Alfonso Ontiveros

A Randomized, Open-Label Comparison of Venlafaxine and Fluoxetine in Depressed Outpatients

In this randomized, open-label, 8-week comparative study, the efficacy and safety of venlafaxine and fluoxetine were assessed in outpatients with major depression. One hundred forty-five patients were assigned to receive venlafaxine 37.5 mg twice daily or fluoxetine 20 mg once daily. On day 15, if clinically indicated to improve patient response, the dosage could be increased at the investigators discretion to venlafaxine 75 mg twice daily or fluoxetine 40 mg once daily. One hundred forty-five patients were evaluated for safety and 110, for efficacy. The mean age was 37 years, and 70% of the patients were female. In both treatment groups, mean scores on the Hamilton Depression Rating Scale decreased significantly between baseline (27.8, venlafaxine; 29.2, fluoxetine) and the end of the study (8.7, venlafaxine; 8.2, fluoxetine). Similarly, mean scores on the Montgomery-Asberg Depression Rating Scale decreased significantly between baseline (31.4, venlafaxine; 31.6, fluoxetine) and the end of the study (8.3, venlafaxine; 7.6, fluoxetine). In venlafaxine patients, the most common adverse events were nausea (44.3%), headache (40.0%), insomnia (31.4%), dizziness (30.0%), and dry mouth (22.9%); in fluoxetine patients, they were headache (32.0%), nausea (28.0%), insomnia (24.0%), anxiety (21.3%), sleepiness (20.0%), and generalized tremor (20.0%). The results of this study indicate that venlafaxine is effective and well tolerated for the treatment of major depression at doses of 37.5 or 75 mg twice daily and not significantly different from fluoxetine 20 or 40 mg once daily.

Heritability of age of onset of psychosis in schizophrenia

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 subjects 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.

A genome-wide scan for schizophrenia and psychosis susceptibility loci in families of Mexican and Central American ancestry.

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.

Methionine sulfoxide reductase: a novel schizophrenia candidate gene.

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.

Genetic structure analysis of three Hispanic populations from Costa Rica, Mexico, and the southwestern United States using Y-chromosome STR markers and mtDNA sequences.

ABSTRACT Two hundred seventeen male subjects from Costa Rica, Mexico, and the Hispanic population of the southwestern United States were studied. Twelve Y-chromosome STRs and the HVSI sequence of the mtDNA were analyzed to describe their genetic structure and to compare maternal and paternal lineages. All subjects are part of two NIMH-funded studies to localize schizophrenia susceptibility genes in Hispanic populations of Mexican and Central American ancestry. We showed that these three populations are similar in their internal genetic characteristics, as revealed by analyses of mtDNA and Y-chromosome STR diversity. These populations are related through their maternal lineage in a stronger way than through their paternal lineage, because a higher number of shared haplotypes and polymorphisms are seen in the mtDNA (compared to Y-chromosome STRs). These results provide evidence of previous contact between the three populations and shared histories. An analysis of molecular variance revealed no genetic differentiation for the mtDNA for the three populations, but differentiation was detected in the Y-chromosome STRs. Genetic distance analysis showed that the three populations are closely related, probably as a result of migration between close neighbors, as indicated by shared haplotypes and their demographic histories. This relationship could be an important common feature for genetic studies in Latin American and Hispanic populations.

A Schizophrenia Gene Locus on Chromosome 17q21 in a New Set of Families of Mexican and Central American Ancestry: Evidence From the NIMH Genetics of Schizophrenia in Latino Populations Study

OBJECTIVE The present study investigated a new set of families of Latin American ancestry in order to detect the location of genes predisposing to schizophrenia and related psychotic disorders. METHOD A genome-wide scan was performed for 175 newly recruited families with at least two siblings suffering from a psychotic disorder. Best-estimate consensus procedures were used to arrive at diagnoses, and nonparametric allele-sharing statistics were calculated to detect linkage. RESULTS Genome-wide significant evidence for linkage for the phenotype of DSM-IV schizophrenia or schizoaffective disorder was found in a region on chromosome 17q21 (lod score, 3.33). A region on chromosome 15q22-23 showed suggestive evidence of linkage with this same phenotype (lod score, 2.11). Analyses using a broader model (any psychosis) yielded evidence of suggestive linkage for the 17q21 region only, and no region achieved genome-wide significance of linkage. CONCLUSIONS The new set of 175 families of Mexican and Central American ancestry delineates two new loci likely to harbor predisposition genes for schizophrenia and schizoaffective disorder. The region with the strongest support for linkage in this sample, 17q21, has been implicated in meta-analyses of schizophrenia genome screens, but the authors found no previous reports of it as a locus for schizophrenia in specific population- or family-based studies, and it may represent the location of a schizophrenia predisposition gene (or genes) of special relevance in Mexican and Central American populations.

The Serotonin Transporter 5-HTTPR Polymorphism is associated with Current and Lifetime Depression in Persons with Chronic Psychotic Disorders

Objective:  Variation in the serotonin transporter gene (SLC6A4) promoter region has been shown to influence depression in persons who have been exposed to a number of stressful life events.

Genome-Wide Methylome Analyses Reveal Novel Epigenetic Regulation Patterns in Schizophrenia and Bipolar Disorder

Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3′-UTRs and 5′-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3′-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.

Suggestive evidence for association between L-type voltage-gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family-based association study

OBJECTIVES   Through recent genome-wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage-dependent, L-type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European-American cohorts. We performed a family-based association study to determine whether CACNA1C is associated with BP in the Latino population. METHODS   This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single-nucleotide polymorphisms (SNPs) that spanned a 602.9-kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family-Based Association Test (version 2.0.3) and Haploview (version 4.2) software. RESULTS   An eight-locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). CONCLUSIONS   Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population.

Identification of circadian gene variants in bipolar disorder in Latino populations

BACKGROUND Variations in circadian genes can impact biological rhythms. Given the rhythm disturbances that characterize bipolar disorder (BD), genes encoding components of molecular clocks are good candidate genes for the illness. METHODS A family based association analysis of circadian gene single nucleotide polymorphisms (SNPs) and BD was conducted in Latino pedigrees. 884 individuals from 207 pedigrees (473BP phenotype and 411 unaffected family members) were genotyped. Family based single marker association testing was performed. Ancestral haplotypes (SNPs found to be in strong LD defined using confidence intervals) were also tested for association with BD. RESULTS Multiple suggestive associations between circadian gene SNPs and BD were noted. These included CSNK1E (rs1534891, p=0.00689), ARNTL (rs3789327, p=0.021172), CSNK1D (rs4510078, p=0.022801), CLOCK (rs17777927, p=0.031664). Individually, none of the SNPs were significantly associated with BD after correction for multiple testing. However, a 4-locus CSNK1E haplotype encompassing the rs1534891 SNP (Z-score=2.685, permuted p=0.0076) and a 3-locus haplotype in ARNTL (Z-score=3.269, permuted p=0.0011) showed a significant association with BD. LIMITATIONS Larger samples are required to confirm these findings and assess the relationship between circadian gene SNPs and BD in Latinos. CONCLUSIONS The results suggest that ARNTL and CSKN1E variants may be associated with BD. Further studies are warranted to assess the relationships between these genes and BD in Latino populations.