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BackgroundClinical intervention in early stages of psychotic disorders is crucial for the prevention of severe symptomatology trajectories and poor outcomes. Genetic variability is studied as a promising modulator of prognosis, thus novel approaches considering the polygenic nature of these complex phenotypes are required to unravel the mechanisms underlying the early progression of the disorder.MethodsThe sample comprised of 233 first-episode psychosis (FEP) subjects with clinical and cognitive data assessed periodically for a 2-year period and 150 matched controls. Polygenic risk scores (PRSs) for schizophrenia, bipolar disorder, depression, education attainment and cognitive performance were used to assess the genetic risk of FEP and to characterize their association with premorbid, baseline and progression of clinical and cognitive status.ResultsSchizophrenia, bipolar disorder and cognitive performance PRSs were associated with an increased risk of FEP [false discovery rate (FDR) ⩽ 0.027]. In FEP patients, increased cognitive PRSs were found for FEP patients with more cognitive reserve (FDR ⩽ 0.037). PRSs reflecting a genetic liability for improved cognition were associated with a better course of symptoms, functionality and working memory (FDR ⩽ 0.039). Moreover, the PRS of depression was associated with a worse trajectory of the executive function and the general cognitive status (FDR ⩽ 0.001).ConclusionsOur study provides novel evidence of the polygenic bases of psychosis and its clinical manifestation in its first stage. The consistent effect of cognitive PRSs on the early clinical progression suggests that the mechanisms underlying the psychotic episode and its severity could be partially independent.

Current antipsychotics (APs) effectively control positive psychotic symptoms, mainly by blocking dopamine (DA) D2 receptors, but have little effect on negative and cognitive symptoms. Increased glutamate (GLU) release would trigger neurotoxicity, leading to apoptosis and synaptic pruning, which is involved in the pathophysiology of schizophrenia. New pharmacological strategies are being developed such as positive allosteric modulators (PAMs) of the metabotropic GLU receptor 2 (mGluR2) that inhibit the presynaptic release of GLU. We previously reported that treatment of adult mice with JNJ-46356479 (JNJ), a recently developed mGluR2 PAM, partially improved neuropathological deficits and schizophrenia-like behavior in a postnatal ketamine mouse model. In the present study, we evaluated, for the first time, the putative neuroprotective and antiapoptotic activity of JNJ in a human neuroblastoma cell line and compared it with the effect of clozapine (CLZ) as a clinical AP with the highest efficacy and with apparent utility in managing negative symptoms. Specifically, we measured changes in cell viability, caspase 3 activity and apoptosis, as well as in the expression of key genes involved in survival and cell death, produced by CLZ and JNJ alone and in combination with a high DA or GLU concentration as apoptosis inducers. Our results suggest that JNJ is not neurotoxic and attenuates apoptosis, particularly by decreasing the caspase 3 activation induced by DA and GLU, as well as increasing and decreasing the number of viable and apoptotic cells, respectively, only when cultures were exposed to GLU. Its effects seem to be less neurotoxic and more neuroprotective than those observed with CLZ. Moreover, JNJ partially normalized altered expression levels of glycolytic genes, which could act as a protective factor and be related to its putative neuroprotective effect. More studies are needed to define the mechanisms of action of this GLU modulator and its potential to become a novel therapeutic agent for schizophrenia.

Schizophrenia (SZ) is a heterogeneous mental disorder, affecting ~1% of the worldwide population. One of the main pathophysiological theories of SZ is the imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, involving N-methyl-D-aspartate receptors (NMDAr). This may lead to local glutamate storms coupled with excessive dendritic pruning and subsequent cellular stress, including nitrosative stress, during a critical period of neurodevelopment, such as adolescence. Nitrosative stress is mediated by nitric oxide (NO), which is released by NO synthases (NOS) and has emerged as a key signaling molecule implicated in SZ. Regarding glutamatergic models of SZ, the administration of NMDAr antagonists has been found to increase NOS levels in the prefrontal cortex (PFC) and ventral hippocampus (HPC). We hypothesized that suboptimal NOS function in adolescence could be a target for early treatments, including clozapine (CLZ) and the novel metabotropic glutamate receptor modulator JNJ-46356479 (JNJ). We analyzed the protein levels of NOS isoforms in adult PFC and HPC of a postnatal ketamine induced murine model of SZ receiving CLZ or JNJ during adolescence by western blot. Endothelial NOS and neuronal NOS increased under ketamine administration in PFC and decreased in CLZ or JNJ treatments. The same trends were found in the HPC in neuronal NOS. In contrast, inducible NOS was increased under JNJ treatment with respect to ketamine induction in the HPC, and the same trends were found in the PFC. Taken together, our findings suggest a misbalance of the NOS system following NMDAr antagonist administration, which was then modulated under early CLZ and JNJ treatments.

We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies. Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP. Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p

Aims: Patients with a first episode of psychosis (FEP) often display different metabolic disturbances even independently of drug therapy. However, antipsychotic (AP) treatment, especially with second-generation APs, is strongly linked to weight gain, which increases patients’ risk of developing obesity and other metabolic diseases. There is an important genetic risk component that can contribute to the appearance of these disturbances. The aim of the present study was to evaluate the effect of polymorphisms in selected candidate genes on obesity and other anthropometric and metabolic traits in 320 AP-treated FEP patients over the course of a 2-year follow-up. Methods: These patients were recruited in the multicentre PEPs study (Phenotype−genotype and environmental interaction; Application of a predictive model in first psychotic episodes). A total of 127 validated single nucleotide polymorphisms (SNPs) in 18 candidate genes were included in the genetic analysis. Results: After Bonferroni correction, SNPs in ADRA2A, FTO, CNR1, DRD2, DRD3, LEPR and BDNF were associated with obesity, abdominal circumference, triglycerides, HDL cholesterol, and/or percentage of glycated haemoglobin. Conclusions: Although our results should be interpreted as exploratory, they support previous evidence of the impact of these candidate genes on obesity and metabolic status. Further research is required to gain a better knowledge of the genetic variants that can be considered relevant metabolic risk factors. The ability to identify FEP patients at higher risk for these metabolic disturbances would enable clinicians to better select and control their AP treatment.

Neurotrophins have been proposed to be involved in biological mechanisms which might underlie different clinical outcomes in schizophrenia. The aims of the present study were to examine the BDNF/NGF plasma levels in a cohort of first-episode schizophrenia (FES) patients in remission as potential biological predictors of relapse; to study the associations between these neurotrophins and the symptomatology severity through different stages after a FES in two independent cohorts. 2EPs-Cohort: 69 first-episode in clinical remission were included. BDNF/NGF plasma levelsand symptom severity were measured at enrollment and at 3-year or at the time of the second episode/relapse. FLAMM-PEPs-Cohort: 65 first-episodes were also included. BDNF/NGF and symptom severity were obtained at enrollment and 2-year follow-up. Symptomatology was assessed with the Marder-PANSS-Factor scores. Plasma neurotrophins did not differ significantly over time and neither BDNF/NGF were predictors of relapse. Besides, in remission stages, baseline BDNF levels showed significant correlations with both positive and negative symptoms (p

Aims Here, we present a clustering strategy to identify phenotypes of antipsychotic (AP) response by using longitudinal data from patients presenting first-episode psychosis (FEP). Method One hundred and ninety FEP with complete data were selected from the PEPs project. The efficacy was assessed using total PANSS, and adverse effects using total UKU, during one-year follow-up. We used the Klm3D method to cluster longitudinal data. Results We identified four clusters: cluster A, drug not toxic and beneficial; cluster B, drug beneficial but toxic; cluster C, drug neither toxic nor beneficial; and cluster D, drug toxic and not beneficial. These groups significantly differ in baseline demographics, clinical, and neuropsychological characteristics (PAS, total PANSS, DUP, insight, pIQ, age of onset, cocaine use and family history of mental illness). Conclusions The results presented here allow the identification of phenotypes of AP response that differ in well-known simple and classic clinical variables opening the door to clinical prediction and application of personalized medicine.

Objective Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with an etiopathophysiology that seems to include immune alterations. Previous studies have suggested that variations in the levels of circulating T cell subpopulations may be involved in psychiatric diseases. However, the role of these cells in OCD remains unexplored. Hence, the present study aimed to examine the levels of T helper 1 (Th1), Th2, Th17 and regulatory T (Treg) cells in patients with early-onset OCD and healthy controls. Methods The assessment was performed in 99 children and adolescents with OCD and 46 control subjects. The percentages of circulating Th1, Th2, Th17 and Treg cells were evaluated using flow cytometry. Results OCD patients had significantly higher levels of Th17 cells and lower percentages of Treg cells than healthy controls (p = 0.001 and p = 0.005, respectively). Furthermore, levels of Th17 cells progressively increased with the duration (p = 0.005) and severity of OCD (p = 0.008), whereas the percentages of Treg cells significantly declined with the duration of the disorder (p = 1.8 × 10−5). Conclusions These results provide more evidence of the involvement of immune dysregulation, specifically an imbalance in the levels of circulating T helper and regulatory T cells, in the pathophysiology of early-onset OCD.

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder whose etiology includes important genetic contributions. In a previous transmission disequilibrium study in which 75 complete trios were included, single-nucleotide polymorphisms (SNPs) in serotoninergic and GABAergic genes were associated with early-onset OCD. Our aim was to assess those findings in an extended collection of early-onset OCD trios.A transmission disequilibrium test for SNPs in HTR1B (rs2000292), SLC18A1 (rs6586896), GAD1 (rs3791860), and GAD2 (rs8190748) was performed in a total of 101 early-onset OCD trios, from which 26 trios were newly recruited for the purpose of the present analysis.All the SNPs were overtransmitted from parents to OCD probands (p 0.012, significant after Bonferroni correction).These results are consistent with the previous findings and constitute more evidence of the role of genetic factors related to serotoninergic and GABAergic pathways in the pathophysiology of early-onset OCD.

Natalia Rodriguez,1,&ast; Albert Martinez-Pinteño,1,&ast; Ana Blázquez,2,3 Ana Encarnación Ortiz,2,3 Elena Moreno,2 Patricia Gassó,1,3 Amalia Lafuente,1,3,4 Luisa Lazaro,2– 5 Sergi Mas1,3,4 1Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, Barcelona, Spain; 2Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, Barcelona, Spain; 3Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; 4G04 Group, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain; 5Department of Medicine, University of Barcelona, Barcelona, Spain&ast;These authors contributed equally to this workCorrespondence: Sergi MasDepartment of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, Casanova 143, Barcelona, E-08036, SpainTel +34934024526Fax +34934035881Email sergimash@ub.eduPurpose: Here, we propose an integrative analysis of genome-wide methylation and gene expression to provide new insight into the biological mechanisms of Cognitive behavioral therapy (CBT) in pediatric obsessive-compulsive disorder (OCD).Patients and Methods: Twelve children and adolescents with OCD receiving CBT for the first time were classified as responders or non-responders after eight weeks of CBT. Differentially methylated positions (DMPs) and gene co-expression modules were identified using specific R software packages. Correlations between the DMPs and gene co-expression modules were investigated.Results: Two genes were enriched with significant DMPs (Δβ > ± 0.2, FDR-adjusted p-value < 0.05): PIWIL1 and MIR886. The yellowgreen module of co-expressed genes was associated with CBT response (FDR-adjusted p-value = 0.0003). Significant correlations were observed between the yellowgreen module and the CpGs in PIWIL1 and MIR886 (p < 0.008). Patients showing hypermethylation in these CpGs presented an upregulation in the genes in the yellowgreen module.Conclusion: Taken together, the preliminary results of this systems-level approach, despite the study limitations, provide evidence that the epigenetic regulation of ncRNAs could be a predictor of CBT response.Limitations: The sample size limited the statistical power, and given that the study was hypothesis-driven, our results should be seen as preliminary.Keywords: cognitive behavioral therapy, CBT, obsessive-compulsive disorder, OCD, Epigenetics, DNA methylation, gene expression

Gene–environment (GxE) interactions have been related to psychosis spectrum disorders, involving multiple common genetic variants in multiple genes with very small effect sizes, and several environmental factors that constitute a dense network of exposures named the exposome. Here, we aimed to analyze GxE in a cohort of 310 first-episode psychotic (FEP) and 236 healthy controls, by using aggregate scores estimated in large populations such as the polygenic risk score for schizophrenia and (PRS-SCZ) and the Maudsley environmental risk score (ERS). In contrast to previous findings, in our study, the PRS-SCZ did not discriminate cases from controls, but the ERS score explained a similar percentage of the variance as in other studies using similar approaches. Our study supports a positive additive interaction, indicating synergy between genetic susceptibility to schizophrenia (PRS-SCZ dichotomized according to the highest quartile distribution of the control population) and the exposome (ERS > 75% of the controls). This additive interaction showed genetic and environmental dose dependence. Our study shows that the use of aggregate scores derived from large and powered studies instead of statistics derived from specific sample characteristics is a powerful tool for the study of the effects of GxE on the risk of psychotic spectrum disorders. In conclusion, by using a genetic risk score and an ERS we have provided further evidence for the role of GxE in psychosis.

Current antipsychotics have limited efficacy in controlling cognitive and negative symptoms of schizophrenia (SZ). Glutamatergic dysregulation has been implicated in the pathophysiology of SZ, based on the capacity of N-methyl-D-aspartate receptor (NMDAR) antagonists such as ketamine (KET) to induce SZ-like behaviors. This could be related to their putative neuropathological effect on gamma-aminobutyric (GABAergic) interneurons expressing parvalbumin (PV), which would lead to a hyperglutamatergic condition. Metabotropic glutamate receptor 2 (mGluR2) negatively modulates glutamate release and has been considered a potential clinical target for novel antipsychotics drugs. Our aim was to evaluate the efficacy of JNJ-46356479 (JNJ), a positive allosteric modulator (PAM) of the mGluR2, in reversing neuropathological and behavioral deficits induced in a postnatal KET mice model of SZ. These animals presented impaired spontaneous alternation in the Y-maze test, suggesting deficits in spatial working memory, and a decrease in social motivation and memory, assessed in both the Three-Chamber and the Five Trial Social Memory tests. Interestingly, JNJ treatment of adult mice partially reversed these deficits. Mice treated with KET also showed a reduction in PV+ in the mPFC and dentate gyrus together with an increase in c-Fos expression in this hippocampal area. Compared to the control group, mice treated with KET + JNJ showed a similar PV density and c-Fos activity pattern. Our results suggest that pharmacological treatment with a PAM of the mGluR2 such as JNJ could help improve cognitive and negative symptoms related to SZ.

Objective: Fluoxetine is an effective and well-tolerated pharmacological treatment for children and adolescents with major depressive disorder (MDD). However, a high percentage of patients do not respond. There is a substantial genetic contribution to this variable clinical outcome. Based on previous genetic results of our group and given the lack of pharmacogenetics studies of antidepressant response with a long follow-up period, we evaluated the influence of single nucleotide polymorphisms (SNPs) in genes related to the serotonergic pathway on remission and recovery in children and adolescents diagnosed with MDD after 12 months of initiating fluoxetine treatment. Methods: The assessment was performed in 46 patients. All of them were visited at least once a month during the 12-month follow-up. Psychiatrists interviewed patients and their parents to explore clinical improvement. A total of 75 genotyped SNPs in 10 candidate genes were included in the genetic association analysis with remission and recovery. Bonferroni correction for multiple testing was applied to avoid false positive results. Results: The HTR2A rs7997012 SNP was significantly associated after Bonferroni correction with clinical improvement. Particularly, the homozygotes for the major allele (GG) showed the highest percentage of remitters and the highest score reductions on the Clinical Global Impressions-Severity (CGI-S) scale. Moreover, although the results were on the border of statistical significance, the GG homozygotes also tended to experience fewer readmissions during the follow-up period Conclusions: These results provide more evidence of the involvement of genetic variants related to the serotonergic pathway in the antidepressant response. Studies with larger cohorts are needed to integrate all relevant variants into clinical predictors of antidepressant response.

Objective: The exact aetiology of obsessive-compulsive disorder (OCD) is unknown, although there is evidence to suggest a gene–environment interaction model. Several lines of evidence suppo...

The serotonin 1B receptor (5-HT 1B ) is important to both the pathogenesis of major depressive disorder and the antidepressant effects of selective serotonin reuptake inhibitors. Although fluoxetine has been shown to be effective and safe in children and adolescents, not all patients experience a proper clinical response, which has led to further study into the main factors involved in this inter-individual variability. Our aim was to study the effect of epigenetic and genetic factors that could affect 5-hydroxytryptamine receptor 1B ( HTR1B ) gene expression, and thereby response to fluoxetine. A total of 83 children and adolescents were clinically assessed 12 weeks after of initiating an antidepressant treatment with fluoxetine for the first time. We evaluated the influence of single nucleotide polymorphisms (SNPs) specifically located in transcription factor binding sites (TFBSs) on their clinical improvement. A combined genetic analysis considering the significant SNPs together with the functional variant rs130058 previously associated in our population was also performed. Moreover, we assessed, for the first time in the literature, whether methylation levels of the HTR1B promoter region could be associated with the pharmacological response. Two, rs9361233 and rs9361235, were significantly associated with clinical improvement after treatment with fluoxetine. The heterozygous genotype combination analysis showed a negative correlation with clinical improvement. The lowest improvement was experienced by patients who were heterozygous for all three SNPs. Moreover, a negative correlation was found between clinical improvement and the average methylation level of the HTR1B promoter. These results give new evidence for the role of epigenetic and genetic factors which could modulate HTR1B expression in the pharmacological response to antidepressants.

In previous work we developed a pharmacogenetic predictor of antipsychotic (AP) induced extrapyramidal symptoms (EPS) based on four genes involved in mTOR regulation. The main objective is to improve this predictor by increasing its biological plausibility and replication. We re-sequence the four genes using next-generation sequencing. We predict functionality "in silico" of all identified SNPs and test it using gene reporter assays. Using functional SNPs, we develop a new predictor utilizing machine learning algorithms (Discovery Cohort, N = 131) and replicate it in two independent cohorts (Replication Cohort 1, N = 113; Replication Cohort 2, N = 113). After prioritization, four SNPs were used to develop the pharmacogenetic predictor of AP-induced EPS. The model constructed using the Naive Bayes algorithm achieved a 66% of accuracy in the Discovery Cohort, and similar performances in the replication cohorts. The result is an improved pharmacogenetic predictor of AP-induced EPS, which is more robust and generalizable than the original.

Schizophrenia (SZ) and bipolar disorder (BD) are severe mental diseases associated with cognitive impairment, mood disturbance, and psychosis. Both disorders are highly heritable and share a common genetic background. The present study assesses, for the first time, differences in genotype frequencies of polymorphisms located in genes involved in neurodevelopment and synaptic plasticity between genetic high-risk individuals (offspring of patients with SZ or BD; N=100: 31 and 69, respectively) and control subjects (offspring of community controls; N=96). Individuals from both groups had similar ages, around 12 years. A higher percentage of men were included in the genetic high-risk group (58%) compared with the control group (40.6%). A total of 244 validated SNPs located in 35 candidate gene regions were analyzed in 196 participants. Multivariate methods based on logistic regression analysis were performed to assess differences in genotype frequencies. Bonferroni correction was applied for the multiple comparisons performed. Two polymorphisms, CACNA1C rs10848683 and SYNE1 rs214950, showed significant differences. The frequency of heterozygotes for CACNA1C rs10848683 in genetic high-risk individuals was double that in controls (OR=3.15; P=0.00016). For SYNE1 rs214950, higher frequencies of heterozygotes (OR=1.97) and homozygotes for the minor allele (OR=17.89; P=0.00020) were found in the genetic high-risk group than in the control group. In conclusion, polymorphisms in CACNA1C and SYNE1 could confer a greater risk of developing SZ and BD in individuals who are already at high risk because of their family history. This could help identify subjects with a very high genetic risk, in whom early detection and early intervention could lead to better prognosis.

Introduction: Differences in response to fluoxetine (FLX) may be influenced by certain genes that are involved in FLX transportation (ABCB1). We examined remission and recovery from the index episode in a cohort of patients treated with FLX, and also investigated associations between genetic variants in ABCB1 and remission, recovery, and suicide risk. Methods: This was a naturalistic 1-year follow-up study of 46 adolescents diagnosed with major depressive disorder (MDD). At 12 months they underwent a diagnostic interview with the K-SADS-PL. Results: It was found that remission was around 69.5% and recovery 56.5%. Remission and recovery were associated with lower scores on the CDI at baseline, with fewer readmissions and suicide attempts, and with lower scores on the CGI and higher scores on the GAF scale. No relationship was found between ABCB1 and remission or recovery. However, a significant association was observed between the G2677T ABCB1 polymorphism and suicide attempts. Conclusion: Other factors such as stressful events, family support, and other genetic factors are likely to be involved in MDD outcome.

This study investigated whether the risk of presenting antipsychotic (AP)-induced extrapyramidal symptoms (EPS) could be related to single-nucleotide polymorphisms (SNPs) in a naturalistic cohort of first episode psychosis (FEP) patients. Two hundred and two SNPs in 31 candidate genes (involved in dopamine, serotonin and glutamate pathways) were analyzed in the present study. One hundred and thirteen FEP patients (43 presenting EPS and 70 non-presenting EPS) treated with high-potency AP (amisulpride, paliperidone, risperidone and ziprasidone) were included in the analysis. The statistical analysis was adjusted by age, gender, AP dosage, AP combinations and concomitant treatments as covariates. Four SNPs in different genes (DRD2, SLC18A2, HTR2A and GRIK3) contributed significantly to the risk of EPS after correction for multiple testing (P

BACKGROUND: Alterations in the innate immune/inflammatory system may underlie the pathophysiology of schizophrenia, but we do not understand the mechanisms involved. The main agents of innate immunity are the Toll-like receptors (TLRs), which detect molecular patterns associated with damage and pathogens. The TLR first reported was TLR4, and it is still the most studied one. METHODS: We aimed to describe putative modifications to the TLR4 proinflammatory pathway using 2 different strategies in 2 cohorts of patients with schizophrenia and matched controls: 1) quantification of protein and mRNA expression in postmortem prefrontal cortex samples from 30 patients with schizophrenia and 30 controls, and 2) identification of single nucleotide polymorphisms associated with the risk of schizophrenia using whole blood samples from 214 patients with schizophrenia and 216 controls. RESULTS: We found evidence of alterations in the expression of the initial elements of the TLR4 signalling pathway (TLR4, Myeloid differentiation primary response gene 88 [MyD88] and nuclear factor-κ B [NF-κB]) in the PFC of patients with schizophrenia. These alterations seem to depend on the presence/absence of antipsychotic treatment at death. Moreover, a polymorphism within the MyD88 gene was significantly associated with schizophrenia risk. LIMITATIONS: The use of 2 different approaches in 2 different cohorts, the lack of a complementary neuropsychiatric group, the possible confounding effects of antipsychotic treatment and suicide are the main limitations of our study. CONCLUSION: The evidence from this dual approach suggests there is an altered innate immune response in patients with chronic schizophrenia in which the TLR4 proinflammatory pathway could be affected. Improved understanding of the stimuli and mechanisms responsible for this response could lead to improved schizophrenia treatment and better control of the side effects of current antipsychotics.

Motivation The selection of a single nucleotide polymorphism (SNP) using bibliographic methods can be a very time-consuming task. Moreover, a SNP selected in this way may not be easily visualized in its genomic context by a standard user hoping to correlate it with other valuable information. Here we propose a web form built on top of Circos that can assist SNP-centered screening, based on their location in the genome and the regulatory modules they can disrupt. Its use may allow researchers to prioritize SNPs in genotyping and disease studies. Results SiNoPsis is bundled as a web portal. It focuses on the different structures involved in the genomic expression of a gene, especially those found in the core promoter upstream region. These structures include transcription factor binding sites (for promoter and enhancer signals), histones and promoter flanking regions. Additionally, the tool provides eQTL and linkage disequilibrium (LD) properties for a given SNP query, yielding further clues about other indirectly associated SNPs. Possible disruptions of the aforementioned structures affecting gene transcription are reported using multiple resource databases. SiNoPsis has a simple user-friendly interface, which allows single queries by gene symbol, genomic coordinates, Ensembl gene identifiers, RefSeq transcript identifiers and SNPs. It is the only portal providing useful SNP selection based on regulatory modules and LD with functional variants in both textual and graphic modes (by properly defining the arguments and parameters needed to run Circos). Availability and implementation SiNoPsis is freely available at https://compgen.bio.ub.edu/SiNoPsis/ Supplementary information Supplementary data are available at Bioinformatics online.

Background: Hyperprolactinemia is a common side-effect of antipsychotics (APs), which may trigger serious secondary problems and compromise the adherence to treatment which is crucial for prognosis, especially in patients presenting with a first-episode of psychosis (FEP). Aims: We evaluated, in some cases for the first time, the effect of polymorphisms in multiple candidate genes on serum prolactin (PRL) levels in an AP-treated FEP cohort recruited in the multicenter PEPs study (Phenotype − genotype and environmental interaction; Application of a predictive model in first psychotic episodes). Methods: PRL concentration was measured in serum from 222 patients. A total of 167 polymorphisms were selected in 23 genes. Genetic association analysis was performed in the whole sample and also in homogenous subgroups of patients treated with APs with a high (N = 101) or low risk (N = 95) of increasing PRL release, which showed significant differences in their PRL levels. Results: After Bonferroni correction, polymorphisms in NTRK2, DRD2 and ACE genes were associated with PRL concentration. Conclusion: Our results give more support to the impact of DRD2, but also of other genes related to dopamine availability such as ACE. Moreover, this study provides the first evidence for the involvement of NTRK2, which suggests that pathways other than the ones related to dopamine or serotonin may participate in the AP-related PRL levels.

Objective: Acute extrapyramidal symptoms (EPS) are frequent and serious adverse reactions to antipsychotic (AP) drugs. Although the proposed mechanism is an excessive blockade of dopamine D2 receptors in the striatopallidal pathway of the striatum, previous studies implicated the mTOR pathway in the susceptibility to EPS. The objective of the present study is to analyze the mTOR-mediated response to risperidone in subpopulations of striatal neurons and its relationship to risperidone-induced motor side effects. Methods: Two mouse strains (A/J and DBA/2J) with different susceptibility to developing EPS were treated with risperidone 1 mg/kg for three consecutive days. Here we monitored, by double labeling immunohistochemistry, ribosomal protein S6 (rpS6) phosphorylation (Ser235/236 and Ser244/247 sites), a marker of mTOR signaling, in the striatonigral pathway (D1-medium spiny neurons (MSNs)), the striatopallidal pathway (D2-MSNs) and striatal cholinergic interneurons. Results: We found that EPS-resistant DBA/2J mice show higher baseline levels of phosphoactivated rpS6 protein in striatal MSNs, compared with EPS-prone A/J mice. Moreover, risperidone differentially targeted rpS6 phosphorylation in direct and indirect pathway neurons in a strain-specific manner: a significant decrease in the phosphorylation of rpS6 at Ser235/236 and Ser240/244 in DRD1-MSNs EPS-resistant DBA/2J mice after; and a significant increase of phospho-Ser235/236-rpS6 in the striatopallidal pathway of the EPS-prone A/J mice in response to risperidone. Conclusions: Our results reveal the vital role of genetic background in the response to risperidone, and point to the mTOR pathway as an important factor in EPS susceptibility. Keywords: Schizophrenia, Antipsychotic, Risperidone, Extrapyramidal symptoms. mTOR pathway, Striatum, Medium spiny neurons

Objectives: The present study therefore aimed to assess the relationship between variability in genes related to the pathophysiology of OCD and the concentration of different neurometabolites in the anterior cingulate cortex (ACC). Methods: we concomitantly assessed neurometabolite concentrations by 3-T 1H-MRS and 262 single nucleotide polymorphism (SNPs) in 35 genes among 41 pediatric OCD patients. Results: There were significant associations, after Bonferroni’s correction, between the concentration of inositol, glutamate and glutamine, and total choline and five polymorphisms located in genes related to serotonin and glutamate (i.e., the vesicular monoamine transporter 1 gene, SLC18A1 [rs6586896]; the serotonin receptor 1B gene, HTR1B [rs6296 and rs6298]; and the glutamate receptor, ionotropic, AMPA1 gene, GRIA1 [rs707176 and rs2963944]). Conclusions: The association observed between these polymorphisms and the neurometabolite concentrations could indicate the presence of a biological interaction between the serotonin and the glutamate pathways that could be involved in the pathophysiology of OCD. More studies with this methodology could increase our understanding of the etiology and pathophysiology of OCD in children.

Background Alterations in white matter (WM) integrity observed in patients with obsessive–compulsive disorder (OCD) may be at least partly determined genetically. Neuroimaging measures of WM microstructure could serve as promising intermediate phenotypes for genetic analysis of the disorder. The objective of the present study was to explore the association between variability in genes related to the pathophysiology of OCD and altered WM microstructure previously identified in child and adolescent patients with the disease. Methods Fractional anisotropy (FA) and mean diffusivity (MD) measured by diffusion tensor imaging (DTI) and 262 single nucleotide polymorphisms (SNPs) in 35 candidate genes were assessed concomitantly in 54 child and adolescent OCD patients. Results Six polymorphisms located in the glutamate transporter gene ( SLC1A1 rs3087879), dopamine transporter gene ( SLC6A3 rs4975646), dopamine receptor D3 ( DRD3 rs3773679), nerve growth factor receptor gene ( NGFR rs734194 and rs2072446), and cadherin 9 gene ( CDH9 rs6885387) showed significant p -values after Bonferroni correction ( p ≤0.00019). More specifically, the vast majority of these associations were detected with MD in the right and left anterior and posterior cerebellar lobes. Limitations Patients were under pharmacological treatment at the time of the DTI examination. Sample size is limited. Conclusions The results provide the first evidence of the involvement of genetic variants related to glutamatergic, dopaminergic, and neurodevelopmental pathways in determining the WM microstructure of child and adolescent patients with OCD, which could be related to the neurobiology of the disorder.

To identify potential candidate genes for future pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we used gene expression arrays to analyze changes induced by risperidone in mice strains with different susceptibility to EPS. We proposed a systems biology analytical approach that combined the identification of gene co-expression modules related to AP treatment, the construction of protein-protein interaction networks with genes included in identified modules and finally, gene set enrichment analysis of constructed networks. In response to risperidone, mice strain with susceptibility to develop EPS showed downregulation of genes involved in the mammalian target of rapamycin (mTOR) pathway and biological processes related to this pathway. Moreover, we also showed differences in the phosphorylation pattern of the ribosomal protein S6 (rpS6), which is a major downstream effector of mTOR. The present study provides new evidence of the involvement of the mTOR pathway in AP-induced EPS and offers new and valuable markers for pharmacogenetic studies.

Schizophrenia (SZ) is a chronic psychiatric disorder whose onset of symptoms occurs in late adolescence and early adulthood. The etiology is complex and involves important gene-environment interactions. Microarray gene-expression studies on SZ have identified alterations in several biological processes. The heterogeneity in the results can be attributed to the use of different sample types and other important confounding factors including age, illness chronicity and antipsychotic exposure. The aim of the present microarray study was to analyze, for the first time to our knowledge, differences in gene expression profiles in 18 fibroblast (FCLs) and 14 lymphoblastoid cell lines (LCLs) from antipsychotic-naive first-episode schizophrenia (FES) patients and healthy controls. We used an analytical approach based on protein-protein interaction network construction and functional annotation analysis to identify the biological processes that are altered in SZ. Significant differences in the expression of 32 genes were found when LCLs were assessed. The network and gene set enrichment approach revealed the involvement of similar biological processes in FCLs and LCLs, including apoptosis and related biological terms such as cell cycle, autophagy, cytoskeleton organization and response to stress and stimulus. Metabolism and other processes, including signal transduction, kinase activity and phosphorylation, were also identified. These results were replicated in two independent cohorts using the same analytical approach. This provides more evidence for altered apoptotic processes in antipsychotic-naive FES patients and other important biological functions such as cytoskeleton organization and metabolism. The convergent results obtained in both peripheral cell models support their usefulness for transcriptome studies on SZ.

Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine. The selection of SNPs was also based on their linkage disequilibrium with TPH2 rs4570625, a genetic variant with questionable functionality, which was previously associated with clinical response in our pediatric population. A total of 83 children and adolescents were clinically evaluated 12weeks after initiating antidepressant treatment with fluoxetine for the first time. Clinical improvement was assessed by reductions in depressive symptoms measured using the Children's Depression Inventory (CDI) scale. The polymorphisms rs11179002, rs60032326 and rs34517220 were, for the first time in the literature, significantly associated with higher clinical improvement. The strongest association was found for rs34517220. In particular, minor allele homozygotes showed higher score reductions on the CDI scale compared with the major allele carriers. Interestingly, this polymorphism is located in a human TPH2 TFBS for two relevant transcription factors in the serotoninergic neurons, Foxa1 and Foxa2, which together with the high level of significance found for this SNP, could indicate that rs34517220 is in fact the crucial functional genetic variant related to the fluoxetine response. These results provide new evidence for the role of regulatory genetic variants that could modulate human TPH2 expression in the SSRI antidepressant response.

Introduction: Recent research demonstrates the heterogeneous etiology of psychotic disorders, where gen-environment (GxE) interaction plays a key role. Large genetic studies have linked many genetic variants with schizophrenia, but each variant is only associated with a small effect and the GxE interaction contribution has not been evaluated. Methods: The PEPs Project was designed to carefully collect a large amount of genetic and environmental exposure data of 335 FEP patients and 253 matched healthy controls. 780 single-nucleotide polymorphisms (from 159 candidate genes) and 16 environmental variables previously reported as the main psychosis non-genetic risk factors were analyzed together using entropy-based measures of information gain. Results: Our analyses identified an interaction between nine SNPs and the exposition to the environmental risk factors of psychosis, showing a clear enrichment of genes linked to serotonin neurotransmission and neurodevelopmental processes. Conclusions: This study has allowed the identification of several GxE-environment interactions involved in the risk of presenting a FEP. Our results highlight the importance of serotonin neurotransmission interacting with certain environmental stimuli. The serotoninergic system may be playing a key role in the regulatory network of stress and other systems implicated in the emergence and development of psychotic disorders. (C) 2017 Elsevier B.V. All rights reserved.

Objectives Adequate quantity and quality of the DNA isolated from saliva samples are crucial for ensuring successful genotyping rates in genetic studies. However, there is little information about these issues when saliva samples are collected from children. The objectives of this study were to assess whether there are differences in DNA quality or quantity isolated from saliva samples of children at different ages and adolescents compared to adults and, if so, to establish a modified protocol to improve and standardize DNA isolation from saliva samples of children. Methods Saliva samples were collected with Oragene DNA Sample Collection Kit from 41 healthy subjects including children of different ages, adolescents, and adults. Quantity and quality of isolated DNA were determined spectrophotometrically. Results DNA concentration and age were positively correlated (r = 0.676, P

There is little known about pharmacogenetic of fluoxetine in children and adolescents. In this study, we evaluate, for the first time, the influence of CYP2D6, CYP2C9 and ABCB1 genotypes on the steady-state plasma concentrations of fluoxetine and its active metabolite (S)-norfluoxetine, and on the clinical improvement in children and adolescent patients receiving fluoxetine treatment. The assessment was performed in 83 patients after 8 and 12 weeks of treatment. Fluoxetine/(S)-norfluoxetine ratio was negatively correlated with the number of active CYP2D6 alleles (r: -0.450; P

One of the leading biological models of obsessive-compulsive disorder (OCD) is the frontal-striatal-thalamic model. This study undertakes an extensive exploration of the variability in genes related to the regulation of the frontal-striatal-thalamic system in a sample of early-onset OCD trios. To this end, we genotyped 266 single nucleotide polymorphisms (SNPs) in 35 genes in 84 OCD probands and their parents. Finally, 75 complete trios were included in the analysis. Twenty SNPs were overtransmitted from parents to early-onset OCD probands and presented nominal pointwise P < 0.05 values. Three of these polymorphisms achieved P < 2 × 10(-4), the significant P-value after Bonferroni corrections: rs8190748 and rs992990 localized in GAD2 and rs2000292 in HTR1B. When we stratified our sample according to gender, different trends were observed between males and females. In males, SNP rs2000292 (HTR1B) showed the lowest P-value (P = 0.0006), whereas the SNPs in GAD2 were only marginally significant (P = 0.01). In contrast, in females HTR1B polymorphisms were not significant, whereas rs8190748 (GAD2) showed the lowest P-value (P = 0.0006). These results are in agreement with several lines of evidence that indicate a role for the serotonin and γ-Aminobutyric acid (GABA) pathways in the risk of early-onset OCD and with the gender differences in OCD pathophysiology reported elsewhere. However, our results need to be replicated in studies with larger cohorts in order to confirm these associations.

Altered apoptosis has been proposed as a potential mechanism involved in the abnormal neurodevelopment and neurodegenerative processes associated with schizophrenia. The aim of this study was to investigate in primary fibroblast cultures whether antipsychotic-naïve patients with first-episode schizophrenia have greater apoptotic susceptibility than healthy controls. Cell growth, cell viability and various apoptotic hallmarks (caspase-3 activity, translocation of phosphatidylserine, chromatin condensation and gene expression of AKT1, BAX, BCL2, CASP3, GSK3B and P53) were measured in fibroblast cultures obtained from skin biopsies of patients (n = 11) and healthy controls (n = 8), both in basal conditions and after inducing apoptosis with staurosporine. Compared to controls, cultured fibroblasts from patients showed higher caspase-3 activity and lower BCL2 expression. When exposed to staurosporine, fibroblasts from patients also showed higher caspase-3 activity; a higher percentage of cells with translocated phosphatidylserine and condensed chromatin; and higher p53 expression compared to fibroblasts from controls. No differences in cell viability or cell growth were detected. These results strongly support the hypothesis that first-episode schizophrenia patients may have increased susceptibility to apoptosis, which may be involved in the onset and progression of the disease.

OBJECTIVE The effect of antipsychotics (APs) on negative symptoms is controversial. The present study assessed negative symptoms in healthy volunteers without any source of primary negative symptoms after single doses of haloperidol and risperidone. METHODS Twenty-five healthy subjects were included in this randomized, placebo-controlled, single-dose (haloperidol 5 mg and risperidone 2.5 mg) crossover and double-blind clinical trial. Negative symptoms were assessed by observer-rated scales and with a self-report scale. Possible confounding effects considered were extrapyramidal symptoms (EPS) and sedative effects. The occupation of striatal dopamine D2 receptors was also determined. RESULTS Risperidone induced a wide range of negative symptoms such as alogia, blunted affect, avolition/apathy, and attention impairment, whereas haloperidol only induced the avolition/apathy subdomain. Most of the effects of risperidone in healthy volunteers, with the exception of its effects on avolition/apathy, were attributable to AP-induced EPS. Haloperidol did not cause significant EPS after administration. No effect of sedation or psychomotor performance was observed on negative symptoms. CONCLUSIONS Single doses of both haloperidol and risperidone induced nonmotor secondary negative symptoms in healthy volunteers. The clinical findings are especially relevant in view of the impact of negative symptoms on poor functioning. They may help to guide clinicians in their choice of APs (http://clinicaltrials.gov/ct2/show/NCT01259973).