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International Review of Psychosis & Bipolarity

Join us in Rome, Italy, 22-24 May 2016

Chair: Professor Paulo Girardi (IT)

Co-Chair: Dr Giulio Perugi (IT)

The ONLY speciality International Conference in Schizophrenia & Bipolar Disorders in Europe in 2016



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Most Recent Articles Published on Psychosis and Bipolarity:

Neuropsychiatric Features in Primary Mitochondrial Disease.

Neurol Clin. 2016 Feb;34(1):247-94

Authors: Marin SE, Saneto RP

Mitochondrial diseases are a clinically heterogeneous group of disorders that ultimately result from dysfunction of the mitochondrial respiratory chain. There is some evidence to suggest that mitochondrial dysfunction plays a role in neuropsychiatric illness; however, the data are inconclusive. This article summarizes the available literature published in the area of neuropsychiatric manifestations in both children and adults with primary mitochondrial disease, with a focus on autism spectrum disorder in children and mood disorders and schizophrenia in adults.

PMID: 26614002 [PubMed - in process]

Social rhythm disrupting events increase the risk of recurrence among individuals with bipolar disorder.

Bipolar Disord. 2015 Nov 28;

Authors: Levenson JC, Wallace ML, Anderson BP, Kupfer DJ, Frank E

OBJECTIVES: As outlined in the social zeitgeber hypothesis, social rhythm disrupting (SRD) life events begin a cascade of social and biological rhythm disruption that may lead to the onset of affective episodes in those vulnerable to bipolar disorder. Thus, the study of SRD events is particularly important in individuals with this chronic condition. The purpose of the current study was to evaluate (i) the extent to which SRD life events increased the risk of recurrence of a bipolar mood episode, and (ii) whether the social rhythm disruption associated with the event conferred an increased risk of recurrence, after accounting for the level of threat associated with the life event.
METHODS: We examined the effect of SRD events on recurrence during preventative treatment in a sample of 118 patients with bipolar disorder who achieved remission from an acute episode after receiving psychotherapy and pharmacotherapy. Life events were measured with the Bedford College Life Events and Difficulty Schedule and were rated for degree of SRD and threat.
RESULTS: Time-dependent Cox proportional hazards models showed that having a higher SRD rating was significantly associated with an increased risk of recurrence, even when accounting for the threat effect of a life event and psychosocial treatment (hazard ratio = 1.33, 95% confidence interval: 1.04-1.70, p = 0.023). However, this finding fell below conventional levels of statistical significance when accounting for other covariates.
CONCLUSIONS: Our findings lend partial support to the social zeitgeber hypothesis.

PMID: 26614534 [PubMed - as supplied by publisher]

Sickness allowance histories among disability retirees due to mental disorders: A retrospective case-control study.

Scand J Public Health. 2015 Nov 27;

Authors: Laaksonen M, Blomgren J, Tuulio-Henriksson A

OBJECTIVES: The aim was to describe sickness allowance histories before disability retirement due to mental disorders and to examine whether receiving sickness allowance due to mental disorders and somatic conditions predicts future disability retirement.
METHOD: Pre-retirement sickness allowance histories were traced backwards for 7 years among Finnish residents aged 25-64 years who had retired due to mental disorders in 2011 (n=5.544). For each retiree, five sex- and age-matched controls were drawn from the non-retired population. Conditional logistic regression was used to calculate the risk for disability retirement by sickness allowance history and to control for the effects of educational level, social class, marital status and the urbanisation level of the municipality.
RESULTS: The proportion of sickness allowance recipients increased steadily during the years preceding disability retirement, and was highest among those who retired due to bipolar disorders or depression. Those who had received sickness allowance due to mental disorders 6-7 years earlier had 6.5 times higher risk and those with sickness allowance 1-2 years earlier 11.7 times higher risk for disability retirement. Sickness allowance due to somatic conditions increased the risk for disability retirement 1.6-1.9 times. Sickness allowance most strongly predicted retirement due to bipolar disorders and depression. Adjustment for covariates had little effect.
CONCLUSION: Those who retired due to mental disorders more often had sickness allowance due to both mental disorders and somatic conditions, but in particular sickness allowance due to mental disorders predicted disability retirement due to mental disorders.

PMID: 26614634 [PubMed - as supplied by publisher]

Birth by Caesarean Section and the Risk of Adult Psychosis: A Population-Based Cohort Study.

Schizophr Bull. 2015 Nov 27;

Authors: O'Neill SM, Curran EA, Dalman C, Kenny LC, Kearney PM, Clarke G, Cryan JF, Dinan TG, Khashan AS

Despite the biological plausibility of an association between obstetric mode of delivery and psychosis in later life, studies to date have been inconclusive. We assessed the association between mode of delivery and later onset of psychosis in the offspring. A population-based cohort including data from the Swedish National Registers was used. All singleton live births between 1982 and 1995 were identified (n = 1 345 210) and followed-up to diagnosis at age 16 or later. Mode of delivery was categorized as: unassisted vaginal delivery (VD), assisted VD, elective Caesarean section (CS) (before onset of labor), and emergency CS (after onset of labor). Outcomes included any psychosis; nonaffective psychoses (including schizophrenia only) and affective psychoses (including bipolar disorder only and depression with psychosis only). Cox regression analysis was used reporting partially and fully adjusted hazard ratios (HR) with 95% confidence intervals (CI). Sibling-matched Cox regression was performed to adjust for familial confounding factors. In the fully adjusted analyses, elective CS was significantly associated with any psychosis (HR 1.13, 95% CI 1.03, 1.24). Similar findings were found for nonaffective psychoses (HR 1.13, 95% CI 0.99, 1.29) and affective psychoses (HR 1.17, 95% CI 1.05, 1.31) (?(2) for heterogeneity P = .69). In the sibling-matched Cox regression, this association disappeared (HR 1.03, 95% CI 0.78, 1.37). No association was found between assisted VD or emergency CS and psychosis. This study found that elective CS is associated with an increase in offspring psychosis. However, the association did not persist in the sibling-matched analysis, implying the association is likely due to familial confounding by unmeasured factors such as genetics or environment.

PMID: 26615187 [PubMed - as supplied by publisher]

Differentiating unipolar and bipolar depression by alterations in large-scale brain networks.

Hum Brain Mapp. 2015 Nov 27;

Authors: Goya-Maldonado R, Brodmann K, Keil M, Trost S, Dechent P, Gruber O

BACKGROUND: Misdiagnosing bipolar depression can lead to very deleterious consequences of mistreatment. Although depressive symptoms may be similarly expressed in unipolar and bipolar disorder, changes in specific brain networks could be very distinct, being therefore informative markers for the differential diagnosis. We aimed to characterize specific alterations in candidate large-scale networks (frontoparietal, cingulo-opercular, and default mode) in symptomatic unipolar and bipolar patients using resting state fMRI, a cognitively low demanding paradigm ideal to investigate patients.
METHODS: Networks were selected after independent component analysis, compared across 40 patients acutely depressed (20 unipolar, 20 bipolar), and 20 controls well-matched for age, gender, and education levels, and alterations were correlated to clinical parameters.
RESULTS: Despite comparable symptoms, patient groups were robustly differentiated by large-scale network alterations. Differences were driven in bipolar patients by increased functional connectivity in the frontoparietal network, a central executive and externally-oriented network. Conversely, unipolar patients presented increased functional connectivity in the default mode network, an introspective and self-referential network, as much as reduced connectivity of the cingulo-opercular network to default mode regions, a network involved in detecting the need to switch between internally and externally oriented demands. These findings were mostly unaffected by current medication, comorbidity, and structural changes. Moreover, network alterations in unipolar patients were significantly correlated to the number of depressive episodes.
CONCLUSION: Unipolar and bipolar groups displaying similar symptomatology could be clearly distinguished by characteristic changes in large-scale networks, encouraging further investigation of network fingerprints for clinical use. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.

PMID: 26611711 [PubMed - as supplied by publisher]

Cognitive deficits in bipolar disorder: from acute episode to remission.

Eur Arch Psychiatry Clin Neurosci. 2015 Nov 26;

Authors: Volkert J, Schiele MA, Kazmaier J, Glaser F, Zierhut KC, Kopf J, Kittel-Schneider S, Reif A

Considerable evidence demonstrates that neuropsychological deficits are prevalent in bipolar disorder during both acute episodes and euthymia. However, it is less clear whether these cognitive disturbances are state- or trait-related. We here present the first longitudinal study employing a within-subject pre- and post-testing examining acutely admitted bipolar patients (BP) in depression or mania and during euthymia, aiming to identify cognitive performance from acute illness to remission. Cognitive performance was measured during acute episodes and repeated after at least 3 months of remission. To do so, 55 BP (35 depressed, 20 hypo-/manic) and 55 healthy controls (HC) were tested with a neuropsychological test battery (attention, working memory, verbal memory, executive functioning). The results showed global impairments in acutely ill BP compared to HC: depressed patients showed a characteristic psychomotor slowing, while manic patients had severe deficits in executive functioning. Twenty-nine remitted BP could be measured in the follow-up (dropout rate 48 %), whose cognitive functions partially recovered, whereas working memory and verbal memory were still impaired. However, we found that subthreshold depressive symptoms and persisting sleep disturbances in euthymic BP were associated with reduced speed, deficits in attention and verbal memory, while working memory was correlated with psychotic symptoms (lifetime). This result indicates working memory as trait related for a subgroup of BP with psychotic symptoms. In contrast, attention and verbal memory are negatively influenced by state factors like residual symptoms, which should be more considered as possible confounders in the search of cognitive endophenotypes in remitted BP.

PMID: 26611783 [PubMed - as supplied by publisher]

Intracellular PAF-Acetylhydrolase Type I.

Enzymes. 2015;38:23-36

Authors: Hattori M, Arai H

Platelet-activating factor (PAF) is a phospholipid mediator whose synthesis and degradation depend on specific sets of enzymes. PAF-acetylhydrolase (PAF-AH) hydrolyzes the acetyl moiety of PAF at its sn-2 position and thereby inactivates it. PAF-AH Ib, originally identified in brain, exists in the cytoplasm of many (probably all) types of mammalian cells and tissues. PAF-AH Ib consists of three subunits (?1, ?2, and ?), in which the ? subunits provide the catalytic activity. The finding that the ? subunit is the product of the causative gene for Miller-Dieker lissencephaly led to extensive analyses of PAF-AH Ib subunits in the field of cell biology and neurobiology. More than 20 molecules are known to bind to PAF-AH Ib subunits, and PAF-AH Ib has been implicated in neuronal development, neuronal functions, Alzheimer's disease, bipolar disorder, cancer, spermatogenesis, and tolerance to hypoxia. However, in almost all of these cases, how the catalytic activity is involved and the identity of the most important substrate of this enzyme are unclear. In this chapter, the structure and functions of PAF-AH Ib and its subunit proteins are summarized and their contributions to human diseases are discussed.

PMID: 26612644 [PubMed - as supplied by publisher]

Proteome and pathway effects of chronic haloperidol treatment in mouse hippocampus.

Proteomics. 2015 Nov 26;

Authors: Schubert KO, Föcking M, Wynne K, Cotter DR

Proteomic exploration of the effects of psychotropic drugs on specific brain areas in rodents has the potential to uncover novel molecular networks and pathways affected by psychotropic medications, and may inform etiologic hypotheses on mental disorders. Haloperidol, a widely used first-generation antipsychotic, has been shown to produce structural and functional changes of the hippocampus, a brain region also implicated in the neuropathology of disorders such as schizophrenia and bipolar disorder. Seven adult male C57BL/6 mice were injected daily intraperitoneally with 0.5 mg/kg of haloperidol, for 28 days. A control group of six animals was injected with vehicle only (saline). Protein levels of post-mortem hippocampus homogenate were determined using label-free liquid chromatography/tandem mass spectrometry (LC/MS/MS). In the treatment group, 216 differentially expressed hippocampal proteins were identified as compared to controls. Ingenuity Pathway Analysis (IPA) implicated oxidative phosphorylation and mitochondrial function as top canonical pathways, and local networks involved in tubulin-mediated cytoskeleton dynamics, clathrin-mediated endocytosis, and extracellular signal-regulated kinase (ERK) - and c-Jun N-terminal kinase (JNK) signaling. The findings of this study could stimulate further research into the cellular mechanisms associated with haloperidol treatment and the pathophysiology of psychotic disorders, assisting treatment biomarker discovery. Data are available via ProteomeXchange with identifier PXD002250. This article is protected by copyright. All rights reserved.

PMID: 26607048 [PubMed - as supplied by publisher]

Mortality in schizophrenia and bipolar disorder: Clinical and serological predictors.

Schizophr Res. 2015 Nov 19;

Authors: Dickerson F, Origoni A, Schroeder J, Schweinfurth LA, Stallings C, Savage CL, Katsafanas E, Banis M, Khushalani S, Yolken R

Persons with schizophrenia and with bipolar disorder have a reduced life expectancy due largely to death from natural causes. The reasons for this increased mortality have not been completely defined. We prospectively assessed a cohort of persons with schizophrenia and one with bipolar disorder with a clinical evaluation and a blood sample from which immune and infectious disease markers were measured. Mortality was determined with data from the National Death Index following a period of up to 14years. We examined the role of demographic, clinical, and serological factors on mortality in bivariate and multivariate models. A total of 43/710 (6.1%) persons with schizophrenia and 12/406 (3.0%) with bipolar disorder died of natural causes. In the schizophrenia group, mortality was predicted by the following variables in a multivariate model: cigarette smoking (RR=6.93, 95% CI 1.59, 30.1, p=0.0099); autoimmune disorder (RR=8.08, 95% CI 2.50, 26.1, p=0.00047); gastrointestinal disorder (GI) (RR=3.53, 95% CI 1.43, 8.69 p=0.0061); and reduced maternal education (RR=0.84, 95% CI 0.72, 0.97), p=0.018. The combination of smoking and an autoimmune disorder yielded an unadjusted relative risk of 18.1 for mortality, and the combination of smoking and a GI disorder an unadjusted relative risk of 9.45, compared with individuals with neither risk factor. In the bipolar disorder group, significant bivariate predictors of mortality included lower cognitive score (RR=0.95, p=.0085) and the presence of type 1 or 2 diabetes (RR=3.90, p=.026). Given the extraordinary high risk of death due to smoking in schizophrenia, smoking cessation remains an urgent priority.

PMID: 26607103 [PubMed - as supplied by publisher]

Electrophysiological and Histological Characterization of Rod-Cone Retinal Degeneration and Microglia Activation in a Mouse Model of Mucopolysaccharidosis Type IIIB.

Sci Rep. 2015;5:17143

Authors: Tse DY, Lotfi P, Simons DL, Sardiello M, Wu SM

Sanfilippo syndrome Type B or Mucopolysaccharidosis IIIB (MPS IIIB) is a neurodegenerative autosomal recessive lysosomal storage disorder in which patients suffer severe vision loss from associated retinopathy. Here we sought to study the underlying retinal functional and morphological changes associated with MPS IIIB disease progression using the established model of MPS IIIB, the B6.129S6-Naglu(tm1Efn)/J mouse line. Electroretinogram (ERG) was recorded from MPS IIIB and wild-type (WT) mice at the age of 28 and 46 weeks, and retinal tissues were subsequently collected for immunohistochemistry analysis. At the 28th week, rod a- and b-wave amplitudes were significantly diminished in MPS IIIB compared to WT mice. The cone a- and b-waves of MPS IIIB mice were not significantly different from those of the control at the 28th week but were significantly diminished at the 46th week, when MPS IIIB mice showed a major loss of rods and rod bipolar cells in both central and peripheral regions and a minor loss of cones in the periphery. Activation of microglia and neovascularization were also detected in the MPS IIIB retina. The new findings that cones and rod bipolar cells also undergo degeneration, and that retinal microglia are activated, will inform future development of therapeutic strategies.

PMID: 26607664 [PubMed - as supplied by publisher]

Neurodevelopmental Origins of Bipolar Disorder: iPSC Models.

Mol Cell Neurosci. 2015 Nov 19;

Authors: Sue O'Shea K, McInnis MG

Bipolar disorder (BP) is a chronic neuropsychiatric condition characterized by pathological fluctuations in mood from mania to depression. Adoption, twin and family studies have consistently identified a significant hereditary component to BP, yet there is no clear genetic event or consistent neuropathology. BP has been suggested to have a developmental origin, although this hypothesis has been difficult to test since there are no viable neurons or glial cells to analyze, and research has relied largely on postmortem brain, behavioral and imaging studies, or has examined proxy tissues including saliva, olfactory epithelium and blood cells. Neurodevelopmental factors, particularly pathways related to nervous system development, cell migration, extracellular matrix, H3K4 methylation, and calcium signaling have been identified in large gene expression and GWAS studies as altered in BP. Recent advances in stem cell biology, particularly the ability to reprogram adult somatic tissues to a pluripotent state, now make it possible to interrogate these pathways in viable cell models. A number of induced pluripotent stem cell (iPSC) lines from BP patient and healthy control (C) individuals have been derived in several laboratories, and their ability to form cortical neurons examined. Early studies suggest differences in calcium signaling, blocks to neuronal differentiation, and changes in neuronal, and possibly glial, lineage specification. Initial observations suggest that differentiation of BP patient-derived neurons to dorsal telencephalic derivatives may be impaired, possibly due to alterations in WNT, Hedgehog or Nodal pathway signaling. These investigations strongly support a developmental contribution to BP and identify novel pathways, mechanisms and opportunities for improved treatments.

PMID: 26608002 [PubMed - as supplied by publisher]

Maternal-Infant interaction in women with unipoloar and bipolar depression.

Appl Nurs Res. 2015 Nov;28(4):381-3

Authors: Logsdon MC, Mittelberg M, Jacob AE, Luther JF, Wisniewski SR, Confer A, Eng H, Wisner KL

BACKGROUND: One percent of women experience bipolar disorder and are likely to suffer from mood disorders during the postpartum period, potentially impacting interaction with their infants. The purpose of this study was to describe maternal-infant interactions in women with bipolar depression at 12months postpartum and to compare interactions to women with unipolar depression and a control group.
METHODS: Using a descriptive design, maternal-infant interactions in women with bipolar disorder (n=40) were videotaped, coded, and analyzed for maternal sensitivity and maternal-infant reciprocity and compared to maternal-infant interaction in women with unipolar depression (n=50) and women without depression (n=40).
RESULTS: Women with bipolar depression had lower scores on both maternal sensitivity and infant reciprocity, but differences were nonsignificant.
CONCLUSIONS: This research is the first study to examine maternal-infant interaction in women with bipolar disorder, and important trends were noted. Future research should examine maternal-infant interaction at earlier time periods.

PMID: 26608442 [PubMed - in process]

Decoding the molecular mechanisms of neuronal migration using in utero electroporation.

Med Mol Morphol. 2015 Nov 25;

Authors: Tabata H, Nagata KI

During the development of the cerebral cortex, excitatory neurons are produced in the ventricular zone lining the lateral ventricle or in the adjacent subventricular zone and migrate toward the brain surface in a process known as radial migration. During radial migration, neurons undergo multiple steps including a multipolar cell phase, a multipolar-bipolar transition, and a locomotion phase. Many genes tightly regulate the cell behavior in each phase. We have established an in utero electroporation method as a rapid in vivo gene transfer system, and this system has greatly contributed to recent advances in our knowledge of the molecular mechanisms underlying each migration phase. Here, we review the cell behaviors of neurons during each phase of radial migration and the molecular mechanisms involved in these phases. Knockdown or functional blocking of these genes using in utero electroporation results in various migration defects and abnormal cell morphologies. Here, we describe these phenotypes as much as possible so that this review can be used as a chart to evaluate the phenotypes of novel gene knockdown experiments. We also discuss the recent application of in utero electroporation in studies examining the functions of neurodevelopmental disorder-related genes.

PMID: 26608533 [PubMed - as supplied by publisher]

Cognitive impairment in manic bipolar patients: important, understated, significant aspects.

Ann Gen Psychiatry. 2015;14:41

Authors: Vrabie M, Marinescu V, Tala?man A, T?utu O, Drima E, Miclu?ia I

BACKGROUND: Bipolar disorder is a chronic mood disorder with episodic progress and high relapse rate. Growing evidence suggests that individuals with bipolar disorder display cognitive impairment which persists even throughout periods of symptom's remission.
METHOD: 137 bipolar patients met the inclusion criteria (depressive episode: DSM-IV-TR criteria for major depressive episode, HAMD score ?17; manic/hypomanic episode: DSM-IV-TR criteria for manic/hypomanic episode, YMRS score ?12, euthymic: 6 months of remission, HAMD score ?8, YMRS score ?6; and mixed: DSM-IV-TR criteria for mixed episode, HAMD score >8 and YMRS score >6) and were therefore enrolled in the study. Patients were free of psychotic symptoms (hallucinations/delusions) at the moment of testing. Control group consisted of 62 healthy subjects without history of neurological and/or psychiatric disorder. Cognitive battery has been applied in order to assess verbal memory, working memory, psychomotor speed, verbal fluency, attention and speed of information processing, and executive function. Following data were collected: demographics, psychiatric history, age of illness onset; current and previous treatment (including hospitalizations). Cognitive deficits were assessed in bipolar patients experiencing manic, depressive, mixed episodes or who were euthymic in mood. Results were compared between the subgroups and with healthy individuals. The association of impaired cognition with illness course was analyzed.
RESULTS: Bipolar patients showed cognitive deficits in all evaluated domains when compared to controls. The lowest scores were obtained for the verbal fluency test. After adjusting for current episode, manic subgroup showed greater cognitive impairment in verbal and working memory, executive function/reasoning and problem solving, compared to depressive, mixed, and euthymic subgroup. Low-neurocognitive performance was directly associated with a predominance of manic episodes and severe course of bipolar illness. An increased number of past manic episodes was the strongest correlated event with the poorest outcomes in verbal memory testing. Other factors correlated with poor verbal memory scores in manic subgroup were age at illness onset (positive correlation), illness length, and hospitalizations (negative correlations).
CONCLUSIONS: Bipolar patients showed cognitive deficits regardless of the phase of illness. Subjects experiencing a manic episode displayed higher deficits in verbal and working memory, executive function/reasoning, and problem solving. Severe course of illness also showed significant contribution in terms of cognitive impairment.

PMID: 26609314 [PubMed - as supplied by publisher]

Isolating the Norepinephrine Pathway Comparing Lithium in Bipolar Patients to SSRIs in Depressive Patients.

Brain (Bacau). 2014 Dec;5(1-4):5-15

Authors: Eugene AR, Masiak J, Masiak M, Kapica J, Weinshilboum RM

INTRODUCTION: The purpose of this investigatory neuroimaging analysis was done to better understand the pharmacodynamics of Lithium by isolating the norepinephrine pathway in the brain. To accomplish this, we compared patients with Bipolar Disorder treated with Lithium to patients diagnosed with Major Depression or Depressive Disorder who are treated with Selective Serotonin Reuptake Inhibitors (SSRIs).
METHODOLOGY: We used Standardized Low Resolution Brain Electrotomography to calculate the whole brain, voxel-by-voxel, unpaired t-tests Statistical non-Parametric Maps. For our first electrophysiological neuroimaging investigation, we compared 46 patients (average age = 34 ± 16.5) diagnosed with Bipolar Affective Disorder to three patient groups all diagnosed with Major Depression or Depressive Episode. The first is with 48 patients diagnosed with Major Depression or Depressive Episode (average age = 49 ± 12.9), the second to 16 male depressive patients (average age = 45 ± 15.1), and the final comparison to 32 depressive females (average age = 50 ± 11.7).
RESULTS: The results of sLORETA three-dimensional statistical non-parametric maps illustrated that Lithium influenced an increase in neurotransmission in the right Superior Temporal Gyrus (t=1.403, p=0.00780), Fusiform Gyrus (t=1.26), and Parahippocampal Gyrus (t=1.29). Moreover, an increased in neuronal function was found was also identified at the Cingulate Gyrus (t=1.06, p=0.01200).
CONCLUSION: We are proposing a translational clinical biological marker for patients diagnosed with Bipolar Disorder to guide physicians during the course of Lithium therapy and have identified neuroanatomical structures influenced by norepinephrine.

PMID: 26609422 [PubMed - as supplied by publisher]

COX-2 gene variants in bipolar disorder-I.

Psychiatr Danub. 2015 Dec;27(4):385-389

Authors: Ozdemircan A, Dasdemir S, Kucukali CI, Bireller ES, Ozturk H, Cakmakoglu B

BACKGROUND: Bipolar disorder-I (BD-I) is a complex illness, and multiple genes and environmental factors determine its pathogenesis. Several studies have ascertained that BD-I and inflammation are linked through shared genetic polymorphisms and gene expression, as well as altered cytokine levels. COX-2 gene polymorphisms affecting COX-2 levels may be associated with BD-I by altering the inflammatory response.
SUBJECTS AND METHODS: We investigated COX-2-765G?C and COX-2-1195A?G gene polymorphisms, which might be related for BD-I. The present analyses are based on 180 subjects with bipolar I disorder-I and 170 non-bipolar subjects. Genotyping of COX-2 gene polymorphisms (COX-2-765G?C, COX-2-1195A?G) were detected by PCR-RFLP.
RESULTS: We found a positive association of COX-2 gene variants for development of BD-I. There were statistically significant differences in COX-2-1195A?G genotypes and alleles between the controls and patients (p:0.000; p:0.000). The indivuals with COX-2-1195A?G AA genotype had seems to be associated for BD-I (p:0.000).
CONCLUSIONS: It seems that there is a protective role of COX-2-1195A?G G+ genotype against BD-I (p:0.000). In addition, there was a weak linkage disequilibrium between COX-2-765G?C and COX-2-1195A?G polymorphisms. Our findings suggest that COX-2-1195A?G AA genotype may faciliate the development of BD-I.

PMID: 26609651 [PubMed - as supplied by publisher]

Subcomponents of brain T2* relaxation in schizophrenia, bipolar disorder and siblings: A Gradient Echo Plural Contrast Imaging (GEPCI) study.

Schizophr Res. 2015 Oct 23;

Authors: Mamah D, Wen J, Luo J, Ulrich X, Barch DM, Yablonskiy D

Investigating brain tissue T2* relaxation properties in vivo can potentially guide the uncovering of neuropathology in psychiatric illness, which is traditionally examined post mortem. We use an MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique that produces inherently co-registered images allowing quantitative assessment of tissue cellular and hemodynamic properties. Usually described as R2* (=1/T2*) relaxation rate constant, recent developments in GEPCI allow the separation of cellular-specific (R2*C) and hemodynamic (BOLD) contributions to the MRI signal decay. We characterize BOLD effect in terms of tissue concentration of deoxyhemoglobin, i.e. CDEOXY, which reflects brain activity. 17 control (CON), 17 bipolar disorder (BPD), 16 schizophrenia (SCZ), and 12 unaffected schizophrenia sibling (SIB) participants were scanned and post-processed using GEPCI protocols. A MANOVA of 38gray matter regions ROIs showed significant group effects for CDEOXY but not for R2*C. In the three non-control groups, 71-92% of brain regions had increased CDEOXY. Group effects were observed in the superior temporal cortex and the thalamus. Increased superior temporal cortex CDEOXY was found in SCZ (p=0.01), BPD (p=0.01) and SIB (p=0.02), with bilateral effects in SCZ and only left hemisphere effects in BPD and SIB. Thalamic CDEOXY abnormalities were observed in SCZ (p=0.003), BPD (p=0.03) and SIB (p=0.02). Our results suggest that increased activity in certain brain regions is part of the underlying pathophysiology of specific psychiatric disorders. High CDEOXY in the superior temporal cortex suggests abnormal activity with auditory, language and/or social cognitive processing. Larger studies are needed to clarify the clinical significance of relaxometric abnormalities.

PMID: 26603058 [PubMed - as supplied by publisher]

Abnormal early brain responses during visual search are evident in schizophrenia but not bipolar affective disorder.

Schizophr Res. 2015 Nov 18;

Authors: VanMeerten NJ, Dubke RE, Stanwyck JJ, Kang SS, Sponheim SR

People with schizophrenia show deficits in processing visual stimuli but neural abnormalities underlying the deficits are unclear and it is unknown whether such functional brain abnormalities are present in other severe mental disorders or in individuals who carry genetic liability for schizophrenia. To better characterize brain responses underlying visual search deficits and test their specificity to schizophrenia we gathered behavioral and electrophysiological responses during visual search (i.e., Span of Apprehension [SOA] task) from 38 people with schizophrenia, 31 people with bipolar disorder, 58 biological relatives of people with schizophrenia, 37 biological relatives of people with bipolar disorder, and 65 non-psychiatric control participants. Through subtracting neural responses associated with purely sensory aspects of the stimuli we found that people with schizophrenia exhibited reduced early posterior task-related neural responses (i.e., Span Endogenous Negativity [SEN]) while other groups showed normative responses. People with schizophrenia exhibited longer reaction times than controls during visual search but nearly identical accuracy. Those individuals with schizophrenia who had larger SENs performed more efficiently (i.e., shorter reaction times) on the SOA task suggesting that modulation of early visual cortical responses facilitated their visual search. People with schizophrenia also exhibited a diminished P300 response compared to other groups. Unaffected first-degree relatives of people with bipolar disorder and schizophrenia showed an amplified N1 response over posterior brain regions in comparison to other groups. Diminished early posterior brain responses are associated with impaired visual search in schizophrenia and appear to be specifically associated with the neuropathology of schizophrenia.

PMID: 26603466 [PubMed - as supplied by publisher]

Cognitive Impairment in Schizophrenia: Interplay of BDNF and Childhood Trauma? A Review of Literature.

Psychiatr Q. 2015 Nov 24;

Authors: Sahu G, Malavade K, Jacob T

Cognitive impairment is a core feature of schizophrenia. These deficits can also serve as an endophenotype for the illness in genetic studies. There is evidence that suggests that cognition can be considered a reasonable target for intervention in both schizophrenia and bipolar disorder. One of the most studied genetic phenotypes for psychosis is brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. BDNF has an established role in neuronal development and cell survival in response to stress and is abnormally expressed in schizophrenia. Studies have shown that childhood trauma is associated with poor prognosis of schizophrenic patients. BDNF-Val66Met polymorphism has been shown to moderate the impact of childhood adversity on later expression of affective symptoms, suggesting the possibility of gene environment interactions. Considering the recent advances of neuroscience an up to date review of relevant literature is warranted in this field. This article reviews the current literature available regarding associations between the Val66Met polymorphism, childhood trauma and cognitive dysfunction in schizophrenia.

PMID: 26603624 [PubMed - as supplied by publisher]

Early stages of pediatric bipolar disorder: retrospective analysis of a Czech inpatient sample.

Neuropsychiatr Dis Treat. 2015;11:2855-2864

Authors: Goetz M, Novak T, Vesela M, Hlavka Z, Brunovsky M, Povazan M, Ptacek R, Sebela A

BACKGROUND: Approximately 30%-60% of adults diagnosed with bipolar disorder (BD) report onset between the ages 15 and 19 years; however, a correct diagnosis is often delayed by several years. Therefore, investigations of the early features of BD are important for adequately understanding the prodromal stages of the illness.
METHODS: A complete review of the medical records of 46 children and adolescents who were hospitalized for BD at two psychiatric teaching centers in Prague, Czech Republic was performed. Frequency of BD in all inpatients, age of symptom onset, phenomenology of mood episodes, lifetime psychiatric comorbidity, differences between very-early-onset (<13 years of age) and early-onset patients (13-18 years), and differences between the offspring of parents with and without BD were analyzed.
RESULTS: The sample represents 0.83% of the total number of inpatients (n=5,483) admitted during the study period at both centers. BD often started with depression (56%), followed by hypomania (24%) and mixed episodes (20%). The average age during the first mood episode was 14.9 years (14.6 years for depression and 15.6 years for hypomania). Seven children (15%) experienced their first mood episode before age 13 years (very early onset). Traumatic events, first-degree relatives with mood disorders, and attention deficit hyperactivity disorder were significantly more frequent in the very-early-onset group vs the early-onset group (13-18 years) (P?0.05). The offspring of bipolar parents were significantly younger at the onset of the first mood episode (13.2 vs 15.4 years; P=0.02) and when experiencing the first mania compared to the offspring of non-BD parents (14.3 vs 15.9 years; P=0.03). Anxiety disorders, substance abuse, specific learning disabilities, and attention deficit hyperactivity disorder were the most frequent lifetime comorbid conditions.
CONCLUSION: Clinicians must be aware of the potential for childhood BD onset in patients who suffer from recurrent depression, who have first-degree relatives with BD, and who have experienced severe psychosocial stressors.

PMID: 26604770 [PubMed - as supplied by publisher]

Bipolar Mood Tendency and Frontal Activation Using a Multichannel Near Infrared Spectroscopy.

Ment Illn. 2015 Sep 30;7(2):5767

Authors: Uehara T, Ishige Y

This study aims to examine the association of frontal functioning with subclinical bipolar spectrum by a newly developed convenient method. We investigated subclinical bipolar tendency and frontal lobe activation during word productions using multi-channel near infrared spectroscopy.
PARTICIPANTS: 44 healthy university students (mean ages 20.5 years old, and 29 female) gave their written informed consent, and we strictly protected privacy and anonymity was carefully preserved. A 13-items self-report questionnaire (Mood Disorders Questionnaire; MDQ) and a 16-channel near-infrared spectroscopy were used to compare frontal activations between two samples divided by median (4 points) of the total MDQ scores and to analyze correlations between relative changes of cerebral blood volume and bipolarity levels. There was no case suspected as bipolar disorders by MDQ screening (mean 3.4, max 10). Significant differences in lower activations were noted in the right and left pre-frontal cortex (PFC) with higher bipolarity scores using the specific software to analyze the NIRS waveform (P<0.05). Total MDQ were correlated significantly with frontal activation negatively in many channels; therefore, we conducted multiple linear regression to select significant frontal activations using the MDQ as a dependent variable. Stepwise method revealed that activation in left lateral PFC was negatively associated to bipolar tendency, and this regression model was significant (R2=0.10, F=4.5, P=0.04). Differences in frontal functioning suggest that subclinical bipolar tendencies might be related to left lateral PFC activations. It should be confirmed whether the identical pattern can be identified for clinical subjects with bipolar disorders.

PMID: 26605032 [PubMed - as supplied by publisher]

Alteration of complex negative emotions induced by music in euthymic patients with bipolar disorder.

J Affect Disord. 2015 Nov 10;191:15-23

Authors: Choppin S, Trost W, Dondaine T, Millet B, Drapier D, Vérin M, Robert G, Grandjean D

BACKGROUND: Research has shown bipolar disorder to be characterized by dysregulation of emotion processing, including biases in facial expression recognition that is most prevalent during depressive and manic states. Very few studies have examined induced emotions when patients are in a euthymic phase, and there has been no research on complex emotions. We therefore set out to test emotional hyperreactivity in response to musical excerpts inducing complex emotions in bipolar disorder during euthymia.
METHODS: We recruited 21 patients with bipolar disorder (BD) in a euthymic phase and 21 matched healthy controls. Participants first rated their emotional reactivity on two validated self-report scales (ERS and MAThyS). They then rated their music-induced emotions on nine continuous scales. The targeted emotions were wonder, power, melancholy and tension. We used a specific generalized linear mixed model to analyze the behavioral data.
RESULTS: We found that participants in the euthymic bipolar group experienced more intense complex negative emotions than controls when the musical excerpts induced wonder. Moreover, patients exhibited greater emotional reactivity in daily life (ERS). Finally, a greater experience of tension while listening to positive music seemed to be mediated by greater emotional reactivity and a deficit in executive functions.
LIMITATIONS: The heterogeneity of the BD group in terms of clinical characteristics may have influenced the results.
CONCLUSIONS: Euthymic patients with bipolar disorder exhibit more complex negative emotions than controls in response to positive music.

PMID: 26605497 [PubMed - as supplied by publisher]

Erratum: Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.

Nature. 2015 Nov 25;

Authors: Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, Zheng Y, Diffenderfer KE, Zhang J, Soltani S, Eames T, Schafer ST, Boyer L, Marchetto MC, Nurnberger JI, Calabrese JR, Oedegaard KJ, McCarthy MJ, Zandi PP, Alda M, Nievergelt CM, Pharmacogenomics of Bipolar Disorder Study, Mi S, Brennand KJ, Kelsoe JR, Gage FH, Yao J

PMID: 26605530 [PubMed - as supplied by publisher]

Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease.

PLoS One. 2015;10(11):e0142267

Authors: Nunes MA, Schöwe NM, Monteiro-Silva KC, Baraldi-Tornisielo T, Souza SI, Balthazar J, Albuquerque MS, Caetano AL, Viel TA, Buck HS

The use of lithium is well established in bipolar disorders and the benefits are being demonstrated in neurodegenerative disorders. Recently, our group showed that treatment with microdose lithium stabilized the cognitive deficits observed in Alzheimer's disease (AD) patients. In order to verify the lithium microdose potential in preventing the disease development, the aim of this work was to verify the effects of chronic treatment with microdose lithium given before and after the appearance of symptoms in a mouse model of a disease similar to AD. Transgenic mice (Cg-Tg(PDGFB-APPSwInd)20Lms/2J) and their non-transgenic litter mate genetic controls were treated with lithium carbonate (1.2 mg/Kg/day in drinking water) for 16 or 8 months starting at two and ten months of age, respectively. Similar groups were treated with water. At the end of treatments, both lithium treated transgenic groups and non-transgenic mice showed no memory disruption, different from what was observed in the water treated transgenic group. Transgenic mice treated with lithium since two months of age showed decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice. It is suitable to conclude that these data support the use of microdose lithium in the prevention and treatment of Alzheimer's disease, once the neurohistopathological characteristics of the disease were modified and the memory of transgenic animals was maintained.

PMID: 26605788 [PubMed - as supplied by publisher]

Executive function impairments in depression and bipolar disorder: association with functional impairment and quality of life.

J Affect Disord. 2015 Nov 12;190:744-753

Authors: Cotrena C, Branco LD, Shansis FM, Fonseca RP

BACKGROUND: The neuropsychological correlates of major depressive (MDD) and bipolar disorder (BD), and their association with quality of life (QOL) and functioning, have not been sufficiently studied in the literature. The present study aimed to compare executive functions, attention, processing speed, QOL and disability between patients with BD type I, BD type II, MDD and healthy controls.
METHOD: 205 participants (n=37 BDI, 81% female; n=35 BDII, 80% female; n=45 MDD, 69% female; n=89C, 46% female) aged between 18 and 67 years were administered an extensive neurocognitive battery consisting of widely used standardized measures such as the Trail Making Test, the Stroop Color-Word Test and a modified version of the Wisconsin Card Sorting Task. Z-scores were compared between groups by ANCOVA. The prevalence of impairments on each measure (Z-score<1.5) was compared between groups using chi-square tests. The associations between cognition, quality of life and functioning were evaluated through correlational analysis.
RESULTS: Patients with MDD showed poor selective and sustained attention, and exhibited impairments in timed tasks, suggesting low efficiency of executive processing. Patients with BDI displayed more widespread cognitive impairment than the remaining groups, and performed worse than subjects with MDD on measures of sustained attention and inhibitory control. Decision-making ability and attentional control were able to distinguish between patients with BDI and BDII. QOL and disability were most impaired in patients with BDI, and more closely associated with cognitive impairment than in the remaining groups.
LIMITATIONS: No control of pharmacological variables, clinical or demographic characteristics.
CONCLUSIONS: Our results provide important information regarding the nature and severity of the cognitive alterations associated with different mood disorders, and may contribute to the diagnosis, rehabilitation and treatment of these conditions.

PMID: 26606718 [PubMed - as supplied by publisher]

[Bipolar disorders and self-stigma].

Rev Med Suisse. 2015 Sep 16;11(486):1696, 1698-701

Authors: Richard-Lepouriel H

Despite wide media coverage in recent years, the stigmatization of people with bipolar disorder still exists. Bipolar people also have their own tendency to self-stigmatize that is to integrate their beliefs, prejudices and stigmatizing behaviors. The consequences are important: shame, guilt, withdrawal and renunciation to lead one's own life according to personal values increasing therefore the risk of mood relapses. Self-stigma is rarely assessed in clinical practice and few strategies have been designed to face them efficiently. Recognizing self-stigmatizing beliefs and challenging them are the first steps of this vast endeavour.

PMID: 26591079 [PubMed - in process]

Effect of the Putative Lithium Mimetic Ebselen on Brain myo-Inositol, Sleep and Emotional Processing in Humans.

Neuropsychopharmacology. 2015 Nov 23;

Authors: Singh N, Sharpley AL, Emir UE, Masaki C, Herzallah MM, Gluck MA, Sharp T, Harmer CJ, Vasudevan SR, Cowen PJ, Churchill GC

Lithium remains the gold standard in treating bipolar disorder but has unwanted toxicity and side effects. We previously reported that ebselen inhibits inositol monophosphatase (IMPase) and exhibits lithium-like effects in animal models through lowering of inositol. Ebselen has been tested in clinical trials for other disorders, enabling us to determine for the first time the effect of a blood-brain barrier penetrant IMPase inhibitor on human central nervous system (CNS) function. We now report that in a double-blind, placebo-controlled trial with healthy participants, acute oral ebselen reduced brain myo-inositol in the anterior cingulate cortex, consistent with CNS target engagement. Ebselen decreased slow-wave sleep and affected emotional processing by increasing recognition of some emotions, decreasing latency time in the acoustic startle paradigm and decreasing the reinforcement of rewarding stimuli. In summary, ebselen affects the phosphoinositide cycle and has CNS effects on surrogate markers that may be relevant to the treatment of bipolar disorder, which can be tested in future clinical trials.Neuropsychopharmacology accepted article preview online, 23 November 2015. doi:10.1038/npp.2015.343.

PMID: 26593266 [PubMed - as supplied by publisher]

Glycogen synthase kinase 3 is part of the molecular machinery regulating the adaptive response to LPS stimulation in microglial cells.

Brain Behav Immun. 2015 Nov 21;

Authors: Ajmone-Cat MA, D'Urso MC, di Blasio G, Brignone MS, De Simone R, Minghetti L

Repeated stimulation of TLR4 signaling by lipopolysaccharide (LPS) in microglia induces a state of tolerance/sensitization consisting in the reprogramming of the expression of pro-inflammatory genes in favor of anti-inflammatory ones. The molecular mechanisms underlying this adaptive response are far to be elucidated. Glycogen synthase kinase 3 (GSK3) has emerged as crucial regulator of TLR signaling, mediating the balance between pro- and anti-inflammatory functions in both periphery and central nervous system. The present study extends this notion identifying GSK3 as part of the molecular machinery regulating the LPS-adaptive response in microglial cells, by using primary microglial cultures and organotypic hippocampal slices (OHSCs). We found that lithium chloride (LiCl), a widely used GSK3 inhibitor and the mainstay treatment for bipolar disorder, reinforced the LPS adaptive response by enhancing both downregulation of pro-inflammatory genes (inducible nitric oxide synthase, interleukin 1?, interleukin 6, tumor necrosis factor ?), and upregulation of genes typically associated to anti-inflammatory functions (interleukin 10 and MRC1). The effects of GSK3 inhibition were mimicked by Wnt3a, added exogenously, and reversed by Inhibitor of Wnt-Response-1-endo, a pharmacological disruptor of the canonical Wnt/?-catenin pathway, and GW9662, a selective peroxisome proliferator activated receptor ? antagonist, suggesting that these two pathways are involved in the regulation of LPS-tolerance/sensitization by GSK. Finally, LiCl treatment of OHSCs enhanced the protective functional consequences of the microglial adaptive response to LPS on oligodendrocyte maturation, as indicated by MBP mRNA upregulation. These results further indicate GSK3 as key component in the orchestration of neuroinflammation and target for neuroprotective strategies.

PMID: 26593276 [PubMed - as supplied by publisher]

Efficacy and acceptability of pharmacotherapy for smoking cessation in adults with serious mental illness: A systematic review and network meta-analysis.

Addiction. 2015 Nov 23;

Authors: Roberts E, Evins AE, McNeill A, Robson D

BACKGROUND AND AIMS: To assess the efficacy and tolerability of adjunctive pharmacotherapy for smoking cessation in adults with serious mental illness (SMI) by means of a systematic review and network meta-analysis.
METHOD: We searched Embase, Medline, PsychINFO and the Cochrane Central Register of Controlled Trials, from database inception to 1 December 2014 for randomised controlled trials (RCTs) published in English. We included all studies of smokers with SMI (including schizophrenia, schizoaffective disorder, bipolar disorder, delusional disorder and depressive psychoses) who were motivated to quit smoking. Pharmacotherapies included nicotine replacement therapy (NRT), bupropion and varenicline delivered as monotherapy or in combination compared with each other or placebo. The efficacy outcome was self-reported sustained smoking cessation, biochemically verified at the longest reported time point. The tolerability outcome was number of patients discontinuing the trial due to any adverse event.
RESULTS: Seventeen study reports were included which represented fourteen individual RCTs. No trials were found in patients with depressive psychoses, delusional disorder or which compared NRT monotherapy with placebo. A total of 356 and 423 participants were included in the efficacy and tolerability analyses respectively. From the network meta-analysis both bupropion and varenicline were more effective than placebo (OR 4.51 95% Credible Interval (CrI) 1.45 to 14.04 and OR 5.17 95% CrI 1.78 to 15.06 respectively). Data were insensitive to an assessment of varenicline versus bupropion (OR 1.15 95% CrI 0.24 to 5.45). There were no significant differences in tolerability. All outcomes were rated by GRADE criteria as very low quality.
CONCLUSIONS: The limited evidence available to date suggests that bupropion and varenicline are effective and acceptable for smoking cessation in adults with serious mental illnesses. This article is protected by copyright. All rights reserved.

PMID: 26594837 [PubMed - as supplied by publisher]

Low social rhythm regularity predicts first onset of bipolar spectrum disorders among at-risk individuals with reward hypersensitivity.

J Abnorm Psychol. 2015 Nov;124(4):944-52

Authors: Alloy LB, Boland EM, Ng TH, Whitehouse WG, Abramson LY

The social zeitgeber model (Ehlers, Frank, & Kupfer, 1988) suggests that irregular daily schedules or social rhythms provide vulnerability to bipolar spectrum disorders. This study tested whether social rhythm regularity prospectively predicted first lifetime onset of bipolar spectrum disorders in adolescents already at risk for bipolar disorder based on exhibiting reward hypersensitivity. Adolescents (ages 14-19 years) previously screened to have high (n = 138) or moderate (n = 95) reward sensitivity, but no lifetime history of bipolar spectrum disorder, completed measures of depressive and manic symptoms, family history of bipolar disorder, and the Social Rhythm Metric. They were followed prospectively with semistructured diagnostic interviews every 6 months for an average of 31.7 (SD = 20.1) months. Hierarchical logistic regression indicated that low social rhythm regularity at baseline predicted greater likelihood of first onset of bipolar spectrum disorder over follow-up among high-reward-sensitivity adolescents but not moderate-reward-sensitivity adolescents, controlling for follow-up time, gender, age, family history of bipolar disorder, and initial manic and depressive symptoms (? = -.150, Wald = 4.365, p = .037, odds ratio = .861, 95% confidence interval [.748, .991]). Consistent with the social zeitgeber theory, low social rhythm regularity provides vulnerability to first onset of bipolar spectrum disorder among at-risk adolescents. It may be possible to identify adolescents at risk for developing a bipolar spectrum disorder based on exhibiting both reward hypersensitivity and social rhythm irregularity before onset occurs. (PsycINFO Database Record

PMID: 26595474 [PubMed - in process]

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