Role In Bipolar Disorder Research Articles

Effect of memantine on C-reactive protein and lipid profiles in bipolar disorder

BackgroundBalance in the immune system plays roles in bipolar disorder (BD) and its metabolic co-morbidities. Memantine is an NMDA receptor antagonist with anti-inflammatory effects. However, the effects of memantine adjunct treatment on metabolic status of BD are unclear. MethodsDuring the 12 weeks period, a total of 191 BD patients were enrolled and split into valproate (VPA) + placebo and VPA + memantine (5mg/day) arms. The fasting plasma levels of high-sensitivity C-reactive protein (CRP) and metabolic indices were assessed. BD patients were stratified according to their initial CRP level. ResultsA cut-off value of initial CRP level of 2322ng/mL discriminated the waist circumference in these BD patients after 12-week VPA treatment. In the high CRP (> 2322ng/mL) group, patients in the VPA + memantine arm had a significantly decreased in their CRP (p= 0.009), total cholesterol (p= 0.002), LDL (p= 0.002) levels, BMI (p= 0.001), and waist circumference (p< 0.001), compared to those in the VPA + placebo arm. However, analysis of the low CRP group did not showed the effect. LimitationsWe recruited BD patients in depressed states and the sample size was relative small. The effects of the fixed dose of memantine on metabolic indices were 12-week follow up in BD patients treated with VPA. ConclusionsBD patients with high initial CRP levels receiving memantine adjunct treatment have a reduced risk of inflammation and metabolic imbalance. Prospective studies are needed to confirm the long-term outcome for memantine adjunct therapy in BD patients.

Distribution and levels of 5-HT1B receptors in anterior cingulate cortex of patients with bipolar disorder, major depressive disorder and schizophrenia – An autoradiography study

The serotonin 1B receptor has recently received more interest as a possible new target for pharmacological treatment of psychiatric disorders. However, the exact mechanisms of action remain unclear. This study aimed to examine the binding distribution and levels of the serotonin 1B receptor in-depth in the anterior cingulate cortex (ACC) and provide more insight in its functional role in bipolar disorder (BD), major depressive disorder (MDD) and schizophrenia (SZ).Serotonin 1B receptor binding distribution was visualized with high resolution autoradiography (ARG), using the radioligand [3H]AZ10419369, in postmortem ACC tissue from patients diagnosed with BD (n=14), MDD (n=12), SZ (n=13) and healthy subjects (n=13). Moreover, a quantification of receptor binding was made with ARG, in relation to patient group, age and gender.In all subject groups a significantly higher specific binding of serotonin 1B receptor was measured in the outer ACC layers compared to the inner ACC layers. Correlation analysis with ARG binding patterns of several radioligands resulted in a significant correlation with glutamatergic N-methyl-D-aspartate receptor binding in the outer layers. No significant difference was found between subject groups in binding levels and distribution. In female subjects a significantly lower receptor binding was found than in male subjects, which was most profound in patients diagnosed with MDD.The binding distribution of the serotonin 1B receptor found in this study supports a role in glutamate transmission in the ACC and was not shown to be significantly altered in BD, MDD or SZ. A gender difference in serotonin 1B receptor binding was found.

Genetic variation in the miR-708 gene and its binding targets in bipolar disorder.

Objectivers12576775 was found to be associated with bipolar disorder (BD) in a genome‐wide association study (GWAS). The GWAS signal implicates genes for the microRNAs miR‐708 and miR‐5579 and the first exon of the Odd Oz/ten‐m homolog 4 gene (ODZ4). In the present study, miR‐708, its surrounding region, and its targets were analyzed for potential BD‐associated functional variants.MethodsThe miR‐708 gene and surrounding regions were screened for variation using high‐resolution melting (HRM) analysis in 1099 cases of BD, followed by genotyping of rare variants in an enlarged sample of 2078 subjects with BD, 1303 subjects with schizophrenia, and 1355 healthy controls. Whole‐genome sequencing data from 99 subjects with BD were analyzed for variation in potential miR‐708 binding sites. The minor allele frequencies (MAFs) of these variants were compared with those reported in reference individuals.ResultsThree variants detected by HRM were selected to be genotyped. rs754333774 was detected in three cases of BD, two cases of schizophrenia, and no controls. This variant is located 260 base pairs upstream from miR‐708 and may play a role in controlling the expression of the miR. Four variants were identified in miR‐708 targets binding sites. The MAFs of each of these variants were similar in BD and reference samples.ConclusionsWe report a single recurrent variant located near the miR‐708 gene that may have a role in BD and schizophrenia susceptibility. These findings await replication in independent cohorts, as do functional analyses of the potential consequences of this variant.

Negative experiences in childhood and the development and course of bipolar disorder.

The aim of this paper is to review the effects of negative childhood experiences on the development and course of bipolar disorder (BD) and to discuss the involved mechanisms. The negative childhood experiences that may play a role in BD are critical or traumatic events including all kinds of abuse, loss of a parent or parents resulting from death, suicide, separation, divorce or prolonged separation. Previous studies indicate that in BD patients negative childhood events are more frequent than in control group. In BD patients these events are associated with an earlier onset and more severe course of the illness, including more frequent relapses, suicidal behavior, substance abuse and somatic diseases. This paper presents the possibility of the specific impact of individual events on the clinical outcome of BD. Mechanisms explaining the impact of negative childhood events on the development and course of BD include the interaction between biological predisposition and stress factors, the concept of kindling and activation of negative cognitive schemas. Early negative experiences cause a modification of the expression of the mediators of stress and neurotransmitters in certain areas of the brain. The interaction of these mediators with the development of neural networks may lead to long-lasting structural and functional changes. Molecular genetic studies indicate the possibility of interactions between environmental factors (stress) and the polymorphisms of serotonin transporter, brain-derived neurotrophic factor (BDNF) and toll-like receptor (TLR2). It has also been hypothesized that childhood experiences affect DNA methylation, acting as a form of molecular memory and modifying brain activity over the next decade.

Assessment of Brain-Derived Neurotrophic Gene and its Polymorphism Frequency in Patients With Bipolar Disorder in Hamadan

Background: Bipolar disorder is a biological brain disorder which is associated with debilitating fluctuation in mood and adverse eects on patients, their families and society. The importance of genetics and its role in bipolar disorder is a controversial issue to discuss. Evidence indicates a relation between the risk of bipolar disorder and specific genes. Amongst the genes whose role has been established in bipolar disorder, the most notable gene is BDNF (Brain-derived neurotrophic factor). Methods: The study is based on a case-control methodology. During 18 months, the blood samples of patients diagnosed with bipo- lar mood disorder who were admitted to Farshchian hospital of Hamadan from March 2011 to September 2012 and for the control group, the blood samples of patients admitted to other parts of Farshchian hospital except psychiatric ward were taken and DNA extraction from white blood cells was performed. In general, 84 patients and 85 controls were examined in this study and an ex- pert in vials containing EDTA anticoagulant collected 4ml of blood samples. These samples were sent to the molecular biology lab of Hamadan University of Medical Science to determine their genetic polymorphisms. Genomic DNA was extracted from periph- eral blood cells using the real extraction DNA kit (DNP Tm kit, Cat# DN8115C, CinnaGen co., Iran). The allele specific polymerase chain reaction technique was used to determine the frequencies of listed genotype. Considering the dierent variations for each gene, primers design was carried out using the Allele ID software (Allele ID 6, premier Bio soft Int, USA). For this purpose, 401 nu- cleotide sequences of targeted gene polymorphisms was chosen as the control sequence and desired primers for this sequence was designed and ordered (Takapouzist Co., Iran). Finally, using the mentioned method the sequences were amplified and examined on 2% agarose gel during electrophoresis. The young mania rating scale (YMRS) was used to evaluate manic symptoms. A written consent was obtained from each individual patient during the study. In addition, all patients in this study were anonymous and ethical considerations were taken into account. Statistical data analysis was performed using SPSS Software and Chi-square test was used to analyze their significance. Results: The results of this study, which was conducted on 84 patients in the case group and 85 patients in the control group indi- cated that the frequencies of evaluated alleles in the case and control groups for AA genotype were 4 and 4, for GA genotype were 23 and 28, and for GG genotype were 53 and 53, respectively. Conclusions: According to the obtained data, there is no significant relationship between genetic and bipolar disorder. Some stud- ies in this field have also confirmed this issue.

Peripheral blood mRNA expressions of stress biomarkers in manic episode and subsequent remission

Theoretical models of the neuroprogressive nature of bipolar disorder (BD) are based on the hypothesis that it is an accelerated aging disease, with the allostatic load playing a major role. Glucocorticoids, oxidative stress markers, inflammatory cytokines and neurotrophins play important roles in BD. The messenger ribonucleic acid (mRNA) expressions of brain-derived neurotrophic factor (BDNF), tissue plasminogen activator (tPA), glucocorticoid receptor (GR), heat shock protein 70 (HSP70), tumour necrosis factor-alpha (TNF-α) were examined in the peripheral blood of 20 adult male, drug-free BD patients during manic and remission periods and in 20 adult male, healthy controls. mRNA expression was measured using the quantitative real-time polymerase chain reaction (qRT-PCR). Compared to the controls, the expressions of BDNF and tPA mRNA were down-regulated in mania. In remission, BNDF and tPA mRNA levels increased, but they were still lower than those of the controls. Between mania and remission periods, only the change in mRNA levels of BDNF reached statistical significance. The results suggest that BDNF and tPA may be biomarkers of BD and that proteolytic conversion of BDNF may be important in the pathophysiology of BD. The change in BDNF levels between mania and remission could be adaptive and used to follow the progression of BD.

Multiple oscillators assure soft margin of diurnal function and are the result of alternate splicing and later genetic rearrangement: Possible role in bipolar disorder

Introduction Appearance of multiple effector proteins on a single receptor seems mysterious. These new effectors appear during alternate splicing, gene duplication and genomic re-arrangement during evolution. In chronobiology, this might have vital protective importance for migration to places with extreme climates. Objectives Residing on a simple light/darkness system of circadian cycle is in contrast with human cultural development. Aims Developing a model of molecular interaction to explain the BMD spectrum. Methods We classify circadian oscillators into one master (CLOCK/BMAL1) and 4 slave oscillators. The master has suppressing action on 4 parallel slave oscillators. In case of disruption of this tract, one of them reigns. Input from the retinal ganglion cells has minor effect (noise) for the parametric oscillation of the master but not slave oscillator. Mutations in the master that disrupts these feedbacks, or increases sensitivity to ganglion cells input or cause hyperactivity of the slave oscillators are explanations for BMD development. Downstream to this, a divergent set of genes ( PER1, 2, 3, NCAN, GSK3-b and CRY1 ), 2 with different functions are activated. Derangement of any of the downstream genes causes incomplete symptoms and signs. Results This model with elegant curves can successfully incorporate many laboratory and clinical findings and explains in a comprehensive way how genetic and environmental factors interact to build up disease picture and spectrum of BMD. In addition, some innovative (less intensive and with less side effects) treatment strategies can be suggested. Conclusions More research in this field is warranted.

TPH2 gene polymorphisms and bipolar disorder: A meta‐analysis

Disturbance of the serotonergic system contributes to the etiology of bipolar disorder (BD). Tryptophan hydroxylase-2 (TPH2) is an important rate-limiting enzyme in the synthetic pathway for brain serotonin and has been suggested to play a role in BD. We performed a systematic review and meta-analysis of all studies to date investigating the association studies between TPH2 and BD published before Aug 2014. All studies were abstracted from PubMed, Embase, HuGNet, and China National Knowledge Infrastructure (CNKI). Manuscripts and the supplementary documents of published genome-wide association studies in the field were also included. Effect sizes of independent loci that have been studied in more than three articles were synthesized using fixed and random effects models. Eight eligible studies addressed association between 63 TPH2 gene single nucleotide polymorphisms (SNPs) with BD, after linkage disequilibrium analysis, 12 independent SNPs were identified. Finally, three SNPs (rs4760820, rs11178998, and rs7954758) were found associated with BD using fixed effects models, and rs4760820 and rs11178998 were still associated with BD even with the more conservative random effects models. rs4760820 and rs11178998 were identified to have strong genetic association with BD in present study though confirmation will require larger sample sizes and in additional populations.

Sodium butyrate and mood stabilizers block ouabain-induced hyperlocomotion and increase BDNF, NGF and GDNF levels in brain of Wistar rats

Bipolar Disorder (BD) is one of the most severe psychiatric disorders. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, and functional impairment. Some preclinical studies have shown that histone deacetylase inhibitors may act on manic-like behaviors. Neurotrophins have been considered important mediators in the pathophysiology of BD. The present study aims to investigate the effects of lithium (Li), valproate (VPA), and sodium butyrate (SB), an HDAC inhibitor, on BDNF, NGF and GDNF in the brain of rats subjected to an animal model of mania induced by ouabain. Wistar rats received a single ICV injection of ouabain or artificial cerebrospinal fluid. From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li, VPA or SB twice a day. In the 7th day after ouabain injection, locomotor activity was measured using the open-field test. The BDNF, NGF and GDNF levels were measured in the hippocampus and frontal cortex by sandwich-ELISA. Li, VPA or SB treatments reversed ouabain-related manic-like behavior. Ouabain decreased BDNF, NGF and GDNF levels in hippocampus and frontal cortex of rats. The treatment with Li, VPA or SB reversed these impairment induced by ouabain. In addition, Li, VPA and SB per se increased NGF and GDNF levels in hippocampus of rats. Our data support the notion that neurotrophic factors play a role in BD and in the mechanisms of the action of Li, VPA and SB.

Functional connectivity and neuronal variability of resting state activity in bipolar disorder--reduction and decoupling in anterior cortical midline structures.

The cortical midline structures seem to be involved in the modulation of different resting state networks, such as the default mode network (DMN) and salience network (SN). Alterations in these systems, in particular in the perigenual anterior cingulate cortex (PACC), seem to play a central role in bipolar disorder (BD). However, the exact role of the PACC, and its functional connections to other midline regions (within and outside DMN) still remains unclear in BD. We investigated functional connectivity (FC), standard deviation (SD, as a measure of neuronal variability) and their correlation in bipolar patients (n = 40) versus healthy controls (n = 40), in the PACC and in its connections in different frequency bands (standard: 0.01-0.10 Hz; Slow-5: 0.01-0.027 Hz; Slow-4: 0.027-0.073 Hz). Finally, we studied the correlations between FC alterations and clinical-neuropsychological parameters and we explored whether subgroups of patients in different phases of the illness present different patterns of FC abnormalities. We found in BD decreased FC (especially in Slow-5) from the PACC to other regions located predominantly in the posterior DMN (such as the posterior cingulate cortex (PCC) and inferior temporal gyrus) and in the SN (such as the supragenual anterior cingulate cortex and ventrolateral prefrontal cortex). Second, we found in BD a decoupling between PACC-based FC and variability in the various target regions (without alteration in variability itself). Finally, in our subgroups explorative analysis, we found a decrease in FC between the PACC and supragenual ACC (in depressive phase) and between the PACC and PCC (in manic phase). These findings suggest that in BD the communication, that is, information transfer, between the different cortical midline regions within the cingulate gyrus does not seem to work properly. This may result in dysbalance between different resting state networks like the DMN and SN. A deficit in the anterior DMN-SN connectivity could lead to an abnormal shifting toward the DMN, while a deficit in the anterior DMN-posterior DMN connectivity could lead to an abnormal shifting toward the SN, resulting in excessive focusing on internal contents and reduced transition from idea to action or in excessive focusing on external contents and increased transition from idea to action, respectively, which could represent central dimensions of depression and mania. If confirmed, they could represent diagnostic markers in BD.

Intracerebral Administration of BDNF Protects Rat Brain Against Oxidative Stress Induced by Ouabain in an Animal Model of Mania.

Several studies have suggested that alterations in brain-derived neurotrophic factor (BDNF) and increased oxidative stress have a central role in bipolar disorder (BD). Intracerebroventricular (ICV) injection of ouabain (OUA) in rats alters oxidative stress parameters and decreases BDNF levels in the brain. In this context, the present study aims to investigate the effects of BDNF ICV administration on BDNF levels and oxidative stress parameters in brains of rats submitted to animal model of mania induced by OUA. Wistar rats received an ICV injection of OUA, artificial cerebrospinal fluid (ACSF), OUA plus BDNF, or ACSF plus BDNF. Locomotor activity and risk-taking behavior in the rats were measured using the open-field test. In addition, we analyzed the BDNF levels and oxidative stress parameters (TBARS, Carbonyl, CAT, SOD, GR, and GPx) in the frontal cortex and hippocampus of rats. The BDNF was unable to reverse the ouabain-induced hyperactivity and risk-taking behavior. Nevertheless, BDNF treatment increased BDNF levels, modulated the antioxidant enzymes, and protected the OUA-induced oxidative damage in the brain of rats. These results suggest that BDNF alteration observed in BD patients may be associated with oxidative damage, both seen in this disorder.

Sleep and Circadian Profiles of Bipolar Disorder: From Chronobiology to Novel Therapeutic Strategies

This review considers evidence that sleep and circadian rhythms are disturbed in bipolar patients during both mood episodes and periods of remission. Indeed, bipolar patients display disturbances of subjective and objective circadian markers, in sleep continuity, and in cortisol and melatonin secretion. Better characterization of sleep and circadian rhythms can improve personalized assessment and help identify treatment focusing on normalizing these disturbances. Therapeutic applications of chronobiology in bipolar disorder, such as specific psychosocial intervention, light therapy and physical exercise are described. The study of sleep and circadian rhythms opens innovative avenues in research concerning the pathophysiology of bipolar disorder, including the possible discovery of biomarkers, and may lead to a better understanding of genes role in bipolar disorder regarding associations of some circadian genes polymorphisms with bipolar disorder. Keywords: Actigraphy, bipolar disorder, circadian rhythms, clock genes, light therapy, physical exercise.

EPA-0848 – Stress reactivity in euthymic bipolar patietns and their unaffected siblings

Bipolar disorder is characterized by depressive and manic mood episodes. Despite an overall high heritability, environmental factors play a critical role in bipolar disorder. Stress negatively influences the clinical course bipolar disorder and may trigger mood episodes. Surprisingly, the study of stress reactivity in bipolar patients has remained relatively unexplored. Moreover, it is unknown whether altered stress reactivity may be a trait marker in unaffected siblings of bipolar disorder patients who possess an increased genetic risk for this disorder. Male and female euthymic bipolar disorder patients (N=49), unaffected siblings (N=27) and healthy controls (N=48) were exposed to a validated social stress test. The endocrine stress response was measured using saliva cortisol levels, whereas salivary alpha-amylase (sAA) were determined as an index for the adrenergic stress response. Exposure to stress resulted in a differential endocrine and adrenergic stress reactivity between bipolar disorder patients and their unaffected sibling. Importantly, bipolar disorder patients displayed a blunted endocrine but exaggerated adrenergic response. Our findings illustrate the importance of measuring stress reactivity in bipolar disorder. These results provide insight into stress system functionality of euthymic bipolar disorder and enable a direct comparison with unaffected siblings who display an increased risk but have not developed bipolar disorder.

Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder.

BackgroundBipolar disorder (BD) is a complex psychiatric phenotype with a high heritability and a multifactorial etiology. Multisite collaborative efforts using genome-wide association studies (GWAS) have identified only a portion of DNA sequence-based risk factors in BD. In addition to predisposing DNA sequence variants, epigenetic misregulation may play an etiological role in BD and account for monozygotic twin discordance, parental origin effects, and fluctuating course of BD. In this study, we investigated DNA methylation of the brain-derived neurotrophic factor (BDNF) gene in BD.MethodsFifty participants with BD were compared to the same number of age- and sex-matched controls for DNA methylation differences at BDNF promoters 3 and 5. DNA methylation reads were obtained using a mass spectrophotometer for 64 cytosine-guanine (CpG) sites in 36 CpG ‘units’ across three amplicons of BDNF promoters 3 and 5.Results and DiscussionMethylation fractions differed between BD participants and controls for 11 of 36 CpG units. Five CpG units, mostly in promoter 5, remained significant after false discovery rate correction (FDR) (p values ≤ 0.004) with medium to large effect sizes (Cohen's d ≥ 0.61). Several of the significant CpGs overlapped with or were immediately adjacent to transcription factor binding sites (TFBSs) - including two of the FDR-significant CpG units in promoter 5. For the CpGs in promoter 3, there was a positive and significant correlation between age at sample collection and DNA methylation fraction (rho = 0.56, p = 2.8 ×10−5) in BD cases, but not in controls. Statistically significant differences in mean methylation fraction at 5/36 CpG units (after FDR), some at or immediately adjacent to TFBSs, suggest possible relevance for the current findings to BD etiopathogenesis. The positive correlation between age and methylation seen in promoter 3 is consistent with age-related decline in BDNF expression previously reported. Future studies should provide more exhaustive epigenetic study of the BDNF locus to better characterize the relationship between BDNF methylation differences and BD.Electronic supplementary materialThe online version of this article (doi:10.1186/2194-7511-1-28) contains supplementary material, which is available to authorized users.

Reduced burden of very large and rare CNVs in bipolar affective disorder

Large, rare chromosomal copy number variants (CNVs) have been shown to increase the risk for schizophrenia and other neuropsychiatric disorders including autism, attention-deficit hyperactivity disorder, learning difficulties, and epilepsy. Their role in bipolar disorder (BD) is less clear. There are no reports of an increase in large, rare CNVs in BD in general, but some have reported an increase in early-onset cases. We previously found that the rate of such CNVs in individuals with BD was not increased, even in early-onset cases. Our aim here was to examine the rate of large rare CNVs in BD in comparison with a new large independent reference sample from the same country. We studied the CNVs in a case-control sample consisting of 1,650 BD cases (reported previously) and 10,259 reference individuals without a known psychiatric disorder who took part in the original Wellcome Trust Case Control Consortium (WTCCC) study. The 10,259 reference individuals were affected with six non-psychiatric disorders (coronary artery disease, types 1 and 2 diabetes, hypertension, Crohn's disease, and rheumatoid arthritis). Affymetrix 500K array genotyping data were used to call the CNVs. The rate of CNVs > 100 kb was not statistically different between cases and controls. The rate of very large (defined as > 1 Mb) and rare (< 1%) CNVs was significantly lower in patients with BD compared with the reference group. CNV loci associated with schizophrenia were not enriched in BD and, in fact, cases of BD had the lowest number of such CNVs compared with any of the WTCCC cohorts; this finding held even for the early-onset BD cases. Schizophrenia and BD differ with respect to CNV burden and association with specific CNVs. Our findings support the hypothesis that BD is etiologically distinct from schizophrenia with respect to large, rare CNVs and the accompanying associated neurodevelopmental abnormalities.

Prävention bipolarer Störungen

In the past, preventive measures for psychoses have focused mainly on schizophrenic disorders. Bipolar disorders are often diagnosed and treated with a significant delay. The expansion of preventive measures for bipolar disorders aims at minimizing the substantial negative consequences associated with the disease. Some of the shared aspects of prevention in psychoses and bipolar disorders are that the first symptoms commonly appear during adolescence and early adulthood and that there is a symptomatic overlap between the disorders. To improve efforts to seek early help, public information about mental illness, low threshold services as well as cooperation between adult, child and adolescent psychiatry are needed for this target group. One differences is that psychotic symptoms play a minor role in bipolar disorders. Specific biological markers, such as disturbances of sleep and circadian rhythm and clinical characteristics, such as substance use and behavioral problems in childhood and youth supplement (subsyndromal) clinical symptoms in a multifactorial risk model. Besides severity and frequency of symptoms, specific periodic course patterns are crucial. Strategies of early intervention require a careful consideration of risks and benefits. Two aims should be distinguished: the improvement of current symptomatology and the prevention of conversion to bipolar disorder. Currently, studies evaluating risks and benefits of such interventions are first conducted. Expertise and resources for early recognition of psychoses and bipolar disorders should be pooled. Common standards are the basis for advancement and implementation of preventive strategies for bipolar disorders.

Bipolar Disorder is associated with the rs6971 polymorphism in the gene encoding 18kDa Translocator Protein (TSPO)

SummaryTSPO mediated transport of cholesterol into the mitochondrion is a necessary step in steroid synthesis. The rs6971 polymorphism in the TSPO gene causes an amino acid substitution (Ala147Thr) within the transmembrane domain where the cholesterol-binding pocket is located, and has been shown to affect the steroidogenic pathway. We report a nominal association between this TSPO polymorphism and the diagnosis of Bipolar Disorder in both the genome-wide dataset of the Wellcome Trust Case–Control Consortium and the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder group (OR = 1.11, p = 0.007; OR = 1.10, p = 0.011, respectively). We propose that the amino acid substitution affects hypothalamic–pituitary–adrenal (HPA) regulation, and hence may predispose to Bipolar Disorder. This supports the hypothesis that HPA dysregulation has a causal role in Bipolar Disorder, and is not just a consequence of the disease.

Sodium butyrate reverses the inhibition of Krebs cycle enzymes induced by amphetamine in the rat brain

There is increasing interest in the possibility that mitochondrial impairment may play an important role in bipolar disorder (BD). The Krebs cycle is the central point of oxidative metabolism, providing carbon for biosynthesis and reducing agents for generation of ATP. Recently, studies have suggested that histone deacetylase (HDAC) inhibitors may have antimanic effects. The present study aims to investigate the effects of sodium butyrate (SB), a HDAC inhibitor, on Krebs cycle enzymes activity in the brain of rats subjected to an animal model of mania induced by D-amphetamine (D-AMPH). Wistar rats were first given D-AMPH or saline (Sal) for 14days, and then, between days 8 and 14, rats were treated with SB or Sal. The citrate synthase (CS), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) were evaluated in the prefrontal cortex, hippocampus, and striatum of rats. The D-AMPH administration inhibited Krebs cycle enzymes activity in all analyzed brain structures and SB reversed D-AMPH-induced dysfunction analyzed in all brain regions. These findings suggest that Krebs cycle enzymes' inhibition can be an important link for the mitochondrial dysfunction seen in BD and SB exerts protective effects against the D-AMPH-induced Krebs cycle enzymes' dysfunction.

C9ORF72 expansion in a family with bipolar disorder

ObjectiveTo investigate the role in bipolar disorder of the C9ORF72 hexanucleotide repeat expansion responsible for frontotemporal lobe dementia and amyotrophic lateral sclerosis.MethodsEighty-nine subjects from a previously described panel of individuals with bipolar disorder ascertained for genetic studies were screened to detect expansion of the C9ORF72 repeat. One two-generation family with bipolar disorder and an expanded repeat was characterized in depth using molecular diagnostics, imaging, histopathology, and neurological and neuropsychological evaluation.ResultsOne proband, with the typical clinical presentation of bipolar disorder, carried an expanded C9ORF72 allele of heterogeneous length between 14 and 20 kilobases (kb) as assessed by Southern blot. The expanded allele was inherited from a parent with atypical, late onset clinical features of bipolar disorder, who subsequently progressed to frontotemporal lobe dementia. The expansion in peripheral blood of the parent ranged from 8.5 to 20 kb. Cultured lymphoblastoid cells from this parent exhibited a homogeneous expansion of only 8.5 kb.ConclusionsThe disease course in the two generations described here demonstrates that expansion of the C9ORF72 may be associated with a form of bipolar disorder that presents clinically with classic phenomenology and progression to neurodegenerative disease. The frequency in our bipolar disorder cohort was only 1%, indicating that C9ORF72 is not a major contributor to bipolar disorder. DNA from cultured cells may be biased towards shorter repeats and nonrepresentative of the endogenous C9ORF72 expansion.

Levels of TNF‐α, soluble TNF receptors (sTNFR1, sTNFR2), and cognition in bipolar disorder

Tumor necrosis factor-alpha (TNF-α) may play an important role in bipolar disorder (BD) pathogenesis. There is only one study about a relationship between TNF-α levels and cognitive impairments in BD. The aim of the present study was to see whether TNF-α, soluble P55 TNF receptor (sTNFR1), and soluble P75 TNF receptor (sTNFR2) levels in BD patients are different from controls and to investigate the relationships between the levels of TNF-α, sTNFR1, and sTNFR2 and the cognitive functions in euthymic BD patients and controls. We assessed 54 BD type I patients and 18 controls by using a battery of neuropsychological tests. Serum TNF-α levels were measured using a commercially available enzyme-linked immunosorbent assay, whereas serum sTNFR1 and sTNFR2 levels were measured using a commercially enzyme-amplified sensitivity immunoassay kit. We found that levels of sTNFR1 and sTNFR2 in BD patients were different from controls. No difference was detected between the BD group and the control group for levels of TNF-α. TNF-α level was found to have a negative correlation with the delayed recall in RAVLT. High levels of sTNFR1 and sTNFR2 in euthymic patients showed that it may support that proinflammatory process continues in euthymic period. This is the first study which showed increased sTNFR2 levels in euthymic period, which could be interpreted as a compensatory mechanism and again the first which deals with verbal memory.