD is high enough for depressed participants to be considered objectively disengaged. Data were gathered as part of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, a double-blind, placebo-controlled clinical trial of antidepressant response. Participants included 195 individuals with moderate to severe MDD (Quick Inventory of Depressive Symptomatology (QIDS-SR) score ≥ 15), not in treatment for depression, and with complete PRT data. Healthy controls (n = 40) had no history of psychiatric illness, a QIDS-SR score < 8, and complete PRT data. Participants with MDD were treated with sertraline or placebo for 8 weeks (stage I of the EMBARC trial). RBD was applied to PRT data using discriminant analysis, and classified MDD participants as reward task engaged (n = 137) or reward task disengaged (n = 58), relative to controls. Reward task engaged/disengaged groups were compared on sociodemographic features, reward-behavior, and sertraline/placebo response (Hamilton Depression Rating Scale scores). Reward task disengaged MDD participants responded only to sertraline, whereas those who were reward task engaged responded to sertraline and placebo (F(1293) = 4.33, p = 0.038). Reward task engaged/disengaged groups did not differ otherwise. RBD was predictive of reward impairment in depressed patients and may have clinical utility in identifying patients who will benefit from antidepressants.

Ketogenic-Mimicking Diet as a Therapeutic Modality for Bipolar Disorder: Biomechanistic Rationale and Protocol for a Pilot Clinical Trial.

There is growing interest in the investigation of ketogenic diets as a potential therapy for bipolar disorder. The overlapping pharmacotherapies utilized for both bipolar disorder and seizures suggest that a mechanistic overlap may exist between these conditions, with fasting and the ketogenic diet representing the most time-proven therapies for seizure control. Recently, preliminary evidence has begun to emerge supporting a potential role for ketogenic diets in treating bipolar disorder. Notably, some patients may struggle to initiate a strict diet in the midst of a mood episode or significant life stressors. The key question addressed by this pilot clinical trial protocol is if benefits can be achieved with a less restrictive diet, as this would allow such an intervention to be accessible for more patients. Recent development of so-called ketone esters, that once ingested is converted to natural ketone bodies, combined with low glycemic index dietary changes has the potential to mimic two foundational components of therapeutic ketosis: high levels of ketones and minimal spiking of glucose/insulin. This pilot clinical trial protocol thus aims to investigate the effect of a 'ketogenic-mimicking diet' (combining supplementation of ketone esters with a low glycemic index dietary intervention) on neural network stability, mood, and biomarker outcomes in the setting of bipolar disorder. Positive findings obtained via this pilot clinical trial protocol may support future target engagement studies of ketogenic-mimicking diets or related ketogenic interventions. A lack of positive findings, in contrast, may justify a focus on more strict dietary interventions for future research.

Family environment and polygenic risk in the bipolar high-risk context.

Background: The interaction of polygenic risk (PRS) and environmental effects on development of bipolar disorder (BD) is understudied, as are high-risk offspring perceptions of their family environment (FE). We tested the association of offspring-perceived FE in interaction with BD-PRS on liability for BD in offspring at high or low familial risk for BD. Methods: Offspring of a parent with BD (oBD; n = 266) or no psychiatric disorders (n = 174), aged 12-21 at recruitment, participated in the US and Australia. Empirically-derived profiles of FE classified offspring by their perceived levels of familial cohesion, flexibility, and conflict. Offspring BD-PRS were derived from Psychiatric Genomics Consortium BD-GWAS. Lifetime DSM-IV bipolar disorders were derived from the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. We used a novel stepwise approach for latent class modeling with predictors and distal outcomes. Results: Fifty-two offspring were diagnosed with BD. For those with well-functioning FE (two-thirds of the sample), higher BD-PRS tracked positively with liability for BD. However, for those with high-conflict FEs, the relationship between BD-PRS and liability to BD was negative, with highest risk for BD observed with lower BD-PRS. In exploratory analyses, European-ancestry offspring with BD had elevated history of suicidal ideation in high-conflict FE compared to well-functioning-FE, and of suicide attempt with low-BD-PRS and high-conflict FE. Conclusions: The data suggest that the relationship of BD-PRS and offspring liability for BD differed between well-functioning versus high-conflict FE, potentially in line with a multifactorial liability threshold model and supporting future study of and interventions improving family dynamics.

Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder.

Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.

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.

Mobile Acceptance and Commitment Therapy in Bipolar Disorder: Microrandomized Trial.

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. TRIAL REGISTRATION: ClinicalTrials.gov NCT04098497; https://clinicaltrials.gov/ct2/show/NCT04098497.

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.

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.

Polygenic Scores and Onset of Major Mood or Psychotic Disorders Among Offspring of Affected Parents.

OBJECTIVE: Family history is an established risk factor for mental illness. The authors sought to investigate whether polygenic scores (PGSs) can complement family history to improve identification of risk for major mood and psychotic disorders. METHODS: Eight cohorts were combined to create a sample of 1,884 participants ages 2-36 years, including 1,339 offspring of parents with mood or psychotic disorders, who were prospectively assessed with diagnostic interviews over an average of 5.1 years. PGSs were constructed for depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuroticism, subjective well-being, p factor, and height (as a negative control). Cox regression was used to test associations between PGSs, family history of major mental illness, and onsets of major mood and psychotic disorders. RESULTS: There were 435 onsets of major mood and psychotic disorders across follow-up. PGSs for neuroticism (hazard ratio=1.23, 95% CI=1.12-1.36), schizophrenia (hazard ratio=1.15, 95% CI=1.04-1.26), depression (hazard ratio=1.11, 95% CI=1.01-1.22), ADHD (hazard ratio=1.10, 95% CI=1.00-1.21), subjective well-being (hazard ratio=0.90, 95% CI=0.82-0.99), and p factor (hazard ratio=1.14, 95% CI=1.04-1.26) were associated with onsets. After controlling for family history, neuroticism PGS remained significantly positively associated (hazard ratio=1.19, 95% CI=1.08-1.31) and subjective well-being PGS remained significantly negatively associated (hazard ratio=0.89, 95% CI=0.81-0.98) with onsets. CONCLUSIONS: Neuroticism and subjective well-being PGSs capture risk of major mood and psychotic disorders that is independent of family history, whereas PGSs for psychiatric illness provide limited predictive power when family history is known. Neuroticism and subjective well-being PGSs may complement family history in the early identification of persons at elevated risk.

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.