Role of DISC1 interacting proteins in schizophrenia risk from genome-wide analysis of missense SNPs.

A balanced translocation affecting DISC1 cosegregates with several psychiatric disorders, including schizophrenia, in a Scottish family. DISC1 is a hub protein of a network of protein-protein interactions involved in multiple developmental pathways within the brain. Gene set-based analysis has been proposed as an alternative to individual analysis of single nucleotide polymorphisms (SNPs) to get information from genome-wide association studies. In this work, we tested for an overrepresentation of the DISC1 interacting proteins within the top results of our ranked list of genes based on our previous genome-wide association study of missense SNPs in schizophrenia. Our data set consisted of 5100 common missense SNPs genotyped in 476 schizophrenic patients and 447 control subjects from Galicia, NW Spain. We used a modification of the Gene Set Enrichment Analysis adapted for SNPs, as implemented in the GenGen software. The analysis detected an overrepresentation of the DISC1 interacting proteins (permuted P-value=0.0158), indicative of the role of this gene set in schizophrenia risk. We identified seven leading-edge genes, MACF1, UTRN, DST, DISC1, KIF3A, SYNE1, and AKAP9, responsible for the overrepresentation. These genes are involved in neuronal cytoskeleton organization and intracellular transport through the microtubule cytoskeleton, suggesting that these processes may be impaired in schizophrenia.

Insight in schizophrenia and risk of suicide: a systematic update.

BACKGROUND: Suicide has been shown to represent the major single cause of premature death among patients with schizophrenia spectrum disorders. Insight has been proposed to increase such risk. However, this subject has not been sufficiently investigated, and inconclusive results have been reported. OBJECTIVE: The objective of this study is to systematically examine the role of insight in the risk of suicide attempts and completed suicide among patients with schizophrenia and related disorders. METHOD: Articles assessing insight and suicidality in patients with schizophrenia spectrum disorders published between 1977 and 2010 were reviewed. A MEDLINE search strategy was used to identify studies using keywords. Application of meta-analytic techniques to selected studies was not possible because of important methodological differences between them. RESULTS: Fifteen studies met predetermined selection criteria. Ten failed to demonstrate a positive association between insight and risk for suicide. DISCUSSION: There is little evidence to support the suggestion that insight may represent a risk factor for suicide in patients with schizophrenia. If there is an association between such risk and insight, it appears to be mediated by other variables such as depression and, above all, hopelessness. Further studies with larger samples and longer follow-up periods in naturalistic conditions, in which insight should be evaluated from a multidimensional approach, are required to analyze this issue in depth, given the crucial implications that it may have on the development of a model for suicide prevention in schizophrenia.

Telepsychogeriatrics: a new horizon in the care of mental health problems in the elderly.

BACKGROUND: The use of telemedicine for the care of mental health problems has developed significantly over the last decade thanks to the emergence of a number of stable telepsychiatry programs in many countries. Parallel to this development, this care modality has also targeted specific populations with higher difficulty in gaining access to mental health services such as the elderly. Telepsychogeriatrics is expected to have an increasing role in providing care to geographically isolated rural communities, with a particular focus on long-term care facilities, in light of the high prevalence of psychiatric disorders in these centers and the lack of available specialized care. METHODS: A thorough search of the literature was conducted using Medline, Web of Science, and PsychINFO databases in order to gather available evidence on the applicability of telepsychiatry, specifically the use of videoconferencing for remote consultation, in the elderly population with mental disorders. A succinct description of the selected studies is given along with a general reflection on the state-of-the-art in the field of psychogeriatric clinical practice and research. RESULTS: Research on the use of telemedicine in this age group has taken into account their special characteristics, and has focused on demonstrating its applicability, the acceptance and satisfaction of elderly users and their healthcare providers, the possibility of carrying out cognitive and diagnostic assessments, and the efficiency of these programs. CONCLUSIONS: Despite limited experience, telepsychogeriatrics appears to be a viable option, well accepted by patients, including those having dementia. More systematized studies are needed in this new field based on larger sample sizes, including comparison with traditional consultations and assessment of the clinical outcomes.

No evidence that major mtDNA European haplogroups confer risk to schizophrenia.

Previous studies suggest that genetic factors could be involved in mitochondrial dysfunction observed in schizophrenia (SZ), some of them claiming a role of mtDNA common variants (mtSNPs) and/or haplogroups (hgs) in developing this disorder. These studies, however, have mainly been undertaken on relatively small cohorts of patients and control individuals and most have not yet been replicated. To further analyze the role of mtSNPs in SZ risk, we have carried out the largest genotyping effort to date using two Spanish case-control samples comprising a total of 942 schizophrenic patients and 1,231 unrelated controls: 454 patients and 616 controls from Santiago de Compostela (Galicia) and 488 patients and 615 controls from Reus (Catalonia). A set of 25 mtSNPs representing main branches of the European mtDNA phylogeny were genotyped in the Galician cohort and a subset of 16 out of these 25 mtSNPs was genotyped in the Catalan cohort. These 16 common variants characterize the most common European branches of the mtDNA phylogeny. We did not observe any positive association of mtSNPs and hgs with SZ. We discuss several deficiencies of previous studies that might explain the false positive nature of previous findings, including the confounding effect of population sub-structure and deficient statistical methodologies. It is unlikely that mtSNPs defining the most common European mtDNA haplogroups are related to SZ.

Testing the antagonistic pleiotropy model of schizophrenia susceptibility by analysis of DAOA, PPP1R1B, and APOL1 genes.

Schizophrenia is a common disease associated with reduced fertility. Therefore, the existence of common susceptibility alleles not removed by natural selection may be considered an evolutionary paradox. The antagonistic pleiotropy model, proposed to explain this paradox, states that an allele may be common because of its overall selective advantage, in spite of deleterious effects on specific traits. Recent work on DAOA, PPP1R1B, and APOL1 suggests that these genes present common alleles associated to increase risk of schizophrenia but conferring an overall selective advantage, related to better cognitive performance (DAOA and PPP1R1B) or protection against pathogens (APOL1). To test if these genes fit the antagonistic pleiotropy model, we searched for recent natural selection at these loci applying the long-range haplotype test on data from the HapMap Project; and performed case-control association analysis in a well-powered sample, including 301 schizophrenic patients and 604 controls from Spain. For DAOA and PPP1R1B, we genotyped the Single-nucleotide polymorphisms (SNPs) needed to replicate previous associations, while for APOL1, we genotyped 15 tagSNPs, and seven putative functional SNPs. We did not detect evidence of recent natural selection. Furthermore, we did not find significant associations. Thus, these genes do not fit the antagonistic pleiotropy model.

An efficient screening method for simultaneous detection of recurrent copy number variants associated with psychiatric disorders.

Several recurrent copy number variants (CNVs) increasing risk to neuropsychiatric diseases have been identified in recent years. They show variable clinical expressivity, being associated with different disorders, and incomplete penetrance. However, due to its very low frequency, the full variety of clinical outcomes associated with each one of these CNVs is unknown. Current methods for detection of CNVs are labor intensive, expensive or not suitable for high throughput analysis. Quantitative interspecies competitive PCR linked to variant minisequencing and detection by mass-spectrometry may overcome these limitations. Here, we present two multiplex assays based on this method to screen for eleven psychiatric risk CNVs, such as 1q21, 16p11.2, 3q29, or 16p13.11 regions, among others. The assays were tested in our collection of 514 schizophrenia patients. Results were compared with MLPA at two CNVs. Additional positive results were confirmed by exome sequencing. A total of fourteen patients were CNV carriers. The method presents high sensitivity and specificity, showing its utility as a cheap, accurate, high throughput screening tool for recurrent CNVs. The method may be very useful for management of psychiatric patients as well as screening of different collections of samples to better identify the full spectrum of clinical variability.

Caffeine consumption in a long-term psychiatric hospital: Tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use.

This study further explores the association between schizophrenia and caffeine use by combining two prior published Spanish samples (250 schizophrenia outpatients and 290 controls from the general population) with two Spanish long-term inpatient samples from the same hospital (145 with schizophrenia and 64 with other severe mental illnesses). The specific aims were to establish whether or not, after controlling for confounders including tobacco smoking, the association between schizophrenia and caffeine is consistent across schizophrenia samples and across different definitions of caffeine use. The frequency of caffeine use in schizophrenia inpatients was not significantly higher than that in non-schizophrenia inpatients (77%, 111/145 vs. 75%, 48/64) or controls but was significantly higher than in schizophrenia outpatients. The frequency of high caffeine users among caffeine users in schizophrenia inpatients was not significantly higher than in non-schizophrenia inpatients (45%, 50/111 vs. 52%, 25/48) or controls, but was significantly lower than in schizophrenia outpatients. Smoking was significantly associated with caffeine use across all samples and definitions. Between 2 and 3% of schizophrenia inpatients, schizophrenia outpatients and non-schizophrenia inpatients showed caffeinism (>700 mg/day in smokers). Several of these smoking patients with caffeinism were also taking other inducers, particularly omeprazole. The lack of consistent association between schizophrenia and caffeine use is surprising when compared with the very consistent association between tobacco smoking and caffeine use across all of our analyses (use and high use in users) and all our samples. The confounding effects of tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use.

Replication of previous genome-wide association studies of psychiatric diseases in a large schizophrenia case-control sample from Spain.

Genome wide association studies (GWAS) has allowed the discovery of some interesting risk variants for schizophrenia (SCZ). However, this high-throughput approach presents some limitations, being the most important the necessity of highly restrictive statistical corrections as well as the loss of statistical power inherent to the use of a Single Nucleotide Polymorphism (SNP) analysis approach. These problems can be partially solved through the use of a polygenic approach. We performed a genotyping study in SCZ using 86 previously associated SNPs identified by GWAS of SCZ, bipolar disorder (BPD) and autistic spectrum disorder (ASD) patients. The sample consisted of 3063 independent cases with DSM-IV-TR diagnosis of SCZ and 2847 independent controls of European origin from Spain. A polygenic score analysis was also used to test the overall effect on the SCZ status. One SNP, rs12290811, located in the ODZ4 gene reached statistical significance (p=1.7×10(-4), Allelic odds ratio=1.21), a value very near to those reported in previous GWAS of BPD patients. In addition, 4 SNPs were close to the significant threshold: rs3850333, in the NRXN1 gene; rs6932590, at MHC; rs2314398, located in an intergenic region on chromosome 2; and rs1006737, in the CACNA1C gene. We also found that 74% of the studied SNPs showed the same tendency (risk or protection alleles) previously reported in the original GWAS (p<0.001). Our data strengthen the polygenic component of susceptibility to SCZ. Our findings show ODZ4 as a risk gene for SCZ, emphasizing the existence of common vulnerability in psychosis.

Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia.

BACKGROUND: Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs). METHODS: We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency >5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures. RESULTS: The 5 independent nsSNPs with false discovery rate q ≤ .25, as well as 13 additional nsSNPs at p < .01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10(-6), allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility. CONCLUSIONS: Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis.

Interaction between COMT haplotypes and cannabis in schizophrenia: a case-only study in two samples from Spain.

Cannabis use is one of the environmental factors with more solid evidence contributing to schizophrenia risk, especially in genetically susceptible individuals. One of the genes that may interact with cannabis is COMT, although available data are scarce. Here, we present a case-only study of the putative COMT-cannabis interaction in schizophrenia. Two Spanish samples from Santiago de Compostela and Valencia were screened for cannabis use. One hundred and fifty five individuals from a total of 748 patients were identified as cannabis users. Five SNPs in COMT, defining three common functional haplotypes with different enzymatic activities, were genotyped and analyzed for association at the SNP, haplotype and genotype levels. An association was detected between cannabis use and low activity variants (P<0.01) in the joint analysis and results were consistent between the two samples. Schizophrenic subjects homozygous for the Met allele at rs4680 doubled the probability of lifetime prevalence of cannabis use in comparison to Val homozygous (Mantel-Haenszel OR=2.07, 95% CI: 1.27-3.26, P=0.0031, in the combined sample). These data are in contrast to those from Caspi et al. (Biol. Psychiatry 57 (2005)1117-1127) who found association between schizophrenia/schizophreniform disorder and homozygosity at the high activity Val variant of rs4680. The results of our study are discussed in the context of previous findings, suggesting the involvement of COMT polymorphisms in the association between cannabis use and schizophrenia as well as the existence of additional factors mediating this association. However, further research is needed to confirm the COMT-cannabis interaction.

Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: new data and meta-analysis.

Catechol-O-methyltransferase (COMT) has been largely studied in relation to schizophrenia susceptibility. Most studies focused on the functional single nucleotide polymorphism (SNP) rs4680 that causes a substitution of Val by Met at codon 158 of the COMT protein. Recent meta-analyses do not support an association between allelic variants at rs4680 and schizophrenia. However, the putative role of overdominance has not been tested in meta-analyses, despite its biological plausibility. In this work, we tested the overdominant model in two Spanish samples (from Valencia and Santiago de Compostela), representing a total of 762 schizophrenic patients and 1042 controls, and performed a meta-analysis of the available studies under this model. A total of 51 studies comprising 13,894 schizophrenic patients and 16,087 controls were included in the meta-analysis, that revealed a small but significant protective effect for heterozygosity at rs4680 (pooled OR=0.947, P=0.023). Post-hoc analysis on southwestern European samples suggested a stronger effect in these populations (pooled OR=0.813, P=0.0009). Thus, the COMT functional polymorphism rs4680 contributes to schizophrenia genetic susceptibility under an overdominant model, indicating that both too high and too low levels of dopamine (DA) signalling may be risk factors. This effect can be modulated by genetic background.

Insight assessment in psychosis and psychopathological correlates: Validation of the Spanish version of the Schedule for Assessment of Insight - Expanded Version

Background and Objectives: Lack of insight is a cardinal feature of psycho -sis. Insight has been found to be a multidimensional concept, including awareness of having a mental illness, ability to relabel psychotic phenomena as abnormal and compliance with treatment., which can be measured with the Schedule for Assessment of Insight(SAI-E). The aim of this study was to validate the Spanish version of SAI-E. Methods: The SAI-E was translated into Spanish and back-translated into English, which was deemed appropriate by the original scale author. Next, the Spanish version of the SAI-Ewas administered to 39 patients with schizophrenia or schizoaffective disorder (DSM-IV criteria)from a North Peruvian psychiatric hospital. The Positive and Negative Syndrome Scalefor Schizophrenia (PANSS) and the Scale of Unawareness of Mental Disorder (SUMD) were also administered. Specifically, internal consistency and convergent validity were assessed. Results: Internal consistency between the 11 items of the SAI-E was found to be good to excellent (α = 0.942). Compliance items did not contribute to internal consistency (A = 0.417,B = 572). Inter-rater reliability was excellent (ICC = 0.99). Regarding concurrent validity, the SAI-E total score correlated negatively with the lack of insight and judgement item of the PANNS (r = -0.91, p < 0.01) and positively with the SUMD total score (r = 0.92, p < 0.001). Conclusions: The Spanish version of the SAI-E scale was demonstrated to have both excellent reliability and external validity in our sample of South American Spanish-speaking patients with schizophrenia spectrum disorders (AU)

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QTc interval in a sample of long-term schizophrenia inpatients.

This naturalistic study attempted to determine the prevalence of prolonged QTc interval in a relatively large population of inpatients hospitalized with chronic schizophrenia, and to explore QTc relationship with demographic variables, metabolic parameters and prescribed treatments. All inpatients from a Spanish long-term psychiatric hospital were cross-sectionally investigated to determine the prevalence of QTc prolongation and metabolic syndrome. The sample with a DSM-IV diagnosis of schizophrenia included 171 Caucasian inpatients, all of Spanish origin. A prolonged QTc interval was defined as >450 ms in men and >470 ms in women. The relationships between QTc and other continuous variables were assessed using a linear regression model with QTc as the dependent variable. Only 10 patients (6%) had a prolonged QTc interval; one case was possibly explained by hypokalemia. Three patients (2%) had a QTc > 500 ms. Gender, old age (> or = 50 years old), current smoking, systolic blood pressure, HDL cholesterol and history of arrhythmia were found to have significant effects on QTc interval in a linear regression analysis. After controlling for significant variables, the mean QTc interval was not significantly influenced by antipsychotic dose, type of antipsychotic treatment, the use of depot antipsychotics, or the number of different antipsychotics prescribed. Our study focused on long-term schizophrenia inpatients with frequent antipsychotic polypharmacy and high antipsychotic doses, and suggested that after excluding the case with hypokalemia length of QTc was associated with history of arrhythmias and with metabolic factors, while the effects of antipsychotic compound or class were not so evident.

Hiponatremia por oxcarbazepina / Oxcarbezepine-induced hyponatremia

Con los años, desde su instauración como tratamiento anticomicial, se han publicado numerosos casos clínicos que relacionan la utilización de oxcarbazepina y la aparición de hiponatremia (sodio sérico < 135 mmol/l), tanto en monoterapia como en combinación con otros fármacos. Se describen posibles mecanismos de acción por los que la oxcarbazepina puede producir hiponatremia, como la liberación inadecuada de vasopresina (SIADH) o el incremento de agua y la pérdida secundaria de sodio ¿mayor sensibilidad tubular a la vasopresina. A partir del caso de un varón de 40 años diagnosticado de esquizofrenia resistente que, tras varias semanas de tratamiento con oxcarbazepina, presenta astenia y fatigabilidad en relación con sodio sérico en 124 mmol/l, revisamos todos los casos clínicos publicados desde 1987 hasta la actualidad centrándonos en las dosis de fármaco administradas, el tratamiento concomitante, la edad y el sexo del paciente, el sodio sérico en sangre periférica, los síntomas presentados y el tratamiento recibido. Se proponen incrementos lentos y graduales de la dosis al introducir la oxcarbazepina, así como determinaciones plasmáticas para evitar un posible descenso del sodio sérico por debajo de 135 mmol/l (AU)

Since oxcarbazepine was establishment as an antiepileptic treatment, numerous case reports have been published associating the use of this drug with the development of hyponatremia (serum sodium < 135 mmol/l), both in monotherapy and associated with other drugs. Possible mechanisms of action through which oxcarbazepine can produce hyponatremia are described, such as an increase in antidiuretic hormone release ¿ syndrome of inappropriate antidiuretic hormone secretion (SIADH) ¿or by means of increase water and secondary sodium loss¿ increased renal tubule sensitivity to antidiuretic hormone. Based on the case of a 40-year-old man with a diagnosis of paranoid schizophrenia, who developed weakness and fatigue closely related to serum sodium of 124 mmol/l after several weeks of oxcarbazepine treatment, we review all the cases published from 1987 to date. The doses of the drug administered, concomitant treatment, patient age and sex, serum sodium in peripheral blood, symptoms, and the treatment received are discussed. We recommend slow and gradual dose increases when oxcarbazepine is introduced, as well as plasma monitoring, to avoid possible decreases in serum sodium below 135 mmol/l (AU)

Depresión y enfermedad cerebrovascular / Depression and cerebrovascular disease

En la actualidad, cuando se habla de la relación entre depresión y enfermedad cerebrovascular se está abordando una realidad compleja. En los últimos veinticinco años ha habido abundante investigación sobre la depresión que se produce en sujetos que han sufrido un ictus. Más recientemente aparece el término "depresión vascular" para referirse a casos de depresión de inicio tardío en los que se presume la participación etiológica de la enfermedad cerebrovascular. Por otra parte, se ha propuesto que la depresión podría asociarse a un riesgo incrementado de enfermedad vascular cerebral. Se revisan de modo general estos conceptos, tratando de destacar su impacto en la práctica clínica psiquiátrica

Currently, the relationship between depression and cerebrovascular disease can be considered complex. In the last 25 years, abundant research has been published on depression in patients who have had a stroke. More recently, the term "vascular depression" has been coined to describe late-onset depression in patients with clinical evidence of cerebrovascular disease. In addition, it has been proposed that depression could be associated with an increased risk of cerebrovascular disease. The present article provides an overview of these concepts, with an emphasis on describing their impact on psychiatric clinical practice