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Objectives Recent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD. Methods A total of 2254 Latino individuals were genotyped for 91 SNPs identified in previous BD and/or SC GWASs, along with selected SNPs in strong linkage disequilibrium with these markers. Family-based single marker and haplotype association testing was performed using the PBAT software package. Empirical P-values were derived from 10 000 permutations. Results Associations of eight a priori GWAS SNPs with BD were replicated with nominal (P≤.05) levels of significance. These included SNPs within nuclear factor I A (NFIA), serologically defined colon cancer antigen 8 (SDCCAG8), lysosomal associated membrane protein 3 (LAMP3), nuclear factor kappa B subunit 1 (NFKB1), major histocompatibility complex, class I, B (HLA-B) and 5′-nucleotidase, cytosolic II (NT5C2) and SNPs within intragenic regions microRNA 6828 (MIR6828)—solute carrier family 7 member 14 (SLC7A14) and sonic hedgehog (SHH)—long intergenic non-protein coding RNA 1006 (LINC01006). Of the 76 ancestral haploblocks that were tested for associations with BD, our top associated haploblock was located in LAMP3; however, the association did not meet statistical thresholds of significance following Bonferroni correction. Conclusions These results indicate that some of the gene variants found to be associated with BD or SC in other populations are also associated with BD risk in Latinos. Variants in six genes and two intragenic regions were associated with BD in our Latino sample and provide additional evidence for overlap in genetic risk between SC and BD.

artículo -- Universidad de Costa Rica. Centro Investigación en Biología Molecular y Celular, 2010. Este documento es privado debido a limitaciones de derechos de autor. Objectives:The aims of this study were to estimate the frequency and course of substances use disorders in Latino patients with schizophrenia and to ascertain risk factors associated with substance use disorders in this population. Method: We studied 518 subjects with schizophrenia recruited for a genetic study from the Southwest United States, Mexico, and Central America (Costa Rica and Guatemala). Subjects were assessed using structured interviews and a best estimate consensus process. Logistic regression, χ 2 , ttest, Fisher's exact test, and Yates' correction, as appropriate, were performed to assess the sociodemographic variables associated with dual diagnosis. We defined substance use disorder as either alcohol or substance abuse or dependence. Results: Out of 518 patients with schizophrenia, 121 (23.4%) had substance use disorders. Comorbid substance use disorders were associated with male gender, residence in the United States, immigration of Mexican men to the United States, history of depressive syndrome or episode, and being unemployed. The most frequent substance use disorder was alcohol abuse/ dependence, followed by marijuana abuse/dependence, and solvent abuse/dependence. Conclusion: This study provides data suggesting that depressive episode or syndrome, unemployment, male gender, and immigration of Mexican men to the United States were factors associated with substance use disorder comorbidity in schizophrenia. Binary logistic regression showed that country of residence was associated with substance use disorder in schizophrenic patients. The percentage of subjects with comorbid substance use disorders was higher in the Latinos living in the United States compared with subjects living in Central America and Mexico. Universidad de Costa Rica. This research was supported by the following grants from the National Institute of Mental Health: MH60881 and MH60875. Dr. Jimenez-Castro was supported by a fellowship of grant D43 TW06152-01 from the National Institute of Mental Health, the National Institute of Drug Abuse and the Fogarty Institute. These institutions had no further role in the study design, in the collection, analysis and interpretation of data, in writing of the report, and in the decision to submit the paper for publication UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)

Depression and suicidal behavior are frequently observed in patients with schizophrenia. The serotonin transporter protein regulates serotonergic signaling at synapses and is encoded by a single gene (SLC6A4; Locus Link ID: 6532), located at 17q11.1-q12 with two polymorphic variants (the short and the long allele). The short allele of serotonin transporter gene has been associated with depression and suicidality in individuals who suffered negative life events and with depression in individuals with chronic psychosis.. Subjects were recruited from a genetic study of schizophrenia conducted in Costa Rica. The authors replicated their previous research, using a more narrow phenotype (only schizophrenic subjects) and a more ethnically homogenous sample (only Costa Rican schizophrenic individuals who were not included in the previous study). The authors hypothesized that subjects with at least one copy of the serotonin transporter promoter gene polymorphism (5-HTTLPR) "s" allele would have a greater history of lifetime depression and suicidability rate than those who had an "l/l" genotype. The authors analyzed 155 subjects with a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnosis of schizophrenia (73% male, age at interview 38.3, SD = 11.23). The genotype distribution was "ss" 58 (37%), "sl" 69 (45%), and "ll" 28 (18%). In the secondary analysis, the authors explored association of the "s" allele with lifetime history of suicide behavior in 173 subjects (18 more subjects than primary analysis because schizophrenic individuals were included regardless of history of depression). The authors found that subjects carrying at least one short allele had a significant increased lifetime risk for depressive syndromes (chi(2) = 5.4, df = 1, P = 0.02; odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.15-6.3). No association was found for suicidal behavior in the same sample (chi(2) = 0.928, P = 0.629). In conclusion, the genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of developing major depression but not suicidal behavior during the course of the schizophrenia in these patients. Due to the small sample size, these results should be followed by definitive replication.

To investigate the role of the apolipoprotein E (APOE) gene in schizophrenia, the authors analyzed 60 families with this mental disorder. An association in the presence of linkage test (APL) and haplotypes analysis were undertaken using the APL v1.1 software. A global allelic transmitted was significant for APOE-epsilon3 (chi(2)=6.24, p=0.01); this allele is mainly carried by female patients (chi(2)=8.33, p=0.003), whereas APOE-219G is preferentially transmitted in males (p=0.02). Furthermore, our results show that haplotypes APOE-epsilon3/APOE-219G are associated with schizophrenia (chi(2)=11.61, p=0.01). These results provide evidence that the APOE gene may play a significant role in the etiology of schizophrenia in the Mexican population.

artículo (arbitrado)--Universidad de Costa Rica, Centro de Investigación en Biología Celular y Molecular. 2009. Este documento es privado debido a limitaciones de derechos de autor. We determined the rates of agreement between diagnoses, using the Diagnostic Interview for Genetic Studies (DIGS) and diagnoses arrived at, using additional sources of information, to establish whether there are differences in agreement between direct interview diagnoses at US and non-US sites in comparison best estimate consensus process and to identify diagnoses that could increase diagnostic error when only the DIGS is used. DIGS diagnoses were compared with consensus diagnoses that used the same DIGS interview, plus Family Interview for Genetic Studies (FIGS) and review of medical records in 342 psychotic subjects. We found similar numbers of subjects diagnosed with schizophrenia (225 by direct interview, and 232 by consensus process). The majority of those “misdiagnosed” by direct interview had mood disorder by the consensus. Over 10% of the total subjects diagnosed by direct interview as not meeting criteria for schizophrenia had schizophrenia by consensus. There were no statistically significant differences between countries (US vs. non-US sites) in the agreement rate between direct interview diagnosis and consensus diagnosis. In conclusion, a final best-estimate process is essential to make diagnostic distinctions and to reduce diagnostic misclassifications for both research studies and in clinical practice Universidad de Costa Rica UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)

artículo (arbitrado). Universidad de Costa Rica, Centro de Investigación en Biología Celular y Molecular, 2008. Este artículo es privado debido a limitaciones de derechos de autor. This study attempted to replicate evidence for association of the Epsin 4 gene (which encodes enthoprotin, a protein involved in vesicular transport) to schizophrenia in a new sample of families segregating schizophrenia drawn from the Latin American population. 1423 subjects (767 with a history of psychosis) from 337 Latino families were genotyped using three single nucleotide polymorphisms (SNPs) spanning the Epsin 4 gene. A family based association test was utilized to test for association of these SNPs to the phenotypes of psychosis and schizophrenia. Haplotypes defined by these three SNPs showed significant association to the phenotype of psychosis in this sample (global p value=0.014, bi-allelic p value=0.047). Variation in the Epsin 4 gene is significantly associated with psychotic disorder in this Latino population. This provides additional support for the involvement of enthoprotin in the pathogenesis of schizophrenia and other psychotic disorders. Universidad de Costa Rica UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)

Functional alterations of components of the endogenous cannabinoid system, in particular of the cannabinoid receptor 1 protein (CB1), are hypothetical contributors to many of the symptoms seen in schizophrenia. Variants within the cannabinoid receptor 1 gene (CNR1) have been shown to be directly associated with the hebephrenic form of schizophrenia in a Japanese population. This finding, however, has yet to be replicated. In the present study we sought to study the same (AAT)n-repeat microsatellite of the CNR1 gene which showed association to hebephrenic schizophrenia in Japan, and to investigate whether this microsatellite showed association to a hebephrenic type of schizophrenia in a family-based association study in a population of the Central Valley of Costa Rica. The Lifetime Dimensions of Psychosis Scale and a best estimate consensus process were utilized to identify subjects with schizophrenia who had an elevated lifetime dimensional score for negative and disorganized symptoms, which we used as a proxy for “hebephrenia.” Using the Family Based Association Test we found association of these hebephrenic subjects and the (AAT)n-repeat marker of the CNR1 (multi-allelic P = 0.0368). Our hypothesis that an association with the (AAT)n-repeat marker of CNR1 would not be found with the more general type of schizophrenia was also confirmed. Schizophrenic subjects with prominent lifetime scores for disorganization and negative symptoms (dimension for hebephrenia) are associated with the CNR1 gene and present a type of symptomatology that resembles chronic cannabinoid-induced psychosis. The current finding points to the possibility of different genetic and pathophysiologic mechanisms underlying different types of schizophrenia. © 2008 Wiley-Liss, Inc.

Schizophrenia is a complex psychiatric disorder, likely to be caused in part by multiple genes. In this study, linkage analyses were performed to identify chromosomal regions most likely to be associated with schizophrenia and psychosis in multiplex families of Mexican and Central American origin. Four hundred and fifty-nine individuals from 99 families, containing at least two siblings with hospital diagnoses of schizophrenia or schizoaffective disorder, were genotyped. Four hundred and four microsatellite markers were genotyped for all individuals and multipoint non-parametric linkage analyses were performed using broad (any psychosis) and narrow (schizophrenia and schizoaffective disorder) models. Under the broad model, three chromosomal regions (1pter-p36, 5q35, and 18p11) exhibited evidence of linkage with non-parametric lod (NPL) scores greater than 2.7 (equivalent to empirical P values of less than 0.001) with the peak multipoint NPL = 3.42 (empirical P value = 0.00003), meeting genomewide evidence for significant linkage in the 1pter-p36 region. Under the narrow model, the same three loci showed (non-significant) evidence of linkage. These linkage findings (1pter-p36, 18p11, and 5q35) highlight where genes for psychosis and schizophrenia are most likely to be found in persons of Mexican and Central American ancestry, and correspond to recent linkages of schizophrenia or psychosis in other populations which were formed in part from emigrants from the Spanish empire of the 15th and 16th centuries. © 2006 Wiley-Liss, Inc.

Linkage studies using multiplex families have repeatedly implicated chromosome 8 as involved in schizophrenia etiology. The reported areas of linkage, however, span a wide chromosomal region. The present study used the founder population of the Central Valley of Costa Rica and phenotyping strategies alternative to DSM-IV classifications in attempts to further delimitate the areas on chromosome 8 that may harbor schizophrenia susceptibility genes. A linkage disequilibrium screen of chromosome 8 was performed using family trios of individuals with a history of psychosis. Four discrete regions showing evidence of association (nominal P values less than 0.05) to the phenotype of schizophrenia were identified: 8p23.1, 8p21.3, 8q13.3 and 8q24.3. The region of 8p23.1 precisely overlaps a region showing strong evidence of linkage disequilibrium for severe bipolar disorder in Costa Rica. The same chromosomal regions were identified when the broader phenotype definition of all individuals with functional psychosis was used for analyses. Stratification of the psychotic sample by history of mania suggests that the 8q13.3 locus may be preferentially associated with non-manic psychosis. These results may be helpful in targeting specific areas to be analyzed in association-based or linkage disequilibrium-based studies, for researchers who have found evidence of linkage to schizophrenia on chromosome 8 within their previous studies.

Objective: This study used the population of the Central Valley of Costa Rica (CVCR) and phenotyping strategies alternative to DSMIV classifications to investigate the association of neuregulin 1 with schizophrenia. Method: Using 134 family trios with a history of psychosis, we genotyped six of the seven markers originally identified to be associated with schizophrenia in Iceland. Results: The neuregulin Icelandic haplotype was not associated with schizophrenia in the CVCR population. However, a novel haplotype was found to be overrepresented in subjects with functional psychosis (global P-value > 0.05). Stratification of the sample by history of mania suggests that this haplotype may be preferentially over-transmitted to persons with a history of manic psychosis. Conclusion: These results suggest that the neuregulin 1 gene is unlikely to play a major role in predisposing to schizophrenia in the CVCR. Further studies in the CVCR and other Latin American populations should be performed in order to corroborate these findings.

The long-standing concept that schizophrenia (SC) and bipolar disorder (BP) represent two distinct illnesses has been recently challenged by findings of overlap of genetic susceptibility loci for these two diseases. We report here the results of a linkage disequilibrium (LD) analysis of chromosome 18 utilizing subjects with SC from the Central Valley of Costa Rica. Evidence of association (P < 0.05) was obtained in three chromosomal regions: 18p11.31 (D18S63), 18q12.3 (D18S474), and 18q22.3-qter (D18S1161, D18S70), all of which overlap or are in close proximity with loci previously shown to be in LD with BP, type I in this population. Since both the SC and bipolar samples contained cases with a history of mania and almost all cases of SC and BP had a history of psychosis, we performed an alternative phenotyping strategy to determine whether presence or absence of mania, in the context of psychosis, would yield distinct linkage patterns along chromosome 18. To address this issue, a cohort of psychotic patients (including a range of DSMIV diagnoses) was divided into two groups based on the presence or absence of mania. Regions that showed association with SC showed segregation of association when the sample was stratified by history of mania. Our results are compared with previous genetic studies of susceptibility to SC or BP, in Costa Rica as well as in other populations. This study illustrates the importance of detailed phenotype analysis in the search for susceptibility genes influencing complex psychiatric disorders in isolated populations and suggests that subdivision of psychoses by presence or absence of past mania syndromes may be useful to define genetic subtypes of chronic psychotic illness.

Adverse effects of antipsychotics are important determinants of patient attitudes towards medications, adherence to treatment, and quality of life. A discussion of adverse effects is therefore a crucial element of treatment and offers a unique opportunity for dialogue between the patient and the clinician. Unfortunately, clinicians in routine clinical practice have had very limited guidance regarding how best to initiate this discussion. In fact, despite the recognition of the importance of adverse effects, their systematic assessment has been, for the most part, confined to research settings, where the main focus has been on extrapyramidal symptoms (EPS). Furthermore, until recently, clinicians tended to discount patient subjective experiences with antipsychotic medications, focusing on the evaluation of objective severity. However, ignoring the subjective experience of patients results in inadequate communication between the patient and the clinician. The Approaches to Schizophrenia (Communication ASC) Steering Group, comprised of psychiatrists from the US, Canada and the UK, identified the need to develop a tool that could be used in routine clinical care settings to facilitate the communication between patients and clinicians regarding adverse effects. In order to be useful the instrument needed to be brief, clinically focused and easy to administer. As for the content, it needed to include the patients’ subjective experiences with antipsychotics and to assess a broad adverse effect profile (i.e. both EPS and non-EPS effects). To address these needs, the Steering Group designed two checklists: the ASC-Self-Report (ASC-SR) and the ASC-Clinic (ASC-C). The ASC-SR is a self-report checklist completed by the patient. It contains a list of common problems experienced by patients receiving antipsychotics. The ASC-C is a clinician-administered version that is designed to be completed by the clinician and the patient together during a regular clinic visit. The experience with the ASC-SR and ASC-C checklists across sites and countries has been encouraging. The vast majority of respondents in a pilot study of the ASC checklists found the ASC-SR user friendly and helpful in their communication with the healthcare team. Likewise, almost half of the healthcare professionals reported that the ASC-C assisted them in identifying previously unrecognized adverse effects. Additional experience in the UK and the US has provided further support for clinical use of the checklists.

In a previous study, we found that cognitive adaptation training (CAT)--a manual-driven program of environmental supports designed to bypass cognitive deficits--improved multiple domains of outcome in schizophrenia patients recently discharged from a State psychiatric facility. The present study examined the efficacy of CAT in a sample of patients who had been in the community at least 3 months. Forty-five medicated schizophrenia patients were randomly assigned for 9 months to one of three conditions: (1) CAT, (2) a condition that controlled for therapist time and provided environmental changes unrelated to cognitive deficits, or (3) follow-up only. Comprehensive assessments were conducted every 3 months by blinded raters. Results of repeated measures analyses of covariance for mixed models indicated that patients participating in CAT had better adaptive function and quality of life, and fewer positive symptoms than those in the two non-CAT conditions. Results indicate that compensatory strategies may improve various outcomes in schizophrenia outpatients.

The present study examined the concurrent and predictive validity of the Allen Cognitive Levels (ACL) Assessment in a sample of 110 medicated patients with schizophrenia who received the ACL at discharge from a state psychiatric facility. Subsamples within this group of patients had received an Activities of Daily Living assessment (n = 64) and a comprehensive neuropsychological test battery (n = 48) at discharge, or a battery of community follow-up measures (n = 30) 1-3.5 years following discharge as part of other investigations. Positive correlations were found between the ACL and concurrent measures of adaptive and cognitive function. With respect to cognitive variables, stepwise multiple regression analysis revealed that the majority of the variance in ACL scores was predicted by neuropsychological test scores assessing higher level cognitive processes, such as visual organization, manipulation of information in working memory, and ability to inhibit a response to a prepotent stimulus. Finally, results revealed positive relationships between the ACL obtained at discharge and community functioning at follow-up. The results of this study provide some evidence for the concurrent and predictive validity of the ACL for patients with schizophrenia and suggest that further study of this assessment tool would be important to pursue in future investigations.

The purpose of this study was to assess ethnic differences in the negative symptom profile of 25 Anglo American and 26 Mexican American subjects with schizophrenia. Subjects were rated at the end of a 1-2-week medication washout period (time 1) and at discharge (time 2) with the Negative Symptoms Assessment (NSA), Brief Psychiatric Research Scale, (BPRS), the [Diagnostic and Statistical Manual of Mental Disorders (4th edition)] DSM-IV negative factor score and LAECA acculturation scale. Total NSA scores were significantly higher among Mexican Americans both at time 1 and time 2. Among the five subscales of the NSA, ethnic differences were significant only for the Cognition subscale at time 1. Results indicate no ethnic differences in core negative symptoms (alogia, avolition, flat affect), but do suggest that a cognition-related factor differs between Mexican American and Anglo American schizophrenic patients.

This demonstration project examined whether medication management coordinators enhanced continuity of care from inpatient facilities to an outpatient public mental health clinic.From 2004 to 2008, patients (N=325) hospitalized with schizophrenia or schizoaffective or bipolar disorder enrolled in a medication management program before discharge or at their first clinic appointment. Medication management coordinators supplemented existing clinic practices by identifying recently hospitalized patients, providing inpatient and outpatient prescribing clinicians with patients' complete medication history, meeting with patients for six months postdischarge to assess clinical status and provide medication education, and advocating guideline-concordant prescribing. Recently discharged patients (N=345) assigned to a different outpatient clinic within the same agency served as the comparison group. Intent-to-treat, repeated-measures analyses for mixed models compared the groups' number of hospital admissions, hospital days, and medication appointments kept and use of nurse or case manager contact hours and emergency or crisis services during the 12 months before enrollment, the six-month intervention, and the six-month follow-up period.After discharge, individuals enrolled in medication management were more likely than comparison patients to attend outpatient appointments, and they had more medication visits and nurse or case manager treatment hours than the comparison group. Use of hospital and crisis or emergency services by all patients decreased. Almost one-third of patients never attended an outpatient appointment after hospital discharge.Although this program succeeded in improving continuity of care, additional interventions may be required to reduce rehospitalization and crisis care.

A 2004 consensus statement by the American Psychiatric Association and other groups noted that metabolic side effects of second-generation antipsychotics require monitoring. To reduce risk, prescribers may consider factors differentially associated with development of metabolic abnormalities, such as age, gender, and race-ethnicity. As part of a study of older patients with schizophrenia (50-102 years), this study evaluated factors associated with antipsychotic switches and switches that incurred a greater or lesser metabolic risk.Administrative data were analyzed for a national cohort of 16,103 Veterans Health Administration patients with schizophrenia receiving second-generation antipsychotics. Multinomial logistic regression predicted the likelihood of switches from 2002 to 2003 and again from 2004 to 2005.At baseline nearly half the patients (45%) had a diagnosis of hypertension, a third (34%) had dyslipidemia, and 15% had a diagnosis of obesity. In both periods diabetes was associated with switches to lower-risk antipsychotics, and older patients were likely to experience neutral or no switches. Women were more likely to experience switches to higher-risk antipsychotics in 2004-2005.General medical conditions potentially associated with antipsychotic-related metabolic concerns were common; however, half of these patients were prescribed medication that made them liable to developing metabolic problems. Modest evidence suggests that metabolic considerations became a higher priority during the study. Future research should investigate the differential impact of antipsychotics on metabolic dysregulation for women and elderly patients. Findings underscore the need to monitor metabolic parameters of older patients taking antipsychotics.

Context Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes. Objective To adjudicate neurocognitive endophenotypes for bipolar disorder. Design All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status. Setting Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas. Participants Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia. Main Outcome Measure Neurocognitive test performance. Results Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory. Conclusion This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.

Schizophrenia (SC) and bipolar disorder (BP) are two of the most severe and incapacitating mental disorders. It has been questioned whether these two conditions designate distinct illnesses with different etiologies or whether they represent different ends of a clinical spectrum with a common etiology. This study compares social and clinical characteristics of 84 SC and 84 BP subjects from the Costa Rican Central Valley (CRCV) using information from the DIGS, FIGS and psychiatric records. Each of these subjects had a best estimate lifetime consensus diagnosis of either bipolar type I or SC. Subjects with SC differed from subjects with BP in social adjustment measures like marital and employment status, and number of children. Both groups were very similar in years of education, age of onset of their illness, history of other psychiatric co-morbidities, and treatment received. The high percentage of psychosis in the BP group (97.6%) may largely explain the similarities found between groups in their clinical characteristics. The differences in social and functional decline support the original dichotomy described by Kraepelin based on chronicity and periodicity between these two psychotic disorders.

Methionine sulfoxide reductase (MSRA) is an antioxidant enzyme implicated in protection against oxidative stress and protein maintenance. We have previously reported the association of marker D8S542, located within the MSRA gene, with schizophrenia in the Central Valley of Costa Rica (CVCR). By performing fine mapping analysis, we have now identified a potential three-marker at risk haplotype within MSRA in the same CVCR sample, with a global P-value slightly above nominal significance (P = 0.0526). By sequencing the MSRA gene in individuals carrying this haplotype, we identified a novel 4-base pair deletion 1,792 bases upstream of the MSRA transcription start site. This deletion was significantly under-transmitted to schizophrenia patients in the CVCR sample (P = 0.0292) using FBAT, and this was replicated in a large independent sample of 321 schizophrenia families from the Hispanic population (P = 0.0367). These findings suggest a protective effect of the deletion against schizophrenia. Further, MSRA mRNA levels were significantly lower in lymphoblastoid cell lines of individuals homozygous for the deletion compared to carriers of the normal allele (P = 0.0135), although significance was only evident when genotypes were collapsed. This suggests that the deleted sequence may play a role in regulating MSRA expression. In conclusion, this work points towards MSRA as a novel schizophrenia candidate gene. Further studies into the mechanisms by which MSRA is involved in schizophrenia pathophysiology may shed light into the biological underpinnings of this disorder.

Schizophrenia is a genetically complex illness with heterogeneous clinical presentation, including variable age of onset. In this study, the heritability, or proportion of variation in age of onset of psychotic symptoms due to genetic factors, was estimated using a maximum likelihood method. The subjects were 717 members of families with more than one member affected with schizophrenia from Mexican and Central American populations. Age of onset of psychosis was determined by best-estimate consensus diagnosis based on the Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, and each subject's medical records. Mean age of onset was 21.44 years (SD 8.07); 20.55 years for males (SD 6.90), and 22.67 for females (SD 9.34). Variance components were estimated using a polygenic model in the SOLAR software package. The sex of the participant was a significant covariate (P = 0.010) accounting for 0.02 of the total variance in age of onset. The heritability of age of onset of psychosis was 0.33 (SE = 0.09; P = 0.00004). These findings suggest that genetic factors significantly contribute to the age of onset of psychotic symptoms in individuals with schizophrenia and that sex influences this trait as well.

Justificación y objetivo: la esquizofrenia es una enfermedad crónica con importantes repercusiones sociales que afecta al 1% de la población mundial. Se describe las características de la esquizofrenia en una muestra de pacientes del Valle Central de Costa Rica. Métodos: estudio descriptivo, transversal en esquizofrénicos diagnosticados a través del proceso de mejor estimado diagnostico según la cuarta edición del Manual Diagnóstico y Estadístico de los Trastornos Mentales (DSMIV). Resultados: de 260 esquizofrénicos, 186 (71.5%) son varones y 74 (28.5%) mujeres, la edad promedio de entrevista es 38.95 años (Desviación Standard (DS): 11.37), menor en los varones (37.54 años, DS: 10.46) que en las mujeres (42.49 (DS: 12.81, p0.05). El número de hospitalizaciones es en promedio 5.49 (DS: 5.24), (p>0.05), los sujetos solteros presentan tendencia a un mayor número de ingresos (17.25 internamientos). El 49.6% ha sufrido al menos un síndrome depresivo mayor, 7.5% de los varones presenta abuso y el 22.0% dependencia al alcohol; 7.7% de sujetos presenta abuso y el 7.3% dependencia a sustancias (p>0.05). Discusión: Nuestros pacientes presentaron características clínicas y demográficas similares a lo observado en otras poblaciones. Más de la mitad de los individuos tenían antecedente de síntomas afectivos siendo los depresivos los más frecuentes. Los varones solteros constituyeron el grupo con peor pronóstico, mayor desempleo y mayor tendencia a presentar reingresos hospitalarios. Sin embargo, dicho hallazgo podría ser explicado por la organización económica de los hogares y el rol social del varón en nuestra sociedad. Conclusión: los varones y las mujeres EZ del VCCR muestran una misma edad de inicio de enfermedad, el subtipo predominante en ambos grupos es el indiferenciado con el antecedente de síntomas depresivos. Los varones presentan un mayor índice de desempleo, mayor consumo de sustancias lícitas e ilícitas y mayor número de hospitalizaciones que las mujeres. Justification and Aim: schizophrenia is a chronic illness with important social consequences. It is found in 1% of the world population. We describe the characteristics of schizophrenia in a sample of patients from the Central Valley of Costa Rica. Methods: descriptive, transversal study of schizophrenic patients diagnosed with the best estimate diagnosis process based on DSMIV criteria. Results: out of 260 schizophrenic subjects, 186 (71.5%) are males and 74 (28.5%) females, average age at interview is 38.95 years (SD: 11.37), lower in males (37.54 years, SD: 10.46) than females (42.49 (SD: 12.81, p0.05), those who are not married have a trend of more hospitalizations (17.25); 49.6% of the subjects have had at least one major depressive syndrome; 7.5% of males present alcohol abuse and 22.0% alcohol dependence; 7.7% have substance abuse and 7.3% substance dependence (p>0.05). Discussion: our sample showed similar clinical and demographic characteristics to other populations. More than half of the sample had affective symptoms, depressive symptoms were the most frequent. Single males had the worse prognosis, lower employment rate and higher number of hospitalizations. Nonetheless, this finding could be explained by the economical organization of the household and the social role of males in our society. Conclusions: schizophrenic males and females from the Central Valley of Costa Rica showed the same age of onset. In both groups, the most frequent schizophrenia type was undifferentiated with history of depressive symptoms. Males had higher unemployment rate, more substance use and more number of hospitalizations than females.

The clinical and sociodemographic profile of suicidal and nonsuicidal schizophrenia patients was investigated in 801 patients with this diagnosis seen at a comprehensive psychiatric facility between 1983 and 1987. Suicidal patients tended to exhibit depression, aggressiveness, substance abuse and a severe and progressive impairment in adaptive functioning.

Previous studies have identified a putative gene locus for both schizophrenia and bipolar disorder in the chromosome 18q21 region. To identify candidate genes associated with these disorders we completed fine mapping analyses (using microsatellite markers) in 152 families from the Central Valley of Costa Rica (CVCR) (376 total subjects, 151 with a history of psychosis, 97 with a history of mania). Microsatellite analyses showed evidence of association at two contiguous markers, both located at the same genetic distance and spanning approximately 11 known genes. In a corollary gene expression study, one of these genes, malic enzyme 2 (ME2), showed levels of gene expression 5.6-fold lower in anterior cingulate tissue from post-mortem bipolar brains. Subsequent analysis of individual SNPs in strong linkage disequilibrium with the ME2 gene revealed one SNP and one haplotype associated with the phenotype of psychosis in the CVCR sample. ME2 interacts directly with the malate shuttle system, which has been shown to be altered in schizophrenia and bipolar disorder, and has roles in neuronal synthesis of glutamate and γ-amino butyric acid. The present study suggests that genetic variation in or near the ME2 gene is associated with both psychotic and manic disorders, including schizophrenia and bipolar disorder.

Background Although genetic factors are known to play an important role in schizophrenia, the identification of genes involved in this disorder has remained elusive. The neuregulin 1 gene is among the few candidate genes to have been implicated in schizophrenia susceptibility in several populations. However, no causal mutations within this gene have been identified. Methods In attempts to identify polymorphisms within the neuregulin 1 gene, we performed DNA sequencing using 12 subjects with a history of psychosis from the Central Valley of Costa Rica. DNA genotyping and association studies were then performed in an extended cohort of 142 affected individuals and their relatives from the same population. Results We identified a novel missense mutation (Val to Leu) in exon 11, which codes for the transmembrane region of the neuregulin 1 protein. Association analysis by the Family Based Association Test (FBAT) revealed that this mutation is associated with psychosis (p = .0049) and schizophrenia (p = .0191) in this population. Conclusions We report the finding of a missense mutation in the neuregulin 1 gene associated with schizophrenia. Additional analyses of an independent sample as well as detailed functional studies should be performed to determine the relevance of this novel polymorphism to the pathophysiology of schizophrenia.

The purpose of this study was to assess ethnic differences in the negative symptom profile of 25 Anglo American and 26 Mexican American subjects with schizophrenia. Subjects were rated at the end of a 1-2-week medication washout period (time 1) and at discharge (time 2) with the Negative Symptoms Assessment (NSA), Brief Psychiatric Research Scale, (BPRS), the [Diagnostic and Statistical Manual of Mental Disorders (4th edition)] DSM-IV negative factor score and LAECA acculturation scale. Total NSA scores were significantly higher among Mexican Americans both at time 1 and time 2. Among the five subscales of the NSA, ethnic differences were significant only for the Cognition subscale at time 1. Results indicate no ethnic differences in core negative symptoms (alogia, avolition, flat affect), but do suggest that a cognition-related factor differs between Mexican American and Anglo American schizophrenic patients.