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Schizophrenia (SZ) is a deleterious brain disorder characterised by its heterogeneity and complex symptomatology consisting of positive, negative and cognitive deficits. Current antipsychotic drugs ameliorate the positive symptomatology, but are inefficient in treating the negative symptomatology and cognitive deficits. The neurodevelopmental glutamate hypothesis of SZ has opened new avenues in the development of drugs targeting the glutamatergic system. One of these new therapies involves the positive allosteric modulators (PAMs) of metabotropic glutamate receptors, mainly types 2/3 (mGluR2/3). mGluR2/3 PAMs are selective for the receptor, present high tolerability and can modulate the activity of the receptor for long periods. There is not much research in clinical trials regarding mGluR2/3 PAMs. However, several lines of evidence from animal models have indicated the efficiency of mGluR2/3 PAMs. In this review, focusing on in vivo animal studies, we will specifically discuss the utilization of SZ animal models and the various methods employed to assess animal behaviour before summarising the evidence obtained to date in the field of mGluR2/3 PAMs. By doing so, we aim to deepen our understanding of the underlying mechanisms and the potential efficiency of mGluR2/3 PAMs in treating SZ. Overall, mGluR2/3 PAMs have demonstrated efficiency in attenuating SZ-like behavioural and molecular deficits in animal models and could be useful for the early management of the disorder or to treat specific subsets of patients., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Current treatment for schizophrenia (SZ) ameliorates the positive symptoms, but is inefficient in treating the negative and cognitive symptoms. The SZ glutamatergic dysfunction hypothesis has opened new avenues in the development of novel drugs targeting the glutamate storm, an inducer of progressive neuropathological changes. Positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2), such as JNJ-46356479 (JNJ), reduce the presynaptic release of glutamate, which has previously been demonstrated to attenuate glutamate- and dopamine-induced apoptosis in human neuroblastoma cell cultures. We hypothesised that JNJ treatment would modify the brain levels of apoptotic proteins in a mouse model of ketamine (KET)-induced schizophrenia. We analysed the levels of proapoptotic (caspase-3 and Bax) and antiapoptotic (Bcl-2) proteins by western blot in the prefrontal cortex and hippocampus of JNJ-treated mice. JNJ attenuated apoptosis in the brain by partially restoring the levels of the antiapoptotic Bcl-2 protein, which is significantly reduced in animals exposed to KET. Additionally, a significant inverse correlation was observed between proapoptotic protein levels and behavioural deficits in the mice. Our findings suggest that JNJ may attenuate brain apoptosis in vivo, as previously described in cell cultures, providing a link between neuropathological deficits and SZ symptomatology., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Schizophrenia and bipolar disorder exhibit substantial clinical overlap, particularly in individuals at familial high risk, who frequently present sub-threshold symptoms before the onset of illness. Severe mental disorders are highly polygenic traits, but their impact on the stages preceding the manifestation of mental disorders remains relatively unexplored. Our study aimed to examine the influence of polygenic risk scores (PRS) on sub-clinical outcomes over a 2-year period in youth at familial high risk for schizophrenia and bipolar disorder and controls. The sample included 222 children and adolescents, comprising offspring of parents with schizophrenia (n = 38), bipolar disorder (n = 80), and community controls (n = 104). We calculated PRS for psychiatric disorders, neuroticism and cognition using the PRS-CS method. Linear mixed-effects models were employed to investigate the association between PRS and cognition, symptom severity and functioning. Mediation analyses were conducted to explore whether clinical features acted as intermediaries in the impact of PRS on functioning outcomes. SZoff exhibited elevated PRS for schizophrenia. In the entire sample, PRS for depression, neuroticism, and cognitive traits showed associations with sub-clinical features. The effect of PRS for neuroticism and general intelligence on functioning outcomes were mediated by cognition and symptoms severity, respectively. This study delves into the interplay among genetics, the emergence of sub-clinical symptoms and functioning outcomes, providing novel evidence on mechanisms underpinning the continuum from sub-threshold features to the onset of mental disorders. The findings underscore the interplay of genetics, cognition, and clinical features, providing insights for personalized early interventions., Competing Interests: Declaration of competing interest CM Díaz-Caneja has received grant support from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (PI17/00481, PI20/00721, JR19/00024) and honoraria from Exeltis and Angelini. The other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Genome-wide association studies (GWAS) have revealed the polygenic nature of treatment-resistant schizophrenia TRS. Gene expression imputation allowed the translation of GWAS results into regulatory mechanisms and the construction of gene expression (GReX) risk scores (GReX-RS).  In the present study we computed GReX-RS from the largest GWAS of TRS to assess its association with clinical features. We perform transcriptome imputation in the largest GWAS of TRS to find GReX associated with TRS using brain tissues. Then, for each tissue, we constructed a GReX-RS of the identified genes in a sample of 254 genotyped first episode of psychosis (FEP) patients to test its association with clinical phenotypes, including clinical symptomatology, global functioning and cognitive performance. Our analysis provides evidence that the polygenic basis of TRS includes genetic variants that modulate the expression of certain genes in certain brain areas (substantia nigra, hippocampus, amygdala and frontal cortex), which at the same time are related to clinical features in FEP patients, mainly persistence of negative symptoms and cognitive alterations in sustained attention, which have also been suggested as clinical predictors of TRS. Our results provide a clinical explanation of the polygenic architecture of TRS and give more insight into the biological mechanisms underlying TRS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Menarini, Rovi and Takeda. The rest of the authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Clinical 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., Methods: The 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., Results: Schizophrenia, 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)., Conclusions: Our 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.

Epigenetic modifications occur sequentially during the lifespan, but their pace can be altered by external stimuli. The onset of schizophrenia and bipolar disorder is critically modulated by stressors that may alter the epigenetic pattern, a putative signature marker of exposure to environmental risk factors. In this study, we estimated the age-related epigenetic modifications to assess the differences between young individuals at familial high risk (FHR) and controls and their association with environmental stressors. The sample included 117 individuals (6-17 years) at FHR (45%) and a control group (55%). Blood and saliva samples were used estimate the epigenetic age with six epigenetic clocks through methylation data. Environmental risk was measured with obstetric complications, socioeconomic statuses and recent stressful life events data. Epigenetic age was correlated with chronological age. FHR individuals showed epigenetic age deacceleration of Horvath and Hannum epigenetic clocks compared to controls. No effect of the environmental risk factors on the epigenetic age acceleration could be detected. Epigenetic age acceleration adjusted by cell counts showed that the FHR group was deaccelerated also with the PedBE epigenetic clock. Epigenetic age asynchronicities were found in the young at high risk, suggesting that offspring of affected parents follow a slower pace of biological aging than the control group. It still remains unclear which environmental stressors orchestrate the changes in the methylation pattern. Further studies are needed to better characterize the molecular impact of environmental stressors before illness onset, which could be critical in the development of tools for personalized psychiatry., (© 2023. The Author(s).)

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.

Objective: Metabolic syndrome is a health-threatening condition suffered by approximately one third of schizophrenia patients and largely attributed to antipsychotic medication. Previous evidence reports a common genetic background of psychotic and metabolic disorders. In this study, we aimed to assess the role of polygenic risk scores (PRSs) on the progression of the metabolic profile in a first-episode psychosis (FEP) cohort., Method: Of the 231 FEP individuals included in the study, 192-220 participants were included in basal analysis and 118-179 in longitudinal 6-month models. Eleven psychopathologic and metabolic PRSs were constructed. Basal and longitudinal PRSs association with metabolic measurements was assessed by statistical analyses., Results: No major association of psychopathological PRSs with the metabolic progression was found. However, high risk individuals for depression and cholesterol-related PRSs reported a higher increase of cholesterol levels during the follow-up (FDR ≤ 0.023 for all analyses). Their effect was comparable to other well-established pharmacological and environmental risk factors (explaining at least 1.2% of total variance)., Conclusion: Our findings provide new evidence of the effects of metabolic genetic risk on the development of metabolic dysregulation. The future establishment of genetic profiling tools in clinical procedures could enable practitioners to better personalize antipsychotic treatment selection and dosage., (Copyright © 2022. Published by Elsevier B.V.)

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 levels and 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<0.05); NGF, with negative symptomatology (p<0.01). Similarly, in the FLAMM-PEPs-Cohort, baseline BDNF/NGF levels showed significant correlations with negative symptoms (and not positive symptomatology) at follow-up (p<0.05). In both cohorts, lower levels correlated with higher symptom severity. Findings did not support a role for BDNF/NGF plasma levels as biomarkers of relapse in FES patients. Nevertheless, baseline BDNF/NGF may lead to be considered potentially useful biomarkers of long-term severity in schizophrenia and of the underlying illness traits, specially of negative symptomatology severity. More longitudinal studies in FES samples and adding a control group are warranted to replicate these findings., Competing Interests: Conflict of Interest Dr. Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Menarini, Rovi and Takeda. Pilar A Sáiz, has been a consultant to and/or has received honoraria or grants from Adamed, CIBERSAM, European Comission, Government of the Principality of Asturias (PCTI-2018–2022 IDI/2018/235), Instituto de Salud Carlos III, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Plan Nacional sobre Drogas and Servier. The rest of authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2022. Published by Elsevier B.V.)

Schizophrenia disorder remains an unsolved puzzle. However, the integration of recent findings from genetics, molecular biology, neuroimaging, animal models and translational clinical research offers evidence that the synaptic overpruning hypothesis of schizophrenia needs to be reassessed. During a critical period of neurodevelopment and owing to an imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, a regionally-located glutamate storm might occur, triggering excessive dendritic pruning with the activation of local dendritic apoptosis machinery. The apoptotic loss of dendritic spines would be aggravated by microglia activation through a recently described signaling system from complement abnormalities and proteins of the MHC, thus implicating the immune system in schizophrenia. Overpruning of dendritic spines coupled with aberrant synaptic plasticity, an essential function for learning and memory, would lead to brain misconnections and synaptic inefficiency underlying the primary negative symptoms and cognitive deficits of schizophrenia. This driving hypothesis has relevant therapeutic implications, including the importance of pharmacological interventions during the prodromal phase or the transition to psychosis, targeting apoptosis, microglia cells or the glutamate storm. Future research on apoptosis and brain integrity should combine brain imaging, CSF biomarkers, animal models and cell biology.

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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-naïve 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-naïve 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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.

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We investigated the relationship between several functional polymorphisms in genes coding for dopamine metabolism and transport enzymes (MAO-A VNTR; MAO-A 941T>G; DAT VNTR; DAT -67A/T; CYP2D6*3; CYP2D6*4; CYP2D6*5; CYP2D6*6) and the frequency of schizophrenia. Participants in the study were 242 subjects diagnosed with schizophrenia and related disorders and 290 hospital-based controls. Genomic DNA was isolated from whole blood and genotyped by several methods. However, there was no association between schizophrenia and the alleles, genotypes or diplotypes that were studied or their interactions. Polymorphisms in genes coding for dopamine metabolism and transport enzymes did not predispose to or protect from schizophrenia and related disorders.

Aims: In this study we explored possible epistasis between CYP2D6 (*3, *4, *5, *6 and *1xN), CYP3A5 (*3), CYP1A2 (*1C and *1F) and ABCB1 (G2677T) in schizophrenia and related disorders., Materials & Methods: A total of 344 patients diagnosed with schizophrenia and related disorders, and 484 healthy controls participated in the present study. We analyzed gene-gene interactions by multifactor dimensionality reduction., Results: A four-way model including ABCB1 G2677T, CYP3A5*3, CYP1A2*1F and CYP2D6*4 variants had the best overall performances (accuracy: 0.573) and a crossvalidation consistency of 10/10 (permutation testing p < 0.004)., Conclusion: Our results suggest a significant involvement of CYPs and transporters in brain metabolism and homeostasis, and provide evidence of gene-gene interactions among xenobiotic metabolizing and transporter genes in the context of schizophrenia.

In a previous linkage disequilibrium mapping study, in the 3' end of ARVCF, we identified one intronic SNP rs165849 and one haplotype block associated with schizophrenia and related disorders. The aim of the present study was to explore whether functional genetic variants in the exonic regions of ARVCF included in this haplotype block are responsible for the association observed. To achieve this objective (1) the nine exons included in this haplotype block were resequenced in a group of 242 patients with schizophrenia and related disorders (Case 1). The SNPs identified were genotyped in a hospital-based control group of 373 subjects (Control 1) and an association study was performed. (2) The SNPs showing significant association in this analysis were genotyped in a new group of 102 patients with schizophrenia and related disorders (Case 2) and in a new group of 111 healthy subjects (Control 2). Three dbSNPs (rs35219372, rs5993890, and rs165815) were identified when the nine exons of ARVCF were resequenced. rs165815 was associated with schizophrenia and related disorders (homozygote CC OR = 3.39, permutated P value = 0.02). When the groups of cases (1 and 2) and controls (1 and 2) were merged, the analysis confirmed the association observed (homozygote CC OR = 3.25 permutated P value = 0.02). Given the role of ARVCF proposed in the neurodevelopmental hypothesis, our results further support the view that chromosome 22 contains a susceptibility gene, possibly ARVCF. The functional variant rs165815, which affects a critical region of ARVCF, is a considerable source of the genetic variability associated with the risk of developing schizophrenia., ((c) 2010 Wiley-Liss, Inc.)

We present a schizophrenia association study using an extensive linkage disequilibrium (LD) mapping approach in seven candidate genes with a well established link to dopamine, including receptors (DRD2, DRD3) and genes involved in its metabolism and transport (ACE, COMT, DAT, MAO-A, MAO-B). The sample included 242 subjects diagnosed with schizophrenia and related disorders and 373 hospital-based controls. 84 tag SNPs in candidate genes were genotyped. After extensive data cleaning 70 SNPs were analyzed for association of single markers and haplotypes. One block of four SNPs (rs165849, rs2518823, rs887199 and rs2239395) in the 3' downstream region of the COMT gene which included a non-dopaminergic candidate gene, the ARVCF (Armadillo like VeloCardio Facial) gene, was associated with the risk of schizophrenia. The genetic region including the ARVCF gene in the 22q11.21 chromosome is associated with schizophrenia in a Spanish series. Our results will assist in the interpretation of the controversy generated by genetic associations of COMT and schizophrenia, which could be the result of different LD patterns between COMT markers and the 3' region of the ARVCF gene.

A number of factors make the angiotensin-converting enzyme (ACE) a candidate gene for psychiatric disorders, including its action on neurotransmitters such as dopamine. An insertion/deletion (I/D) polymorphism in an ACE gene intron is associated with ACE levels. Here we examine whether the ACE I/D polymorphism is a risk factor for schizophrenia. Participants comprised 243 subjects diagnosed with schizophrenia and related disorders, and 291 hospital-based controls. The D allele of the ACE gene was identified as a protective factor, significantly reducing the risk of developing schizophrenia and related disorders (by 40%) and of developing schizophrenia (by 50%). This protection is explained by the additive genotype risk model, in which the protection increases with the number of D alleles. Our results indicate that the ACE D allele is involved in the development of schizophrenia.

Background and Objective: Cathecol-O-methyl transferase (COMT) is one of the most plausible susceptibility genes of schizophrenia risk. The main genetic variant (G158A or rs4680) studied is functional. It has been shown that G-A transition at COMT codon 158 makes COMT more thermolabile and less active at physiological temperature. Genetic variants in the P2 promoter have been suggested to cause alterations in brain COMT protein levels. A variant in the P2 promoter (-278A/G or rs1800706) has recently been associated with psychotic disorders. We studied whether polymorphisms in COMT (G158A, -278A/G) are risk factors for schizophrenia in a Spanish population., Patients and Method: 243 subjects diagnosed of schizophrenia and related disorders following the DSM-IV criteria and 291 hospital-based controls participated in an association study., Results: The heterozygotes for the COMT -278A/G polymorphism showed a 60% reduction in the schizophrenia risk (p = 0.009). No significant differences were observed between the other COMT genotypes or haplotypes in cases and controls., Conclusions: Our results suggest that the COMT -278A/G polymorphism may have a role in schizophrenia. The results are in agreement with recent findings in this field that indicate a minor influence of COMT G158A on schizophrenia risk and a greater importance of polymorphisms in the P2 promoter regions of COMT, such as -278A/G.

Objective: In this study we examined the relationship between dopamine D2 receptor (DRD2) polymorphisms (TaqIA, TaqIB, -141C Ins/Del) and dopamine D3 receptor (DRD3) Ser9Gly polymorphism and the risk of schizophrenia in a Spanish population., Methods: Two hundred and forty-three schizophrenia patients and 291 healthy controls from the general population participated in a case-control study., Results: No significant differences were observed in the allele or genotype frequencies of TaqIA, TaqIB or Ser9Gly polymorphisms between the schizophrenia patients and the healthy controls. The frequency of the -141C Del allele was significantly lower in the former group (odds ratio=0.4, P=0.01). The -141C Del allele, which produces lower expression of DRD2, may protect against dopaminergic hyperactivity in schizophrenia., Conclusion: This study is one of the few studies of Caucasian participants that supports the results obtained in the original Japanese study, in which the -141C Ins/Del polymorphism was first described. Furthermore, our findings reinforce the hypothesis that excess dopaminergic activity leads to schizophrenia.

Background: Monoamine oxidase B (MAO-B) enzyme is involved in the oxidative metabolism of dopamine. We studied whether the A644G polymorphism in intron 13 of the MAO-B gene is a risk factor for schizophrenia., Methods: 242 subjects diagnosed with schizophrenia and related disorders and 290 hospital-based controls participated in the study. Genomic DNA was isolated from whole blood and genotyped with the allele-specific oligonucleotide polymerase chain reaction method., Results: This polymorphism was studied by diagnosis subgroups and the G allele was identified as a risk factor for developing schizophrenia (p = 0.006). When we performed a sex-specific analysis, the G allele was only a risk factor for developing schizophrenia in women (p = 0.01). Although the frequency of the G allele is higher in male patients than in male controls, no statistically significant association with schizophrenia was found., Conclusion: Our results support the involvement of the MAO-B gene in schizophrenia, particularly in women., (Copyright 2008 S. Karger AG, Basel.)

Introduction: Impaired dopamine transporter (DAT) function may be involved in antipsychotic (AP)-induced extrapyramidal symptoms (EPS). A polymorphism involving a variable number of tandem repeats (VNTR) has been described in the DAT gene (SLC6A3)., Objective: We studied whether the SLC6A3 VNTR polymorphism is a risk or protection factor for AP-induced EPS. We also investigated the relationship between the polymorphism and DAT availability in the schizophrenic patient's brain., Methods: Sixty-one patients receiving AP therapy participated in the EPS study. Of these, thirty-two cases presented EPS (Simpson-Angus >3) and twenty-nine without EPS (Simpson-Angus < or =3). The DAT expression was studied in fifteen AP-naive patients by [(123)I] FP-CIT SPECT., Results: No significant differences were observed for the more common alleles ((*)9R and (*)10R) or for genotype frequencies between patients with EPS and those without EPS. The frequency of the (*)9R and (*)10R alleles was similar to that described in other European populations. There were no significant differences in striatal DAT binding among the three major VNTR genotype groups., Conclusions: Our results suggest that the VNTR polymorphism did not influence AP-induced EPS and did not affect DAT gene expression or protein function.

Background: A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood. Aims: To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive–compulsive symptoms (OCS). Method: Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample. Results: A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04–0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = −0.28, 95% CI −0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction. Conclusions: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians' therapeutic decisions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Schizophrenia (SZ) is a deleterious brain disorder affecting cognition, emotion and reality perception. The most widely accepted neurochemical-hypothesis is the imbalance of neurotransmittersystems. Depleted GABAergic-inhibitory function might produce a regionally-located dopaminergic and glutamatergic-storm in the brain. The dopaminergic-release may underlie the positive psychoticsymptoms while the glutamatergic-release could prompt the primary negative symptoms/cognitive deficits. This may occur due to excessive synaptic-pruning during the neurodevelopmental stages of adolescence/early adulthood. Thus, although SZ is not a neurodegenerative disease, it has been suggested that exaggerated dendritic-apoptosis could explain the limited neuroprogression around its onset. This apoptotic nature of SZ highlights the potential therapeutic action of anti-apoptotic drugs, especially at prodromal stages. If dysregulation of apoptotic mechanisms underlies the molecular basis of SZ, then anti-apoptotic molecules could be a prodromal therapeutic option to halt or prevent SZ. In fact, risk alleles related in apoptotic genes have been recently associated to SZ and shared molecular apoptotic changes are common in the main neurodegenerative disorders and SZ. PRISMA-guidelines were considered. Anti-apoptotic drugs are commonly applied in classic neurodegenerative disorders with promising results. Despite both the apoptotic-hallmarks of SZ and the widespread use of anti-apoptotic targets in neurodegeneration, there is a strikingly scarce number of studies investigating anti-apoptotic approaches in SZ. We analyzed the anti-apoptotic approaches conducted in neurodegeneration and the potential applications of such anti-apoptotic therapies as a promising novel therapeutic strategy, especially during early stages. [ABSTRACT FROM AUTHOR]

• The polygenic risk score for educational attainment (PRS-EA), rather than psychopathological PRS (schizophrenia or bipolar disorder), was associated with lower risk and a later onset of relapse. • These results could indicate that the biological mechanisms beyond the risk of suffering a psychotic episode and the mechanisms of its prognosis could be independent. • The combination of polygenic scores and clinical data are potentially useful predictors of relapse. Little is known about genetic predisposition to relapse. Previous studies have linked cognitive and psychopathological (mainly schizophrenia and bipolar disorder) polygenic risk scores (PRS) with clinical manifestations of the disease. This study aims to explore the potential role of PRS from major mental disorders and cognition on schizophrenia relapse. 114 patients recruited in the 2EPs Project were included (56 patients who had not experienced relapse after 3 years of enrollment and 58 patients who relapsed during the 3-year follow-up). PRS for schizophrenia (PRS-SZ), bipolar disorder (PRS-BD), education attainment (PRS-EA) and cognitive performance (PRS-CP) were used to assess the genetic risk of schizophrenia relapse.Patients with higher PRS-EA, showed both a lower risk (OR=0.29, 95% CI [0.11–0.73]) and a later onset of relapse (30.96± 1.74 vs. 23.12± 1.14 months, p=0.007. Our study provides evidence that the genetic burden of neurocognitive function is a potentially predictors of relapse that could be incorporated into future risk prediction models. Moreover, appropriate treatments for cognitive symptoms appear to be important for improving the long-term clinical outcome of relapse. [ABSTRACT FROM AUTHOR]

Abstract: Previously one intronic DRD3 SNP, rs167771, was associated with risperidone-induced extrapyramidal side-effects (EPS). The aim of the present study was to search hitherto unidentified common functional variants or rare variants, in DRD3 associated with risperidone-induced EPS. 126 subjects treated with risperidone participated in this study. We sequenced the seven exons of DRD3. After sequencing we localized five dbSNPs and four new rare variants. None of the dSNPs or rare variants seems to be functional after bioinformatics analysis. Our results suggest that, rather than exonic regions, regulatory regions and introns could be related to the associations reported for DRD3 and the incidence of locomotor side-effects. [Copyright &y& Elsevier]

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.780single-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. [ABSTRACT FROM AUTHOR]