Bipolar Disorder Status Research Articles

High affective temperamental load as a clinical marker of bipolar disorder: applications in low-resource settings

Objective We aimed to test the performance of the short version of the Temperamental Evaluation of Memphis, Pisa, Paris, and San Diego-Auto questionnaire (Short-TEMPS-A) as a tool for bipolar disorder (BD) status detection in an outpatient sample with affective disorders, using Cyclothymic-Hyperthymic High Temperamental Load (HTL-CH) as the criterion for a positive test. Methods We enrolled 201 euthymic female and male adult outpatients (73.1% female; mean age 47.3 ± 16 years), with BD (42.79%), and other affective disorders (major depressive disorder (20.9%), or anxiety disorders (36.32%)) in a public general hospital in South-Central Chile. Diagnosis was made using the Structured Clinical Interview for axis I. All subjects completed the Short-TEMPS-A. HTL-CH was defined using a cutoff of ≥75% in the hyperthymic or cyclothymic subscales of the Short-TEMPS-A. We estimated the HTL-CH likelihood of BD versus non-BD using multiple logistic regression modeling to control for possible confounders. The performance of HTL-CH as a tool for BD status evaluation was assessed using area under receiver operating characteristic curve (AUC ROC) analysis. Results Patients with HTL-CH had an OR = 7.55 (CI95% = 2.11–26.96) of having a BD status. HTL-CH showed good psychometric properties for BD status detection, correctly classifying 74.13% of patients. AUC ROC was 0.74 (CI95%=0.68–0.81). Conclusions HTL-CH, as assessed by the Short-TEMPS-A, was able to detect BD status accurately and reliably in affective outpatients. The Short-TEMPS-A might be a useful tool in aiding clinicians to detect BD, particularly during initial assessment of affective patients in low-resource settings.

Cognition in older age bipolar disorder: An analysis of archival data across the globe

BackgroundCognitive deficits in bipolar disorder (BD) impact functioning and are main contributors to disability in older age BD (OABD). We investigated the difference between OABD and age-comparable healthy comparison (HC) participants and, among those with BD, the associations between age, global cognitive performance, symptom severity and functioning using a large, cross-sectional, archival dataset harmonized from 7 international OABD studies. MethodsData from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database, spanning various standardized measures of cognition, functioning and clinical characteristics, were analyzed. The sample included 662 euthymic to mildly symptomatic participants aged minimum 50years (509 BD, 153 HC), able to undergo extensive cognitive testing. Linear mixed models estimated associations between diagnosis and global cognitive performance (g-score, harmonized across studies), and within OABD between g-score and severity of mania and depressive symptoms, duration of illness and lithium use and of global functioning. ResultsAfter adjustment for study cohort, age, gender and employment status, there was no significant difference in g-score between OABD and HC, while a significant interaction emerged between employment status and diagnostic group (better global cognition associated with working) in BD. Within OABD, better g-scores were associated with fewer manic symptoms, higher education and better functioning. LimitationsCross-sectional design and loss of granularity due to harmonization. ConclusionMore research is needed to understand heterogenous longitudinal patterns of cognitive change in BD and understand whether particular cognitive domains might be affected in OABD in order to develop new therapeutic efforts for cognitive dysfunction OABD.

Cerebrospinal fluid erythropoietin, oxidative stress, and cognitive functions in patients with bipolar disorder and healthy control participants: A longitudinal case-control study

Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients’ cognitive outcomes.

Interactive relationships of Type 2 diabetes and bipolar disorder with cognition: evidence of putative premature cognitive ageing in the UK Biobank Cohort

Type 2 diabetes (T2D) is disproportionately prevalent in bipolar disorder (BD) and is associated with cognitive deficits in psychiatrically healthy cohorts. Whether there is an interaction effect between T2D and BD on cognition remains unclear. Using the UK Biobank, we explored interactions between T2D, BD and cognition during mid and later life; and examined age-related cognitive performance effects in BD as a function of T2D. Data were available for 1511 participants with BD (85 T2D), and 81,162 psychiatrically healthy comparisons (HC) (3430 T2D). BD and T2D status were determined by validated measures created specifically for the UK Biobank. Diagnostic and age-related associations between T2D status and cognition were tested using analyses of covariance or logistic regression. There was a negative association of T2D with visuospatial memory that was specific to BD. Processing speed and prospective memory performance were negatively associated with T2D, irrespective of BD diagnosis. Cognitive deficits were evident in BD patients with T2D compared to those without, with scores either remaining the same (processing speed) or improving (visuospatial memory) as a function of participant age. In contrast, cognitive performance in BD patients without T2D was worse as participant age increased, although the age-related trajectory remained broadly equivalent to the HC group. BD and T2D associated with cognitive performance deficits across the mid-life period; indicating comorbid T2D as a potential risk factor for cognitive dysfunction in BD. In comparison to BD participants without T2D and HCs, age-independent cognitive impairments in BD participants with comorbid T2D suggest a potential premature deterioration of cognitive functioning compared to what would normally be expected.

Initial Psychometric Properties of 7 NeuroUX Remote Ecological Momentary Cognitive Tests Among People With Bipolar Disorder: Validation Study.

BackgroundAs smartphone technology has become nearly ubiquitous, there is a growing body of literature suggesting that ecological momentary cognitive testing (EMCT) offers advantages over traditional pen-and-paper psychological assessment. We introduce a newly developed platform for the self-administration of cognitive tests in ecologically valid ways.ObjectiveThe aim of this study is to develop a Health Insurance Portability and Accountability Act–compliant EMCT smartphone-based platform for the frequent and repeated testing of cognitive abilities in everyday life. This study examines the psychometric properties of 7 mobile cognitive tests covering domains of processing speed, visual working memory, recognition memory, and response inhibition within our platform among persons with and without bipolar disorder (BD). Ultimately, if shown to have adequate psychometric properties, EMCTs may be useful in research on BD and other neurological and psychiatric illnesses.MethodsA total of 45 persons with BD and 21 demographically comparable healthy volunteer participants (aged 18-65 years) completed smartphone-based EMCTs 3 times daily for 14 days. Each EMCT session lasted approximately 1.5 minutes. Only 2 to 3 tests were administered in any given session, no test was administered more than once per day, and alternate test versions were administered in each session.ResultsThe mean adherence to the EMCT protocol was 69.7% (SD 20.5%), resulting in 3965 valid and complete tests across the full sample. Participants were significantly more likely to miss tests on later versus earlier study days. Adherence did not differ by diagnostic status, suggesting that BD does not interfere with EMCT participation. In most tests, age and education were related to EMCT performance in expected directions. The average performances on most EMCTs were moderately to strongly correlated with the National Institutes of Health Toolbox Cognition Battery. Practice effects were observed in 5 tests, with significant differences in practice effects by BD status in 3 tests.ConclusionsAlthough additional reliability and validity data are needed, this study provides initial psychometric support for EMCTs in the assessment of cognitive performance in real-world contexts in BD.

ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which are key events in the initiation and/or progression of several diseases, are correlated with alterations at ER-mitochondria contact sites, the so-called "Mitochondria-Associated Membranes" (MAMs). These intracellular structures are also implicated inNLRP3 inflammasome activation which is an important driver of sterile inflammation, however, the underlying molecular basis remains unclear. This work aimed to investigate the role of ER-mitochondria communication during ER stress-induced NLRP3 inflammasome activation in both peripheral and central innate immune systems, by using THP-1 human monocytes and BV2 microglia cells, respectively, as in vitro models. Markers of ER stress, mitochondrial dynamics and mass, as well as NLRP3 inflammasome activation were evaluated by Western Blot, IL-1βsecretion was measured by ELISA, and ER-mitochondria contacts were quantified by transmission electron microscopy. Mitochondrial Ca2+ uptake and polarization were analyzed with fluorescent probes, and measurement of aconitase and SOD2 activities monitored mitochondrial ROS accumulation. ER stress was demonstrated to activate the NLRP3 inflammasome in both peripheral and central immune cells. Studies in monocytes indicate that ER stress-induced NLRP3 inflammasome activation occurs by a Ca2+-dependent and ROS-independent mechanism, which is coupled with upregulation of MAMs-resident chaperones, closer ER-mitochondria contacts, as well as mitochondrial depolarization and impaired dynamics. Moreover, enhanced ER stress-induced NLRP3 inflammasome activation in the immune system was found associated with pathological conditions since it was observed in monocytes derived from bipolar disorder (BD) patients, supporting a pro-inflammatory status in BD. In conclusion, by demonstrating that ER-mitochondria communication plays a key role in the response of the innate immune cells to ER stress, this work contributes to elucidate the molecular mechanisms underlying NLRP3 inflammasome activation under stress conditions, and to disclose novel potential therapeutic targets for diseases associated with sterile inflammation.

Associations among smartphone app-based measurements of mood, sleep and activity in bipolar disorder

The recent popularization of smart technology presents new opportunities for continual, digital-monitoring of patient status. In this project, we used a smartphone app to track the mood, sleep, and activity levels of 159 outpatients with bipolar disorder (BD). The participants were asked to report their daily wake/sleep time and emotional status in the app, while daily activity data were automatically collected via GPS. We performed repeated-measures correlation analysis to examine possible correlations between the readouts. Mood, sleep and activity levels all showed intra-variable correlations with readings on the next day, in the next week, and in the next month. Furthermore, mood and sleep at the reference time were positively correlated with activity in subsequent weeks or months, and activity was positively correlated with mood and sleep in the same time ranges. Thus, our results were in line with previous studies, showing that mood, sleep, and activity levels are interdependent in patients with BD. With the association between mood on future activity level was most significant, and the correlations between each readout and the others were dependent on time frame. Our findings suggest our smartphone app has potential to provide an informative and reliable means for real-time tracking of BD status.

Association between neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and C-reactive protein levels and metabolic status in patients with a bipolar disorder

Objectives Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and C-Reactive Protein (CRP) are markers of inflammation that are elevated in bipolar disorder (BD) and are also related to a higher risk of metabolic syndrome (MetS). This study aimed at investigating for the first time the association between NLR, PLR, and CRP and the metabolic status in BD. Methods We assessed the association between biomarkers and the metabolic status: number of metabolic risk factors, presence of MetS, insulin sensitivity (Quantitative Insulin Sensitivity Check Index, QUICKI) and insulin resistance (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR index), in a sample of 219 outpatients with BD. Results 25.9% of the sample met the criteria for MetS. High levels of CRP were found in 12% of the sample. Older age, low PLR, high NLR, and high CRP levels significantly predicted a higher number of MetS risk factors (p < 0.001). Older age and low PLR were associated with a greater likelihood of developing MetS (p = 0.007). Conclusions Although further studies are needed to replicate and validate these findings, inflammatory biomarkers as CRP, PLR and NLR could be useful tools to identify patients with a BD at risk for a metabolic adverse outcome.

Chronic Migraine Preventive Treatment by Prefrontal-Occipital Transcranial Direct Current Stimulation (tDCS): A Proof-of-Concept Study on the Effect of Psychiatric Comorbidities.

Chronic migraine (CM) is often complicated by medication overuse headache (MOH) and psychiatric comorbidities that may influence the clinical outcome. This study aimed to investigate the relationship between psychiatric comorbidities and the effect of transcranial direct current stimulation (tDCS) in patients with CM with or without MOH. We recruited 16 consecutive CM patients who had an unsatisfactory response to at least three pharmacological preventive therapies. They were treated with anodal right-prefrontal and cathodal occipital tDCS (intensity: 2 mA, time: 20 min) three times per week for 4 weeks. All patients underwent a psychopathological assessment before and after treatment, and five of them were diagnosed with bipolar disorder (BD). After treatment, all the patients showed a significant decrease of severe and overall headache days per month. Despite having a higher migraine burden at baseline, patients with CM and BD showed a significantly greater reduction of severe headaches and psychiatric symptoms. Overall, tDCS seems to be effective in the treatment of CM patients with a poor response to different classes of pharmacological therapies, whereas BD status positively influences the response of migraineurs to tDCS.

Association Between Accelerated Epigenetic Aging and Poorer Functional Status in Bipolar Disorder

Bipolar disorder (BD) has been previously associated with functional impairment and accelerated epigenetic aging, although the link between these two features has not yet been explored. The present study investigated the relationship between two novel second-generation measures of epigenetic aging acceleration (GrimAge and PhenoAge) and functioning in BD and controls.

Impact of metabolic syndrome and clinical features on functioning in patients with bipolar disorder: a cross-sectional study.

Objective:The metabolic syndrome (MS) is highly prevalent among patients with bipolar disorder (BD), and may affect progression, functioning, and comorbid conditions in BD. The aim of this study was to investigate the effect of clinical variables and MS on overall functioning and specific areas of functioning in patients with BD.Methods:A total of 210 participants (140 participants with BD I and BD II in remission and 70 non-psychiatric control subjects) were included. The investigators administered the Young Mania Rating Scale (YMRS), the Bipolar Depression Rating Scale (BDRS), the Global Assessment of Functioning Scale (GAF), and the Bipolar Disorder Functioning Scale (BDFS). The participants completed the Beck Depression Scale (BDS) and the Beck Anxiety Scale (BAS). MS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. Hierarchical regression analysis was used to investigate potential correlations of comorbid MS with clinical variables and level of functioning.Results:Level of functioning did not differ between patients with and without MS. However, there were significant correlations between the level of functioning subscales and the number of depressive episodes (p = 0.033), level of general functioning (p = 0.012), duration of illness (p = 0.012), BDS (p = 0.005), BDRS (p = 0.021), BAS total scores (p = 0.021), number of hypomanic episodes (p = 0.022), number of hospitalizations (p = 0.003), employment status (p = 0.032), and diagnosis of BD I (p = 0.007) and BD II (p = 0.044).Conclusion:Our findings suggest that clinical variables had a greater effect on functioning than MS in BD patients.

Platelet mass index as an indicator of platelet activation in manic episode

BackgroundDiscovering the biological basis of bipolar disorder has been the focus of studies in recent years. Alterations in platelet parameters were found to be associated with episodes of bipolar disorder. This study aimed to compare the differences in platelet parameters especially the platelet mass index as an inflammation marker between the patients with bipolar mania and healthy controls. Methods68 male inpatients with manic episodes and 60 age-gender matched healthy controls were included in the study. Platelet mass index, mean platelet volume and platelet counts were compared between controls and manic patients. ResultsPlatelet mass index of manic group was significantly higher than the controls (p = 0.002). Statistically significant difference was also observed between groups in terms of mean platelet volume (p = 0.012). For platelet counts; there was no statistically significant difference between manic and control groups (p = 0.171). LimitationThe limitations of this study is that, platelet mass index was not measured in manic patients after manic episodes subsided. Other limitations are relatively small sample size, cross-sectional nature and lacking the data about other inflammation and cardiovascular marker, and lack of the longitudinal outcomes of multiple drugs and effects of lifestyle factors. ConclusionPlatelet mass index reflects platelet functionality and is thought to be a useful parameter for plaque formation capacity of platelets. In our study, we have shown an increment in platelet activation in manic episode compared to healthy controls; which may reflect the inflammation process and cardiovascular status in bipolar disorder.

Executive functioning but not IQ or illness severity predicts occupational status in bipolar disorder

BackgroundBipolar disorder is associated with significant functional deficits including occupational functioning. Despite the high rates of unemployment and sick leave in the patient population, only a limited number of studies have examined factors associated with occupational functioning in bipolar disorder. The aim of the study was to investigate the relative importance of demographic, clinical, and neuropsychological factors on occupational dysfunction in bipolar disorder.MethodsA sample of 120 partially or fully remitted bipolar disorder I and II patients were included in the study. Patients were stratified into an active and an inactive group based on the number of hours per week working or studying. Active (n = 86) and inactive (n = 34) patients were compared with respect to demographic factors, clinical characteristics, medication, measures of psychosocial functioning, and cognitive functioning (i.e., IQ and executive functions). No other cognitive domains were examined.ResultsUnivariate analyses revealed better overall cognitive function in active patients in terms of IQ and executive functioning. However, only executive functioning accounted for a significant amount of the variance in occupational status when other significant predictors were taken into account.ConclusionsExecutive functioning was a more powerful predictor of occupational status in bipolar disorder patients than IQ and other clinical factors, including illness severity.

Common and distinct global functional connectivity density alterations in patients with bipolar disorder with and without auditory verbal hallucination during major depressive episodes.

Although an increasing number of studies has explored the neural mechanisms of auditory verbal hallucination (AVH) using many modalities, including neuroimaging, neurotransmitters, and electroencephalography, the etiology of AVH remains unclear. In this study, we investigated the neuroimaging characteristics of AVH in patients with bipolar disorder (BD) experiencing depressive episodes with and without AVH. For this study, we recruited 80 patients with BD and depressive status (40 with and 40 without AVH), and 40 healthy individuals. Their global functional connectivity density (gFCD) was screened by functional magnetic resonance imaging. Differences in gFCD among the three groups were tested using voxel-wise one-way analysis of covariance. Patients in both BD groups demonstrated increased gFCD in the central parietal lobe, insular lobe, and middle cingulate cortex, and decreased gFCD in the posterior parietal cortex, lateral prefrontal cortex, and occipital lobe (all bilateral). We defined these alterations as the common aberrant gFCD pattern for BD with and without AVH. Compared with the other two groups, patients in the BD with AVH group demonstrated increased gFCD in the Broca and Wernicke regions, and decreased gFCD in the hippocampus (all bilateral). We defined these alterations as the distinct aberrant gFCD pattern for BD with AVH. To our knowledge, this report is the first to date to describe gFCD alterations in patients with BD with and without AVH. Our findings suggest that disturbances in brain activity and information communication capacity in patients with BD and AVH are located mainly in the left frontoparietal network, control network, and memory circuit. However, these observations were made only in patients with BD during depressive episodes, and without consideration of many factors, such as the treatment mode, symptom relapse, and BD subtype. Hence, the conclusions of this study merely provide clues for further study, and do not fully represent brain alterations in patients with BD and AVH. Further large-sample cohort studies are needed to clarify and expand on these findings.

TNF-α-308 G/A variant may be associated with bipolar disorder in a Turkish population

ABSTRACT Background: Tumor necrosis factor alpha (TNF-α) is a proinflammatory multifunctional cytokine produced by macrophages. A dysregulation of the immune system contribute to the pathogenesis of bipolar disorder (BD). In this study, we aimed to investigate the relationship between the TNF-α gene -308G/A promoter variant and the risk of BD. Methods: A total of 104 BD patients and 94 healthy controls were enrolled in the study. Genomic DNA was isolated and TNF-α -308G/A variant was analyzed using PCR-RFLP method. Results: TNF-α -308G/A variant GG genotype and G allele were more prevalent in BD patients compared to the controls (p = 0.002 and p = 0.017, respectively). The patients carrying GG genotype had a 5.927-fold higher risk of developing BD. Then, we divided patients into two groups as smokers and non-smokers. TNF-α -308G/A variant GA genotype was higher in non-smoker BD patients than smoker patients (p = 0.027). We found that TNF-α -308G/A AA genotype and A allele increased in smoker patients compared to non-smoker patients (p = 0.008, p = 0.002, respectively). Discussion: Our results provided evidence that TNF-α -308G/A variant may contribute to development of BD in a Turkish cohort. In addition, this variant plays a relevant role in the smoker status of BD.

Genetic risk scores for major psychiatric disorders and the risk of postpartum psychiatric disorders

Postpartum psychiatric disorders are heritable, but how genetic liability varies by other significant risk factors is unknown. We aimed to (1) estimate associations of genetic risk scores (GRS) for major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ) with postpartum psychiatric disorders, (2) examine differences by prior psychiatric history, and (3) compare genetic and familial risk of postpartum psychiatric disorders. We conducted a nested case-control study based on Danish population-based registers of all women in the iPSYCH2012 cohort who had given birth before December 31, 2015 (n = 8850). Cases were women with a diagnosed psychiatric disorder or a filled psychotropic prescription within one year after delivery (n = 5829 cases, 3021 controls). Association analyses were conducted between GRS calculated from Psychiatric Genomics Consortium discovery meta-analyses for MD, BD, and SCZ and case-control status of a postpartum psychiatric disorder. Parental psychiatric history was associated with postpartum psychiatric disorders among women with previous psychiatric history (OR, 1.14; 95% CI 1.02–1.28) but not without psychiatric history (OR, 1.08; 95% CI: 0.81–1.43). GRS for MD was associated with an increased risk of postpartum psychiatric disorders in both women with (OR, 1.44; 95% CI: 1.19–1.74) and without (OR, 1.88; 95% CI: 1.26–2.81) personal psychiatric history. SCZ GRS was only minimally associated with postpartum disorders and BD GRS was not. Results suggest GRS of lifetime psychiatric illness can be applied to the postpartum period, which may provide clues about distinct environmental or genetic elements of postpartum psychiatric disorders and ultimately help identify vulnerable groups.

Schizophrenia, Bipolar Disorder, and Alzheimer\u2019s Disease are not Causal Factors of Bone Mineral Density: A Mendelian Randomization Analysis

Until recently, it remains unclear whether schizophrenia, bipolar disorder (BD), and Alzheimer’s disease (AD) is associated with bone mineral density (BMD). We aimed to investigate the causal effects of schizophrenia, BD and AD on BMD with Mendelian randomization (MR) analysis. Single-nucleotide polymorphisms (SNPs) strongly associated with these three neuropsychiatric diseases as instrumental variables were selected from genome-wide association studies in the MR Base database. We analyzed the effects of these SNPs on the femoral neck BMD (FN-BMD), lumbar spine BMD (LS-BMD) and forearm BMD (FA-BMD), and evaluated the heterogeneities and pleiotropy of these genetic variants. We also evaluated the potential confounding factors in the association between these three neuropsychiatric diseases and the BMD level. It was found that none of these genetic variants were significantly associated with BMD or confounding factors. Using these genetic variants, we did not find statistically significant causal effects of per unit increase in the log-odds of having schizophrenia, BD or AD with FN-BMD, LS-BMD and FA-BMD changes (e.g. schizophrenia and FN-BMD, MR-Egger OR 0.9673, 95% CI 0.8382 to 1.1163, p = 0.6519). The MR results also revealed that directional pleiotropy was unlikely to bias the causality (e.g., schizophrenia and FN-BMD, intercept = 0.0023, p = 0.6887), and no evidence of heterogeneity was found between the genetic variants (e.g., schizophrenia and FN-BMD, MR-Egger Q = 46.1502, I2 = 0.0899, p = 0.3047). Our MR study did not support causal effects of increased risk of schizophrenia, BD and AD status with BMD level.

Oxidative Status in Bipolar Disorder (BD) and Its Correlation with Age, Gender and Body Mass Index (BMI)

Bipolar disorder (BD) is a chronic psychiatric illness which molecular foundations have yet to be elucidated. Oxidative stress appears to be a promising field of study to understand the formation of this disease in molecular level. The objective was to investigate the oxidative status of BD and its association with age, gender and body mass index (BMI). A cross-sectional study was conducted in a tertiary university hospital in Cheras, Malaysia on 55 patients with BD diagnosed using Mini Neuropsychiatric Interview (MINI). Peripheral markers of oxidative stress which include superoxide dismutase (SOD), glutathione peroxidise (GPx), catalase (CAT), malondialdehyde (MDA) and DNA damage were examined in subjects with BD (n=55) and compared to healthy controls (n=28). BD patients had significantly higher concentrations of MDA compared to healthy controls (p<0.001). Concentration of MDA was significantly higher in BD patients aged 40 and above compared to those aged 39 years and below (p<0.05). The concentration of MDA did not show significant difference between male and female BD patients, likewise between patients with BMI below and above 25. The percentage of normal DNA in healthy controls was significantly higher than that of BD patients (p<0.001), while percentage of mildly and severely damaged DNA in BD patients was significantly higher than that of healthy controls (mildly damaged: p<0.001; severely damaged: p<0.001). The severity of DNA damage in the BD patients was similar when compared between age, gender and BMI. SOD activity of BD patients was found to be comparable to that of healthy subjects as well as when compared between gender and age, but was significantly lower in subjects with BMI above 25 (p<0.05). CAT activity was significantly higher in BD patients compared to controls (p<0.001), while no significant difference was found when compared between gender, age and BMI. GPx activity did not show significant difference when compared between BD and healthy controls, gender, age and BMI. Multiple linear regression analysis showed that the percentage of normal DNA increases with age in BD patients (p<0.001), while the percentage of damaged DNA decreases with age (mildly damaged: p<0.002; severely damaged: p<0.001). Percentage of normal and damaged DNA are not significantly correlated with BMI, while all antioxidative enzymes (SOD, GPx, CAT) and MDA concentration did not show significant correlation with age and BMI. In conclusion, age and BMI are associated with the oxidative status of BD patients regardless of gender.

SA28 - ASSOCIATIONS IN THE UK BIOBANK COHORT BETWEEN GENETIC RISK SCORE FOR CALCIUM VOLTAGE-GATED CHANNEL SUBUNIT ALPHA 1 C (CACNA1C) POLYMORPHISMS AND BOTH MOOD DISORDER PHENOTYPES AND CHRONOTYPE PREFERENCE

Background Variants of the Calcium Voltage-Gated Channel Subunit Alpha 1 C (CACNA1C) gene have been associated with several neuropsychiatric disorders, most notably Bipolar Disorder (BD) (Cross Disorder Group of PGC., 2013). Previous studies of the function of BD-associated CACNA1C SNPs have tended to study single SNPs in isolation within relatively small samples (Bigos et al., 2010). Circadian rhythm disruption is recognised as a core clinical feature of BD, with BD individuals commonly reporting an evening chronotype preference (Bellivier et al., 2015). Given that CACNA1C has a key role in the regulation of circadian rhythms (Shi et al., 2008), we hypothesised that a CACNA1C Genetic Risk Score (GRS) would be associated both with mood disorder phenotypes and chronotype preference within 95,073 UK Biobank participants. Methods A Genetic Risk Score (GRS) combining several BD-associated CACNA1C SNPs was used to investigate the association between CACNA1C, several mood disorder-related phenotypes (mood instability, neuroticism, BD status, MDD status) and chronotype. In light of evidence of a potential sex-specific effect of CACNA1C variants, secondary analyses were stratified by sex (Dao et al., 2010; Heilbronner et al., 2015). Results There was no association between CACNA1C GRS and any of the mood disorder phenotypes, or chronotype, after adjusting for confounding factors (age, sex, social deprivation and genetic principal components). However, there was preliminary evidence of an association between higher CACNA1C GRS score and BD status in females (p=0.03). Discussion Overall, we did not find association between CACNA1C GRS and a range of mood disorder phenotypes or chronotype preference within the UK Biobank cohort, but there was evidence of a potential sex-specific effect of CACNA1C variants on BD status in females. There is currently considerable interest in the repurposing of calcium channel blockers (CBBs) as new treatments for BD (Keers et al., 2009). Our findings, which require replication in other cohorts, suggest that there may be a sex difference in therapeutic effect of CCBs used to treat BD.

SU24 - POTENTIAL ALTERATIONS IN LEUKOCYTE MITOCHONDRIAL DNA COPY NUMBER FROM PATIENTS WITH BIPOLAR DISORDER TYPE I

Background Mitochondrial dysfunction has been well documented in patients with Bipolar Disorder (BD). Studies demonstrated that alternations in mtDNA copy number have been associated with mitochondrial dysfunction and increased oxidative stress. However, association between mtDNA copy number and BD compared to controls has been inconclusive so far. In this study, we aimed to assess whether mtDNA copy number is altered in BD type I (BDI) compared to controls. We also explored whether the total number of heteroplasmic Single Nucleotide Variants (SNVs) for a given subject, another marker for oxidative stress, is altered in BDI. Methods One hundred BDI patients were selected for Whole Genome Sequencing (WGS) experiment using leukocyte DNA from the Mayo Clinic Bipolar Disorder Biobank. In addition, 1000 patients from the Mayo Clinic Biobank, a control biobank, were also selected for the experiment. After applying basic quality control filtering (e.g., low sequencing coverage and sample contamination) to nuclear DNA sequencing data, this study used 99 BD1 patients and 961 controls. MtDNA copy number was defined as the relative quantity of mtDNA compared to nuclear DNA. For each SNV, likelihood functions were estimated under two models (heteroplasmy and homoplasmy) taking into account sequencing error, and log-likelihood ratio (LLR) was calculated. The total number of heteroplasmic SNVs for a given subject was calculated by counting the sites with LLR ≥ 5. Adjusting for age and sex, regression models were used to test the association between BD status and mtDNA copy number and the total number of heteroplasmic SNVs after log-transformation. Results BDI patients were younger compared to controls (median age at the biobank enrollment: 45 in BDI vs 61 in controls) with more females in cases (60% vs 50%). Overall, older age and male sex were associated with lower mtDNA copy number (P Discussion This small study potentially supports recent findings on a slight decrease in mtDNA copies among BDI and more copies in females. This study also shows that mtDNA copy number decreases with age, while the degree of heteroplasmy increases. Although the underlying mechanism for this observation is not clear, it may reflect mitochondrial DNA replication and degradation due to mitochondrial dysfunction and premature cellular senescence in BD.