A co-adaptive brain-computer interface for end users with severe motor impairment.
PLoS One. 2014;9(7):e101168
Authors: Faller J, Scherer R, Costa U, Opisso E, Medina J, Müller-Putz GR
Co-adaptive training paradigms for event-related desynchronization (ERD) based brain-computer interfaces (BCI) have proven effective for healthy users. As of yet, it is not clear whether co-adaptive training paradigms can also benefit users with severe motor impairment. The primary goal of our paper was to evaluate a novel cue-guided, co-adaptive BCI training paradigm with severely impaired volunteers. The co-adaptive BCI supports a non-control state, which is an important step toward intuitive, self-paced control. A secondary aim was to have the same participants operate a specifically designed self-paced BCI training paradigm based on the auto-calibrated classifier. The co-adaptive BCI analyzed the electroencephalogram from three bipolar derivations (C3, Cz, and C4) online, while the 22 end users alternately performed right hand movement imagery (MI), left hand MI and relax with eyes open (non-control state). After less than five minutes, the BCI auto-calibrated and proceeded to provide visual feedback for the MI task that could be classified better against the non-control state. The BCI continued to regularly recalibrate. In every calibration step, the system performed trial-based outlier rejection and trained a linear discriminant analysis classifier based on one auto-selected logarithmic band-power feature. In 24 minutes of training, the co-adaptive BCI worked significantly (p?=?0.01) better than chance for 18 of 22 end users. The self-paced BCI training paradigm worked significantly (p?=?0.01) better than chance in 11 of 20 end users. The presented co-adaptive BCI complements existing approaches in that it supports a non-control state, requires very little setup time, requires no BCI expert and works online based on only two electrodes. The preliminary results from the self-paced BCI paradigm compare favorably to previous studies and the collected data will allow to further improve self-paced BCI systems for disabled users.
PMID: 25014055 [PubMed - indexed for MEDLINE]
A systematic review and meta-analysis of premature mortality in bipolar affective disorder.
Acta Psychiatr Scand. 2015 Mar 3;
Authors: Hayes JF, Miles J, Walters K, King M, Osborn DP
OBJECTIVE: To review and complete meta-analysis of studies estimating standardised mortality ratios (SMRs) in bipolar affective disorder (BPAD) for all-cause and cause-specific mortalities.
METHOD: Cause-specific mortality was grouped into natural and unnatural causes. These subgroups were further divided into circulatory, respiratory, neoplastic and infectious causes, and suicide and other violent deaths. Summary SMRs were calculated using random-effects meta-analysis. Heterogeneity was examined via subgroup analysis and meta-regression.
RESULTS: Systematic searching found 30 studies meeting inclusion criteria. Summary SMR for all-cause mortality = 2.05 (95% CI 1.89-2.23), but heterogeneity was high (I(2) = 96.2%). This heterogeneity could not be accounted for by date of publication, cohort size, mid-decade of data collection, population type or geographical region. Unnatural death summary SMR = 7.42 (95% CI 6.43-8.55) and natural death = 1.64 (95% CI 1.47-1.83). Specifically, suicide SMR = 14.44 (95% CI 12.43-16.78), other violent death SMR = 3.68 (95% CI 2.77-4.90), deaths from circulatory disease = 1.73 (95% CI 1.54-1.94), respiratory disease = 2.92 (95% CI 2.00-4.23), infection = 2.25 (95% CI 1.70-3.00) and neoplasm = 1.14 (95% CI 1.10-1.21).
CONCLUSION: Despite considerable heterogeneity, all summary SMR estimates and a large majority of individual studies showed elevated mortality in BPAD compared to the general population. This was true for all causes of mortality studied.
PMID: 25735195 [PubMed - as supplied by publisher]
Late-life homicide-suicide: a national case series in New Zealand.
Psychogeriatrics. 2015 Mar 3;
Authors: Cheung G, Hatters Friedman S, Sundram F
Homicide-suicide is a rare event, but it has a significant impact on the family and community of the perpetrator and victim(s). The phenomenon of late-life homicide-suicide has not been previously studied in New Zealand, and there is only limited data in the international literature. The aim of this study is to systematically review coroners' records of late-life homicide-suicides in New Zealand. After ethics approval was granted, the Coronial Services of New Zealand was approached to provide records of all closed cases with a suicide verdict (age 65+) over a five-year period (July 2007-December 2012). Of the 225 suicides, 4 cases of homicide-suicide were identified (an estimated incidence of 0.12 per 100?000 per persons year). All four perpetrators were men; three had been farmers. Their ages ranged from 65 to 82. One case occurred in the context of an underlying psychiatric illness (psychotic depression in bipolar disorder). Firearms were used in three cases. Two cases were categorized as spousal/consortial subtype, one case as filicide-suicide, and one case as siblicide-suicide. The prospect of major social upheaval in the form of losing their homes was present in all four cases. The findings of this case series were consistent with the limited existing literature on homicide-suicide. Age-related biopsychosocial issues were highlighted in this case series of late-life homicide-suicide. Additionally, evaluating firearm licences in high-risk groups may represent a prevention strategy.
PMID: 25735608 [PubMed - as supplied by publisher]
Prevalence of psychiatric co-morbidity in treatment-seeking problem gamblers: A systematic review and meta-analysis.
Aust N Z J Psychiatry. 2015 Mar 3;
Authors: Dowling NA, Cowlishaw S, Jackson AC, Merkouris SS, Francis KL, Christensen DR
OBJECTIVE: The aim of this paper was to systematically review and meta-analyse the prevalence of co-morbid psychiatric disorders (DSM-IV Axis I disorders) among treatment-seeking problem gamblers.
METHODS: A systematic search was conducted for peer-reviewed studies that provided prevalence estimates of Axis I psychiatric disorders in individuals seeking psychological or pharmacological treatment for problem gambling (including pathological gambling). Meta-analytic techniques were performed to estimate the weighted mean effect size and heterogeneity across studies.
RESULTS: Results from 36 studies identified high rates of co-morbid current (74.8%, 95% CI 36.5-93.9) and lifetime (75.5%, 95% CI 46.5-91.8) Axis I disorders. There were high rates of current mood disorders (23.1%, 95% CI 14.9-34.0), alcohol use disorders (21.2%, 95% CI 15.6-28.1), anxiety disorders (17.6%, 95% CI 10.8-27.3) and substance (non-alcohol) use disorders (7.0%, 95% CI 1.7-24.9). Specifically, the highest mean prevalence of current psychiatric disorders was for nicotine dependence (56.4%, 95% CI 35.7-75.2) and major depressive disorder (29.9%, 95% CI 20.5-41.3), with smaller estimates for alcohol abuse (18.2%, 95% CI 13.4-24.2), alcohol dependence (15.2%, 95% CI 10.2-22.0), social phobia (14.9%, 95% CI 2.0-59.8), generalised anxiety disorder (14.4%, 95% CI 3.9-40.8), panic disorder (13.7%, 95% CI 6.7-26.0), post-traumatic stress disorder (12.3%, 95% CI 3.4-35.7), cannabis use disorder (11.5%, 95% CI 4.8-25.0), attention-deficit hyperactivity disorder (9.3%, 95% CI 4.1-19.6), adjustment disorder (9.2%, 95% CI 4.8-17.2), bipolar disorder (8.8%, 95% CI 4.4-17.1) and obsessive-compulsive disorder (8.2%, 95% CI 3.4-18.6). There were no consistent patterns according to gambling problem severity, type of treatment facility and study jurisdiction. Although these estimates were robust to the inclusion of studies with non-representative sampling biases, they should be interpreted with caution as they were highly variable across studies.
CONCLUSIONS: The findings highlight the need for gambling treatment services to undertake routine screening and assessment of psychiatric co-morbidity and provide treatment approaches that adequately manage these co-morbid disorders. Further research is required to explore the reasons for the variability observed in the prevalence estimates.
PMID: 25735959 [PubMed - as supplied by publisher]
Effects of 10 to 30 years of lithium treatment on kidney function.
J Psychopharmacol. 2015 Mar 3;
Authors: Aiff H, Attman PO, Aurell M, Bendz H, Ramsauer B, Schön S, Svedlund J
Long-term lithium treatment is associated with end-stage renal disease, but there is little evidence of a clinically significant reduction in renal function in most patients. We previously found that 1.5% of people who took lithium from the 1960s and 1970s developed end-stage renal disease; however, none of the patients who started after 1980 had end-stage renal disease. Here we aimed to study the prevalence and extent of kidney damage during the course of long-term lithium treatment since 1980. We retrieved serum lithium and creatinine levels from 4879 patients examined between 1 January 1981 and 31 December 2010. Only patients who started their lithium treatment during the study period and had at least 10 years of cumulative treatment were included. The study group comprised 630 adult patients (402 women and 228 men) with normal creatinine levels at the start of lithium treatment. There was a yearly increase in median serum creatinine levels already from the first year of treatment. About one-third of the patients who had taken lithium for 10-29 years had evidence of chronic renal failure but only 5% were in the severe or very severe category. The results indicate that a substantial proportion of adult patients who are treated with lithium for more than a decade develop signs of renal functional impairment, also when treated according to modern therapeutic principles. Our results emphasise that lithium treatment requires continuous monitoring of kidney function.
PMID: 25735990 [PubMed - as supplied by publisher]
Recovery, as Experienced by Women with Borderline Personality Disorder.
Psychiatr Q. 2015 Mar 4;
Authors: Larivière N, Couture É, Blackburn C, Carbonneau M, Lacombe C, Schinck SA, David P, St-Cyr-Tribble D
Studies examining recovery through the service users' perspectives have mainly included persons with schizophrenia or bipolar disorder. Giving voice to those with borderline personality disorder (BPD) would enrich our understanding of recovery, as their specific experiences may bring new dimensions, obstacles and facilitators. The objective of this study was to qualitatively capture the experience of recovery in women with BPD. Participants were women between 18 and 65 years old who had a diagnosis of BPD and completed at least 2 years in a program for persons with BPD. During the first meeting, they produced a picture collage, followed by an interview on their experience of recovery. The second meeting was a phone interview to discuss new thoughts. In addition, their medical records were reviewed. A thematic analysis of the interviews was conducted and organized with the Person-Environment-Occupation model. Although recovery was not the best term to name their experience, they all talked about a process towards stability and wellbeing (n = 12). Dimensions of recovery included, for example, letting go of the past (person), being involved in meaningful activities (occupation) and having healthy relationships (environment). Facilitators included social support and participation in a specialized therapy program. The main obstacle was unstable family relationships. The findings from this study showed similar dimensions to previous recovery studies, new perspectives on certain dimensions, as well as new ones. They also reinforced the importance to incorporate intervention outcomes that target the person with BPD, their social environment and meaningful occupations.
PMID: 25736797 [PubMed - as supplied by publisher]
Risk of Subsequent Dementia Among Patients With Bipolar Disorder or Major Depression: A Nationwide Longitudinal Study in Taiwan.
J Am Med Dir Assoc. 2015 Feb 27;
Authors: Chen MH, Li CT, Tsai CF, Lin WC, Chang WH, Chen TJ, Pan TL, Su TP, Bai YM
BACKGROUND: Both major depression and bipolar disorder are associated with an increased risk of developing dementia. However, the differential risk of dementia between major depression and bipolar disorder is rarely investigated.
METHODS: Using the Taiwan National Health Insurance Research Database, a total of 2291 patients aged ?55 years (major depression: 1946 and bipolar disorder: 345) and 2291 age-and sex-matched controls were enrolled between 1998 and 2008, and followed to the end of 2011. Participants who developed dementia during the follow-up were identified.
RESULTS: Both patients with bipolar disorder [hazard ratio (HR) 5.58, 95% confidence interval (CI) 4.26-7.32] and those with major depression (HR 3.02, 95% CI 2.46-3.70) had an increased risk of developing dementia in later life, after adjusting for demographic data and medical comorbidities. The sensitivity tests after excluding the 1-year (bipolar disorder: HR 4.73, 95% CI 3.50-6.35; major depression: HR 2.62, 95% CI 2.11-3.25) and 3-year (HR 3.92, 95% CI 2.78-5.54; HR 2.21, 95% CI 1.73-2.83, respectively) follow-up duration also revealed consistent findings. Furthermore, patients with bipolar disorder were associated with an 87% increased risk (HR 1.87, 95% CI 1.48-2.37) of subsequent dementia compared with patients with major depression.
CONCLUSIONS: Midlife individuals with bipolar disorder or major depression were associated with an elevated risk of developing dementia in later life. Further studies may be required to clarify the underlying mechanisms among major depression, bipolar disorder, and dementia, and to investigate whether prompt intervention may decrease this risk.
PMID: 25737262 [PubMed - as supplied by publisher]
Circuit- and Diagnosis-Specific DNA Methylation Changes at ?-Aminobutyric Acid-Related Genes in Postmortem Human Hippocampus in Schizophrenia and Bipolar Disorder.
JAMA Psychiatry. 2015 Mar 4;
Authors: Ruzicka WB, Subburaju S, Benes FM
Importance: Dysfunction related to ?-aminobutyric acid (GABA)-ergic neurotransmission in the pathophysiology of major psychosis has been well established by the work of multiple groups across several decades, including the widely replicated downregulation of GAD1. Prior gene expression and network analyses within the human hippocampus implicate a broader network of genes, termed the GAD1 regulatory network, in regulation of GAD1 expression. Several genes within this GAD1 regulatory network show diagnosis- and sector-specific expression changes within the circuitry of the hippocampus, influencing abnormal GAD1 expression in schizophrenia and bipolar disorder.
Objective: To investigate the hypothesis that aberrant DNA methylation contributes to circuit- and diagnosis-specific abnormal expression of GAD1 regulatory network genes in psychotic illness.
Design, Setting, and Participants: This epigenetic association study targeting GAD1 regulatory network genes was conducted between July 1, 2012, and June 30, 2014. Postmortem human hippocampus tissue samples were obtained from 8 patients with schizophrenia, 8 patients with bipolar disorder, and 8 healthy control participants matched for age, sex, postmortem interval, and other potential confounds from the Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, Massachusetts. We extracted DNA from laser-microdissected stratum oriens tissue of cornu ammonis 2/3 (CA2/3) and CA1 postmortem human hippocampus, bisulfite modified it, and assessed it with the Infinium HumanMethylation450 BeadChip (Illumina, Inc). The subset of CpG loci associated with GAD1 regulatory network genes was analyzed in R version 3.1.0 software (R Foundation) using the minfi package. Findings were validated using bisulfite pyrosequencing.
Main Outcomes and Measures: Methylation levels at 1308 GAD1 regulatory network-associated CpG loci were assessed both as individual sites to identify differentially methylated positions and by sharing information among colocalized probes to identify differentially methylated regions.
Results: A total of 146 differentially methylated positions with a false detection rate lower than 0.05 were identified across all 6 groups (2 circuit locations in each of 3 diagnostic categories), and 54 differentially methylated regions with P?<?.01 were identified in single-group comparisons. Methylation changes were enriched in MSX1, CCND2, and DAXX at specific loci within the hippocampus of patients with schizophrenia and bipolar disorder.
Conclusions and Relevance: This work demonstrates diagnosis- and circuit-specific DNA methylation changes at a subset of GAD1 regulatory network genes in the human hippocampus in schizophrenia and bipolar disorder. These genes participate in chromatin regulation and cell cycle control, supporting the concept that the established GABAergic dysfunction in these disorders is related to disruption of GABAergic interneuron physiology at specific circuit locations within the human hippocampus.
PMID: 25738424 [PubMed - as supplied by publisher]
The Relationship between Bipolar Disorder and Cannabis Use in Daily Life: An Experience Sampling Study.
PLoS One. 2015;10(3):e0118916
Authors: Tyler E, Jones S, Black N, Carter LA, Barrowclough C
OBJECTIVES: Although cannabis use is common in bipolar disorder and may contribute to worse clinical outcomes, little is understood about the relationship between this drug and bipolar disorder over the course of daily life. The aim of study was to examine the effect of cannabis on affect and bipolar symptoms in a group of individuals with bipolar disorder.
METHODS: Twenty-four participants with bipolar disorder type I or type II completed diaries for 6 days using Experience Sampling Methodology to investigate the temporal associations between cannabis, affect and bipolar disorder symptoms.
RESULTS: The results indicated that higher levels of positive affect increase the odds of using cannabis (OR:1.25 ,CI:1.06-1.47, P=0.008). However, neither negative affect, manic nor depressive symptoms predicted the use of cannabis. Cannabis use was associated with subsequent increases in positive affect (?=0.35, CI:0.20-0.51, P=0.000), manic symptoms (?=0.20,CI:0.05-0.34, P=0.009) and depressive symptoms (?= 0.17,CI:0.04-0.29, P=0.008).
CONCLUSION: The findings indicate that cannabis use is associated with a number of subsequent psychological effects. However there was no evidence that individuals with BD were using cannabis to self-medicate minor fluctuations in negative affect or bipolar disorder symptoms over the course of daily life. The findings in relation to existing literature and clinical implications are discussed.
PMID: 25738578 [PubMed - as supplied by publisher]
CREB signalling in bipolar disease (commentary on Gaspar et al.): commentary on Gaspar et al. 2014.
Eur J Neurosci. 2014 Jul;40(1):2205
Authors: Jagannath A, Foster RG
PMID: 25040051 [PubMed - indexed for MEDLINE]
Validation and assessment of variant calling pipelines for next-generation sequencing.
Hum Genomics. 2014;8:14
Authors: Pirooznia M, Kramer M, Parla J, Goes FS, Potash JB, McCombie WR, Zandi PP
BACKGROUND: The processing and analysis of the large scale data generated by next-generation sequencing (NGS) experiments is challenging and is a burgeoning area of new methods development. Several new bioinformatics tools have been developed for calling sequence variants from NGS data. Here, we validate the variant calling of these tools and compare their relative accuracy to determine which data processing pipeline is optimal.
RESULTS: We developed a unified pipeline for processing NGS data that encompasses four modules: mapping, filtering, realignment and recalibration, and variant calling. We processed 130 subjects from an ongoing whole exome sequencing study through this pipeline. To evaluate the accuracy of each module, we conducted a series of comparisons between the single nucleotide variant (SNV) calls from the NGS data and either gold-standard Sanger sequencing on a total of 700 variants or array genotyping data on a total of 9,935 single-nucleotide polymorphisms. A head to head comparison showed that Genome Analysis Toolkit (GATK) provided more accurate calls than SAMtools (positive predictive value of 92.55% vs. 80.35%, respectively). Realignment of mapped reads and recalibration of base quality scores before SNV calling proved to be crucial to accurate variant calling. GATK HaplotypeCaller algorithm for variant calling outperformed the UnifiedGenotype algorithm. We also showed a relationship between mapping quality, read depth and allele balance, and SNV call accuracy. However, if best practices are used in data processing, then additional filtering based on these metrics provides little gains and accuracies of >99% are achievable.
CONCLUSIONS: Our findings will help to determine the best approach for processing NGS data to confidently call variants for downstream analyses. To enable others to implement and replicate our results, all of our codes are freely available at http://metamoodics.org/wes.
PMID: 25078893 [PubMed - indexed for MEDLINE]
Wnt Signaling Regulates Multipolar-to-Bipolar Transition of Migrating Neurons in the Cerebral Cortex.
Cell Rep. 2015 Feb 24;
Authors: Boitard M, Bocchi R, Egervari K, Petrenko V, Viale B, Gremaud S, Zgraggen E, Salmon P, Kiss JZ
The precise timing of pyramidal cell migration from the ventricular germinal zone to the cortical plate is essential for establishing cortical layers, and migration errors can lead to neurodevelopmental disorders underlying psychiatric and neurological diseases. Here, we report that Wnt canonical as well as non-canonical signaling is active in pyramidal precursors during radial migration. We demonstrate using constitutive and conditional genetic strategies that transient downregulation of canonical Wnt/?-catenin signaling during the multipolar stage plays a critical role in polarizing and orienting cells for radial migration. In addition, we show that reduced canonical Wnt signaling is triggered cell autonomously by time-dependent expression of Wnt5A and activation of non-canonical signaling. We identify ephrin-B1 as a canonical Wnt-signaling-regulated target in control of the multipolar-to-bipolar switch. These findings highlight the critical role of Wnt signaling activity in neuronal positioning during cortical development.
PMID: 25732825 [PubMed - as supplied by publisher]
Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities.
Mol Psychiatry. 2015 Mar 3;
Authors: Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, Nehme R, van der Ven K, Hsu J, Wolf P, Fleishman M, O'Dushlaine C, Rose S, Chambert K, Lau FH, Ahfeldt T, Rueckert EH, Sheridan SD, Fass DM, Nemesh J, Mullen TE, Daheron L, McCarroll S, Sklar P, Perlis RH, Haggarty SJ
Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD, we applied a family-based paradigm to derive and characterize a set of 12 induced pluripotent stem cell (iPSC) lines from a quartet consisting of two BD-affected brothers and their two unaffected parents. Initially, no significant phenotypic differences were observed between iPSCs derived from the different family members. However, upon directed neural differentiation, we observed that CXCR4 (CXC chemokine receptor-4) expressing central nervous system (CNS) neural progenitor cells (NPCs) from both BD patients compared with their unaffected parents exhibited multiple phenotypic differences at the level of neurogenesis and expression of genes critical for neuroplasticity, including WNT pathway components and ion channel subunits. Treatment of the CXCR4(+) NPCs with a pharmacological inhibitor of glycogen synthase kinase 3, a known regulator of WNT signaling, was found to rescue a progenitor proliferation deficit in the BD patient NPCs. Taken together, these studies provide new cellular tools for dissecting the pathophysiology of BD and evidence for dysregulation of key pathways involved in neurodevelopment and neuroplasticity. Future generation of additional iPSCs following a family-based paradigm for modeling complex neuropsychiatric disorders in conjunction with in-depth phenotyping holds promise for providing insights into the pathophysiological substrates of BD and is likely to inform the development of targeted therapeutics for its treatment and ideally prevention.Molecular Psychiatry advance online publication, 3 March 2015; doi:10.1038/mp.2015.7.
PMID: 25733313 [PubMed - as supplied by publisher]
Genome-wide methylome analyses reveal novel epigenetic regulation patterns in schizophrenia and bipolar disorder.
Biomed Res Int. 2015;2015:201587
Authors: Li Y, Camarillo C, Xu J, Arana TB, Xiao Y, Zhao Z, Chen H, Ramirez M, Zavala J, Escamilla MA, Armas R, Mendoza R, Ontiveros A, Nicolini H, Jerez Magaña AA, Rubin LP, Li X, Xu C
Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3'-UTRs and 5'-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3'-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.
PMID: 25734057 [PubMed - in process]
Diagnostic Precursors to Bipolar Disorder in Offspring of Parents With Bipolar Disorder: A Longitudinal Study.
Am J Psychiatry. 2015 Mar 3;:appiajp201414010035
Authors: Axelson D, Goldstein B, Goldstein T, Monk K, Yu H, Hickey MB, Sakolsky D, Diler R, Hafeman D, Merranko J, Iyengar S, Brent D, Kupfer D, Birmaher B
Objective: The authors sought to identify diagnostic risk factors of manic, mixed, or hypomanic episodes in the offspring of parents with bipolar disorder ("high-risk offspring"). Method: High-risk offspring 6-18 years old (N=391) and demographically matched offspring (N=248) of community parents without bipolar disorder were assessed longitudinally with standardized diagnostic instruments by staff blind to parental diagnoses. Follow-up assessments were completed in 91% of the offspring (mean follow-up interval, 2.5 years; mean follow-up duration, 6.8 years). Results: Compared with community offspring, high-risk offspring had significantly higher rates of subthreshold mania or hypomania (13.3% compared with 1.2%), manic, mixed, or hypomanic episodes (9.2% compared with 0.8%), and major depressive episodes (32.0% compared with 14.9%). They also had higher rates of attention deficit hyperactivity disorder (30.7% compared with 18.1%), disruptive behavior disorders (27.4% compared with 15.3%), anxiety disorders (39.9% compared with 21.8%), and substance use disorders (19.9% compared with 10.1%), but not unipolar major depressive disorder (major depression with no bipolarity; 18.9% compared with 13.7%). Multivariate Cox regressions showed that in the high-risk offspring, subthreshold manic or hypomanic episodes (hazard ratio=2.29), major depressive episodes (hazard ratio=1.99), and disruptive behavior disorders (hazard ratio=2.12) were associated with subsequent manic, mixed, or hypomanic episodes. Only subthreshold manic or hypomanic episodes (hazard ratio=7.57) were associated when analyses were restricted to prospective data. Conclusions: Subthreshold manic or hypomanic episodes were a diagnostic risk factor for the development of manic, mixed, or hypomanic episodes in the offspring of parents with bipolar disorder and should be a target for clinical assessment and treatment research. Major depressive episodes and disruptive behavior disorders are also indications for close clinical monitoring of emergent bipolarity in high-risk offspring.
PMID: 25734353 [PubMed - as supplied by publisher]
Prevalence of Huntington's disease gene CAG trinucleotide repeat alleles in patients with bipolar disorder.
Bipolar Disord. 2015 Feb 26;
Authors: Ramos EM, Gillis T, Mysore JS, Lee JM, Alonso I, Gusella JF, Smoller JW, Sklar P, MacDonald ME, Perlis RH
OBJECTIVES: Huntington's disease is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms that are caused by huntingtin gene (HTT) CAG trinucleotide repeat alleles of 36 or more units. A greater than expected prevalence of incompletely penetrant HTT CAG repeat alleles observed among individuals diagnosed with major depressive disorder raises the possibility that another mood disorder, bipolar disorder, could likewise be associated with Huntington's disease.
METHODS: We assessed the distribution of HTT CAG repeat alleles in a cohort of individuals with bipolar disorder. HTT CAG allele sizes from 2,229 Caucasian individuals diagnosed with DSM-IV bipolar disorder were compared to allele sizes in 1,828 control individuals from multiple cohorts.
RESULTS: We found that HTT CAG repeat alleles > 35 units were observed in only one of 4,458 chromosomes from individuals with bipolar disorder, compared to three of 3,656 chromosomes from control subjects.
CONCLUSIONS: These findings do not support an association between bipolar disorder and Huntington's disease.
PMID: 25726852 [PubMed - as supplied by publisher]
Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder.
Eur Neuropsychopharmacol. 2015 Feb 16;
Authors: Machado-Vieira R, Zanetti MV, Teixeira AL, Uno M, Valiengo LL, Soeiro-de-Souza MG, Oba-Shinjo SM, de Sousa RT, Zarate CA, Gattaz WF, Marie SK
Strong evidence implicates intracellular signaling cascades dysfunction in the pathophysiology of Bipolar Disorder (BD). Regulation of AKT/mTOR pathway is a critical signaling pathway in synaptic neurotransmission and plasticity, also modulating cell proliferation and migration. Gene expression of the AKT/mTOR pathway was assessed in 25 BD (DSM-IV-TR criteria) unmedicated depressed individuals at baseline and after 6 weeks of lithium therapy and 31 matched healthy controls. Decreases in blood AKT1 and mTOR mRNA expression, as well as in BAD/BCL-2 expression ratio were observed in short-term BD patients during depressive episodes in comparison to healthy controls. There was no significant change in the expression of AKT1, mTOR, BCL-2, BAD and NDUFA6 after lithium therapy in the total group of BD subjects. However, the changes in AKT1 expression after lithium treatment were positively correlated with depression improvement. An integrated activity within this pathway was observed at both baseline and post-treatment. The present results support an integrated AKT/mTOR signaling pathway activity in a similar fashion to the described in previous human postmortem and rodents brain studies. Overall, the results reinforce a role for AKT1 and mTOR in the pathophysiology of BD and support the relevance of blood mRNA expression as a valid surrogate biological source to study brain intracellular signaling cascades changes and convergent molecular pathways in psychiatric disorders.
PMID: 25726893 [PubMed - as supplied by publisher]
Five-year outcome of bipolar I and II disorders: findings of the Jorvi Bipolar Study.
Bipolar Disord. 2015 Mar 2;
Authors: Pallaskorpi S, Suominen K, Ketokivi M, Mantere O, Arvilommi P, Valtonen H, Leppämäki S, Isometsä E
OBJECTIVES: The long-term outcome of bipolar disorder (BD) has been extensively investigated. However, previous studies may be biased towards hospitalized patients with bipolar I disorder (BD-I), and generalizability to the current treatment era remains uncertain. In this naturalistic study, we followed a secondary-care cohort of patients with BD.
METHODS: In the Jorvi Bipolar Study, 191 patients with BD-I and bipolar II disorder (BD-II) were followed using a life-chart method. Interviews were conducted at six months, 18 months, and five years. Time to full remission, time to first recurrence, total time ill, their predictors, and BD-I versus BD-II differences were investigated among the 151 patients remaining in follow-up.
RESULTS: Nearly all subjects recovered from the index episode, but almost all (90%) had a recurrence, and most had multiple recurrences. The patients spent about one-third of their time in illness episodes and 15% of their time with subthreshold symptoms; half of the time they were euthymic. After controlling for confounders, no difference in time spent in depressive states between patients with BD-I and BD-II persisted. Among patients with a depressive index phase, cluster C personality disorders [hazard ratio (HR) = 0.452, p = 0.040] and higher 17-item Hamilton Depression Scale score (HR = 0.951, p = 0.022) predicted longer time to remission, whereas lifetime psychotic symptoms (HR = 2.162, p = 0.016) predicted shorter time to first recurrence.
CONCLUSIONS: Among patients with BD, chronicity as uninterrupted persistence of illness was rare, but multiple recurrences were the norm. Patients with BD spent only half of their time euthymic. Patients with BD-I and BD-II may differ little in proneness to depressive states. Severity of depression, cluster C personality disorders, and psychotic symptoms predicted outcome.
PMID: 25726951 [PubMed - as supplied by publisher]
Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder.
Expert Opin Ther Targets. 2015 Mar 2;:1-17
Authors: Bellivier F, Geoffroy PA, Etain B, Scott J
Introduction: Disruptions in sleep and circadian rhythms are observed in individuals with bipolar disorders (BD), both during acute mood episodes and remission. Such abnormalities may relate to dysfunction of the molecular circadian clock and could offer a target for new drugs. Areas covered: This review focuses on clinical, actigraphic, biochemical and genetic biomarkers of BDs, as well as animal and cellular models, and highlights that sleep and circadian rhythm disturbances are closely linked to the susceptibility to BDs and vulnerability to mood relapses. As lithium is likely to act as a synchronizer and stabilizer of circadian rhythms, we will review pharmacogenetic studies testing circadian gene polymorphisms and prophylactic response to lithium. Interventions such as sleep deprivation, light therapy and psychological therapies may also target sleep and circadian disruptions in BDs efficiently for treatment and prevention of bipolar depression. Expert opinion: We suggest that future research should clarify the associations between sleep and circadian rhythm disturbances and alterations of the molecular clock in order to identify critical targets within the circadian pathway. The investigation of such targets using human cellular models or animal models combined with 'omics' approaches are crucial steps for new drug development.
PMID: 25726988 [PubMed - as supplied by publisher]
Peripheral and central glucose utilizations modulated by mitochondrial DNA 10398A in bipolar disorder.
Psychoneuroendocrinology. 2015 Feb 12;55C:72-80
Authors: Li CT, Bai YM, Hsieh JC, Lee HC, Yang BH, Chen MH, Lin WC, Tsai CF, Tu PC, Wang SJ, Su TP
Bipolar disorder (BD) is highly heritable and associated with dysregulation of brain glucose utilizations (GU). The mitochondrial DNA (mtDNA) 10398A polymorphism, as a reported BD risk factor, leads to deficient glycolytic energy production by affecting mitochondrial matrix pH and intracellular calcium levels. However, whether mtDNA-10398A has functional effects on the brain and how our body responds remain elusive. We compared peripheral and central glucose-utilizing patterns between mtDNA A10398G polymorphisms in BD and their unaffected siblings (BDsib). Since siblings carry identical mtDNA, we hypothesized that certain characteristics co-segregate in BD families. We recruited twenty-seven pairs of non-diabetic BD patients and their BDsib and 30 well-matched healthy control subjects (HC). The following were investigated: mtDNA, fasting plasma glucose/insulin, cognitive functions including Montreal Cognitive Assessment (MoCA), and brain GU at rest. Insulin resistance was rechecked in sixty-one subjects (19-BD, 18-BDsibib, and 24-HC) six months later. We found that BD-pairs (BD+BDsib) carried more mtDNA-10398A and had higher fasting glucose, even after controlling for many covariates. BD-pairs had abnormally lower dorso-prefrontal-GU and higher cerebellar-GU, but only BD demonstrated lower medio-prefrontal-GU and MoCA. Subjects carrying mtDNA-10398A had significantly lower prefrontal-GU (FWE-corrected p<0.05). An abnormal inverse pattern of insulin-GU and insulin-MoCA correlation was found in BD-pairs. The insulin-MoCA correlation was particularly prominent in those carrying mtDNA-10398A. mtDNA-10398A predicted insulin resistance 6 months later. In conclusion, mtDNA-10398A was associated with impaired prefrontal-GU. An up-regulation of glucose utilizations was found in BD-pairs, probably compensating for mtDNA-10398A-related energy loss.
PMID: 25727318 [PubMed - as supplied by publisher]
Quantitative T1? mapping links the cerebellum and lithium use in bipolar disorder.
Mol Psychiatry. 2015 Feb;20(2):149
Authors: Johnson CP, Follmer RL, Oguz I, Warren LA, Christensen GE, Fiedorowicz JG, Magnotta VA, Wemmie JA
PMID: 25727373 [PubMed - in process]
Differential effectiveness of right unilateral versus bilateral electroconvulsive therapy in resistant bipolar depression.
Am J Psychiatry. 2015 Mar 1;172(3):294
Authors: Kotzalidis GD, Pacchiarotti I, Rapinesi C, Murru A, Colom F, Vieta E
PMID: 25727540 [PubMed - in process]
The use of agomelatine in OCD: effects on the motivational aspects and dysregulated circadian rhythms.
Expert Opin Investig Drugs. 2015 Mar 1;:1-9
Authors: Perugi G, Quaranta G, Bucci N
Introduction: A considerable proportion of subjects with obsessive-compulsive disorder (OCD) have shown resistance or an incomplete response to the standard first-line treatment of serotonin reuptake inhibitors. In particular, patients often continue to show disrupted circadian rhythms with related sleep disturbances and comorbidity with bipolar spectrum disorders. Areas covered: This paper discusses the possible role of agomelatine in the treatment of motivational aspects and dysregulated circadian rhythms of OCD. In particular, the article highlights the pharmacokinetics and pharmacodynamics of agomelatine. Additionally, the article highlights its clinical efficacy, safety and tolerability and provides perspectives on its future development as a potential therapy for the treatment of OCD. Expert opinion: Agomelatine offers the effective resynchronization of circadian rhythm with an improvement in patients' reward mechanism, incentive motivation and general OCD symptoms. Indeed, the authors believe that agomelatine could be a valid alternative drug in treatment-resistant OCD patients, particularly those suffering with bipolar spectrum comorbidity and related sleep disturbances.
PMID: 25727766 [PubMed - as supplied by publisher]
Towards a complex system understanding of bipolar disorder: A Map Based Model of a Complex Winnerless Competition.
J Theor Biol. 2015 Feb 26;
Authors: Hadaeghi F, Hashemi Golpayegani MR, Murray G
Bipolar disorder is characterized by repeated erratic episodes of mania and depression, which can be understood as pathological complex system behavior involving cognitive, affective and psychomotor disturbance. In order to illuminate dynamical aspects of the longitudinal course of the illness, we propose here a novel complex model based on the notion of competition between recurrent maps, which mathematically represent the dynamics of activation in excitatory (Glutamatergic) and inhibitory (GABAergic) pathways. We assume that manic and depressive states can be considered stable sub attractors of a dynamical system through which the mood trajectory moves. The model provides a theoretical framework which can account for a number of complex phenomena of bipolar disorder, including intermittent transition between the two poles of the disorder, rapid and ultra-rapid cycling of episodes and manicogenic effects of antidepressants.
PMID: 25728789 [PubMed - as supplied by publisher]
Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology.
Schizophr Res. 2015 Feb 23;
Authors: Schubert KO, Föcking M, Cotter DR
Neuropathological changes of the hippocampus have been associated with psychotic disorders such as schizophrenia and bipolar disorder. Recent work has particularly implicated hippocampal GABAergic interneurons in the pathophysiology of these diseases. However, the molecular mechanisms underlying structural and cellular hippocampal pathology remain poorly understood. We used data from comprehensive difference-in-gel electrophoresis (2-D DIGE) investigations of postmortem human hippocampus of people with schizophrenia and bipolar disorder, covering the acidic (isoelectric point (pI) between pH4 and 7) and, separately, the basic (pI between pH6 and 11) sub-proteome, for Ingenuity Pathway Analysis (IPA) of implicated protein networks and pathways. Comparing disease and control cases, we identified 58 unique differentially expressed proteins in schizophrenia, and 70 differentially expressed proteins in bipolar disorder, using mass spectrometry. IPA implicated, most prominently, 14-3-3 and aryl hydrocarbon receptor signaling in schizophrenia, and gluconeogenesis/glycolysis in bipolar disorder. Both disorders were characterized by alterations of proteins involved in the oxidative stress response, mitochondrial function, and protein-endocytosis, -trafficking, -degradation, and -ubiquitination. These findings are interpreted with a focus on GABAergic interneuron pathology in the hippocampus.
PMID: 25728835 [PubMed - as supplied by publisher]
Molecular modeling and docking study on dopamine D2-like and serotonin 5-HT2A receptors.
J Mol Graph Model. 2015 Feb 14;57C:143-155
Authors: Duan X, Zhang M, Zhang X, Wang F, Lei M
Psychiatric disorders, such as schizophrenia, bipolar disorder and major depression, are paid more and more attention by human due to their upward tendency in modern society. D2-like and 5-HT2A receptors have been proposed as targets of antipsychotic drugs. Atypical antipsychotic drugs have been deemed to improve the treatment of positive, negative and extrapyramidal symptoms. Unfortunately, no experimental structures for these receptors are available except D3 receptor (D3R). Therefore, it is necessary to construct structures of D2-like and 5-HT2A receptors to investigate the interaction between these receptors and their antagonists. Accordingly, homology models of dopamine D2, D3, D4 and serotonin 5-HT2A receptors have been built on the high-resolution crystal structure of the ?2-adrenergic receptor, and refined by molecular dynamics simulations. The backbone root-mean-square deviation (RMSD) of D3R model relative to crystal structure is 1.3?, which proves the reliability of homology modeling. Docking studies reveal that the binding modes of four homology models and their antagonists are consistent with experimental site-directed mutagenesis data. The calculated pKi values agree well with the experimental pKi ones. Antagonists with linear structures such as butyrophenones and benzisoxazolyl piperidines are easily docked into D2-like and 5-HT2A receptors. Polycyclic aromatic compounds have weaker affinity with four receptors. Homology models of D2-like and 5-HT2A receptors will be helpful for predicting the affinity of novel ligands, and could be used as three-dimensional (3D) templates for antipsychotic virtual screening and further drug discovery.
PMID: 25728902 [PubMed - as supplied by publisher]
Rare variants in neuronal excitability genes influence risk for bipolar disorder.
Proc Natl Acad Sci U S A. 2015 Feb 17;
Authors: Ament SA, Szelinger S, Glusman G, Ashworth J, Hou L, Akula N, Shekhtman T, Badner JA, Brunkow ME, Mauldin DE, Stittrich AB, Rouleau K, Detera-Wadleigh SD, Nurnberger JI, Edenberg HJ, Gershon ES, Schork N, The Bipolar Genome Study, Price ND, Gelinas R, Hood L, Craig D, McMahon FJ, Kelsoe JR, Roach JC
We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.
PMID: 25730879 [PubMed - as supplied by publisher]
Suicidal behavior in the context of disrupted rhythmicity in bipolar disorder-Data from an association study of suicide attempts with clock genes.
Psychiatry Res. 2015 Jan 16;
Authors: Pawlak J, Dmitrzak-Weglarz M, Maciukiewicz M, Wilkosc M, Leszczynska-Rodziewicz A, Zaremba D, Kapelski P, Hauser J
Suicidal behavior exhibits both circadian and annual rhythms. We were seeking an association between selected candidate clock genes and suicidal behavior in bipolar patients. The study included 441 bipolar patients and 422 controls and we genotyped 41 SNPs of the CLOCK, ARNTL, TIMELESS, PER3 genes. The main positive findings built up associations between selected polymorphisms and:
PMID: 25724486 [PubMed - as supplied by publisher]
Affective processing bias in youth with primary bipolar disorder or primary attention-deficit/hyperactivity disorder.
Eur Child Adolesc Psychiatry. 2015 Feb 28;
Authors: Seymour KE, Kim KL, Cushman GK, Puzia ME, Weissman AB, Galvan T, Dickstein DP
High rates of comorbidity and overlapping diagnostic criteria between pediatric bipolar disorder (BD) and attention-deficit/hyperactivity disorder (ADHD) contribute to diagnostic and treatment confusion. To advance what is known about both disorders, we compared effect of emotional stimuli on response control in children with primary BD, primary ADHD and typically developing controls (TDC). Participants included 7-17 year olds with either "narrow-phenotype" pediatric BD (n = 25), ADHD (n = 25) or TDC (n = 25). Groups were matched on participant age and FSIQ. The effect of emotional stimuli on response control was assessed using the Cambridge Neuropsychological Test Automated Battery Affective Go/No-Go task (CANTAB AGN). We found a group by target valence interaction on commission errors [F(2,71) = 5.34, p < 0.01, ? p (2) = 0.13] whereby ADHD, but not TDC participants, made more errors on negative than positive words [t(24) = -2.58, p < 0.05, r = 0.47]. In contrast, there was a nonsignificant trend for BD participants to make fewer errors on negative versus positive words compared to ADHD and TDC participants. Between-subjects effects showed that ADHD participants made more errors than TDC, but not BD participants. Our main finding advances what is known about the effect of emotional stimuli on response control in children with ADHD. Our results suggesting a positive affective processing bias in children with ADHD compliment emerging literature show that difficulties with emotional processing and regulation may be core features of ADHD. Further, given the observed pattern of results in children with ADHD compared to BD children, our behavioral results suggest the importance of examining differences in the brain-behavior mechanisms involved in affective processing in children with ADHD compared to BD children.
PMID: 25724546 [PubMed - as supplied by publisher]
Chronic Lithium Treatment Increased Intracellular S100ß Levels in Rat Primary Neuronal Culture.
Acta Med Iran. 2015 Feb;53(2):89-96
Authors: Emamghoreishi M, Keshavarz M, Nekooeian AA
S100ß? a neurotrophic factor mainly released by astrocytes, has been implicated in the pathogenesis of bipolar disorder. Thus, lithium may exert its neuroprotective effects to some extent through S100ß. Furthermore, the possible effects of lithium on astrocytes as well as on interactions between neurons and astrocytes as a part of its mechanisms of actions are unknown. This study was undertaken to determine the effect of lithium on S100? in neurons, astrocytes and a mixture of neurons and astrocytes. Rat primary astrocyte, neuronal and mixed neuro-astroglia cultures were prepared from cortices of 18-day's embryos. Cell cultures were exposed to lithium (1mM) or vehicle for 1day (acute) or 7 days (chronic). RT-PCR and ELISA determined S100? mRNA and intra- and extracellular protein levels. Chronic lithium treatment significantly increased intracellular S100? in neuronal and neuro-astroglia cultures in comparison to control cultures (P<0.05). Acute and chronic lithium treatments exerted no significant effects on intracellular S100? protein levels in astrocytes, and extracellular S100? protein levels in three studied cultures as compared to control cultures. Acute and chronic lithium treatments did not significantly alter S100? mRNA levels in three studied cultures, compared to control cultures. Chronic lithium treatment increased intracellular S100ß protein levels in a cell-type specific manner which may favor its neuroprotective action. The findings of this study suggest that lithium may exert its neuroprotective action, at least partly, by increasing neuronal S100ß level, with no effect on astrocytes or interaction between neurons and astrocytes.
PMID: 25725177 [PubMed - as supplied by publisher]