Vulnerability For Schizophrenia Research Articles

Statistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes

Although schizophrenia is generally considered to occur as a consequence of multiple genes that interact with one another, very few methods have been developed to model epistasis. Phenotype definition has also been a major challenge for research on the genetics of schizophrenia. In this report we use novel statistical techniques to address the high dimensionality of genomic data, and we apply a refinement in phenotype definition by basing it on the occurrence of brain changes during the early course of the illness, as measured by repeated MR scans (i.e., an “intermediate phenotype.” The method combines a machine learning algorithm, the ensemble method using stochastic gradient boosting, with traditional general linear model statistics. We began with fourteen genes that are relevant to schizophrenia based on association studies or their role in neurodevelopment and then used statistical techniques to reduce them to five genes and 17 SNPs that had a significant statistical interaction: 5 for PDE4B, 4 for RELN, 4 for ERBB4, 3 for DISC1, and one for NRG1. Five of the SNPs involved in these interactions replicate previous research, in that these five SNPs have previously been identified as schizophrenia vulnerability markers or implicate cognitive processes relevant to schizophrenia. This ability to replicate previous work suggests that our method has potential for detecting a meaningful epistatic relationships among the genes that influence brain abnormalities in schizophrenia.

Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia

The symptoms of schizophrenia involve profound dysfunction of the prefrontal cortex (PFC). PFC networks create our “mental sketch pad”, and PFC dysfunction contributes to symptoms such as cognitive deficits, thought disorder, delusions and hallucinations. Neuropathological studies of schizophrenia have shown marked loss of dendritic spines in deep layer III, the sublayer where PFC microcircuits reside. The microcircuits consist of recurrent excitatory pyramidal cell networks that interconnect on spines, and excite each other via NMDA receptor signaling. The pyramidal cell persistent firing is sculpted by lateral inhibition from GABAergic basket and chandelier cells, thus creating tuned, persistent firing needed for accurate representational knowledge (i.e., working memory). The strength of pyramidal cell network connections is markedly and flexibly altered by intracellular signaling pathways in dendritic spines, a process called dynamic network connectivity (DNC). DNC proteins such as HCN channels are concentrated on dendritic spines in deep layer III. Under optimal conditions, network inputs to pyramidal cells are strengthened by noradrenergic alpha-2A inhibition of cAMP–HCN channel signaling, and sculpted by dopamine D1-cAMP–HCN channel weakening of inappropriate inputs. However, with stress exposure, high levels of cAMP–HCN channel signaling produces a collapse in network firing. With chronic stress exposure, spines reduce in size and are lost, and this process involves increased PKC signaling. Importantly, molecules that normally strengthen PFC networks connections and/or reverse the stress response, are often genetically altered in schizophrenia. As exposure to stress is a key factor in the precipitation of schizophrenic symptoms, these dysregulated signaling pathways in deep layer III may interact with already vulnerable circuitry to cause spine loss and the descent into illness.

Movement disorders in nonpsychotic siblings of patients with nonaffective psychosis

Movement disorders such as dyskinesia and Parkinsonism have frequently been reported in (drug-naïve) patients with nonaffective psychosis. Therefore movement disorders may be related to schizophrenia. Siblings of patients with nonaffective psychosis also appear to have subtle forms of movement disorders. This suggests that motor abnormalities may also be related to the risk of developing the disease. Subtle forms are not always detected with the use of the standard observation-based clinical rating scales, which are less sensitive than mechanical instrument measurement. This study compared the presence and severity of dyskinesia and Parkinsonism in 42 non-psychotic siblings of patients with nonaffective psychosis and in 38 controls as measured by mechanical instruments and clinical rating scales. There were no significant differences in movement disorders between siblings and controls on the basis of clinical assessments. However, mechanical measurements indicated that siblings compared to controls displayed significantly more dyskinesia and Parkinsonism signs. These results suggest that motor signs could be markers of vulnerability for psychosis or schizophrenia. In addition this study shows that mechanical instrument measurement of movement disorders is more sensitive than assessment with clinical rating scales. Therefore, it may be used in screening programs for populations at risk for psychosis.

Birth characteristics and schizotypy: Evidence of a potential “second hit”

Schizophrenia is associated with a modest increase in winter births as well as increased odds of being born in more densely populated and midrange latitude regions. It is unclear the degree to which these findings hold for individuals with schizotypy, defined in terms of the personality organization that is a potential precursor to schizophrenia-spectrum disorders. This issue is important for understanding whether birth factors contribute to general schizophrenia vulnerability or whether they reflect a secondary “hit” that increases the likelihood of psychosis onset in vulnerable individuals. The present project examined season of birth, birthplace population and birth location in a large group of young adults from the southeastern United States. Individuals with extreme schizotypy scores did not differ from those without schizotypy in season of birth, birthplace latitude or population. However, 60% of individuals within the schizotypy group who reported a diagnosis of schizophrenia or prior hospitalization were born during winter months; a dramatic difference from other individuals within the schizotypy group. We also found that individuals with negative/schizoid traits showed a birthplace population less than half that of other individuals with schizotypy. Season of birth appears to be a “second hit” that is related to expression of psychopathology onset in vulnerable individuals. This finding, and the unexpected inverse relationship between birthplace population and negative/schizoid traits, is discussed.

Cannabis use and cognitive dysfunction

Byline: Amresh. Shrivastava, Megan. Johnston, Ming. Tsuang This review considers the effects of cannabis on cognitive functioning, in both short and long term. Although the general impression supported by many studies is that cannabis causes cognitive decline, particularly with long-term usage, some research suggests that this may not be the case. Nevertheless, certain specific neuropsychological parameters have been found to be affected. Most commonly and consistently reported are response time, prolongation of word viewing time, basic oculomotor deficit, residual verbal memory and executive functioning. The pathways to cognitive dysfunction are given particular focus, including the role of the central nervous system (CNS) cannabinoid system. Finally, the psychiatric effects of cannabis are considered in light of the idea that cognitive function may be the common denominator in the association between cannabis and psychotic disorders. Effect of Cannabis on Cognition Cannabis is one of the most commonly abused illicit drugs. The World Health Organization [sup][1] reports that almost 3% of the world's adult population abuses cannabis, with many more individuals reporting less frequent use. Adolescents in particular consume high levels of cannabis, starting generally between 12 and 16 years of age. This is an important factor from a psychiatric and developmental point of view. [sup][2] Cannabis use is of important consideration in light of its recognized acute and long-term health effects. [sup][1],[3] Active compounds of cannabis, called cannabidols, have 64 active isomers, each having different effects on human health and behavior. Only one metabolite, tetrahydrocannabinol (THC), is reported to be an active metabolite responsive for its effects. [sup][4] Studies show that it induces both psychical and physical dependencies, [sup][5] but the perception of withdrawal is weak on account of its slow elimination. [sup][6] There is a widely held belief that cannabis is inert to the brain, [sup][7] and although the psychological consequences are quite evident, the population at large seems unconvinced. There is much debate about the nature of cannabis dependence, as it is considered non-addicting due to the absence of a withdrawal state. This presumption has also been proved wrong. [sup][6] The general impression supported by many studies is that cannabis causes cognitive decline, particularly with long-term usage. Majority of studies have suggested a significant cognitive decline in cannabis abusers compared to non-abusers and healthy controls. [sup][8],[9],[10] A report by Bartholomew et al. [sup][11] suggested that cannabis use has a detrimental effect on prospective memory ability in young adults but users may not be aware of these deficits. Cannabis is known to produce substantial acute effects on human cognition and visuomotor skills. Many recent studies additionally revealed rather long-lasting effects on basic oculomotor control, especially after chronic use. [sup][12] Even so, it is still unknown to what extent these deficits play a role in everyday tasks that strongly rely on an efficient saccade system, such as reading. Cannabis has a negative impact on cognition; however, the current body of research literature does not provide evidence of significant, long-term effects due to cannabis use. Several acute effects are noted and some are suggestive of negative mental health consequences. [sup][13] Evidence from both animal and human studies suggests that the severity of the effects of cannabis use on cognitive development is dependent on the age when cannabis use begins. [sup][14] One possible explanation is that those who begin cannabis use early in adolescence are more likely to become heavily dependent. It is plausible that chronic cannabis abuse will then interfere with educational and vocational training. From a more biological perspective, however, use of cannabis during critical developmental periods in the still maturing brain may induce persistent alterations in brain structure and brain function. …

Dysfunctional Brain Networks and Genetic Risk for Schizophrenia: Specific Neurotransmitter Systems

Multiple neurotransmitter circuits are disturbed in schizophrenia, and the dopamine hypothesis of schizophrenia prevails as the hypothesis with most empirical support. On the other hand, schizophrenia is highly heritable with a pattern consistent with both common and rare allelic variants and gene × environment interaction. Advances in the field of neuroimaging have expanded our knowledge of intermediate phenotypes, the neurobiological processes that convey the risk from the genes to the complex phenotype. In this article, we review the recent and continuously accumulating evidence from in vivo imaging studies aiming at characterizing neurochemical intermediate phenotypes of schizophrenia. Dopaminergic alterations in schizophrenia are shared by individuals at genetic risk who do not express the illness, suggesting a "dopamine hypothesis of schizophrenia vulnerability." This hypothesis has the potential to help us better understand the dopaminergic dysfunction in the context of the complex pathophysiological process leading to schizophrenia. In the future, neurotransmitter imaging studies should investigate the gene × environment interaction in schizophrenia, and try to identify neurobiological correlates of heightened sensitivity to environmental stressors (e.g., cannabis, childhood trauma, and other psychosocial stress) in genetically vulnerable individuals.

Expression of Interneuron Markers in the Dorsolateral Prefrontal Cortex of the Developing Human and in Schizophrenia

The onset of schizophrenia symptoms in late adolescence implies a neurodevelopmental trajectory for the disease. Indeed, the γ-aminobutyric acid (GABA) inhibitory system shows protracted development, and GABA-ergic deficits are widely replicated in postmortem schizophrenia studies. The authors examined expression of several interneuron markers across postnatal human development and in schizophrenia to assess whether protracted development of certain interneuron subpopulations may be associated with a particular vulnerability in schizophrenia. RNA was extracted postmortem from dorsolateral prefrontal cortex of individuals from age 6 weeks to 49 years (N=68) and from a cohort of normal comparison subjects and schizophrenia patients (N=74, 37 pairs). Expression levels of parvalbumin, cholecystokinin, somatostatin, neuropeptide Y, calretinin, calbindin, and vasoactive intestinal peptide were measured by quantitative reverse transcription-polymerase chain reaction. Changes in calretinin protein levels were examined by Western blot. Interneuron marker genes followed one of three general expression profiles: either increasing (parvalbumin, cholecystokinin) or decreasing (somatostatin, calretinin, neuropeptide Y) in expression over postnatal life, with the most dramatic changes seen in the first few years before reaching a plateau; or increasing to peak expression in the toddler years before decreasing (calbindin, vasoactive intestinal peptide). mRNA expression of all genes, with the exception of calbindin (which increased), showed a reduction (8%-31%) in schizophrenia. Somatostatin showed the most dramatic reduction (31%) in schizophrenia. It appears that a heterogeneous population of interneurons is implicated in schizophrenia. Further studies are needed to determine whether specific interneuron subpopulations are altered or whether common or distinct upstream pathways are responsible for interneuron deficits in schizophrenia.

Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: Patterning, proliferation, and mitochondrial functions of 22q11 genes

DiGeorge, or 22q11 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by deletion of a minimum of 32 contiguous genes on human chromosome 22, and presumably results from diminished dosage of one, some, or all of these genes—particularly during development. Nevertheless, the normal functions of 22q11 genes in the embryo or neonate, and their contribution to developmental pathogenesis that must underlie 22q11DS are not well understood. Our data suggests that a substantial number of 22q11 genes act specifically and in concert to mediate early morphogenetic interactions and subsequent cellular differentiation at phenotypically compromised sites—the limbs, heart, face and forebrain. When dosage of a broad set of these genes is diminished, early morphogenesis is altered, and initial 22q11DS phenotypes are established. Thereafter, functionally similar subsets of 22q11 genes—especially those that influence the cell cycle or mitochondrial function—remain expressed, particularly in the developing cerebral cortex, to regulate neurogenesis and synaptic development. When dosage of these genes is diminished, numbers, placement and connectivity of neurons and circuits essential for normal behavior may be disrupted. Such disruptions likely contribute to vulnerability for schizophrenia, autism, or attention deficit/hyperactivity disorder seen in most 22q11DS patients.

The failure of the schizophrenia concept and the argument for its replacement by hebephrenia: applying the medical model for disease recognition

The failure of the schizophrenia concept and the argument for its replacement by hebephrenia: applying the medical model for disease recognition

FOXP2 gene and language impairment in schizophrenia: association and epigenetic studies

BackgroundSchizophrenia is considered a language related human specific disease. Previous studies have reported evidence of positive selection for schizophrenia-associated genes specific to the human lineage. FOXP2 shows two important features as a convincing candidate gene for schizophrenia vulnerability: FOXP2 is the first gene related to a language disorder, and it has been subject to positive selection in the human lineage.MethodsTwenty-seven SNPs of FOXP2 were genotyped in a cohort of 293 patients with schizophrenia and 340 controls. We analyzed in particular the association with the poverty of speech and the intensity of auditory hallucinations. Potential expansion of three trinucleotide repeats of FOXP2 was also screened in a subsample. Methylation analysis of a CpG island, located in the first exon of the gene, was performed in post-mortem brain samples, as well as qRT-PCR analysis.ResultsA significant association was found between the SNP rs2253478 and the item Poverty of speech of the Manchester scale (p = 0.038 after Bonferroni correction). In patients, we detected higher degree of methylation in the left parahippocampus gyrus than in the right one.ConclusionsFOXP2 might be involved in the language disorder in patients with schizophrenia. Epigenetic factors might be also implicated in the developing of this disorder.

Social skill and social cognition in adolescents at genetic risk for psychosis

Adolescents at genetic high risk (GHR) for schizophrenia have shown social skill impairments and there is some evidence to suggest they have Theory of Mind (ToM) deficits; however no research has used a standardized, performance-based behavioral measure to assess social functioning in this population nor evaluated ToM with a well-validated measure. We evaluated the psychometric properties of a new, theoretically-derived assessment of social functioning in GHR adolescents: the “High-Risk Social Challenge” task (HiSoC). The second aim was to explore whether GHR adolescents would show social skill and ToM deficits as compared to a non-psychiatric control (NPC) group. The present study evaluated social functioning with the HiSoC and ToM with the Eyes Test in 23 GHR adolescents and 31 NPCs. The HiSoC demonstrated high levels of reliability and validity. The GHR adolescents showed social skill impairments, but not ToM deficits. The results suggest that the HiSoC is a potentially useful new measure of social functioning in GHR adolescents. Furthermore, the findings add to the current body of literature that indicates that social skill impairments are related to schizophrenia vulnerability.

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

Schizophrenia is a highly complex inheritable disease characterized by numerous genetic susceptibility elements, each contributing a modest increase in risk for the disease. Although numerous linkage or association studies have identified a large set of schizophrenia-associated loci, many are controversial. In addition, only a small portion of these loci overlaps with the large cumulative pool of genes that have shown changes of expression in schizophrenia. Here, we applied a genomic gene-function approach to identify susceptibility loci that show direct effect on gene expression, leading to functional abnormalities in schizophrenia. We carried out an integrated analysis by cross-examination of the literature-based susceptibility loci with the schizophrenia-associated expression gene list obtained from our previous microarray study (Journal of Human Genetics (2009) 54: 665-75) using bioinformatic tools, followed by confirmation of gene expression changes using qPCR. We found nine genes (CHGB, SLC18A2, SLC25A27, ESD, C4A/C4B, TCP1, CHL1 and CTNNA2) demonstrate gene-function correlation involving: synapse and neurotransmission; energy metabolism and defense mechanisms; and molecular chaperone and cytoskeleton. Our findings further support the roles of these genes in genetic influence and functional consequences on the development of schizophrenia. It is interesting to note that four of the nine genes are located on chromosome 6, suggesting a special chromosomal vulnerability in schizophrenia.

The effect of G72 genotype on neural correlates of memory encoding and retrieval

Polymorphisms in the G72 (also named d-amino acid oxidase activator, DAOA) gene increase the vulnerability for schizophrenia and affective psychosis. Three recent genetic neuroimaging studies showed that variation in G72 influences the brain activity in the medial temporal lobe (MTL), supporting the hypothesis that G72 might play a modulatory role on brain activity in MTL structures. In the present study we therefore investigated the effect of G72 on the neural correlates of long-term memory encoding and retrieval in a large sample of healthy subjects (n=83) using functional magnetic resonance imaging. A face encoding and a face retrieval memory task were chosen because on the one hand they specifically activate MTL structures and on the other hand they tap into memory processes that are compromised in patients with schizophrenia and affective disorder. Despite a strong a-priori hypothesis of genotype group activation differences in the MTL along with a large sample size we did neither find an effect of G72 genotype status on brain activity in the MTL nor in any other brain regions. The present data therefore do not support the view of a general modulatory role of G72 on MTL brain activity, at least not in the domain of long-term memory encoding and retrieval. Our results highlight the importance of replication studies in genetic neuroimaging.

Les effets du cannabis sur la santé

Cannabis remains the most widely used illicit substance throughout the world with approximately 166 million consumers annually. In comparison with the general population, cannabis users have a reduced socioeconomic level, a higher prevalence of unemployment and a lesser overall satisfaction with life. Cannabis use represents a risk factor for physical and mental illness. In vulnerable patients, cannabis worsens certain mental disorders, especially anxiety disorder and suicidal conduct. The relationship between cannabis and schizophrenia is very close. Patients with certain schizophrenia vulnerability who use cannabis increase their risk of developing the disease. Genetic, biological and environmental factors are likely to be implicated in this process.

Neurological soft signs in psychometrically identified schizotypy

Patients with schizophrenia often exhibit structural brain abnormalities, as well as neurological soft signs (NSS), consistent with its conceptualization as a neurodevelopmental disorder. NSS are mild, presumably nonlocalizing, neurological impairments that are inferred from performance deficits in domains such as sensory integration, motor coordination, and motor sequencing. The vulnerability for schizophrenia is presumed to be expressed across a broad continuum of impairment referred to as schizotypy. It is hypothesized that nondisordered people along the schizotypy continuum should exhibit elevated rates of NSS. The present study examined the relation of psychometrically identified positive and negative schizotypy with NSS using the Neurological Evaluation Scale in a nonclinically ascertained sample of young adults (n=177). As hypothesized, negative, but not positive, schizotypy was related to increased NSS in tasks that assessed fine and gross motor coordination, motor sequencing, eye movement abnormalities, and memory recall. However, positive schizotypy was associated with increased NSS in tasks related to sensory integration dysfunction. In general, the positive×negative schizotypy interaction term was unrelated to individual NSS tasks. The findings support: a) the theory that the vulnerability for schizophrenia is expressed across a broad continuum of subclinical and clinical impairment referred to as schizotypy; b) the multidimensional structure of schizotypy; and c) the notion that schizotypy is an appropriate construct for understanding the etiology and development of schizophrenia-spectrum disorders.

Deficits in Implicit Attention to Social Signals in Schizophrenia and High Risk Groups: Behavioural Evidence from a New Illusion

BackgroundAn increasing body of evidence suggests that the apparent social impairments observed in schizophrenia may arise from deficits in social cognitive processing capacities. The ability to process basic social cues, such as gaze direction and biological motion, effortlessly and implicitly is thought to be a prerequisite for establishing successful social interactions and for construing a sense of “social intuition.” However, studies that address the ability to effortlessly process basic social cues in schizophrenia are lacking. Because social cognitive processing deficits may be part of the genetic vulnerability for schizophrenia, we also investigated two groups that have been shown to be at increased risk of developing schizophrenia-spectrum pathology: first-degree relatives of schizophrenia patients and men with Klinefelter syndrome (47,XXY).ResultsWe compared 28 patients with schizophrenia, 29 siblings of patients with schizophrenia, and 29 individuals with Klinefelter syndrome with 46 matched healthy control subjects on a new paradigm. This paradigm measures one's susceptibility for a bias in distance estimation between two agents that is induced by the implicit processing of gaze direction and biological motion conveyed by these agents. Compared to control subjects, patients with schizophrenia, as well as siblings of patients and Klinefelter men, showed a lack of influence of social cues on their distance judgments.ConclusionsWe suggest that the insensitivity for social cues is a cognitive aspect of schizophrenia that may be seen as an endophenotype as it appears to be present both in relatives who are at increased genetic risk and in a genetic disorder at risk for schizophrenia-spectrum psychopathology. These social cue–processing deficits could contribute, in part, to the difficulties in higher order social cognitive tasks and, hence, to decreased social competence that has been observed in these groups.

P.3.04 Cognitive functions and level of stress in schizophrenia-like psychoses before treatment and during quetiapine therapy

Cogent evidence has shown that schizophrenia vulnerability is enhanced by psychosocial stress in adolescence, yet the underpinnings of this phenomenon remain elusive. One of the animal models that best capture the relationship between juvenile stress and schizophrenia is isolation rearing (IR). This manipulation, which consists in subjecting rats to social isolation from weaning through adulthood, results in neurobehavioral alterations akin to those observed in schizophrenia patients. In particular, IR-subjected rats display a marked reduction of the prepulse inhibition (PPI) of the startle reflex, which are posited to reflect imbalances in dopamine neurotransmission in the nucleus accumbens (NAcc). We recently documented that the key neurosteroidogenic enzyme 5α-reductase (5αR) plays an important role in the dopaminergic regulation of PPI; given that IR leads to a marked down-regulation of this enzyme in the NAcc, the present study was designed to further elucidate the functional role of 5αR in the regulation of PPI of IR-subjected rats.We studied the impact of the prototypical 5αR inhibitor finasteride (FIN) on the PPI deficits and NAcc steroid profile of IR-subjected male rats, in comparison with socially reared (SR) controls.FIN (25–100 mg/kg, i.p.) dose-dependently countered IR-induced PPI reduction, without affecting gating integrity in SR rats. The NAcc and striatum of IR-subjected rats displayed several changes in neuroactive steroid profile, including a reduction in pregnenolone in both SR and IR-subjected groups, as well as a decrease in allopregnanolone content in the latter group; both effects were significantly opposed by FIN.These results show that 5αR inhibition counters the PPI deficits induced by IR, possibly through limbic changes in pregnenolone and/or allopregnanolone concentrations.

Abnormal prefrontal cortical activity and connectivity during response selection in first episode psychosis, chronic schizophrenia, and unaffected siblings of individuals with schizophrenia

The search for genes conferring liability for schizophrenia may be aided by the identification of endophenotypes. Response selection is a heritable cognitive function that is impaired in patients with schizophrenia and their unaffected siblings. The abnormalities in cerebral function that presumably underlie the deficit in patients and unaffected siblings remain to be elucidated. Cerebral neurophysiology during performance of a 4-choice reaction time (CRT) task in 25 patients with schizophrenia (15 medication free first episode (FEP) and 10 chronic patients), 32 controls, and 12 unaffected siblings of individuals with schizophrenia was investigated using fMRI. CRT was impaired in both medication free FEP and chronic patients with schizophrenia, and unaffected siblings. FEP patients, chronic patients, and unaffected siblings demonstrated greater BOLD response in the right dorsolateral prefrontal cortex (dlPFC) during CRT task blocks. The nature of the altered activation in the dlPFC was further examined using functional connectivity analysis. This revealed marked reductions in connectivity between the right dlPFC and multiple brain regions in both patient groups and, to a lesser degree, unaffected siblings. The magnitude of connectivity between right dlPFC and inferior parietal lobule correlated with task performance in the combined patient/unaffected siblings group, but not controls suggesting that the network of brain regions recruited to perform the task differed as a function of genetic liability for schizophrenia. The findings suggest that altered activity and connectivity of the right dlPFC appears to be related to genetic vulnerability for schizophrenia and may represent a potential endophenotype of the disorder.

GABAergic promoter hypermethylation as a model to study the neurochemistry of schizophrenia vulnerability

The neuronal GABAergic mechanisms that mediate the symptomatic beneficial effects elicited by a combination of antipsychotics with valproate (a histone deacetylase inhibitor) in the treatment of psychosis (expressed by schizophrenia or bipolar disorder patients) are unknown. This prompted us to investigate whether the beneficial action of this combination results from a modification of histone tail covalent esterification or is secondary to specific chromatin remodeling. The results suggest that clozapine, or sulpiride associated with valproate, by increasing DNA demethylation with an unknown mechanism, causes a chromatin remodeling that brings about a beneficial change in the epigenetic GABAergic dysfunction typical of schizophrenia and bipolar disorder patients.

Schizophrenia and Idiopathic Unconjugated Hyperbilirubinemia (Gilberts Syndrome)

Idiopathic unconjugated hyperbilirubinemia (Gilberts syndrome, GS) is a relatively common congenital hyperbilirubinemia occurring in 3-7% of the world population. It has been recognized as a benign familial condition in which hyperbilirubinemia occurs in the absence of structural liver disease or hemolysis, and the plasma concentration of conjugated bilirubin is normal. Recently, it was reported that uncojugated bilirubin had neurotoxicity in the developing nervous system. The ‘neurodevelopmental hypothesis’ of schizophrenia was proposes that a yet-unidentified event occurring in utero or early postnatal life. We have observed that patients suffering from schizophrenia frequently present an increased unconjugated bilirubin plasma concentration when admitted to the hospital. Therefore, we had notice the relation between unconjugated bilirubin and the etiology and vulnerability of schizophrenia. Our reported findings suggest that there are significant biological and clinical character differences between schizophrenic patients with GS and without GS. From the viewpoint of heterogeneity of schizophrenia, there may be poor outcome for the subtype of schizophrenia with GS. Keywords: Schizophrenia, (Gilbert's Syndrome), Hyperbilirubinemia, liver disease, neurodevelopmental hypothesis, etiology, heterogeneity