Paced finger-tapping abnormalities in bipolar disorder indicate timing dysfunction

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.

The nuclear-encoded mitochondrial complex I subunit gene, NDUFV2, has been implicated in the pathogenesis of bipolar disorder (BD) in Japanese by virtue of association of variants in its promoter with BD and decreased NDUFV2 messenger ribonucleic acid (mRNA) levels in B lymphoblasts (BLCL) in BD patients compared to controls. We sought to determine if these same changes occur in non-Japanese populations and, if so, their relationship to altered basal intracellular Ca(2+) ([Ca(2+)](B)) in BLCL from BD patients. Bipolar disorder patients and healthy subjects included 298 subjects of European Caucasian descent. The 5'-nuclease allelic discrimination TaqMan assay was used to detect selected single nucleotide polymorphisms (SNPs) in promoter, introns and 3'UTR regions, spanning the NDUFV2 gene. NDUFV2 mRNA levels and [Ca(2+)](B) in BLCLs were determined. The A allele of the NDUFV2 SNP rs1156044 was significantly associated (Bonferroni-corrected) with BD (p = 0.013) but differed in allele (rs1156044 G allele) from that previously reported as associated with BD. There was a trend for elevated BLCL [Ca(2+)](B) associated with SNP rs977581 in BD patients, but NDUFV2 mRNA levels in BLCLs did not differ between patients and controls, nor represented genotypes. While genetic variants of NDUFV2 may increase risk for BD, the role of its altered expression and the link to intracellular Ca(2+) abnormalities in BD remains equivocal.

of a G72 susceptibility haplotype on fiber tract integrity in young healthy probands. They found clusters of increased fractional anisotropy in homozygous risk haplotype carriers in the right periinsular and inferior parietal region. Both regions have been hypothesized to be involved in the pathophysiology of bipolar disorder and schizophrenia, and alterations in fractional anisotropy may reflect changes in neuropil such as morphology of dendrites. In a functional magnetic resonance imaging (fMRI) study using a working memory task, Stegmayer et al. [4] found reduced functional interactions of the right amygdala with cortical regions supporting verbal working memory in 18 bipolar patients compared with 18 healthy controls. The results point to a disturbed right-hemispheric cognitive–emotional interaction between the amygdala and cortical regions, leading to deficits in working memory. In bipolar disorder, poorer prognosis is related to weight gain and obesity. Lackner et al. [5] investigated body mass index, obesity measures, lipometry, metabolic parameters and monoamines in a large sample of bipolar patients compared with healthy controls. In the patient group, they found increased abdominal fat accumulation and measures of the metabolic syndrome along with correlation with epinephrine levels. The glutamate system has been reported to be involved in the pathophysiology of both bipolar disorder and major depression. Quinolinic acid is produced by activated microglia and is an agonist at the glutamatergic N-methyl-d-aspartate (NMDA) receptor. In a postmortem study, Busse et al. [6] investigated immunohistochemistry of quinolinic acid in hippocampal subregions of 12 patients with depression, among them 6 unipolar and 6 bipolar, and 10 healthy controls. Quinolinic-positive microglia was reduced in unipolar and bipolar patients in the right CA1 subregion. A degradation of quinolinic acid may be involved in the In the new DSM-5 and ICD-11 classification systems, pure mania and mania with mild depression are subsumed under bipolar disorder. In a comprehensive review, Angst and Grobler [1] vote for improved differential diagnoses of unipolar mania. This is clinically relevant since the disorder has a prevalence of approximately 1.8 %, and clinical follow-up studies demonstrated good diagnostic stability. Moreover, mania is associated with a hyperthymic temperament, more psychotic symptoms and higher heritability compared with depression. In contrast, the concept of bipolar disorder has been widely investigated in neurogenetic studies. For example, the dopaminergic system has been suggested to be affected in bipolar disorder, but the impact of the genetic variants of the human dopamine transporter DAT1 (SLC6A3) is inconsistent. Huang et al. [2] investigated the association of 18 polymorphisms of the DAT1 gene with bipolar disorder and explored its influence on specific personality traits such as novelty seeking and harm avoidance. Several polymorphisms had a weak association with bipolar disorder, and the promotor G-A-C-G haplotype was overrepresented in their sample of 492 patients compared with 436 healthy controls. Bipolar II patients had the highest harm avoidance score and a significant association between rs40184 of DAT1 and this personality trait in patients with bipolar disorder. G72 (D-amino acid oxidase activator, DAOA) is a susceptibility gene for bipolar disorder and schizophrenia. In a diffusion tensor imaging (DTI) study, Nickl-Jockschat et al. [3] investigated the influence

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

Introduction:Bipolar disorder (BD) is one of the most encountered disorders in psychiatric clinics. Despite extensive research and advancements in BD treatment, little is known about the disease’s primary etiopathogenesis and relationship with different pathophysiological traits. The present study is aimed to evaluate the pathophysiological role of oxidative and nitrosative stress in BD patients and identify their familial aggregation.Methods:Blood samples from healthy individuals, drug-naive symptomatic BD patients, and their first-degree relatives were obtained, and intracellular reactive oxygen/nitrogen species (ROS/RNS), total nitrites, neuronal nitric oxide synthase (nNOS) mRNA expression, myeloperoxidase (MPO) activity in polymorphonuclear neutrophils (PMNs), and serum cortisol levels were assessed.Results:ROS, MPO activity, total-nitrite content, nNOS expression in PMNs, and serum cortisol concentration were considerably more in BD patients than in healthy volunteers. All these variables showed a substantial correlation with the YMRS score for disease severity and the presence of one or more manic episodes. Additionally, a positive correlation was noted between the MPO activity and serum cortisol levels of BD patients and their first-degree relatives.Conclusions:The results of the present study advance our knowledge about the role of oxidative and nitrosative stress in BD pathophysiology and its familial aggregation. Additionally, the study demonstrates a direct correlation between the disease severity and levels of ROS/RNS, MPO, total nitrite, and nNOS transcripts in PMNs. However, future research with larger and more diverse participant populations is required to understand these pathways for use as potential biomarkers for a deeper understanding of BD pathophysiology and to improve therapeutic strategies.

A study of genetic and environmental contributions to structural brain changes over time in twins concordant and discordant for bipolar disorder

A systematic review of evidence for the role of inflammatory biomarkers in bipolar patients

Bipolar disorder (BD) is a debilitating mood disorder with no specific biological marker. No novel treatment has been developed specifically for BD in the last several decades. Although the pathophysiology of BD remains unclear, there is strong evidence in the literature supporting the role of mitochondrial dysfunction in BD. In this systematic review, we identified and investigated 12 studies that measure lactate, which is a direct marker for mitochondrial dysfunction, in BD patients and healthy controls. Six studies measured lactate levels in the brain through proton echo-planar spectroscopy or magnetic resonance spectroscopy and five of these studies reported significantly elevated lactate levels in patients with BD. Two studies reporting cerebrospinal fluid lactate levels also found significantly elevated lactate in BD compared to healthy controls. Two other studies that reported peripheral lactate levels did not demonstrate significant findings. The meta-analysis, using standardized means and a random-effect model for five studies that measured brain lactate levels, corroborated the findings of the systematic review. Although the meta-analysis had a nearly significant overall effect (Z = 1.97, P = 0.05), high statistical heterogeneity (I2 = 86%) and possible publication bias suggest that the results should be interpreted with caution. To validate lactate abnormalities in BD, further studies should be carried out, including larger sample sizes, not excluding female patients, and using standardized methodologies. Peripheral lactate levels and other bioenergetic markers should be thoroughly studied to better understand the role of mitochondrial dysfunction in BD and to help develop more objective diagnostic tools.

Over the past two decades, brain-imaging studies have examined the mechanisms possibly involved in the pathophysiology of bipolar and unipolar mood disorders. The available findings suggest subtle anatomical changes in sub-regions of the prefrontal cortex, medial temporal lobe and cerebellum, and functional abnormalities in brain circuits inter-connecting these same brain regions and the striatum in patients suffering from bipolar disorder. 1H magnetic resonance spectroscopy (MRS) studies reported decreased N-acetyl aspartate (NAA) levels in the dorsolateral prefrontal cortex, and 31P-MRS studies found abnormalities in membrane phospholipids in frontal and temporal regions in bipolar individuals. Few studies have utilized in-vivo receptor imaging to study bipolar patients. Even though preliminary findings from cross-sectional studies indicate anatomical, neurochemical, and functional brain abnormalities in bipolar patients in key regions involved in mood regulation, the relationship of such abnormalities with illness phase and their clinical relevance needs further investigation. The potential for utilization of brain-imaging tools to elucidate the pathophysiology of bipolar disorder is still largely unrealized, and it is anticipated that important new developments in this area will come about over the next years and beyond.

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.

Bipolar disorder (BD) is one of the most prevalent psychiatric disorders in clinical practice. The etiology of the BD is not thoroughly understood. Endocannabinoid system, which is involved in regulation of emotion, stress, memory, and cognition, may have an important role in the pathophysiology of BD. Mutations on the cannabinoid-1 receptor (CNR1) gene are associated with several psychiatric disorders. The main cannabinoid (CB) receptor is CB1 and its activation inhibits neuronal depolarization. One previous study showed rs1049353 polymorphism of CNR1 gene is associated with major depression but not with BD. In this study, we aimed to investigate the rs6454674, rs806368 and rs1049353 CNR1 gene polymorphisms in Turkish BD patients. A total of 96 patients and 58 healthy controls were included in the current case-control study. Blood samples of study participants were collected into sterile tubes and processed to obtain genomic DNA. Restriction Fragment Length Polymorphism analysis were done by digesting the PCR products with HpyCH4III and BseGI enzymes for the rs6454674 and rs806368 restriction sites, respectively. Single-Strand Conformation Polymorphism (SSCP) analysis was also performed. Among three polymorphisms investigated in this study, only rs6454674 polymorphism was significantly different between BD patients and controls (rs6454674 T/G; p=0.042, rs806368 T/C; p>0.05, rs1049353 A/G; p>0.05). Furthermore, we found that the mean of the yearly manic attacks was statistically higher in patients who have heterozygote (0.91±0.67) rs6454674 T/G polymorphisms compared to those with homozygote (p=0.043) polymorphism. The post-hoc analysis showed that the main differences were between the heterozygotes genotype and non-mutant (GG) homozygotes (0.42±0.31; p=0.037) but not in homozygote mutant genotype (0.74±0.74; p=0.149). When patients were compared with the other clinical parameters, and mutated alleles and genotypes for each polymorphism, we did not find any significant difference. These results suggest that a heterozygote advantage exists for the CNR1 gene rs6454674 polymorphism in manic episode frequency in Turkish BD patients. The results of our study should be confirmed in future studies with larger sample size.

BackgroundOne of the genes suggested to play an important role in the pathophysiology of bipolar disorder (BPD) is PDLIM5, which encodes LIM domain protein. Our main objective was to examine the effect of olanzapine treatment on PDLIM5 mRNA expression in the peripheral blood leukocytes of BPD patients.MethodsWe measured the expression of PDLIM5 mRNA from 16 patients with BPD Type I after 0, 4, and 8 weeks of treatment with olanzapine using quantitative real-time PCR. The Young Mania Rating Scale was used to evaluate the severity of manic symptoms in BPD patients. We also compared PDLIM5 mRNA expression in treatment-naïve BPD patients with that in healthy control subjects.ResultsNo significant difference was found in PDLIM5 mRNA expression between patients before olanzapine treatment and following 4 and 8 weeks of treatment (p>0.05). Although we observed a significant reduction in the severity of manic symptoms in all BPD patients (p<0.05), the effectiveness of the medication did not significantly correlate with the expression of PDLIM5 mRNA (p>0.05). Interestingly, PDLIM5 mRNA expression differed significantly between treatment-naïve BPD patients and healthy control subjects (p=0.002).ConclusionPDLIM5 mRNA expression did not appear to be a reflection of the efficacy of olanzapine in reducing the manic symptoms of BPD. The significant difference in expression of PDLIM5 mRNA in the peripheral blood leukocytes of treatment-naïve BPD patients versus that of healthy control subjects, however, suggests that it may be a good biological marker for BPD.

Pattern of heat shock factor and heat shock protein expression in lymphocytes of bipolar patients: Increased HSP70-glucocorticoid receptor heterocomplex

Recent studies have pointed to neuroinflammation and neurotrophic factors as crucial mediators in the pathophysiology origins of mood disorders. The aim of this review is to assess the potential association between cognitive impairment, brain imaging abnormalities, and inflammatory biomarkers in patients affected by bipolar disorder (BD). Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, we systematically searched PubMed, Google Scholar, Scopus, and Web of Science databases, with no year restriction, up until August 2023, for human studies that examined the relationship between inflammatory markers and cognitive impairment in BD patients. Studies based on neuroimaging, such as MRI, DTI, and fMRI, were also included, along with those examining the moderating role of specific inflammatory markers in the alteration of the brain. 59 human clinical studies satisfied the criteria for consideration. Most of the studies reviewed concur that inflammatory state, measured by peripheral blood levels of CRP and cytokines, constitutes an important contributor to cognitive impairment observed in patients with BD. Robust evidence indicates an association between cognitive impairment and CRP, IL-1RA, IL-6, and TNF-α with its receptors, whereas there is no convincing evidence for the involvement of other neuroinflammatory biomarkers. Neuroimaging studies suggest that brain structural/functional abnormalities seen in BD could also be linked to a neuroinflammatory condition. Current data provide evidence of a link between cognitive impairments observed in BD patients and mechanisms of neuroinflammation. Emerging evidence indicates that systemic inflammation might also play an important role in the deterioration of brain structures critical to cognitive functions in patients with BD. The convergence of findings across these studies strengthens our understanding of the complex neurobiological underpinnings of these disorders. Identification of BD specific inflammatory markers may be of assistance for future early therapeutic interventions.

P.2.f.001 Lithium treatment is not associated with functional or autoimmunitarian thyroideal abnormalities in bipolar disorder I