Female Bipolar Disorder Patients Research Articles

Association among abnormal glycolipids, reproductive hormones, and cognitive dysfunction in female patients with bipolar disorder

BackgroundPatients with bipolar disorder (BD) show abnormalities in glucolipid metabolism and reproductive hormone levels, which are of concern in women with BD. This study was dedicated to investigating the glucolipid and reproductive hormone levels of female patients, and to preliminarily investigating their relationships with cognition.MethodsA total of 58 unmedicated female BD patients, 61 stable-medicated female BD patients, and 63 healthy controls (HC) were recruited in this study. Serum glycolipid indexes and reproductive hormones were measured. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop Color-Word Test (Stroop test).ResultsPatients with BD showed significant cognitive impairment (p < 0.05), which was not affected by medication. Triglycerides (TG), luteinizing hormone (LH), and high-density lipoprotein cholesterol (HDL-c) were altered in stable-medicated BD patients. In addition, regression analysis showed that progesterone (PRGE) and prolactin (PRL) were negatively associated with cognitive performance in stable-medicated BD patients.ConclusionsFemale BD patients may have cognitive deficits and abnormal levels of glycolipids and reproductive hormones. And abnormal levels of glycolipids and reproductive hormones may be associated with cognitive dysfunction in female BD patients.

Chronic exposure to imipramine induces a switch from depression-like to mania-like behavior in female serotonin transporter knockout rats: Role of BDNF signaling in the infralimbic cortex

BackgroundBipolar disorder (BD) is a highly burdensome psychiatric disorder characterized by alternating states of mania and depression. A major challenge in the clinic is the switch from depression to mania, which is often observed in female BD patients during antidepressant treatment such as imipramine. However, the underlying neural basis is unclear. MethodsTo investigate the potential neuronal pathways, serotonin transporter knockout (SERT KO) rats, an experimental model of female BD patients, were subjected to a battery of behavioral tests under chronic treatment of the antidepressant imipramine. In addition, the expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling was examined in the prefrontal cortex. ResultsChronic exposure to imipramine reduced anxiety and sociability and problem-solving capacity, and increased thigmotaxis and day/night activity in all animals, but specifically in female SERT KO rats, compared to female wild-type (WT) rats. Further, we found an activation of BDNF-TrkB-Akt pathway signaling in the infralimbic, but not prelimbic, cortex after chronic imipramine treatment in SERT KO, but not WT, rats. LimitationsRepeated testing behaviors could potentially affect the results. Additionally, the imipramine induced changes in behavior and in the BDNF system were measured in separate animals. ConclusionsOur study indicates that female SERT KO rats, which mirror the female BD patients with the 5-HTTLPR s-allele, are at higher risk of a switch to mania-like behaviors under imipramine treatment. Activation of the BDNF-TrkB-Akt pathway in the infralimbic cortex might contribute to this phenotype, but causal evidence remains to be provided.

SCN11A mRNA levels in female bipolar disorder PBMCs as tentative biomarker for distinct patient sub-phenotypes.

Bipolar disorder (BD) is a complex neuropsychiatric disorder characterized by recurrent mania and depression episodes and requiring lifelong treatment with mood stabilizing drugs. Several lines of evidence, including with BD patient iPSC-derived neurons, suggest that neuronal hyperexcitability may underlie the key clinical symptoms of BD. Indeed, higher mRNA levels of SCN11A, coding for the voltage-gated sodium channel NaV 1.9 implicated in nociception, were detected in iPSC-derived neurons from BD patients, and were normalized by in vitro lithium. Here we studied SCN11A expression in peripheral blood mononuclear cells (PBMCs) from well-phenotyped female BD patients and controls and evaluated their association with several clinical sub-phenotypes. We observed higher mRNA levels of SCN11A in PBMCs from female BD patients with no records of alcohol dependence (p = .0050), no records of psychosis (p = .0097), or no records of suicide attempts (p = .0409). A trend was observed for higher SCN11A expression (FD = 1.91; p = .052) in BD PBMCs compared with controls. Datamining of published postmortem gene expression datasets indicated higher SCN11A expression in dorsolateral prefrontal cortex and orbitofrontal cortex tissues from BD patients compared with controls. Higher phenotype-associated expression levels in PBMC from BD patients were also observed for ID2 (alcohol dependence, suicide attempts) and HDGFRP3 (seasonal BD pattern). Our findings suggest that higher PBMC SCN11A expression levels may be associated with certain behavioral BD sub-phenotypes, including lack of alcohol dependence and psychosis, among BD patients. The NaV 1.9 voltage-gated sodium channel thus deserves consideration as a tentative phenotype modifier in BD.

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.

Risk of obstructive sleep apnea in patients with bipolar disorder: A nationwide population-based cohort study in Taiwan.

Previous studies have found a high prevalence of risk factors for obstructive sleep apnea (OSA) in patients with bipolar disorder (BD). This study aimed to determine whether BD patients are associated with an increased risk of incident OSA. Using the National Health Insurance Research Database of Taiwan, 3650 BD patients and 18 250 non-BD controls matched by sex and age were enrolled between 2000 and 2010 and followed until the end of 2013. Patients who developed OSA confirmed by a polysomnographic examination during the follow-up period were identified. Cox regression analysis was performed to examine the risk of OSA between BD patients and comparative controls. BD patients were prone to developing OSA in the crude analysis (hazard ratio [HR]: 1.63, 95% confidence interval [CI]: 1.07-2.49). After adjusting for demographics and comorbidities, the HR declined and was only marginally significant (HR: 1.54, 95%CI: 0.99-2.37). The stratification analysis by sex revealed that the risk trend with BD and subsequent OSA was mainly contributed by male BD patients (HR: 1.72, 95%CI: 1.02-2.91) and female BD patients weakened the overall association. Additionally, this study found that older age, higher income, living in urbanized areas, and some metabolic comorbidities were potential risk factors for developing OSA. This study shows that male BD patients are associated with an increased risk of OSA, which has direct implications for the development of targeted prevention interventions or the implementation of a screening algorithm for OSA to reduce its negative health impact.

Sensorimotor Gating in Depressed and Euthymic Patients with Bipolar Disorder: Analysis on Prepulse Inhibition of Acoustic Startle Response Stratified by Gender and State.

Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating. The findings on PPI deficits in bipolar disorder (BD) are inconsistent among studies due to various confounding factors such as gender. This study aimed to assess sensorimotor gating deficits in patients with BD stratified by gender and state (depressed/euthymic), and to explore related clinical variables. Subjects were 106 non-manic BD patients (26 BD I and 80 BD II; 63 with depression and 43 euthymic) and 232 age-, gender-, and ethnicity-matched (Japanese) healthy controls. Depression severity was assessed using the Hamilton Depression Rating Scale-21. The electromyographic activity of the orbicularis oculi muscle was measured by a computerized startle reflex test unit. Startle magnitude, habituation, and PPI were compared among the three clinical groups: depressed BD, euthymic BD, and healthy controls. In a second analysis, patients were divided into four groups using the quartile PPI levels of controls of each gender, and a ratio of the low-PPI group (<1st quartile of controls) was compared. Effects of psychosis and medication status were examined by the Mann-Whitney U test. Clinical correlates such as medication dosage and depression severity with startle measurements were examined by Spearman's correlation. Male patients with depression, but not euthymic male patients, showed significantly lower PPI at a prepulse of 86 dB and 120 ms lead interval than did male controls. More than half of the male patients with depression showed low-PPI. In contrast, PPI in female patients did not differ from that in female controls in either the depressed or euthymic state. Female patients with active psychosis showed significantly lower PPI than those without psychosis. Female patients on typical antipsychotics had significantly lower PPI, than those without such medication. PPI showed a significant positive correlation with lamotrigine dosage in male patients and lithium dosage in female patients. These findings suggest that sensorimotor gating is impaired in male BD patients with depression. However, we obtained no evidence for such abnormalities in female BD patients except for those with current psychosis. The observed associations between medication and startle measurements warrant further investigation.

Cingulate abnormalities in bipolar disorder relate to gender and outcome: a region-based morphometry study [corrected

Structural magnetic resonance imaging (MRI) studies reported gray matter (GM) loss in bipolar disorder (BD) in cingulate cortices, key regions subserving emotional regulation and cognitive functions in humans. The aim of this study was to further explore cingulate GM volumes in a sizeable group of BD patients with respect to healthy controls, particularly investigating the impact of gender and clinical variables. 39 BD patients (mean Age = 48.6 ±9.7, 15 males and 24 females) and 39 demographically matched healthy subjects (mean Age = 47.9 ± 9.1, 15 males and 24 females) underwent a 1.5T MRI scan. GM volumes within the cingulate cortex were manually detected, including anterior and posterior regions. BD patients had decreased left anterior cingulate volumes compared with healthy controls (F = 6.7, p = 0.01). Additionally, a significant gender effect was observed, with male patients showing reduced left anterior cingulate cortex (ACC) volumes compared to healthy controls (F = 5.1, p = 0.03). Furthermore, a significant inverse correlation between right ACC volumes and number of hospitalizations were found in the whole group of BD patients (r = -0.51, p = 0.04) and in male BD patients (r = -0.88, p = 0.04). Finally, no statistically significant correlations were observed in female BD patients. Our findings further confirm the putative role of the ACC in the pathophysiology of BD. Interestingly, this study also suggested the presence of gender-specific GM volume reductions in ACC in BD, which may also be associated to poor outcome.

Pituitary gland shrinkage in bipolar disorder: The role of gender

BackgroundHyperactivity of the Hypothalamic-Pituitary-Adrenal Axis (HPAA) has been consistently reported in mood disorders. However, only few studies investigated the Pituitary gland (PG) in Bipolar Disorder (BD) and the results are so far contrasting. Therefore, the aim of this study is to explore the integrity of the PG as well as the role of gender and the impact of clinical measurements on this structure in a sample of BD patients compared to healthy controls (HC). Methods34 BD patients and 41 HC underwent a 1.5 T MRI scan. PG volumes were manually traced for all subjects. Psychiatric symptoms were assessed by means of the Brief Psychiatry Rating Scale, the Hamilton Depression Rating Scale and the Bech Rafaelsen Mania Rating Scale. ResultsWe found decreased PG volumes in BD patients compared to HC (F = 24.9, p < 0.001).Interestingly, after dividing the sample by gender, a significant PG volume decrease was detected only in female BD patients compared to female HC (F = 9.1, p < 0.001), but not in male BD compared to male HC (F = −0.12, p = 0.074). No significant correlations were observed between PG volumes and clinical variables. ConclusionsOur findings suggest that BD patients have decreased PG volumes, probably due to the long-term hyperactivity of the HPAA and to the consequent strengthening of the negative feedback control towards the PG volume itself. This alteration was particularly evident in females, suggesting a role of gender in affecting PG volumes in BD. Finally, the absence of significant correlations between PG volumes and clinical variables further supports that PG disruption is a trait feature of BD, being independent of symptoms severity and duration of treatment.

RNA sequencing of bipolar disorder lymphoblastoid cell lines implicates the neurotrophic factor HRP-3 in lithium’s clinical efficacy

Objectives: Lithium remains the oldest and most effective treatment for mood stabilisation in bipolar disorder (BD), even though at least half of patients are only partially responsive or do not respond. This study aimed to identify biomarkers associated with lithium response in BD, based on comparing RNA sequencing information derived from lymphoblastoid cell lines (LCLs) of lithium-responsive (LR) versus lithium non-responsive (LNR) BD patients, to assess gene expression variations that might bear on treatment outcome.Methods: RNA sequencing was carried out on 24 LCLs from female BD patients (12 LR and 12 LNR) followed by qPCR validation in two additional independent cohorts (41 and 17 BD patients, respectively).Results: Fifty-six genes showed nominal differential expression comparing LR and LNR (FC ≥ |1.3|, P ≤ 0.01). The differential expression of HDGFRP3 and ID2 was validated by qPCR in the independent cohorts.Conclusions: We observed higher expression levels of HDGFRP3 and ID2 in BD patients who favourably respond to lithium. Both of these genes are involved in neurogenesis, and HDGFRP3 has been suggested to be a neurotrophic factor. Additional studies in larger BD cohorts are needed to confirm the potential of HDGFRP3 and ID2 expression levels in blood cells as tentative favourable lithium response biomarkers.

M37 - RNA-Sequencing of Bipolar Disorder Patients Lymphoblastoid Cell Lines Implicates A Novel Neurotrophic Factor In The Efficacy of Lithium As Mood Stabilizing Drug

Background Lithium remains one of the oldest and most effective treatments for mood stabilization in bipolar disorder (BD), and is still the first-line BD treatment even that individual response is variable. Indeed, at least 30% of patients are only partially responsive, and more than 30% do not respond to lithium therapy. Biomarker predictors for lithium response have been studied by using electroencephalography, neuroimaging and molecular genetics reporting findings that mostly remain modest and unconfirmed. Human lymphoblastoid cell lines (LCLs) and, recently, also iPS cell-derived neurons from BD patients have been employed for searching genes and non-coding RNAs whose expression is modulated by lithium using gene candidate approaches and microarray gene expression technologies. RNA-sequencing (RNA-seq) provides advantages over microarray technologies; it allows detecting transcript differences with low background noise avoiding cross-hybridization issues and allows a large dynamic range of expression level evaluation. Methods This study aimed to identify biomarkers predictive for lithium response, based on comparing RNA-seq information derived from LCLs of lithium responsive (LR) vs. lithium non-responsive (LNR) BD patients, for assessing the patients’ genomic variability related to their therapeutic response to lithium. RNA-seq was carried out on 24 LCLs from female BD patients collected at UCSD classified as 12 LR and 12 LNR (according to combined Alda scale) and followed by a RT-PCR validation in an independent cohort of 41 BD patients (25 LR and 16 LNR) collected at JHMI. Results Our RNA-seq study found few genes with borderline significance differential expression (p=0.06) comparing LR and LNR BD LCLs after correcting for multiple-testing. After filtering for p FC Discussion HDGFRP3 is a protein coding gene found to have growth promoting activity for neurons as well as inducing differentiation of endothelial cells. HDGFRP3 is the only HDGF family member whose expression is almost restricted to the CNS. It is strongly expressed in the adult mice bulbus olfactorius, piriform cortex and amygdala and in cultured cells is predominantly expressed in neurons and slightly in glial cells. In mouse cortical neurons it promotes neuritogenesis via its interaction with microtubules and soluble HRP-3 acts a neurotrophic factor. Thus, we found an upregulation of HRP-3 in LCLs from lithium responder BD patients, suggesting its involvement in lithium response likely via its neurotrophic activity.

Sex differences in cognitive dysfunction among bipolar disorder patients

Introduction Studies have proposed that cognitive deficits are present in a variety of mood states in bipolar disorder (BD). In addition, a few studies have pointed to the presence of sex-related differences in cognitive dysfunction in BD. Aim of the work This comparative study aimed to study the cognitive functioning of BD patients in different episodes, and detect any sex-related differences in cognitive functioning in the studied sample. Patients and methods The recruited sample consisted of 150 patients selected at random from El Maamoura Mental Hospital over 6 months. Four groups were formed: group I, comprising 38 (19 male and 19 female) BD patients having manic episodes; group II, comprising 26 (12 male and 14 female) BD patients having depressive episodes; group III, comprising 36 (20 male and 16 female) patients in remission (euthymic); and group IV, comprising 50 controls matched for age, sex, and education. Clinical and psychiatric evaluations were carried out and psychometric assessment was performed using the 17-item Hamilton Depressive Scale and the Young Mania Rating Scale, as well as cognitive assessments using three tests: Wisconsin's Card Sorting Test (WCST), the digit span subtest of the WAIS-R and DSST (the digit symbol subtest of the WAIS-R). Results The BD patients in the three groups having BD showed significant cognitive deficits compared with controls. Manic and depressive patients showed impairment in attention, working memory, and executive functions. Euthymic patients showed significant impairment in working memory and executive functions. Only euthymic patients revealed a statistically significant sex-related difference in terms of short-term memory, attention, and working memory, with women being worse than men. Interestingly, in the control group a difference in executive functions was reported wherein healthy control women performed significantly better than control men on the WCST-128 (completed significantly more number of categories and committed significantly fewer perseverative errors). Conclusion Cognitive dysfunction should be regarded as a core feature of BD as it was present across all mood states in our sample. In addition, discrepancy has been found between male and female euthymic patients regarding cognitive functions, suggesting a sex-related difference in the clinical expression of BD.

Sex-specific urinary biomarkers for diagnosing bipolar disorder.

Sex-based differences are prominent in affective disorders, but there are no biomarkers available to support sex-specific, laboratory-based diagnostics for male and female bipolar disorder (BD) patients. Here, a NMR-based metabonomic approach was used to preliminarily identify sex-specific urinary metabolite biomarkers for diagnosing male and female BD patients. A male-specific biomarker panel consisting of four metabolites (α-hydroxybutyrate, choline, formate, and N-methylnicotinamide) effectively discriminated between male BD and healthy controls (HC) subjects, achieving an area under the receiver operating characteristic curve (AUC) of 0.942. A female-specific biomarkers panel consisting of four metabolites (α-hydroxybutyrate, oxalacetate, acetone, and N-methylnicotinamide) effectively discriminated between female BD and HC subjects, achieving an AUC of 0.909. The male-specific biomarker panel displayed low discriminatory power in the female group, and the female-specific biomarker panel displayed low discriminatory power in the male group. Moreover, several other metabolites showed different trends between male and female BD subjects. These findings suggest that male and female BD patients have distinct biomarker fingerprints and that these two sex-specific biomarker panels may serve as effective diagnostic tools in distinguishing male and female BD patients from their healthy counterparts. Our work may provide a window into the mechanisms underlying the pathoetiology of BD in both men and women.

Childhood maltreatment and coping in bipolar disorder.

A personal history of childhood maltreatment has been associated with unfavorable outcomes in bipolar disorder (BD). The impact of early life stressors on the course of BD may be influenced by individual differences in coping skills. The coping construct relies on neurocognitive mechanisms that are usually influenced by childhood maltreatment. The objective of the present study was to verify the association between childhood maltreatment and coping skills in individuals with BD Type 1. Thirty female euthymic outpatients with BD Type 1 were evaluated using the Childhood Trauma Questionnaire and two additional instruments to measure their coping preferences: Ways of Coping Questionnaire (coping strategies) and Brief COPE (coping styles). Reports of physical abuse (B = .64, p < .01) and emotional abuse (B = .44, p = .01) were associated with the use of maladaptive strategies that focused on emotional control. Adaptive strategies and styles of coping, such as focusing on the problem, were chosen less frequently by women who had experienced emotional neglect (B = .53, p < .01) and physical abuse (B = -.48, p < .01) in childhood. The small sample size in the present study prevented subgroup analyses. The sample did not include male BD participants. Our results indicate that early traumatic events may have a long-lasting deleterious influence on coping abilities in female BD patients. Future prospective studies may investigate whether the negative impact of childhood maltreatment over the course of BD is mediated by individual differences in coping abilities.

Bipolar disorder and comorbid obsessive-compulsive disorder is associated with higher rates of anxiety and impulse control disorders.

Issler CK, Monkul ES, Amaral JAMS, Tamada RS, Shavitt RG, Miguel EC, Lafer B. Bipolar disorder and comorbid obsessive-compulsive disorder is associated with higher rates of anxiety and impulse control disorders. Although bipolar disorder (BD) with comorbid obsessive-compulsive disorder (OCD) is highly prevalent, few controlled studies have assessed this comorbidity. The objective of this study was to investigate the clinical characteristics and expression of comorbid disorders in female BD patients with OCD. We assessed clinically stable female outpatients with BD: 15 with comorbid OCD (BD+OCD group) and 15 without (BD/no-OCD group). All were submitted to the Structured Clinical Interview for DSM-IV, with additional modules for the diagnosis of kleptomania, trichotillomania, pathological gambling, onychophagia and skin picking. The BD+OCD patients presented more chronic episodes, residual symptoms and previous depressive episodes than the BD/no-OCD patients. Of the BD+OCD patients, 86% had a history of treatment-emergent mania, compared with only 40% of the BD/no-OCD patients. The following were more prevalent in the BD+OCD patients than the BD/no-OCD patients: any anxiety disorder other than OCD; impulse control disorders; eating disorders; and tic disorders. Female BD patients with OCD may represent a more severe form of disorder than those without OCD, having more depressive episodes and residual symptoms, and being at a higher risk for treatment-emergent mania, as well as presenting a greater anxiety and impulse control disorder burden.

Use of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to Investigate Group and Gender Differences in Schizophrenia and Bipolar Disorder

Gender differences exist in schizophrenia and bipolar disorder (BD), therefore the aim of the present study was to clarify the role of gender in cognitive deficits in these disorders. Cognitive performance was examined in schizophrenia (24M : 14F) and BD (16M : 24F) patients compared with age-, IQ- and gender-matched control participants (21M : 22F). The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess five cognitive domains: immediate memory/learning, visuospatial ability, language, attention, and delayed memory, which are summed to provide a Total score. In comparison to controls, schizophrenia patients showed deficits on all domains, while BD patients had impaired immediate memory/learning, language and Total score. Schizophrenia patients showed deficits compared to BD in the Total score, immediate and delayed memory and visuospatial ability. The Total and domain scores were not different in men and women across or within groups. There were gender effects on four of the 12 individual cognitive tasks, in which female patients outperformed male patients. Further, there were gender differences across groups for three of the individual tasks: female schizophrenia patients showed poorer story memory and story recall compared to male schizophrenia patients; female BD patients had enhanced figure copy performance compared to male BD patients. The RBANS highlighted the cognitive deficits in schizophrenia and BD patients compared to controls and also each other. There were no overall gender differences in cognition.

Anterior genu corpus callosum and impulsivity in suicidal patients with bipolar disorder

Suicidality is a life-threatening symptom in patients with bipolar disorder (BD). Impulsivity and mood instability are associated with suicidality in mood disorders. Evidence suggests that gray and white matter abnormalities are linked with impulsivity in mood disorders, but little is known about the association between corpus callosum (CC) and impulsivity in BD. We examined the relationship between CC areas, impulsivity and suicidality in BD patients. We studied 10 female BD patients with a history of suicide attempt (mean±SD age 36.2±10.1 years), 10 female BD patients without suicide attempt history (44.2±12.5 years) and 27 female healthy subjects (36.9±13.8 years). Impulsivity was evaluated by the Barratt Impulsivity Scale (BIS). We traced MR images to measure the areas of the CC genu, anterior body, posterior body, isthmus and splenium. The genu was divided into anterior, middle and posterior regions. The suicidal and non-suicidal BD patients had significantly higher BIS total, attention and non-planning scores than the healthy subjects (ps<0.01), and the suicidal BD patients had significantly higher BIS motor scores than the non-suicidal BD and healthy subjects (ps<0.01). There were no significant differences among the three groups on any regional CC areas, although the suicidal BD patients had the smallest areas. The suicidal BD patients showed a significant inverse correlation between anterior genu area and the BIS total (r=−0.75, p=0.04), motor (r=−0.79, p=0.02) and non-planning scores (r=−0.79, p=0.02). These correlations were not found in the non-suicidal BD patients or healthy subjects. The results suggest that the anterior medial frontal region may be involved in the pathophysiology of impulsive and suicidal behaviors in BD.

Cognitive function and serum levels of brain‐derived neurotrophic factor in patients with bipolar disorder

Brain-derived neurotrophic factor (BDNF) is an important contributor to the pathophysiology of bipolar disorder (BD), and abnormalities in the BDNF-signaling system may be implicated in the cognitive decline observed in BD patients. We aimed to investigate serum BDNF levels in BD patients and its relation to neurocognitive function. We measured serum BDNF levels using an enzyme-linked immunosorbent assay method in 65 euthymic type I BD patients and 50 healthy controls, and administered a neuropsychological test battery to assess attention and mental control, perceptual-motor skills, executive functions, verbal fluency and abstraction, visuospatial attention, and memory. We found no significant differences regarding serum BDNF levels in BD patients and healthy controls. We found significant positive associations between serum BDNF levels and illness duration, and manic and depressive episodes in female BD patients only. Serum BDNF levels were lower in patients medicated with antipsychotics and/or lithium, whereas patients on valproate and/or antidepressants showed higher serum BDNF levels. Patients performed significantly worse on 11 out of 16 neurocognitive tests as compared to controls. We found a significant positive association between serum BDNF levels and a test of verbal fluency in both BD patients and controls. Present results support the hypothesis that BDNF normalizes with mood stabilization and pharmacological treatment. Our findings in young and physically healthy patients with short illness duration and few mood episodes may explain the lack of association between serum BDNF levels and neurocognitive performance, even though cognitive performance in patients was overall significantly worse as compared to healthy controls.

Increased hexosaminidase activity in antipsychotic-induced extrapyramidal side effects: Possible association with higher occurrence in bipolar disorder patients

Dystonic movements and Parkinsonism are frequently seen in gangliosidoses and these conditions have been reported to modify dopaminergic plasticity. We investigated whether the activity of hexosaminidase, a type-two ganglioside (GM2) degrading enzyme, correlates with drug-induced extrapyramidal system (EPS) side effects in psychiatric patients. We compared hexosaminidase activity in the lymphocytes of 29 EPS-positive patients, 13 EPS-negative patients, and 30 healthy volunteers. The activities of A and B isoforms of hexosaminidase were higher in EPS-positive patients than EPS-negative patients and healthy controls. Multivariate analysis suggested an interaction with increased B isoform activity and EPS side effects in female bipolar disorder patients. Higher levels of hexosaminidase enzyme activity may explain the frequent occurrence of antipsychotic-induced extrapyramidal side effects in mood disorder patients.

Family history influences age of onset in bipolar I disorder in females but not in males

Age of onset (AO) has been proposed as a promising criterion by which to select homogeneous subgroups for the genetic analysis of bipolar disorder. This is the first study to investigate the effect of the interaction between gender and family history (FH)-type on AO in bipolar disorder. In accordance with the literature, no difference in AO was observed between females and males in our sample of 264 Romanian bipolar I probands. Cox regression, however, showed a strong influence of FH-type on AO (P = 0.006). This was due to a significant variation in AO according to the type of FH in females (P = 0.002) but not in males (P = 0.64). Female bipolar disorder patients with a negative FH (FH(-)) had a later AO than females with either a FH of bipolar and/or schizoaffective disorder (P = 0.001) or a FH of recurrent unipolar major depression only (P = 0.04). Females with FH(-) had a later AO than males with FH(-) (P = 0.03). No sex difference was observed for AO in the group with a FH of recurrent unipolar depression. In the group with a FH of bipolar and/or schizoaffective disorder, females had an earlier AO than males (P = 0.01). A trend for support was observed in an independent sample of 217 German bipolar I patients for an influence of FH-type on AO in females (P = 0.09) but not in males (P = 0.15). Female bipolar disorder patients with FH(-) had a later AO than females with either a FH of bipolar and/or schizoaffective disorder (P = 0.04) or a FH of recurrent unipolar major depression only (P = 0.05). Females with FH(-) had a later AO than males with FH(-) (P = 0.05). Other comparisons were statistically not significant, which may be due to limited sample size. Our findings emphasize that the interaction between gender and FH-type is a source of heterogeneity for AO in bipolar disorder.

Association analysis between a functional polymorphism in the monoamine oxidase A gene promoter and severe mood disorders

Monoamine oxidase A (MAOA) has been suggested to be involved in human behaviour and physiology due to its key role in the metabolism of several different biological amines including the neurotransmitters serotonin, norepinephrin and dopamine.Recently, a 30 bp repeat in the MAOA gene promoter (uMAOA) has been demonstrated to be polymorphic and to affect transcriptional activity. In the context of an association case-control study design, we analysed the uMAOA polymorphism in 389 unrelated patients affected by severe mood disorders (88 bipolar subjects and 301 major depressive individuals) and in 156 controls. No association was found between the uMAOA locus and bipolar disorder or major depression. However, an increase of high-activity uMAOA alleles was found in major depression female patients presenting a seasonal pattern (chi2=3.013, P=0.05) or psychotic symptoms in their episodes (chi2=2.679, P=0.07). In female bipolar disorder patients, long alleles were associated with longest times of admission (F=4.604, P=0.037). A trend for association with seasonal pattern was also defined in this group (data not corrected for multiple testing). Our results suggest that MAOA gene variation may modulate the expression of some clinical aspects of severe mood disorders, especially in females, and support the existence of a genetic and aetiologic heterogeneity underlying the diagnoses of bipolar disorder and major depression.