Vergence eye movements in bipolar disorder.

Background: Up to 60% of bipolar disorder (BD) patients develop alcohol use disorders (AUD) at some point in their lives. The causes of this highly prevalent comorbidity are unknown. High trait impulsivity characterizes both isolated BD and AUD and may be a link to explain the association between BD and AUD. In this study, our aims were to investigate whether BD patients with comorbid AUD would present higher trait impulsivity levels compared to BD patients without comorbid AUD, and whether trait impulsivity levels differ within subgroups of BD according to the subcategory of AUD (abuse vs. dependence, alcoholism alone vs. alcoholism plus drug use disorders). Sampling and Methods: Forty-seven outpatients with BD with comorbid AUD (alcoholic BD group) were compared to 66 outpatients with BD alone (nonalcoholic BD group) and to 90 healthy controls (HC). BD and AUD diagnoses were obtained using the Structured Clinical Interview for DSM-IV diagnoses. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11), a self-report instrument that measures trait impulsivity in three domains: nonplanning, attentional and motor. Results: Alcoholic BD patients scored significantly higher than nonalcoholic BD and HC on the total and on each subscale BIS scores. Within the alcoholic BD patients, alcohol abusers and alcohol dependents did not statistically differ from each other on the BIS-11 scores. BD patients with AUD plus drug use disorders presented statistically higher nonplanning impulsivity than BD patients with AUD alone. Conclusions: This was a cross-sectional study and causal inferences about the relationship between impulsivity and the comorbidity phenomenon cannot be made. Increased impulsivity may be a trait marker for the co-occurrence between BD and AUD, and mediate some severe manifestations of this comorbidity.

Early identification of patients with bipolar disorder during their first depressive episode is beneficial to the outcome of the disorder and treatment, but traditionally this has been a great challenge to clinicians. Recently, brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the pathophysiology of bipolar disorder and major depressive disorder (MDD), but it is not clear whether BDNF levels can be used to predict bipolar disorder among patients in their first major depressive episode. To explore whether BDNF levels can differentiate between MDD and bipolar disorder in the first depressive episode. A total of 203 patients with a first major depressive episode as well as 167 healthy controls were recruited. After 3 years of bi-annual follow-up, 164 patients with a major depressive episode completed the study, and of these, 21 were identified as having bipolar disorder and 143 patients were diagnosed as having MDD. BDNF gene expression and plasma levels at baseline were compared among the bipolar disorder, MDD and healthy control groups. Logistic regression and decision tree methods were applied to determine the best model for predicting bipolar disorder at the first depressive episode. At baseline, patients in the bipolar disorder and MDD groups showed lower BDNF mRNA levels (P<0.001 and P = 0.02 respectively) and plasma levels (P = 0.002 and P = 0.01 respectively) compared with healthy controls. Similarly, BDNF levels in the bipolar disorder group were lower than those in the MDD group. These results showed that the best model for predicting bipolar disorder during a first depressive episode was a combination of BDNF mRNA levels with plasma BDNF levels (receiver operating characteristics (ROC) = 0.80, logistic regression; ROC = 0.84, decision tree). Our findings suggest that BDNF levels may serve as a potential differential diagnostic biomarker for bipolar disorder in a patient's first depressive episode.

Brain-derived neurotrophic factor in bipolar disorder: Associations with age at onset and illness duration

EPA-0988 – Cognitive and affective theory of mind in schizophrenia and euthymic bipolar disorder

Regulation of inflammatory pathways in schizophrenia: A comparative study with bipolar disorder and healthy controls

Immune system dysregulation plays a key role in the physiopathology of bipolar disorder (BD) and major depressive disorder (MDD). However, whether interleukins might be biomarkers to distinguish these 2 affective disorders is unclear. Here, we assessed the differences in serum levels of interleukin 6 (IL-6) and interleukin 8 (IL-8) as well as C-reactive protein (CRP) in patients with MDD and BD. In total, we enrolled 21 MDD patients, 26 BD patients, and 20 healthy controls. We collected a total of 35 samples from BD patients in 3 different phases, depression phase, manic phase, and remission stage, and 27 samples from MDD patients in acute and remission phases. Serum IL-6 and IL-8 levels were assessed with solid phase sandwich ELISA-based quantitative arrays, and CRP levels were determined with an automatic analyzer. Both serum IL-6 and IL-8 levels were elevated in BD patients but not MDD patients. Subgroup analysis indicated elevated serum IL-6 in both the depression and manic phases in BD patients. The serum CRP levels did not change in either BD or MDD patients. However, sex differences in CRP concentrations were observed in healthy controls. Furthermore, there were linear correlations between the CRP levels and Bech-Rafaelsen Mania Rating Scale (BRMS) scores in BD patients. IL-6 and IL-8 levels may serve as biomarkers to differentiate between MDD and BD patients, even when the clinical manifestations are atypical. IL-6 may be used for the differential diagnosis of MDD and depressive episodes in BD.

Bipolar disorder (BD) is a chronic and severe mental illness. Evidence shows accelerated oxidation-induced DNA damage in BD as indicated by increased levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), the most prevalent DNA base damage product.1 The base excision repair (BER) is the major repair mechanism for oxidation-induced DNA damage. It is responsible for recognizing and removing oxidized DNA base lesions by activation of DNA glycosylases.2 A DNA glycosylase in the initial steps of the BER pathway, 8-Oxoguanine DNA glycosylase-1 (OGG1), is specialized for excision of 8-OH-guanine lesions.2 Previous studies have indicated decreased expression of the OGG1 gene in BD.3, 4 We aimed to investigate oxidation-induced DNA damage together with BER activity in BD. The impact of sex and mood state on the DNA damage and repair process was also explored as both variables are known to be associated with susceptibility for DNA damage and repair mechanisms.5, 6 Forty-eight patients with DSM-IV BD type I (28 euthymic, 20 manic; 43 medicated) and 49 healthy controls (HC) were included in the study. Individuals were excluded from the study if they had: any Axis I psychiatric diagnosis (other than BD); acute infection; any neurological disorders; history of head trauma or brain surgery; any chronic medical condition; any substance use disorder (except for tobacco use); pregnancy; or current breastfeeding. Each participant provided a 10-mL blood sample between 09.00 and 10.00 hours. Absolute levels of 8-OHdG and OGG1 protein were assessed in plasma samples using enzyme-linked immunosorbent assays according to the manufacturer's instructions (catalogue no: E-EL-0028; catalogue no: E-EL-H1939; Elabscience, Wuhan, China). Statistical analyses were completed using spss 25.0 (IBM, Armonk, NY, USA). Group differences with regard to clinical features, and plasma levels of 8-OHdG and OGG1 were tested using independent samples t, χ2, and analysis of variance tests. Linear regression models were used to identify the impacts of clinical variables on dependent variables. A two-way analysis of covariance was applied to test the interactions among clinical variables and OGG1 levels. The Omnibus F-test was used to identify the main effects of BD diagnosis and sex on OGG1 levels. The patient and HC groups did not differ with regard to age, sex, or body mass index (Table S1). The number of smokers was higher in the patient group compared to the HC group (χ2 = 8.838, P = 0.003). Levels of 8-OHdG did not differ either between patients (4.07 ± 1.83 pg/mL) and HC (4.20 ± 1.53 pg/mL; t = 0.599, d.f. = 76, P = 0.551) or between euthymic and manic states (P = 0.783; Fig. S1). Plasma levels of OGG1 were significantly higher in BD patients (24.26 ± 5.07 pg/mL) compared to those in HC (20.43 ± 6.23 pg/mL; t = 3.215, d.f. = 91, P = 0.002; Fig. 1). Both the euthymic (24.36 ± 5.04 pg/mL) and manic (24.15 ± 5.23 pg/mL) BD groups had significantly higher plasma levels of OGG1 in comparison to HC (20.43 ± 6.23 pg/mL; F = 5.134, d.f. = 2, P = 0.008; post-hoc euthymic patients vs HC: P = 0.047; manic patients vs HC: P = 0.019); however, OGG1 levels did not differ between the manic and euthymic states (P = 0.836; Fig. 1). A linear regression analysis that included age, sex, body mass index, smoking status, and BD diagnosis showed significant impacts of BD diagnosis (P = 0.002) and sex (P < 0.001) on the levels of OGG1. A two-way analysis of covariance revealed a significant interaction effect of BD diagnosis and sex on the levels of OGG1 (F = 7.997, d.f. = 1, P = 0.006). Omnibus F-test confirmed that the BD diagnosis had a significant impact on the levels of OGG1 only in women (P < 0.001), but not in men (P = 0.968). Both euthymic and manic women showed significantly elevated levels of OGG1 in comparison to HC women (Fig. 1). In the patient group, the linear regression analyses including age, sex, body mass index, smoking status, and medications did not show any significant impact of the variables on OGG1 levels. Unchanged levels of 8-OHdG may not indicate absence of DNA damage as we have previously shown increases in other DNA base lesion markers in euthymic BD.4 The increased protein levels of OGG1 are in contrast to the previously reported lower gene expression of OGG1 in BD.3, 4 However, previous studies investigated the intracellular expression levels of mRNA of OGG1 in leukocytes, whereas we analyzed extracellular protein levels of OGG1. The protein expression does not necessarily reflect mRNA levels due to differentially regulated transcription and translation processes.7 More importantly, the plasma protein levels may include the OGG1 proteins released from various types of tissues in the body, so plasma levels may imply globally increased OGG1 levels.8 The significant effect of female sex on the OGG1 levels in the BD group is in line with previously reported female susceptibility to DNA oxidation/damage in mood disorders and under psychological and environmental stressors (e.g., smoking, radiation).5, 9, 10 Our findings could be suggestive of a defective DNA repair process as an associated mechanism to the increased DNA damage with a higher susceptibility of women with BD. Further investigations involving brain tissue as well as peripheral samples, and using other measurements (e.g., immune blotting, chromatography) with consideration of the medication and sex effect to validate our findings are needed. None of the authors declare any conflicts of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

IntroductionAlthough schizophrenia (SCZ) and bipolar disorder (BD) share elements of pathology, their neural underpinnings are still under investigation. Here, structural Magnetic Resonance Imaging (MRI) data collected from a large sample of BD and SCZ patients and healthy controls (HC) were analyzed in terms of gray matter volume (GMV) using both voxel based morphometry (VBM) and a region of interest (ROI) approach.MethodsThe analysis was conducted on two datasets, Dataset1 (802 subjects: 243 SCZ, 176 BD, 383 HC) and Dataset2, a homogeneous subset of Dataset1 (301 subjects: 107 HC, 85 BD and 109 SCZ). General Linear Model analyses were performed 1) at the voxel-level in the whole brain (VBM study), 2) at the regional level in the anatomical regions emerged from the VBM study (ROI study). The GMV comparison across groups was integrated with the analysis of GMV correlates of different clinical dimensions.ResultsThe VBM results of Dataset1 showed 1) in BD compared to HC, GMV deficits in right cingulate, superior temporal and calcarine cortices, 2) in SCZ compared to HC, GMV deficits in widespread cortical and subcortical areas, 3) in SCZ compared to BD, GMV deficits in insula and thalamus (p<0.05, cluster family wise error corrected). The regions showing GMV deficits in the BD group were mostly included in the SCZ ones. The ROI analyses confirmed the VBM results at the regional level in most of the clusters from the SCZ vs. HC comparison (p<0.05, Bonferroni corrected). The VBM and ROI analyses of Dataset2 provided further evidence for the enhanced GMV deficits characterizing SCZ. Based on the clinical-neuroanatomical analyses, we cannot exclude possible confounding effects due to 1) age of onset and medication in BD patients, 2) symptoms severity in SCZ patients.ConclusionOur study reported both shared and specific neuroanatomical characteristics between the two disorders, suggesting more severe and generalized GMV deficits in SCZ, with a specific role for insula and thalamus.

Affective temperaments and neurocognitive functioning in bipolar disorder

Bipolar disorder is a chronic, disabling disease that is characterized by the recurrence of thymic episodes. The role of the immune-inflammatory system in the etiopathogenesis of this affection arouses the interest of research. The aim of this work was to determine the plasma levels of the high sensitivity C reactive protein (hs-CRP) in patients with bipolar disorder in remission phase by comparing them to a control group.A case-control cross-sectional study was conducted from 56 subjects with bipolar disorder in clinical remission, and 56 volunteers and healthy control subjects.Mean plasma hs-CRP was significantly higher in patients with bipolar disorder than control subjects. In bipolar patients, a hs-CRP elevation was significantly associated with the disease severity item mean score.Through this study, bipolar disorder appears to be associated with a state of chronic inflammation. This should lead to randomized controlled trials evaluating the value of anti-inflammatory drugs in the management of bipolar disorder.

Chronotype is trait-like construct reflecting long-term morningness-eveningness preferences. Higher eveningness scores are linked to sleep disturbances, night-eating, and addictive behaviors but remain understudied in subjects with bipolar disorder (BD). This study aimed to explore the clinical and behavioral factors associated with chronotype in a euthymic cohort with BD. Adult individuals (18-45 years) with DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) diagnosis of BD in clinical remission (≥3 months) were enrolled, if they did not have current psychiatric or substance use disorder as per Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST score < 27). Participants were assessed using the validated Hindi version of Composite Scale of Morningness-Eveningness (CSM), the National Institute of Mental Health (NIMH)-Life Chart Method, IGLSI (International Group for Study of Lithium) Scale for typical/atypical features, Pittsburgh Sleep Quality Index, Cognitive complaints in BD Rating Assessment, Seasonal Pattern Assessment Questionnaire, Bipolar Eating Disorder Scale, Internet Disorder Scale, and Functioning Assessment Short Test. After data normalization, exploratory factor analysis was conducted using principal component analysis with varimax rotation on the study variables excluding the CSM. Subsequently, regression analysis was performed with CSM as the dependent variable. The mean age of the sample was 32.43 ± 7.68 years (n = 100; 35% females). Factor analysis revealed a latent structure with three factors: Factor 1 (global functioning), Factor 2 (disordered biological functions and rhythms), and Factor 3 (dysfunction due to sleep and internet use). The regression model was found to be statistically significant [F (3,96) = 5.520, P = 0.002; R2 = 0.147, adjusted R2 = 0.120). Factor-2 was a significant predictor of CSM score (B = -2.201, SE: 0.606, P < 0.001). For every unit increase in Factor 2 score, the CSM total score reduced on average by 2.2 units. This study highlights the role of disrupted sleep, eating behaviors, and seasonality in influencing the chronotype and their interconnectedness in individuals with BD.

EPA-0243 – Brain connectivity abnormalities in bipolar disorder during a working memory task

About two-thirds of patients with bipolar disorder (BD) have a lifetime history of at least one psychotic symptom. To compare the neurocognitive performance of four groups: BD patients with and without a history of psychotic symptoms (BD HPS+ and BD HPS-, respectively); patients with schizophrenia (SZ); and healthy control (HC) subjects. In this cross-sectional study, 35 stabilized patients with SZ, 79 euthymic (44 HPS+ and 35 HPS-) patients with BD, and 50 HC were administered a comprehensive battery of neuropsychological tests. There was worse neurocognitive functioning in both BD and SZ patients compared to HC. Overall, data from both groups of BD patients did not differ on sociodemographic, clinical, or neurocognitive variables. However, BD HPS+ patients had significantly more negative symptoms, as measured by the Positive and Negative Syndrome Scale (PANSS), and showed a trend toward worse performance on executive functions compared to BD HPS- patients. Moreover, both BD groups had better performance on all neurocognitive tests compared to SZ group. Neurocognitive dysfunction may be more marked in SZ than in BD, yet qualitatively similar. A history of past psychotic symptoms in BD was not associated with more severe cognitive impairment during euthymia. Therefore, BD with psychotic symptoms does not appear to be a distinct neurocognitive phenotype.

Dysregulation of circadian rhythms has been thought to be associated with psychiatric disorders such as bipolar disorder (BD) and depression. We aimed to evaluate the relationship between clinical specifiers of BD, mainly seasonal pattern (SP), and the variable number tandem repeat (VNTR) variant of the PERIOD3 (PER3) gene (rs57875989) in BD patients by comparing genotype distributions with healthy controls considering clinical parameters. A sample of 98 BD patients and 97 healthy volunteers were included in the study. The Clinical Interview for DSM-IV Axis-I Disorders (SCID-I) was administered to all participants. The patients were evaluated with some scales (Sociodemographic and Clinical Data Form, The Young Mania Rating Scale (YMRS), the Hamilton Depression Rating Scale (HAM-D), and The Clinical Global Impression Scale (CGI)) in terms of clinical features and symptom severity. Blood samples were obtained from participants to isolate their DNA. PCR-RFLP was used to determine the PER3 gene variant. The PER3 genotype (4/4, 4/5, 5/5) distribution of BD was found to be significantly different from the control group. There was a statistically significant difference in the PER3 genotype distribution between BD patients with SP and BD patients without SP. Again, the PER3 allele (4, 5) distributions of BD patients with the SP were statistically different from the control group. The BD patients' PER3 genotype distributions with a family history of BD were significantly different from the BD patients without family history or control group. It was found that the VNTR variant of the PER3 gene (rs57875989) may be associated with the SP and family history of BD as well as the BD itself. Further studies with the VNTR variant of the PER3 gene (rs57875989) in different ethnic populations are also required to determine these polymorphisms' exact role in BD.

Facial emotion recognition in euthymic patients with bipolar disorder and their unaffected first-degree relatives