Risk Of Developing Schizophrenia Research Articles

Dysbindin-1, BDNF, and GABAergic Transmission in Schizophrenia.

Schizophrenia is a psychiatric disorder characterized by hallucinations, anhedonia, disordered thinking, and cognitive impairments. Both genetic and environmental factors contribute to schizophrenia. Dysbindin-1 (DTNBP1) and brain-derived neurotrophic factor (BDNF) are both genetic factors associated with schizophrenia. Mice lacking Dtnbp1 showed behavioral deficits similar to human patients suffering from schizophrenia. DTNBP1 plays important functions in synapse formation and maintenance, receptor trafficking, and neurotransmitter release. DTNBP1 is co-assembled with 7 other proteins into a large protein complex, known as the biogenesis of lysosome-related organelles complex-1 (BLOC-1). Large dense-core vesicles (LDCVs) are involved in the secretion of hormones and neuropeptides, including BDNF. BDNF plays important roles in neuronal development, survival, and synaptic plasticity. BDNF is also critical in maintaining GABAergic inhibitory transmission in the brain. Two studies independently showed that DTNBP1 mediated activity-dependent BDNF secretion to maintain inhibitory transmission. Imbalance of excitatory and inhibitory neural activities is thought to contribute to schizophrenia. In this mini-review, we will discuss a potential pathogenetic mechanism for schizophrenia involving DTNBP1, BDNF, and inhibitory transmission. We will also discuss how these processes are interrelated and associated with a higher risk of schizophrenia development.

Association between brain-derived neurotropic factor gene variant (rs6265; C > T) and schizophrenia, its psychopathology and intelligence

Background and objectivesThe etiology of schizophrenia (SCZ) is not yet known, but the genetic factor has an essential role. Its heritability is estimated up to 85 percent. This study aimed to determine whether the selected brain-derived neurotropic factor (BDNF) gene variant (rs6265) is associated with SCZ, its psychopathology and intelligence quotient (IQ). MethodsRs6265 was genotyped in 159 participants, including 71 unrelated patients with SCZ (males = 40 [56%]) and 88 healthy controls (males = 35 [40%]). Psychopathology assessment was done by using positive and negative symptoms scale (PANSS), and IQ was measured by Wechsler adult intelligence scale (WAIS). COCAPHASE and CLUMP22 softwares were used to compare allele and genotype frequencies respectively. Two-way multivariate ANOVA was done using SPSS22 to evaluate the effects of the group (patients and healthy control) and the genotype on the test scores, including PANSS and WAIS scores, considering sex and smoking status as covariates. ResultsThe study showed that the BDNF rs6265 C allele and CC genotypes, psychopathology, including PANSS scores, and also IQ were significantly different in all, male and female patients compared to healthy participants. For rs6265, we found significantly higher frequencies of the C allele (P = 0.04) in all participants with SCZ.The findings also revealed that BDNF polymorphism (rs6265) increased significantly the risk of SCZ in different genetic models. ConclusionThe results showed that the BDNF rs6265 may be associated with the risk of SCZ development in an Iranian group of patients with SCZ. These results may be helpful in better understanding the role of the BDNF gene in the pathogenesis of the disorder.

The role of the interaction between the FKBP5 gene and stressful life events in the pathophysiology of schizophrenia: A narrative review

Stressful life events have been associated with increased risk for development of schizophrenia and play a pivotal role in its psychopathology. Genes related to stress response, such as FKBP5 gene associated with hypothalamic–pituitary–adrenal (HPA) axis, modulate brain response to childhood trauma and determine individual susceptibility for development and course of psychosis. It this review we provide an overview of FKBP5 gene role in human neurophysiology, its association with HPA axis and its role in stress response system in animals and humans. Moreover, we took a closer look on the studies showing the interaction between FKBP5 gene and stressful life events in the pathophysiology of schizophrenia. We explain how interactions between trauma and FKBP5 gene polymorphisms contribute to development of the disease, severity of psychotic symptoms and cognitive disturbances. We also discuss epigenetic modifications that may contribute to altered HPA axis reactivity to stress entailing higher risk for development of psychosis. Considering the pivotal role of FKBP5 gene in physiopathology of schizophrenia we discuss a possible use of new therapeutic agents that may influence HPA axis activity related to the FKBP5 protein especially in individuals exposed to early trauma.

Lipids and mental disorders: Evidence, uncertainties and perspectives

Brain is an organ with the highest lipid concentration in the body. Cellular membrane lipids can affect both the positioning and the functioning of membrane proteins, thus regulating several cell actions. Changes in the lipid composition of cell membrane can modulate the microenvironment and consequently the function of its proteins, e.g. neurotransmission. Some of the first studies on the subject have shown a negative correlation between serum cholesterol levels and depression, suicidality and behavioral disorders. Several studies -but not all- have found decreased concentrations of ω-3 polyunsaturated fatty acids (ω-3-PUFA) in plasma or erythrocyte membranes of patients with depression, bipolar disorder or after a suicide attempt. In some cases, positive results after their administration have been reported. The effect of ω-3-PUFA in affective disorders is attributed to their action on neurotransmission, neuroplasticity as well as to their anti-inflammatory and anti-oxidative properties. Besides, decreased levels of ω-3-PUFA have been found in erythrocytes or platelets of schizophrenic patients. Some studies have shown in schizophrenics an increased rate of membrane phospholipids breakdown and a decreased ratio of ω-3-PUFA incorporation in phospholipids, possibly because of increased activity of phospholipase A2, an enzyme with crucial role in signaling transduction. Deficient dietetic ingestion of ω-3-PUFA may increase the risk for development of schizophrenia, while a diet rich in ω-3-PUFA may have a preventive role for the disease or improve its course. Although there is no evidence for their action as a monotherapy, they may be useful as an add-on therapy to drug treatment. Some authors suggest that abnormal sphingolipid metabolism, leading to accumulation of ceramides, may be responsible for the development of mood and anxiety disorders, as well as for induction of inflammation or oxidative stress, mechanisms possibly responsible for the physical symptoms of depression. Some drugs seem to combine inhibition of sphingomyelinase (an enzyme catalyzing the production of ceramides) and antidepressant effect. Despite the multitude of related studies, many aspects of the subject remain obscure. Current research focuses on the validity of preventive (especially in the perinatal period) or therapeutic administration of ω-3-PUFA as well as to the pharmacological manipulation of enzymes involved in lipid metabolism (e.g. sphingomyelinase) for the treatment of psychiatric disorders.

Childhood Affective Indicators of Risk for Adulthood Psychopathology: The New York High-Risk Project Findings.

There are relatively few investigations of the emotion expressivity of children at risk for the later development of schizophrenia and schizophrenia-spectrum disorders. Using data from the New York High-Risk Project, we compared children’s emotional expressivity during a semi-structured videotaped interview. Data were coded for 173 child subjects: 61 with schizophrenic parents (HRSz); 54 with affectively ill parents (HRAff); and 58 with psychiatrically “normal” parents (NC). A child’s affective responses were rated for the presence of discrete positive, negative, or neutral emotions by coders naive to group membership. Responses were also rated for anxiety, flat affect, inappropriate affect, and emotional withdrawal/disengagement. Compared with the two other two groups, HRSz children displayed significantly more negative affect in response to questions regarding their most negative experiences and, when questioned about their self-concept, they displayed significantly less positive affect. Both HRSz and HRAff children showed more inappropriate affect than NC children. Significantly more HRSz children were rated as demonstrating a lack of emotional engagement. Children making inappropriate displays of positive affect while discussing a negative topic were most likely to manifest a psychiatric disorder as an adult. These findings suggest that inappropriate affect may be a nonspecific indicator of risk for psychopathology. Emotional withdrawal in childhood may be a potential indicator of risk for schizophrenia.

Association of schizophrenia with variations in genes encoding transcription factors

Alterations in neuronal plasticity and immune system play a key role in pathogenesis of schizophrenia. Identification of genetic factors contributing to these alterations will significantly encourage elucidation of molecular etiopathomechanisms of this disorder. Transcription factors c-Fos, c-Jun, and Ier5 are the important regulators of neuronal plasticity and immune response. In the present work we investigated a potential association of schizophrenia with a number of single nucleotide polymorphisms of c-Fos-,c-Jun and Ier5 encoding genes (FOS, JUN, and IER5 respectively). Genotyping of DNA samples of patients with schizophrenia and healthy individuals was performed using polymerase chain reaction with allele specific primers. The results obtained demonstrated association between schizophrenia and FOS rs1063169, FOS rs7101, JUN rs11688, and IER5 rs6425663 polymorphisms. Namely, it was found that the inheritance of FOS rs1063169*T, JUN rs11688*A, and IER5 rs6425663*T minor variants decreases risk for development of schizophrenia whereas the inheritance of FOS rs7101*T minor variant, especially its homozygous form, increases risk for development of this disorder.

Prenatal tobacco smoke exposure, risk of schizophrenia, and severity of positive/negative symptoms

Prenatal exposure to cigarette smoke causes chronic fetal hypoxia, dysregulation of endocrine equilibrium, and disruption of fetal neurodevelopment associated with brain malfunction, all of which potentially could induce vulnerability to schizophrenia. A total of 212 schizophrenia patients aged 14–30years, and 212 matched controls were studied. Prenatal tobacco smoke exposure of the schizophrenia patients was compared to that of the normal controls by applying logistic regression analysis and controlling for several confounding factors. The outcomes of interest were comparison of the frequency of maternal and paternal smoking between patients and controls, as well as the severity of positive and negative symptoms between the offspring of smoking and nonsmoking parents. Among the mothers of schizophrenia patients and controls, 92 (43.4%) and 46 (21.7%) smoked, respectively. Maternal smoking during pregnancy had a significant unique contribution on increasing the risk for development of schizophrenia (p=0.001), and a greater severity of negative symptoms (p=0.023). Paternal smoking did not have a significant effect on the risk of schizophrenia, or severity of negative symptoms. The findings suggest that maternal smoking during pregnancy puts offspring at an increased risk for later schizophrenia, with increased severity of negative symptoms. Given the wide practice of smoking during pregnancy, fetal exposure to tobacco smoke could be a major preventable neurodevelopmental factor that increases vulnerability to schizophrenia.

Implication of a rare deletion at distal 16p11.2 in schizophrenia.

Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication. To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples. Genetic association study of microarray data. Samples of DNA were collected at 9 sites from different countries. Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parent-offspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12,398 cases and 17,945 controls. Statistically increased rate of specific copy number variations in cases vs controls. One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13,850 cases (0.094%) and 3 of 19,954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P = .001, Fisher exact test). Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia.

N400 in schizophrenia patients

The purpose of this article is to review major findings in event related potential (ERP) research in schizophrenia patients, specifically focusing on the N400 component. Patients with chronic schizophrenia have difficulty using 'context' (understanding the meaning of the word relative to the sentence) in sentence processing studies and often show differences from control populations in language experiments using word priming. Both of these observations are associated with an abnormal N400 ERP component when compared with nonpsychotic individuals. Many studies of language function rely on priming paradigms that use pairs of words such that the first word in a pair is a 'prime' and a second word in a pair is a 'target', separated from the prime by a period of time known as the Stimulus Onset Asynchrony (SOA). If the SOA is short (i.e., below 400 ms) then it is believed that a priming study examines primarily processes of initial activation within semantic networks; if it is long (i.e., more than 400 ms) then it is believed that a priming study examines primarily processes of context use, generating predictions and matching these predictions against upcoming semantic information. Priming paradigms that use long SOAs are consistently associated with a more negative N400 (hence lack of priming) in schizophrenia, whereas priming paradigms using a short SOA produce either a normal N400 priming response or hyperpriming as shown by a reduced N400 and related to a hypothesized too rapid automatic spread of activation within the semantic memory pathway. Apparent differences among reported study results are likely due to paradigm differences that tap into different aspects of language processing. Although the presence of both hyperactivation within semantic networks and difficulties with the use of context is well known in schizophrenia, it is unclear whether these abnormalities are also present prior to illness onset in people who are at risk for development of schizophrenia or even present at the onset of illness. In order to clarify the findings reviewed here, future studies will be needed that focus on examining the N400 response in young people at high risk for developing the illness using multiple paradigms that probe different aspects of language function.

Prenatal Care for Women with Schizophrenia

The goal of prenatal care is a healthy pregnancy and prevention of adverse maternal and fetal outcomes. Women with schizophrenia who become pregnant pose unique challenges to the delivery of prenatal care and are at high risk for adverse perinatal outcomes. Pregnancy in these women should be considered high risk. Offspring of women with schizophrenia are genetically predisposed to developing schizophrenia. Obstetric complications such as diabetes, prematurity, and fetal growth retardation also place the offspring at greater risk for development of schizophrenia, regardless of the genetic vulnerability. Pregnant women with schizophrenia are at greater risk for inadequate prenatal care and known obstetric complications, which are further risk factors for schizophrenia in the offspring. Thus, the genetic and obstetric environment of the fetus predisposes to the development of schizophrenia. This risk may be mitigated by increased vigilance in providing prenatal care to these women and preventing or minimizing illness and treatment emergent complications during pregnancy. In this article we review: 1) the barriers to adequate prenatal care in women with schizophrenia, 2) factors associated with the illness and its treatment requiring attention and monitoring during prenatal visits, and 3) the multi-disciplinary, collaborative approach to the delivery of prenatal care for these women. Keywords: Schizophrenia, antipsychotics, pregnancy, prenatal care, trimester, women