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Atrial fibrillation (AF) is the most prevalent heart rhythm disorder in the general population. Stroke prevention is one of the leading management objectives in the treatment of AF patients. The variables associated with the non-initiation of thromboprophylaxis in patients with thrombotic risk consulting for an episode of AF in Emergency Departments (ED) were investigated. This was a multipurpose, analytical, non-interventionist, multicenter Spanish study with a prospective 30-day follow-up. All patients >= 18 years of age consulting to the ED for the casual finding of AF in an electrocardiogram (ECG) performed 12 h prior to the consultation or with symptoms related to AF were enrolled from September 1, 2016 to February 28, 2017. Patients not previously received thromboprophylaxis were selected. Multivariate analysis was performed to calculate the odds ratio (OR) and the 95% confidence interval (CI). A total of 634 patients, not received thromboprophylaxis and at high thrombotic risk, were included. Of these, 251 (39.6%) did not receive thromboprophylaxis at ED discharge. In the multivariate analysis, non-initiation of anticoagulation at discharge from the ED was mostly related to cognitive impairment (OR 3.95; (95% CI 2.02-7.72), cancer history (OR 2.12; (95%CI 1.18-3.81), AF duration < 48 h (OR 2.49; (95% CI 1.48-4.21) and patients with re-establishment of sinus rhythm (OR 3.65; (95% CI 1.47-9.06). Reinforcement of the use of CHA(2)DS(2)-VASC as a stroke risk scale and empowerment of ED physicians is a must to improve this gap in care.

Background:Although pharmacogenetics for major depressive disorder (MDD) is gaining momentum, the role of genetics in differences in response to antidepressant treatment is controversial, as they depend on multifactorial and polygenic phenotypes. Previous studies focused on the genes of the serotonergic system, leaving apart other pathological factors such as the inflammatory pathway. The main objective of the study was to assess whether treatment response might be associated with specific inflammation-related genetic variants or their methylation status.Methods:41 SNPs in 8 inflammatory genes: interleukin (IL) 1-β, IL2, IL6, IL6R, IL10, IL18, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were genotyped in 153 patients with MDD, who were evaluated with the Mausdley Staging Method to determine treatment response profiles. Pyrosequencing reactions and methylation quantification were performed in a PyroMark Q24 in 5 selected CpG islands of IL1- β, IL6 and IL6R. Linear and logistic regression analyses were conducted, including age and gender as covariates using PLINK 1.07.Results:Allelic distribution of IL1- β rs1143643 was significantly associated with MSM scores (FDR corrected p = 0.04). Allelic distribution of IL6R rs57569414 showed a trend towards significance with MSM scores (p = 0.002; FDR corrected p = 0.07). Haplotype analyses showed associations between allelic combinations of IL1-β and IL10 with treatment response (FDR corrected p < 0.01). Methylation percentage of treatment responders was only higher in an IL6R CpG island (p < 0.05).Conclusions:These exploratory findings suggest that IL1-β and, marginally, IL6R polymorphisms may affect treatment response in major depression. If confirmed, these results may account for the heterogeneous phenotypes of major depression that underlie differences in treatment response.

The genetic etiology of autism spectrum disorder (ASD) is multifactorial with contributions from rare variants, polygenic risk, and sex. How combinations of factors determine risk for ASD is unclear. In 11,313 ASD families (N = 37,375 subjects), we investigated the effects rare and polygenic risk individually and in combination. We show that genetic liability for ASD differs by sex, with females having a greater polygenic load, and males having a lower liability threshold as evident by a negative correlation of rare and polygenic risk. Multiple genetic factors were associated with differing sets of behavioral traits with effects that differed by sex. Furthermore, the correlation of parental age with genetic risk for ASD was attributable tode novomutations and sex-biased effects of inherited risk in parents. Our results demonstrate that a phenotypic spectrum of ASD is attributable to the relative loadings and gene-by-sex effects of rare and common variation.

Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic modifications such as DNA methylation may modulate gene × environment interactions and impact on neurodevelopment. We conducted an epigenome wide study (Illumina Infinium HumanMethylation450k beadchip) in a group of BPD patients with (N = 49) and without (N = 47) childhood traumas and in a control group (N = 44). Results were confirmed in a replication cohort (N = 293 BPD patients and N = 114 controls) using EpiTYPER assays. Differentially methylated CpG sites were observed in several genes and intragenic regions in the X chromosome (PQBP1, ZNF41, RPL10, cg07810091 and cg24395855) and in chromosome 6 (TAP2). BPD patients showed significantly lower methylation levels in these CpG sites than healthy controls. These differences seemed to be increased by the existence of childhood trauma. Comparisons between BPD patients with childhood trauma and patients and controls without revealed significant differences in four genes (POU5F1, GGT6, TNFRSF13C and FAM113B), none of them in the X chromosome. Gene set enrichment analyses revealed that epigenetic alterations were more frequently found in genes controlling oestrogen regulation, neurogenesis and cell differentiation. These results suggest that epigenetic alterations in the X chromosome and oestrogen-regulation genes may contribute to the development of BPD and explain the differences in presentation between genders. Furthermore, childhood trauma events may modulate the magnitude of the epigenetic alterations contributing to BPD.

De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.

Antipsychotic drugs fail to achieve adequate response in 30–50% of treated patients and about 50% of them develop severe and lasting side effects. Treatment failure results in poorer prognosis with devastating repercussions for the patients, carers and broader society. Our study evaluated the clinical benefits of a pharmacogenetic intervention for the personalisation of antipsychotic treatment. Pharmacogenetic information in key CYP polymorphisms was used to adjust clinical doses in a group of patients who started or switched treatment with antipsychotic drugs (PharmG+, N = 123), and their results were compared with those of a group of patients treated following existing clinical guides (PharmG−, N = 167). There was no evidence of significant differences in side effects between the two arms. Although patients who had their antipsychotic dose adjusted according to CYPs polymorphisms (PharmG+) had a bigger reduction in side effects than those treated as usual (PharmG−), the difference was not statistically significant (p > 0.05 for all comparisons). However, PharmG+ patients treated with CYP2D6 substrates that were carriers of CYP2D6 UMs or PMs variants showed a significantly higher improvement in global, psychic and other UKU side effects than PharmG− patients (p = 0.02, p = 0.05 and p = 0.01, respectively). PharmG+ clozapine treated patients with CYP1A2 or CYP2C19 UM and PMs variants also showed higher reductions in UKU scores than PharmG− clozapine patients in general. However, those differences were not statistically significant. Pharmacogenetic interventions may improve the safety of antipsychotic treatments by reducing associated side effects. This intervention may be particularly useful when considering treatment with antipsychotics with one major metabolic pathway, and therefore more susceptible to be affected by functional variants of CYP enzymes., This research was funded by grants from the Institute Carlos III (FIS PI11/02006; FIS PI16/01029). A.G.-R. was partially funded by a private grant from the Jové family. Genotyping was partially conducted by the CEGEN-PRB2-ISCIII node, which is supported by grant PT13/001, ISCIIISGEFI/ FEDER.

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

This study investigated the possible association of 40 polymorphisms within 4 noradrenergic genes with BPD risk and the modulating effect of childhood trauma on these associations in 481 BPD subjects and 442 controls. COMT rs5993882, DBH rs77905 and SLC6A2 rs1814270 showed associations with BPD, which were modulated by childhood trauma. However, none of these findings survived Bonferroni correction. Further investigation is needed to clarify the involvement of these genes in BPD pathogenesis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Secreted protein acidic and rich in cysteine (SPARC) is a glycoprotein of the extracellular matrix whose expression can be altered in malignant pancreatic cells and in the adjacent stromal fibroblasts. We evaluated the possible role of SPARC gene variants as prognostic markers for locally advanced and metastatic pancreatic cancer. We analyzed eight tagging single-nucleotide polymorphisms (TagSNPs) in the SPARC gene in 74 patients with pancreatic ductal adenocarcinoma treated with chemotherapy alone or combined with radiotherapy. TagSNPs were chosen using the HapMap genome browser and Haploview software 4.2 based on two predefined criteria: (1) coefficient cutoff of 0.80 and (2) minor allele frequency (MAF) >= 0.10. Univariate analyses revealed significant associations between four SNPs (rs17718347, rs2347128, rs3210714, and rs967527) and PFS. The rs3210714 genetic variant was also associated with OS. In the multivariate analyses, rs17718347 (HR 0.4; 95% CI 0.2-0.8; p = 0.013) and rs2347128 (HR 0.5; 95% CI 0.3-0.9; p = 0.049) remained statistically associated with PFS. In addition, patients harboring the T-A-G haplotype (rs17718347, rs1978707, rs2347128) had a better PFS (p = 0.002). Our findings suggest that SPARC polymorphisms may be useful in predicting outcome in patients with locally advanced and metastatic pancreatic cancer.

The hypothalamus-pituitary-adrenal axis (HPA) is essential in the regulation of stress responses. Increased methylation of the promoter region of the glucocorticoid receptor gene (NR3C1) has been described both in subjects with history of childhood trauma and in patients with Borderline Personality Disorder (BPD). However, no data on the possible association between a higher methylation of this gene and clinical severity is available. The aim of this study was to evaluate the association between NR3C1 methylation status, the history of childhood trauma, and current clinical severity in subjects with BPD. A sample of 281 subjects with BPD (diagnosed by SCID-II and DIB-R semi-structured diagnostic interviews) was recruited. Clinical variables included previous hospitalizations, self-injurious behavior, and self-reported history of childhood trauma. DNA was extracted from peripheral blood. The results indicated a significant positive correlation between NR3C1 methylation status and childhood maltreatment (specifically physical abuse). In addition, a positive correlation between methylation status and clinical severity (DIB-R total score and hospitalizations) was observed. These findings suggest that NR3C1 methylation in subjects with BPD may be associated not only with childhood trauma but also with clinical severity, adding new evidence to the involvement of gene-environment interactions in this disorder. (C) 2014 Elsevier Ltd. All rights reserved.

Several genetic factors have been identified that, in combination with clinical and environmental factors, contribute to the variability in response to treatment with antipsychotic drugs. Functional polymorphisms in genes coding for cytochrome-P450 (CYP) enzymes, responsible for the metabolism of over 85 % of drugs, have been associated with the development of drug-induced side-effects, and functional polymorphisms in dopamine and serotonin genes may be associated with adverse reactions and treatment efficacy. Recent estimations have suggested that selecting the drug and clinical dose according to the patient’s genetic profile may result in a significant improvement of treatment efficacy (10–15 %) and safety (15–20 %). This information has prompted the development of commercial kits to facilitate the clinical application of pharmacogenetic information. However, prospective studies confirming the clinical and economical benefits of these tests are required before their widespread implementation in clinical practice.

Background: Methotrexate (MTX) is the most used drug for the treatment of rheumatoid arthritis (RA) although outcome differs among patients. Aim: To evaluate whether polymorphisms in pharmacokinetic genes are associated with outcome in RA patients receiving MTX. Patients & methods: We analyzed 28 SNPs in SLC19A1/RFC1, ABCB1, FPGS and GGH genes. Results: We studied 194 RA patients receiving MTX monotherapy. Two FPGS SNPs, rs10987742 and rs10106, were associated with response (p = 0.033 and p = 0.041, respectively). The FPGS rs10106 variant was also associated with MTX survival (p = 0.005) and toxicity (p = 0.021). Three ABCB1 SNPs, rs868755, rs10280623 and rs1858923, were associated with toxicity (p = 0.025, p = 0.048 and p = 0.031, respectively). Conclusion: FPGS and ABCB1 genetic variants can influence the outcome in RA patients receiving MTX monotherapy.

Genetic studies on human personality have provided little satisfactory results to date mainly because of the complexity of this trait. Neonatal temperament using observational measures is an alternative phenotype to approach genetics to human behavior. An association study was conducted on 117 Caucasian newborns. Their temperament was evaluated using the Neonatal Behavior Assessment Scale 48 h after birth. Thirteen polymorphisms in the SLC6A4, DRD4 and TFAP2B genes were genotyped. Linear regression was performed to analyze data, and Bonferroni correction was applied. To check the functional effect of the TFAP2B Indel Intron 2 polymorphism, reporter gene luciferase assays using a mouse cortical neural progenitor cell line and quantitative polymerase chain reaction (qPCR) studies in human post-mortem brain samples were performed. A significant association was found between 5-HTTLPR, 5-HTTLPR + rs25531 and TFAP2B Indel Intron 2 with Range of State cluster as well as an interaction between rs25531 and TFAP2B Indel Intron 2 with Range of State. DRD4 variable number tandem repeat exon 3 was associated with orientation. A 30% increase in the luciferase levels of the TFAP2B 5-repeat alleles compared with the 6-repeat alleles (P-value = 0.03) was found using the pGL3 promoter vector. The qPCR experiments showed the same trend as the in vitro studies, although no significant results were obtained. This study supports a role of the SLC6A4, DRD4 and TFAP2B genes in the temperament, including a gene-gene interaction between SLC6A4 and TFAP2B. It also provides evidence about an effect of the TFAP2B polymorphism in TFAP2B gene transcription.

Introduction Preterm birth is associated with a range of neurodevelopmental deficits, including corpus callosum (CC) abnormalities, which persist into late adolescence and early adulthood. A common single-nucleotide polymorphism in the catechol-o-methyl transferase (COMT) gene (Val158Met) is associated with cognition and brain structure and may play a role in neurodevelopment. It is not known whether this polymorphism is associated with CC morphometry in individuals born preterm. Methods Structural MRI scans were acquired in 33 adults born very preterm (before 33 weeks' gestation) and 29 healthy controls. DNA was collected and COMT Val158Met polymorphism status determined using standard available assays. The mid-sagittal area of four antero-posterior subdivisions of the CC was measured. The effect of COMT Val158Met polymorphism on cross-sectional CC areas was studied using multivariate analysis and generalised linear models, adjusted for the effects of the clinical sample group (preterm vs. control), age and sex. Results The COMT Val/Val homozygous genotype was observed to be significantly associated with reduced size of the total corpus callosum, and this relationship was present for the anterior, midposterior and posterior quarters of the CC. Conclusions The COMT Val158Met polymorphism possibly influences the morphometry of the corpus callosum associated with very preterm births. Further studies with larger sample sizes are warranted to conclusively establish the effects of individual genotypes of the COMT gene on corpus callosum in preterm born adults.

Acetyl-coenzyme A carboxylase alpha (ACACA) single-nucleotide polymorphism (SNP) (rs2229416) was significantly associated with hypertriglyceridemia, during exploration of antipsychotic direct effects on lipids. Neuropeptide Y (NPY) gene (rs1468271) and ACACB gene (rs2241220) SNPs were significantly associated with severe hypercholesterolemia. In the same sample (173 patients on olanzapine, quetiapine, chlorpromazine or mirtazapine [increasing the risk of hyperlipidemia] and 184 controls taking other antipsychotics), three (rs1266175, rs12453407 and rs9906543) of eight additional ACACA SNPs were significantly associated with hypertriglyceridemia in those taking drugs of interest, but not in controls. Five other ACACA SNPs, three additional NPY SNPs, and seven additional ACACB SNPs were not significant.

There is strong biological evidence relating alterations in the serotonergic system with mental disorders. These alterations may be originated at the DNA level by sequence mutations that alter the functioning of serotonin receptors and transporter. To test this hypothesis we investigated three genetic variants of the 5-HT2A receptor (−1438G/A, 102T/C and His452Tyr) and two variants of the serotonin transporter (a VNTR in the second intron and a 44 bp insertion/delition in the promoter region of the gene) in a clinical sample recruited in a human isolate and in surrounding areas in Northern Spain (N = 257) and in ethnically matched controls (N = 334). No clear association was found between 5-HT2A variants and psychosis. However, marginal associations were observed between the 5-HTT LPR and VNTR variants and psychosis (P ≤ 0.05) indicating a minor contribution to psychosis of genetic alterations in this gene. © 2003 Wiley-Liss, Inc.

Pharmacogenetic research into neurotransmitter-related genes is helping to unravel genetic factors that determine antipsychotic response. Several genetic mutations in neurotransmitter receptors targeted by antipsychotic drugs have been found to be related to clinical response. Modern molecular genetic techniques will facilitate the identification of those mutations that determine treatment response. Future psychiatric prescription will include the genetic characterization of neurotransmitter receptors for the selection of the most beneficial drug according to the individual's pharmacogenetic profile.

Catechol-O-methyltransferase (COMT) plays a major role in the breakdown of catecholamines. An amino acid polymorphism (val-108-met) determines high and low activity of the enzyme. A recent study in a small sample of patients with velo-cardio-facial syndrome who had bipolar affective disorder suggested that the Met (low activity) COMT allele might be associated with rapid-cycling in this population. We therefore tested the hypothesis that the Met allele might be associated with rapid cycling bipolar disorder in the wider population. We studied a sample of British Caucasian DSM-IV bipolar patients, of whom 55 met criteria for rapid cycling at some time during the illness and 110 met stringent criteria for a definite non-rapid cycling course. The COMT genotype was determined using a PCR assay. The low activity allele was more frequent in the group of rapid cyclers: 0.55 vs 0.42 (one-tailed chi 2 = 5.12, d.f. = 1, P = 0.012), and bearers of low activity alleles showed a dose-dependent increased risk of lifetime occurrence of rapid cycling: chi 2 test of linear association = 4.84, d.f. = 1, P = 0.014. Our data support the hypothesis that variation in the COMT gene modifies the course of bipolar disorder.

Introduction: Abnormalities in the neurophysiological measures P300 amplitude and latency constitute endophenotypes for psychosis. Disrupted-in-Schizophrenia-1 (DISC1) has been proposed as a promising susceptibility gene for schizophrenia, and a previous study has suggested that it is associated with P300 deficits in schizophrenia. Methods: We examined the role of variation in DISC1 polymorphisms on the P300 endophenotype in a large sample of patients with schizophrenia or psychotic bipolar disorder (n = 149), their unaffected relatives (n = 130), and unrelated healthy controls (n = 208) using linear regression and haplotype analysis. Results: Significant associations between P300 amplitude and latency and DISC1 polymorphisms/haplotypes were found. Those homozygous for the A allele of single-nucleotide polymorphism (SNP) rs821597 displayed significantly reduced P300 amplitudes in comparison with homozygous for the G allele (P = .009) and the heterozygous group (P = .018). Haplotype analysis showed a significant association for DISC1 haplotypes (rs3738401|rs6675281|rs821597|rs821616|rs967244|rs980989) and P300 latency. Haplotype GCGTCG and ACGTTT were associated with shorter latencies. Discussion: The P300 waveform appears to be modulated by variation in individual SNPs and haplotypes of DISC1. Because DISC1 is involved in neurodevelopment, one hypothesis is that disruption in neural connectivity impairs cognitive processes illustrated by P300 deficits observed in this sample.

We analyzed the blood transcriptome of 36 drug naive schizophrenia patients and 40 healthy matched controls by next-generation sequencing. Among the 22 278 genes analyzed, we found significant differential expression (P-value adjusted

Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT 1A receptor gene as putative risk factors in major depression

This study investigated possible associations between selected polymorphisms in the dopamine receptor genes DRD1 and DRD3 with the presence of psychotic phenomena or aggressive behaviour in a community based cohort of 134 patients with late onset Alzheimer's disease. An association was found between the presence of psychotic symptoms and aggressive behaviour and the DRD1 polymorphism and between the presence of psychosis, but not aggression, and the DRD3 polymorphism. Specifically, carriers of the DRD1 B2 allele were more likely to be aggressive or experience hallucinations whereas homozygous carriers of the DRD3 1 allele were more likely to experience delusions.

Interest exists in identifying the factors that specifically contribute to the increased prevalence of cardiovascular disease observed in psychiatric disease. The apolipoprotein-E (APOE) gene codes for a protein that has a key role in metabolism of cholesterol and triglycerides, with increased levels of apoE found in specific areas of post-mortem schizophrenic brains. This study investigated whether apoE variants influence the prevalence of cardiovascular risk factors (obesity, diabetes and dyslipidaemia), in patients receiving antipsychotic treatment, due to extension of the risk seen in the general population, but also due to the role of the APOE gene in mediating antipsychotic-induced side effects. Seven polymorphisms (rs741780, rs483082, rs429358, rs7412, rs10119, rs439401 and rs405509) were genotyped in 427 American Caucasian patients who were either receiving, or had been prescribed risperidone. Our results support the hypothesis that APOE gene variants influence the prevalence of diabetes and possibly overweight in psychiatric patients. Unfortunately, due to the cross sectional nature of this study, the contribution of antipsychotic treatment was not determined. These associations warrant prospective study to assess interaction between APOE gene variants and the propensity of antipsychotics to induce cardiovascular risk factors.

There are high expectations about the capabilities of pharmacogenetics to tailor psychotropic treatment and ‘‘personalize’’ treatment. While a large number of associations, with generally small effect size, have been discovered, a ‘‘test’’ with widespread use and adoption is still missing. A more realistic picture, recognizing the important contribution of clinical and environmental factors toward overall clinical outcome has emerged. In this emerging view, genetic findings, if considered individually, may have limited clinical applications. Thus, in recent years, combinations of information in several genes have been used for the selection of appropriate therapeutic doses and for the prediction of agranulocytosis, hyperlipidemia, and response to antipsychotic and antidepressant medications. While these tests based on multiple genes show greater predictive ability than individual allele tests, their net impact on clinical consequence and costs is limited, thus leading to limited penetration into widespread clinical use. As one looks at other branches of medicine, there are successful examples of pharmacogenetic tests guiding treatment, and thus, it is reasonable to hope that with the incorporation of clinical and environmental information and the identification of new genes drawn from genome-wide analysis, will improve the predictive utility of these tests leading to their increased use by clinicians.

The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients’ metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and −141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (−759−T/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients’ metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

The psychopathology of Alzheimer's disease (AD) is varied and includes both behavioural and psychological symptoms. Behavioural and psychological symptoms are common and contribute to the difficulties experienced by carers. However, the mechanism whereby these symptoms occur in some individuals with AD is not understood. We hypothesized that common genetic polymorphisms in neurotransmitter systems are risk factors for these symptoms in the course of AD. A total of 211 subjects from a population-based prospective study of psychopathology within late-onset AD were genotyped for the 5-HT2A receptor polymorphism 102-T/C and the 5-HT2C receptor polymorphism Cys23Ser. Associations were found between the presence of the C102 allele and the presence of visual (Fisher's exact test, one-tailed, P = 0.003) and auditory hallucinations (Fisher's exact test, one-tailed, P = 0.004) and between the presence of the Ser23 allele and visual hallucinations (chi2 = 7.5, df = 1, P = 0.006) (P = 0.03, 0.04 and 0.06, respectively, after Bonferroni correction). In addition, there was an association between the Cys23Ser polymorphism and hyperphagia (chi2 = 6.7, df = 2, P = 0.03) (P = 0.3 after Bonferroni correction). We conclude that common 5-HT2A and 5-HT2C genetic polymorphisms previously showing only weak associations with psychotic illness are associated with psychotic symptoms in AD but are clinically silent until the onset of the neurodegenerative process.

Abnormalities of the serotonergic system have classically been associated with the origin of affective disorders through the biochemical action of therapeutic agents and their role in affective and perceptual states. In the present study, we hypothesized that genetic variation in the 5-hydroxytryptamine (serotonin) type 2A (5-HT2A ) receptor gene (HTR2A) might have an effect on the aetiology of bipolar affective disorder. Four different polymorphisms in the HTR2A gene were studied in 88 patients with bipolar affective disorder and 113 healthy controls, all of Spanish origin. No significant association was observed between any of the four polymorphisms at the HTR2A locus, whether tested individually or as haplotypes, and bipolar affective disorder. The lack of association suggests that HTR2A is not a major risk factor for bipolar affective disorder.

There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.

Pharmacogenetic research into complex traits, such as response to antipsychotic treatment has proved a difficult task. Nevertheless, investigation of drug metabolic enzymes has revealed polymorphisms in specific cytochrome P450 genes responsible for treatment-induced toxic reactions. However, the picture becomes more complicated when drug target sites are investigated in search of genetic influence. Most antipsychotic drugs are multitarget, denoting a complex mechanism of action. Although individual genes have been reported to influence antipsychotic response, no single gene can account for the variability observed in treatment response. Current investigations focus on single gene variants that may be associated with particular side effects or symptoms as well as contributing to general response. The scope of this article is to review recent advances of pharmacogenetic research on antipsychotic drugs and the strategies under development for the individualization of treatment.

Using administrative data records from the Spanish Employment Agency we examine whether or not there is evidence of state dependence in unemployment under benefits in Spanish young workers. For this fact, we use a mixed proportional hazard model that allows for state dependence through lagged duration dependence in order to disentangle the effects of unobserved individual heterogeneity and the true state dependence. We have found evidence that past unemployment experience and unobserved individual components affect the experience of longer future unemployment spells under benefits. However, we appreciate in workers with completed past unemployment spells that the correlation between the duration of succesive unemployment spells is only due to the unobserved components across individuals. Besides, we observe that workers in their second unemployment experience under benefits present higher hazard rates that in their first unemployment experience under benefits.

Psychiatric treatment requires the use of drugs which are in many cases associated with severe side effects and inadequate response. In the past decade extensive research has investigated the link between gene alterations and treatment response and several strong associations have been reported. The identification of genes influencing treatment outcome will facilitate the pre-treatment selection of the most beneficial drug according to an individual's pharmacogenetic profile. Recent advances indicate that this goal is achievable in the near future. The scope of this communication is to review all the recent findings in psychopharmacogenetics leading to the individualization of treatment.

Clozapine is a potent atypical antipsychotic which binds to a variety of neurotransmitter receptors including serotonin (5-HT) receptors. However, the precise neurochemical site of clozapine's therapeutic action is unknown. We hypothesize that genetic variation in the neurotransmitter receptors to which the drug binds may influence clozapine response. To test this hypothesis we genotyped a novel -1438-G/A polymorphism detected in the promoter region, and a His452Tyr polymorphism described in the coding region of the 5-HT2A receptor gene in two independent samples of clozapine-treated patients including responders and non-responders. Although the strong association between these polymorphisms and clozapine response observed in the first sample (sample I) was not statistically significant in the second sample (sample II), the results in both samples were in the same direction. Homozygosity for the allele G-1438 was higher among non-responders (56% in sample I, 43% in sample II) than in responders (28% in sample I and 32% in sample II) in both samples. Similarly, the frequency of allele Tyr452 was higher in non-responders (11% in sample I, 16% in sample II) than in responders (6% in sample I and 10% in sample II). A combined analysis of both samples showed association between both polymorphisms and clozapine response. These results provide further evidence suggesting that genetic variation at 5-HT2A receptors may influence clozapine response and strengthen the candidacy of these receptors as important therapeutic targets.

1. The atypical antipsychotic drug clozapine, used in the treatment of resistant schizophrenia, is metabolized partly by the hepatic cytochrome P450 enzyme CYP2D6. Two phenotypes with respect to the activity of the enzyme are recognized (extensive metabolisers (EM) and poor metabolisers (PM)), resulting from allelic variation in the gene, CYP2D6. 2. Genotype was determined in 123 schizophrenic patients currently being treated with clozapine, in order to determine if EM or PM status influences response to this drug. Patients were divided into responders and non-responders using the Global Assessment Scale, and genotyped for the A and B poor metaboliser mutations by digesting PCR products with HpaII or BstNI. 3. Fifty-nine patients were heterozygous for allele B and for allele A. Eight patients were determined as poor metabolisers since they were homozygous either for A and B. Poor metabolisers were equally distributed between responders and nonresponders and no correlation between CYP2D6 alleles and response to clozapine was found. 4. The results are consistent with recent findings showing that CYP1A2, rather than CYP2D6, is the major enzyme responsible for the metabolism of clozapine.

Objective: Catechol O-methyltransferase (COMT) is an enzyme that inactivates catecholamines. Two common COMT alleles determine high and low activity of the enzyme. Previous studies using biochemical methods found lower enzyme activity in patients with major depression and bipolar disorder in comparison with control values, suggesting that a dysfunction in catecholamine metabolism may be related to the etiology of depression. Method: The authors studied two recently described DNA polymorphisms at the COMT gene (a silent C256G mutation and a structural mutation, Val-108-Met) in 88 patients with bipolar disorder and in 113 healthy comparison subjects, all of Spanish origin. Results: The frequency of the C256 allele was 0.58 in the patients and 0.54 in the comparison subjects. The frequency of the Val108 variant was 0.57 for both the patients and the comparison subjects. No allelic or genotypic associations were observed. Conclusions: The lack of association suggests that the COMT gene is not a major risk factor for bipolar disorder. (Am J Psychiatry 1997; 154:113‐115)