Bipolar Disorder Phenotype Research Articles

Non-Affective Memory and Visuomotor Performance as Possible Endophenotypes for Bipolar Disorder

Cognitive impairment is a serious problem in the treatment of bipolar disorder (BD) affective functional recovery. Neuropsychological deficits have been considered as possible intermediate phenotypes for BD. We conducted a cross-sectional study on neuropsychological performance of BD patients, their non-bipolar siblings, and healthy controls (HC).

The black sheep of the family- whole-exome sequencing in family of lithium response discordant bipolar monozygotic twins

Twin studies are among the most promising strategies for studying heritable disorders, including bipolar disorder (BD).The aim of the present study was to identify distinguishing genes between monozygotic (MZ) twins with different BD phenotype and compare them to their non-affected siblings.Whole-exome sequencing (WES) can identify rare and structural variants that could detect the polygenetic burden of complex disorders. WES was performed on a family composed of two MZ twins with BD, their unaffected brother and unaffected parents. The twins have a discordant response to lithium and distinct course of illness. Following WES, six genes of particular interest emerged: Neurofibromin type 1 (NF1), Biorientation of chromosomes in cell division 1 (BOD1), Golgi-associated gamma adaptin ear-containing ARF binding protein 3 (GGA3), Disrupted in schizophrenia 1 (DISC1), Neuromedin U receptor 2 (NMUR2), and Huntingtin interacting protein 1-related (HIP1R). Interestingly, many of these influence glutamatergic pathways and thus the findings may have therapeutical implications. These results may provide important insights to unveil genetic underpinnings of BD and the response to lithium

Eye gaze and facial displays of emotion during emotional film clips in remitted patients with bipolar disorder.

Aberrant emotional reactivity is a putative endophenotype for bipolar disorder (BD), but the findings of behavioral studies are often negative due to suboptimal sensitivity of the employed paradigms. This study aimed to investigate whether visual gaze patterns and facial displays of emotion during emotional film clips can reveal subtle behavioral abnormalities in remitted BD patients. Thirty-eight BD patients in full or partial remission and 40 healthy controls viewed 7 emotional film clips. These included happy, sad, and neutral scenarios and scenarios involving winning, risk-taking, and thrill-seeking behavior of relevance to the BD phenotype. Eye gaze and facial expressions were recorded during the film clips, and participants rated their emotional reactions after each clip. BD patients showed a negative bias in both facial displays of emotion and self-rated emotional responses. Specifically, patients exhibited more fearful facial expressions during all film clips. This was accompanied by less positive self-rated emotions during the winning and happy film clips, and more negative emotions during the risk-taking/thrill-related film clips. These findings suggest that BD is associated with trait-related abnormalities in subtle behavioral displays of emotion processing. Future studies comparing patients with BD and unipolar depression are warranted to clarify whether these differences are specific to BD. If so, assessments of visual gaze and facial displays of emotion during emotional film clips may have the potential to be implemented in clinical assessments to aid diagnostic accuracy.

Missing a beat: assessment of circadian rhythm abnormalities in bipolar disorder in the genomic era.

Circadian rhythm abnormalities have been recognized as a central feature of bipolar disorder (BD) but a coherent biological explanation for them remains lacking. Using genetic mutation of 'clock genes', robust animal models of mania and depression have been developed that elucidate key aspects of circadian rhythms and the circadian clock-mood connection. However, translation of this knowledge into humans remains incomplete. In recent years, very large genome-wide association studies (GWAS) have been conducted and the genetic underpinnings of BD are beginning to emerge. However, these genetic studies in BD do not match well with the evidence from animal studies that implicate the circadian clock in mood regulation. Even larger GWAS have been conducted for circadian phenotypes including chronotype, rhythm amplitude, sleep duration, and insomnia. These studies have identified a diverse set of associated genes, including a minority with previously well-characterized functions in the circadian clock. Taken together, the data from recent GWAS of BD and circadian phenotypes indicate that the genetic organization of the circadian clock, both in health and in BD is complex. The findings from GWAS elucidate potentially novel circadian mechanism that may be partly distinct from those identified in animal models. Pleiotropy, epistasis and nongenetic factors may play important roles in regulating circadian rhythms, some of which may underlie circadian rhythm disturbances in BD.

Preliminary analysis of resting state functional connectivity in young adults with subtypes of bipolar disorder.

A precision medicine approach to bipolar disorder (BD) requires greater knowledge of neural mechanisms, especially within the BD phenotype. The present study evaluated differences in resting state functional connectivity (RSFC) between young adults followed longitudinally since childhood with full-threshold type I BD (BD-I)-characterized by distinct manic episodes-or a more sub-syndromal presentation of BD (BD Not Otherwise Specified [BD-NOS]), compared to one another and to healthy controls (HC). Independent Components Analysis (ICA), a multivariate data-driven method, and dual regression were used to explore whether connectivity within resting state networks (RSNs) differentiated the groups, especially for characteristic fronto-limbic alterations in BD. Young adults (ages 18-30) with BD-I (n = 28), BD-NOS (n = 14), and HCs (n = 52) underwent structural and RSFC neuroimaging. ICA derived 30 components from RSFC data; a subset of these components, representing well-characterized RSNs, was used for between-group analyses. Participants with BD-I had significantly greater connectivity strength between the executive control network and right caudate vs. HCs. Participants with BD-NOS had significantly greater connectivity strength between the sensorimotor network and left precentral gyrus vs. HCs, which was significantly related to psychiatric symptoms. Limitations included small BD-NOS sample size and variation in BD mood state and medication status. Results for BD-I participants support prior findings of fronto-limbic alterations characterizing BD. Alterations in the sensorimotor network for adults with BD-NOS aligns with the small but growing body of evidence that sensorimotor network alterations may represent a marker for vulnerability to BD. Further study is required to evaluate specificity.

Is obesity changing the phenotype of bipolar disorder from predominately euphoric toward mixed presentations?

Bipolar DisordersVolume 20, Issue 8 p. 685-686 DEBATE Is obesity changing the phenotype of bipolar disorder from predominately euphoric toward mixed presentations? Roger S. McIntyre, Corresponding Author Roger S. McIntyre roger.mcintyre@uhn.ca orcid.org/0000-0003-4733-2523 University of Toronto, Toronto, Canada Brain and Cognition Discovery Foundation (BCDF), Toronto, Canada Depression and Bipolar Support Alliance (DBSA), Chicago, Illinois Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Canada Guangzhou Medical University, Guangzhou, China College of Medicine, Korea University, Seoul, Republic of Korea Correspondence Roger S. McIntyre, University Health Network, Toronto, ON, Canada. Email: roger.mcintyre@uhn.caSearch for more papers by this author Roger S. McIntyre, Corresponding Author Roger S. McIntyre roger.mcintyre@uhn.ca orcid.org/0000-0003-4733-2523 University of Toronto, Toronto, Canada Brain and Cognition Discovery Foundation (BCDF), Toronto, Canada Depression and Bipolar Support Alliance (DBSA), Chicago, Illinois Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Canada Guangzhou Medical University, Guangzhou, China College of Medicine, Korea University, Seoul, Republic of Korea Correspondence Roger S. McIntyre, University Health Network, Toronto, ON, Canada. Email: roger.mcintyre@uhn.caSearch for more papers by this author First published: 09 November 2018 https://doi.org/10.1111/bdi.12717Citations: 4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume20, Issue8December 2018Pages 685-686 RelatedInformation

Genetic association study of CSNK1E gene in bipolar disorder and circadian characteristics

Background: A circadian rhythm disturbance is one of the essential components of the phenotype of bipolar disorder. It has been reported that casein kinase 1 epsilon (CSNK1E), a member of the clock gene family, is associated with psychiatric phenotypes.Objectives: We performed a genetic association study to determine the genetic role of CSNK1E in bipolar disorder and circadian rhythm disturbances in the Korean population.Methods: The present study included 215 patients with bipolar disorder and 773 controls. Circadian characteristics were measured by the Korean version of the Composite Scale of Morningness (CS). Single-nucleotide polymorphisms (SNPs) of CSNK1E, rs1534891 and rs2075984, were genotyped. Chi-square analyses were performed to evaluate associations involving alleles and genotypes. Haplotype analysis was also performed, and the permutation p value was calculated. We also tested further associations involving these SNPs and scores on the CS.Results: We found a positive association between SNP rs2075984 and bipolar disorder in both the allelic (p = .003) and genotypic (p = .006) distributions. No allelic or genotypic association between SNP rs1534891 and bipolar disorder was observed. A significant association of haplotype with bipolar disorder was found (p = .033). However, no association between the CS and the genotype of either SNP was found in the total sample.Conclusion: CSNK1E SNP rs2075984 seemed to play a significant role in the development of bipolar disorder in this Korean sample. This association does not seem to relate to the phase preference measured by the CS. Further studies on CSNK1E with larger samples and more SNPs are necessary.

Mapping the Heterogeneous Phenotype of Schizophrenia and Bipolar Disorder Using Normative Models

Schizophrenia and bipolar disorder are severe and complex brain disorders characterized by substantial clinical and biological heterogeneity. However, case-control studies often ignore such heterogeneity through their focus on the average patient, which may be the core reason for a lack of robust biomarkers indicative of an individual's treatment response and outcome. To investigate the degree to which case-control analyses disguise interindividual differences in brain structure among patients with schizophrenia and bipolar disorder and to map the brain alterations linked to these disorders at the level of individual patients. This study used cross-sectional, T1-weighted magnetic resonance imaging data from participants recruited for the Thematically Organized Psychosis study from October 27, 2004, to October 17, 2012. Data were reanalyzed in 2017 and 2018. Patients were recruited from inpatient and outpatient clinics in the Oslo area of Norway, and healthy individuals from the same catchment area were drawn from the national population registry. Interindividual differences in brain structure among patients with schizophrenia and bipolar disorder. Voxel-based morphometry maps were computed, which were used for normative modeling to map the range of interindividual differences in brain structure. This study included 218 patients with schizophrenia spectrum disorders (mean [SD] age, 30 [9.3] years; 126 [57.8%] male), of whom 163 had schizophrenia (mean [SD] age, 31 [8.7] years; 105 [64.4%] male) and 190 had bipolar disorder (mean [SD] age, 34 [11.3] years; 79 [41.6%] male), and 256 healthy individuals (mean [SD] age, 34 [9.5] years; 140 [54.7%] male). At the level of the individual, deviations from the normative model were frequent in both disorders but highly heterogeneous. Overlap of more than 2% among patients was observed in only a few loci, primarily in frontal, temporal, and cerebellar regions. The proportion of alterations was associated with diagnosis and cognitive and clinical characteristics within clinical groups. Patients with schizophrenia, on average, had significantly reduced gray matter in frontal regions, cerebellum, and temporal cortex. In patients with bipolar disorder, mean deviations were primarily present in cerebellar regions. This study found that group-level differences disguised biological heterogeneity and interindividual differences among patients with the same diagnosis. This finding suggests that the idea of the average patient is a noninformative construct in psychiatry that falls apart when mapping abnormalities at the level of the individual patient. This study presents a workable route toward precision medicine in psychiatry.

Distinct patterns of blood oxygenation in the prefrontal cortex in clinical phenotypes of schizophrenia and bipolar disorder

BackgroundSchizophrenia (SZ) and bipolar disorder (BD) are characterized by different clinical symptoms, and have previously been considered as categorically separate. However, several lines of evidence controversially suggest that these two disorders may run on a continuum. While it is therefore important to evaluate the subtle differences between SZ and BD, few studies have investigated the difference of brain functioning between the two by focusing on the common symptoms of cognitive functioning and impulsivity, rather than positive/negative and mood symptoms. Recent developments in near-infrared spectroscopy (NIRS) technology have enabled noninvasive assessment of brain function in people with psychiatric disorders. MethodsNear-infrared spectroscopy (NIRS) using 24-channels was conducted during the verbal fluency task (VFT) and Stroop color-word task (SCWT) in 38 patients diagnosed with SZ, 34 patients with BD, and 26 age- and sex-matched healthy controls. ResultsOxyhemoglobin changes in the prefrontal cortex (PFC) were significantly lower particularly in the SZ compared to control group during the VFT. On the other hand, these were significantly lower particularly in the BD and SZ group to control group during the SCWT. Regression analysis showed that hemodynamic changes were significantly correlated with verbal memory and impulsivity in both disorders. ConclusionThese findings suggest that different hemodynamic responses in the prefrontal cortex might reflect cognitive functioning and impulsivity, providing a greater insight into SZ and BD pathophysiology.

Brain Structure and Function in Women with Comorbid Bipolar and Premenstrual Dysphoric Disorder.

Hormonal fluctuations associated with female reproductive life events may precipitate or worsen affective episodes in women with bipolar disorder (BD). Previous studies have shown that women with BD report higher rates of premenstrual dysphoric disorder (PMDD) than controls. Further, bipolar women who report premenstrual worsening of mood display a worse course of their bipolar illness. Despite this, the neural correlates of comorbid BD and PMDD have not been investigated. Eighty-five [CTRL, n = 25; PMDD, n = 20; BD, n = 21; BD with comorbid PMDD (BDPMDD), n = 19], regularly cycling women, not on hormonal contraception, underwent two MRI scans: during their mid-follicular and late luteal menstrual phases. We investigated resting-state functional connectivity (Rs-FC), cortical thickness, and subcortical volumes of brain regions associated with the pathophysiology of BD and PMDD between groups, in the mid-follicular and late luteal phases of the menstrual cycle. All BD subjects were euthymic for at least 2 months prior to study entry. Women in the BDPMDD group displayed greater disruption in biological rhythms and more subthreshold depressive and anxious symptoms through the menstrual cycle compared to other groups. Rs-FC was increased between the L-hippocampus and R-frontal cortex and decreased between the R-hippocampus and R-premotor cortex in BDPMDD vs. BD (FDR-corrected, p < 0.05). Cortical thickness analysis revealed decreased cortical thickness of the L-pericalcarine, L-superior parietal, R-middle temporal, R-rostral middle frontal, and L-superior frontal, as well as increased cortical thickness of the L-superior temporal gyri in BDPMDD compared to BD. We also found increased left-caudate volume in BDPMDD vs. BD (pCORR < 0.05). Women with BD and comorbid PMDD display a distinct clinical and neurobiological phenotype of BD, which suggests differential sensitivity to endogenous hormones.

P.1.a.029 - Genetics of specific clinical phenotypes of bipolar disorder: a focus on mania with psychosis

P.1.a.029 - Genetics of specific clinical phenotypes of bipolar disorder: a focus on mania with psychosis

Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype

ObjectivesFear of Harm (FOH) is a pediatric onset phenotype of bipolar disorder (BD) characterized by BD plus treatment resistance, separation anxiety, aggressive obsessions, parasomnias, and thermal dysregulation. Intranasal ketamine (InK) in 12 youths with BD-FOH produced marked improvement during a two-week trial. Here we report on the open effectiveness and safety of InK in maintenance treatment of BD-FOH from the private practice of one author. MethodsAs part of a chart review, patients 18 years or older and parents of younger children responded to a clinical effectiveness and safety survey. Effectiveness was assessed from analysis of responses to 49 questions on symptomatology plus qualitative content analyses of written reports and chart review. Adverse events (AEs) were analyzed by frequency, duration and severity. Peak InK doses ranged from 20 to 360mg per administration. ResultsSurveys were completed on 45 patients treated with InK for 3 months to 6.5 years. Almost all patients were “much” to “very much” improved clinically and in ratings of social function and academic performance. Significant reductions were reported in all symptom categories. There were 13 reports of persistent AEs, none of which resulted in discontinuation. Acute emergence reactions were sporadically observed in up to 75%, but were mild and of brief duration. LimitationsRetrospective review from a single practice without placebo control with potential for response and recall bias. ConclusionsInK every 3–4 days at sub-anesthetic doses appeared to be a beneficial and well-tolerated treatment. Use of InK may be considered as a tertiary alternative in treatment refractory cases. Randomized control trials are warranted.

Effects of risk for bipolar disorder on brain function: A twin and family study

Bipolar disorder (BPD) is associated with altered regional brain function during the performance of cognitive tasks. The relative contribution of genetic and environmental risk factors for BPD to these changes has not yet been quantified. We sought to address this issue in a functional neuroimaging study of people who varied in their risk for BPD. Functional magnetic resonance imaging was used to study 124 subjects (29 twin and 9 sibling pairs with at least one member with BPD, and 24 healthy twin pairs) performing a working memory task. We assessed the influence of risk for BPD on regional brain function during the task in a two stage process. Firstly, we identified areas where there were group differences in activation. Secondly, we estimated the heritability and phenotypic correlation of activation and BPD using genetic modeling. BPD was associated with increased activation in the anterior cingulate, orbitofrontal, medial prefrontal, and left precentral cortices, and in the precuneus. Within these regions, activation in the orbitofrontal cortex rendered the most significant heritability estimate (h2=0.40), and was significantly correlated with BPD phenotype (rph=0.29). A moderate proportion of the genetic influences (rg=0.69) acting on both BPD and on the degree of orbitofrontal activation were shared. These findings suggest that genetic factors that confer vulnerability to BPD alter brain function in BPD.

DNA hypomethylation of Synapsin II CpG islands associates with increased gene expression in bipolar disorder and major depression.

BackgroundThe Synapsins (SYN1, SYN2, and SYN3) are important players in the adult brain, given their involvement in synaptic transmission and plasticity, as well as in the developing brain through roles in axon outgrowth and synaptogenesis. We and others previously reported gene expression dysregulation, both as increases and decreases, of Synapsins in mood disorders, but little is known about the regulatory mechanisms leading to these differences. Thus, we proposed to study DNA methylation at theses genes’ promoter regions, under the assumption that altered epigenetic marks at key regulatory sites would be the cause of gene expression changes and thus part of the mood disorder etiology.MethodsWe performed CpG methylation mapping focusing on the three genes’ predicted CpG islands using the Sequenom EpiTYPER platform. DNA extracted from post-mortem brain tissue (BA10) from individuals who had lived with bipolar disorder (BD), major depressive disorder (MDD), as well as psychiatrically healthy individuals was used. Differences in methylation across all CpGs within a CpG island and between the three diagnostic groups were assessed by 2-way mixed model analyses of variance.ResultsWe found no significant results for SYN1 or SYN3, but there was a significant group difference in SYN2 methylation, as well as an overall pattern of hypomethylation across the CpG island. Furthermore, we found a significant inverse correlation of DNA methylation with SYN2a mRNA expression.ConclusionsThese findings contribute to previous work showing dysregulation of Synapsins, particularly SYN2, in mood disorders and improve our understanding of the regulatory mechanisms that precipitate these changes likely leading to the BD or MDD phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-016-0989-0) contains supplementary material, which is available to authorized users.

A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.

l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of ‘brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes.

High-resolution chromosome ideogram representation of recognized genes for bipolar disorder

Bipolar disorder (BPD) is genetically heterogeneous with a growing list of BPD associated genes reported in recent years resulting from increased genetic testing using advanced genetic technology, expanded genomic databases, and better awareness of the disorder. We compiled a master list of recognized susceptibility and genes associated with BPD identified from peer-reviewed medical literature sources using PubMed and by searching online databases, such as OMIM. Searched keywords were related to bipolar disorder and genetics. Our compiled list consisted of 290 genes with gene names arranged in alphabetical order in tabular form with source documents and their chromosome location and gene symbols plotted on high-resolution human chromosome ideograms. The identified genes impacted a broad range of biological pathways and processes including cellular signaling pathways particularly cAMP and calcium (e.g., CACNA1C, CAMK2A, CAMK2D, ADCY1, ADCY2); glutamatergic (e.g., GRIK1, GRM3, GRM7), dopaminergic (e.g., DRD2, DRD4, COMT, MAOA) and serotonergic (e.g., HTR1A, HTR2A, HTR3B) neurotransmission; molecular transporters (e.g., SLC39A3, SLC6A3, SLC8A1); and neuronal growth (e.g., BDNF, IGFBP1, NRG1, NRG3). The increasing prevalence of BPD calls for better understanding of the genetic etiology of this disorder and associations between the observed BPD phenotype and genes. Visual representation of genes for bipolar disorder becomes a tool enabling clinical and laboratory geneticists, genetic counselors, and other health care providers and researchers easy access to the location and distribution of currently recognized BPD associated genes. Our study may also help inform diagnosis and advance treatment developments for those affected with this disorder and improve genetic counseling for families.

Gender by onset age interaction may characterize distinct phenotypic subgroups in bipolar patients

ObjectiveAlthough bipolar disorder (BD) is a common recurrent condition with highly heterogeneous illness course, data are limited regarding clinical implications of interactions between gender and onset age. We assessed relationships between onset age and demographic/illness characteristics among BD patients stratified by gender. MethodsDemographic and unfavorable illness characteristics, descriptive traits, and clinical correlates were compared in 502 patients from Stanford University BD Clinic patients enrolled in the Systematic Treatment Enhancement Program for BD between 2000 and 2011, stratified by gender, across pre-, peri-, and post-pubertal (<12, 13–16, and >17 years, respectively) onset-age subgroups. ResultsAmong 502 BD patients, 58.2% were female, of whom 21.9% had pre-pubertal, 30.7% peri-pubertal, and 47.4% post-pubertal onset. Between genders, although demographics, descriptive characteristics, and most clinical correlates were statistically similar, there were distinctive onset-age related patterns of unfavorable illness characteristics. Among females, rates of 6/8 primary unfavorable illness characteristics were significantly higher in pre-pubertal and peri-pubertal compared to post-pubertal onset patients. However, among males, rates of only 3/8 unfavorable illness characteristics were significantly higher in only pre-pubertal versus post-pubertal onset patients, and none between peri-pubertal versus post-pubertal onset patients. LimitationsCaucasian, insured, suburban, American specialty clinic-referred sample limits generalizability, onset age based on retrospective recall. DiscussionWe describe different phenotypic presentations across age at illness onset groups according to gender. Among females and males, peri-pubertal and post-pubertal onset age groups were more different and more similar, respectively. Further investigation is warranted to assess implications of gender-by-onset-age interactions to more accurately delineate distinctive BD phenotypes.

Neuropsychological and social cognitive function in young people at genetic risk of bipolar disorder.

Impairments in key neuropsychological domains (e.g. working memory, attention) and social cognitive deficits have been implicated as intermediate (endo) phenotypes for bipolar disorder (BD), and should therefore be evident in unaffected relatives. Neurocognitive and social cognitive ability was examined in 99 young people (age range 16-30 years) with a biological parent or sibling diagnosed with the disorder [thus deemed to be at risk (AR) of developing BD], compared with 78 healthy control (HC) subjects, and 52 people with a confirmed diagnosis of BD. Only verbal intelligence and affective response inhibition were significantly impaired in AR relative to HC participants; the BD participants showed significant deficits in attention tasks compared with HCs. Neither AR nor BD patients showed impairments in general intellectual ability, working memory, visuospatial or language ability, relative to HC participants. Analysis of BD-I and BD-II cases separately revealed deficits in attention and immediate memory in BD-I patients (only), relative to HCs. Only the BD (but not AR) participants showed impaired emotion recognition, relative to HCs. Selective cognitive deficits in the capacity to inhibit negative affective information, and general verbal ability may be intermediate markers of risk for BD; however, the extent and severity of impairment in this sample was less pronounced than has been reported in previous studies of older family members and BD cases. These findings highlight distinctions in the cognitive profiles of AR and BD participants, and provide limited support for progressive cognitive decline in association with illness development in BD.

Genetics of emotional reactivity in bipolar disorders

BackgroundEmotional reactivity has been proposed as a relevant intermediate phenotype of bipolar disorder (BD). Our goal was to identify genetic factors underlying emotional reactivity in a sample of bipolar patients. MethodsAffect intensity (a proxy measure of emotional reactivity) was measured in a sample of 281 euthymic patients meeting DSM-IV criteria for BD. We use a validated dimensional tool, the 40-item self-report Affect Intensity Measure scale developed by Larsen and Diener. Patients with BD were genotyped for 475. 740 SNPs (using Illumina HumanHap550 Beadchips or HumanHap610 Quad chip). Association was investigated with a general mixed regression model of the continuous trait against genotypes, including gender as covariate. ResultsFour regions (1p31.3, 3q13.11, 11p15.1 and 11q14.4) with a p-value lower or equal to 5×10−6 were identified. In these regions, the joint effect of the four variants accounted for 24.5% of the variance of AIM score. Epistasis analysis did not detect interaction between these variants. In the 11p15.1 region, the rs10766743 located in the intron of the NELL1 gene remained significant after correction for multiple testing (p=2×10−7). ConclusionsThese findings illustrate that focusing on quantitative intermediate phenotypes can facilitate the identification of genetic susceptibility variants in BD.

Childhood abuse, family history and stressors in older patients with bipolar disorder in relation to age at onset

ObjectivesThe aim of this study is to explore the family history of psychiatric disorders, childhood abuse, and stressors in older patients with Bipolar Disorder (BD) and the association of these variables with the age at onset of BD. MethodsThe Questionnaire for Bipolar Disorder (QBP) and the Mini International Neuropsychiatric Interview (MINI-Plus) were obtained from 78 patients aged 60 and over to determine diagnosis, age at onset of the first affective episode, childhood abuse, family history of psychiatric disorders and past and recent stressful life events. ResultsIncreased family history of psychiatric disorders was the only factor associated with an earlier age at onset of BD. Less family history of psychiatric disorders and more negative stressors were significantly associated with a later age at onset of the first (hypo)manic episode. LimitationsAge at onset, history of childhood abuse, and past stressful life events were assessed retrospectively. Family members of BD patients were not interviewed. ConclusionsOur findings suggest that age at onset can define distinct BD phenotypes. More specifically there was a stronger heredity of BD and other psychiatric disorders in patients with an early age of onset of BD. Negative stressors may play a specific role in patients with a late age at onset of a first (hypo)manic episode.