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The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). This study was supported by the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust at King’s College London. Further support to EB: Mental Health Research UK’s John Grace QC award, BMA Margaret Temple grants 2016 and 2006, MRC—Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship, the NIHR Biomedical Research Centre at UCLH, and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London. Further support to co-authors: The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to CI). The BMA Margaret Temple grant 2016 to JT. A 2014 European Research Council Marie Curie award to A Díez-Revuelta. HI has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 747429. A Medical Research Council doctoral studentship to JH-S, IA-Z and AB. A Mental Health Research UK studentship to RM. VB is supported by a Wellcome Trust Seed Award in Science (200589/Z/16/Z). FWO Senior Clinical Fellowship to RvW. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organisations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Centre and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Centre Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical centre The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Centre Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta). The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundació (CI 2005-0308007), Fundacion Ramón Areces and Fundacion Marqués de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data.

Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s (PD) or Alzheimer’s (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), and with a protective HLA association recently reported in amyotrophic lateral sclerosis (ALS). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. An HLA-DRB1*04-mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Human genetics research lacks diversity; over 80% of genome-wide association studies (GWAS) have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine. This systematic review provides an overview of research involving Parkinson’s disease (PD) genetics in under-represented populations (URP), and sets a baseline to measure the future impact of current efforts in those populations.We searched PubMed and EMBASE until October 2021 using search strings for “PD”, “genetics”, the main “URP”, and “lower-to-upper-middle-income countries”. Inclusion criteria were original studies, written in English, reporting genetic results on PD patients from non-European populations. Two levels of independent reviewers identified and extracted relevant information.We observed considerable imbalances in PD genetic studies among URP. Asian participants from China were described in the majority of the articles published (61%), but other populations were less well studied, for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just seven studies using a genome-wide approach published up to 2021 including URP.This review provides insight into the significant lack of population diversity in PD research highlighting the urgent need for better representation. The Global Parkinson’s Genetics Program (GP2) and similar initiatives aim to impact research in URP, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future.

BackgroundParkinson disease (PD) is a major cause of disability affecting >6 million people worldwide. The incidence/prevalence of PD is generally higher in males than females. It is unclear whether male predominance is observed in low- and middle-income countries, where the fastest apparent rate of increase of PD has been observed.MethodsWe searched MEDLINE, SCOPUS and OVID for articles published between 2014-2021 for incidence of PD, 2011-2021 for prevalence, and updated previously published systematic reviews for which the last date of inclusion had been 2014 and 2011. We included 32 articles for prevalence and 30 for incidence. We calculated male/female (M/F) prevalence and incidence ratios, and investigated heterogeneity in estimates.ResultsThe combined M/F prevalence ratio was 1.18 (95% CI 1.03-1.36) and incidence ratio was1.37 (95% CI 1.22-1.53), lowest in Asian populations. These were not influenced by study type, national economy or mean participant age. The female-to-male gap in life expectancy did partly account for data heterogeneity.ConclusionThe sex gap for prevalence of PD was smaller than has previously been reported. More studies are needed to understand the determinants of sex imbalance in PD.

Introduction There have been no specific guidelines regarding which genes should be tested in the clinical setting for Parkinson's disease (PD) or parkinsonism. We evaluated the types of clinical genetic testing offered for PD as the first step of our gene curation. Methods The National Institutes of Health (NIH) Genetic Testing Registry (GTR) was queried on 12/7/2020 to identify current commercial PD genetic test offerings by clinical laboratories, internationally. Results We identified 502 unique clinical genetic tests for PD, from 28 Clinical Laboratory Improvement Amendments (CLIA)-approved clinical laboratories. These included 11 diagnostic PD panels. The panels were notable for their differences in size, ranging from 5 to 62 genes. Five genes for variant query were included in all panels (SNCA, PRKN, PINK-1, PARK7 (DJ1), and LRRK2). Notably, the addition of the VPS35 and GBA genes was variable. Panel size differences stemmed from inclusion of genes linked to atypical parkinsonism and dystonia disorders, and genes in which the link to PD causation is controversial. Conclusion There is an urgent need for expert opinion regarding which genes should be included in a commercial laboratory multi-gene panel for PD. Deborah Mascalzoni is part of Movement Society Disorder (MDS) Task Force on Recommendations for Clinical Genetic Testing in Parkinson's Disease

Background: Structural brain abnormalities are already present during the early phases of psychosis, but factors underlying brain volume changes are still not well understood. The neuregulin 1 gene (NRG1), influencing neurodevelopment and neuroplasticity, has been associated with schizophrenia. Our aim was to examine whether variations in the NRG1 gene (SNP8NRG221132, SNP8NRG6221533 and SNP8NRG243177 polymorphisms) influence longitudinal changes in the brain during a first episode of psychosis (FEP). Methods: A 3-year follow-up magnetic resonance imaging (MRI) study was performed. Fifty-nine minimally medicated patients who were experiencing FEP and 14 healthy control individuals underwent genotyping and structural brain MRI at baseline and at 1- and 3-year follow-up. A comparison of brain volumes, gray matter, white matter (WM), lateral ventricles (LV), cortical cerebrospinal fluid, and thalamus and caudate was made between the groups according to their genotype. Results: In patients, the SNP8NRG6221533 risk C allele was significantly associated with increased LV volume across time. C allele carriers had significantly less WM compared with subjects homozygous for the T allele after the follow-up. No other significant differences were observed among subgroups. No significant changes according to the genotypes were found in healthy individuals. Conclusion: Our findings suggest that variations of neurodevelopment-related genes, such as the NRG1 gene, can contribute to brain abnormalities described in early phases of schizophrenia and progressive changes during the initial years of the illness. To our knowledge, it is the first time that a relation between NRG1 polymorphisms and longitudinal brain changes is reported.

Dystrobrevin-binding protein 1 gene (dysbindin or DTNBP1) has been associated with schizophrenia and cognitive performance. Its expression in areas implicated in cognition such as the dorsolateral prefrontal cortex, as well as its role in dopaminergic and glutamatergic system, has been replicated by several studies. The main aim of this study was to examine the association between DTNBP1 variability and cognitive performance in a sample of 238 patients with a first episode of a non-affective psychosis.Patients, and a comparison sample of 47 healthy subjects, completed an extensive neuropsychological battery. Five single nucleotide polymorphisms (SNPs) within DTNBP1 (rs2619528, rs2619538, rs3213207, rs2619539 and rs760761) and three haplotypes (GACAC, GAGAC and GTGAC) were analysed.In the group of patients, we found a significant association between two of the DTNBP1 SNPs and one of the haplotypes (rs2619539, rs3213207 and GACAC) and a measure of premorbid IQ [Wechsler Adult Intelligence Scale-3rd Edition (WAIS-III) Vocabulary subtest]. Moreover, one of these SNPs, rs2619539, was also associated with our measure of working memory (WAIS-III Backward digits subtest) and two haplotypes, GAGAC and GTGAC, with our measure of verbal memory (Rey Auditory Verbal Learning Test), of visual memory (Rey Complex Figure Test) in the case of GAGAC, and of speed of processing (WAIS-III Digit Symbol-coding) in the case of GTGAC.Our findings add further evidence suggesting an association between dysbindin gene variability and cognitive abnormalities in schizophrenia, providing preliminary evidence of this association since the time of illness onset among minimally medicated patients.

OBJECTIVE: DISC1 gene is one of the main candidate genes for schizophrenia since it has been associated to the illness in several populations. Moreover, variations in several DISC1 polymorphisms, and in particular Ser704Cys SNP, have been associated in schizophrenic patients to structural and functional modifications in two brain areas (pre-frontal cortex and hippocampus) that play a central role in the genesis of psychotic symptoms. This study tested the association between Ser704Cys DISC1 polymorphism and the clinical onset of psychosis. METHODS: Two hundred and thirteen Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys) SNP of the DISC1 gene. The clinical severity of the illness was assessed using SAPS and SANS scales. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects. RESULTS: Patients homozygous for the Ser allele of the Ser704Cys DISC1 SNP had significantly (p

The aim of the study was to identify predictors associated with a lower likelihood of achieving a clinical remission 1 year after the first break of the illness. Participants were 174 consecutive subjects included in a first episode programme with no prior treatment with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone in a randomized, open-label, prospective clinical trial. The main outcome variable was the remission criteria developed by the Remission in Schizophrenia Working Group. Clinical variables were included in a logistic regression analysis in order to predict the remission state at 1 year. At 1 year, 31% of patients met criteria for remission. The logistic regression analysis revealed that the strongest predictors of achieving clinical remission 1 year away from a first episode of non-affective psychosis were the length of duration of untreated psychosis (DUP), the severity of negative symptomatology and the educational level attained at baseline. The results suggest that: (1) patients with a lengthy DUP, a greater severity of negative symptomatology at baseline and with a lower education level are in a higher risk of not achieving a clinical remission during the first year of treatment; and (2) early intervention clinical programs should aim to reduce the length of DUP in order to provide a better outcome for patients.

Preventing relapse during the first years of illness has a critical impact on lifelong outcomes in schizophrenia. A better understanding and improvement in factors which influence relapse should diminish the risk of relapse and consequently improve the outcome of the illness.To identify factors associated with relapse after 3 years of a first episode in a sample of non-affective psychosis patients who are representative of clinical practice in an epidemiological catchment.We analyzed socio-demographic and clinical data from a cohort of patients who were treated in a specialized early intervention service and who were at risk of relapse during a 3-year follow-up. Univariate analyses, logistic regression and survival analyses were performed. The analyzed variables included gender, age at onset, duration of untreated psychosis, clinical severity at baseline, insight at baseline, premorbid functioning, substance use, family history of psychosis and adherence to medication.Of the 140 patients considered to be at risk for relapse, 91 (65%) individuals relapsed at least once over the three-year period. The relapse rates at 1 year and 2 years were 20.7% and 40.7%, respectively. Adherence to medication was the only significant predictor of relapse after a three-year follow-up [hazard ratio (HR) 4.8, 95% confidence interval (CI) 2.9-7.7; p 0.001]. Comparison of the mean time of relapse between adherent and non-adherent patients also revealed statistically significant differences (933 and 568 days, respectively). 50% of patients will relapse despite being categorized as treatment adherents.Non-adherence to medication is the biggest predictive factor of relapse after a first episode of psychosis.

Brief report.-- El pdf es la versión post-print.-- et al., The aim of this study was to use a region-of-interest approach with magnetic resonance imaging to examine the volume of the straightgyrus volume change in first-episodeschizophrenia-spectrumpatients compared with healthy subjects over a 1-year follow-up period. We did not find a differential pattern of volumetric change between the two groups., The present study was performed at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Instituto de Salud Carlos IIIPI020499, PI050427, PI060507, SENY Fundació Research GrantCI 2005-0308007 and Fundación Marqués de ValdecillaAPI07/011.

Rationale: To enhance the effectiveness of antipsychotics in first-episode psychosis is crucial in order to achieve the most favourable prognosis. Difference in effectiveness between antipsychotics is still under debate. Objective: The purpose of this study is to determine the long-term (3-year) effectiveness and efficacy of haloperidol, risperidone and olanzapine in first-episode schizophrenia-spectrum disorders. Method: This is a prospective, randomized, open-label study. Data for the present investigation were obtained from a large epidemiologic and 3-year longitudinal intervention programme of first-episode psychosis. One hundred seventy-four patients were randomly assigned to haloperidol (N=56), olanzapine (N=55), or risperidone (N=63) and followed up for 3 years. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on per-protocol populations was conducted in the analysis for clinical efficacy. Results: The treatment discontinuation rate for any cause differed significantly between treatment groups (χ 2=10.752; p=0.005), with a higher rate in haloperidol than in risperidone and olanzapine. The difference in the discontinuation rate between risperidone and olanzapine showed a tendency towards significance (χ 2=3.022; p=0.082). There was a significant difference in the mean time to all-cause discontinuation between groups (log-rank χ 2 =12.657;df=2; p=0.002). There were no significant advantages to any of the three treatments in reducing the psychopathology severity. Conclusions: After 3 years of treatment, a lower effectiveness was observed in haloperidol compared to second-generation antipsychotics (SGAs). The use of SGAs for the treatment of early phases of nonaffective psychosis may enhance the effectiveness of antipsychotics. © 2011 Springer-Verlag., The present study was carried out at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain under the following grant support: Instituto de Salud Carlos III PI020499, PI050427, PI060507, Plan Nacional de Drogas Research Grant 2005-Orden sco/3246/2004, SENY Fundació Research Grant CI 2005–0308007 and Fundación Marqués de Valdecilla API07/011.

The aim of this study was to investigate the long-term effectiveness and efficacy of haloperidol, risperidone and olanzapine in first-episode schizophrenia-spectrum disorders. This was a prospective, randomized, open-label study. Data for the present investigation were obtained from a large epidemiological and 3-year longitudinal intervention programme of first-episode psychosis conducted at the University Hospital Marques de Valdecilla, Santander, Spain. One hundred and seventy-four patients were randomly assigned to haloperidol ( N = 56), olanzapine ( N = 55), or risperidone ( N = 63) and followed up for 1 year. The primary effectiveness measure was all causes of treatment discontinuation. Effectiveness analyses were based on intend-to-treat populations. In addition, an analysis based on per protocol populations was conducted in the analysis for clinical efficacy. The treatment discontinuation rate for any cause was higher with haloperidol than with risperidone and olanzapine (χ2 = 8.517; p = 0.014). The difference in discontinuation rate between risperidone and olanzapine was not significant (χ2 = 0.063; p = 0.802). There were no significant advantages of any of the three treatments in reducing the severity of psychopathology. Risperidone and olanzapine demonstrated higher effectiveness relative to haloperidol, but the three antipsychotics were equally effective in reducing the severity of psychopathology. Specific clinical programmes and the use of second-generation antipsychotics may enhance the effectiveness of antipsychotic treatments.

Aim: To investigate pre-morbid, socio-demographic, clinical and cognitive variables as predictors of insight in a large and representative sample of first-episode psychosis patients. Methods: The abbreviated Scale to Assess Unawareness of Mental Disorder was used to assess insight dimensions. Patients with good and poor insight were independently compared on insight dimensions and logistic regression analyses were conducted to identify explanatory variables associated with each insight dimension. Results: The patients with good and poor insight of having a mental disorder differed in duration of untreated psychosis, diagnosis and attention, but only attention appeared as a predictor. The insight of the need for medication groups showed differences in age of onset, depression, severity of disorganized symptoms and hospitalization rate. Nevertheless, age of onset and disorganized symptoms seem to be the predictors. Groups of insight of the social consequences differed in duration of untreated psychosis, the negative and disorganized symptoms severity, disability, education, diagnosis and hospitalization rate. However, exclusively, the severity of disorganized symptoms seems to predict insight of social consequences. Conclusion: When independently analysed, the three insight dimensions showed different rates of affectation and different predictors. These results suggest that there must be different mechanisms underlying the lack of insight. First-episode psychosis is a crucial period for treatment adherence formation, an issue strongly associated with good insight. Thus, a more accurate evaluation of the predictors of lack of insight into each dimension is warranted to achieve a better comprehension of the lack of insight in schizophrenia and in turn, to implement treatment programmes seeking to improve it.

Genetic factors play an important role in the understanding of clinical response to antipsychotic treatments. We aimed to assess the effect of the catechol-O-methyltransferase (COMT) genotype in the short-term (6 weeks) clinical response of 161 first-episode psychosis patients. COMT genotype was not related to clinical response at 6 weeks. Val homozygote patients showed higher negative symptoms than Met homozygote patients. The COMT Val158 genotype seems to be related to the severity of negative symptoms rather than to clinical response.

Weight gain is one of the major adverse effects of antipsychotics. Although mechanisms remain unclear, genetic susceptibility has become increasingly attractive as a potential mechanism that could explain a significant part of interindividual variability. Most investigations have explored genes related with the mechanism of action of antipsychotic drugs. An alternative approach to investigate the role that genetic factors play in weight gain secondary to antipsychotic treatment is to study those genetic variants that have been found associated with obesity. The aim of this study was to determine whether the fat mass and obesity-associated gene (FTO) rs9939609 variant, the single nucleotide polymorphism that has shown the strongest association with common obesity in different populations, influences weight gain during the first year of antipsychotic treatment. We investigated also the genetic variants in other 3 strong candidates genes involved in the leptin-signaling pathway including leptin, leptin receptor, and Src homology 2. We carried out a prospective study on 239 patients with first-episode psychosis. Two hundred five patients completed the follow-up at 1 year (85.8%). Before antipsychotic treatment, the homozygous subjects for the risk allele A of the FTO rs9939609 variant had a higher body mass index at baseline (24.2 ± 3.8 kg/m2) than the AT/TT group (22.82 ± 3.3 kg/m2; F = 5.744; P = 0.018). After 1 year, the magnitude of weight increase was similar in the 3 genotypes defined by the rs9939609 variant. These results suggest that the pharmacological intervention accompanied by changes in energy intake and expenditure could suppress the genetic susceptibility conferred by the FTO genotype. None of the other single nucleotide polymorphisms evaluated were associated with weight gain during the first 12 months of antipsychotic therapy.

BackgroundThe thickness of the cortical mantle is a sensitive measure for identifying alterations in cortical structure. We aimed to explore whether first episode schizophrenia patients already show a significant cortical thinning and whether cortical thickness anomalies may significantly influence clinical and cognitive features.MethodWe investigated regional changes in cortical thickness in a large and heterogeneous sample of schizophrenia spectrum patients (n=142) at their first break of the illness and healthy controls (n=83). Magnetic resonance imaging brain scans (1.5 T) were obtained and images were analyzed by using brains2. The contribution of sociodemographic, cognitive and clinical characterictics was investigated.ResultsPatients showed a significant total cortical thinning (F=17.55, d=−0.62, pp'sd's>0.53). No significant group×gender interactions were observed (all p's>0.15). There were no significant associations between the clinical and pre-morbid variables and cortical thickness measurements (all r'sr=−0.24, p=0.021) and parietal cortical thickness (r=−0.27, p=0.009) was found in patients (thicker cortex was associated with lower attention). Our data revealed a similar pattern of cortical thickness changes related to age in patients and controls.ConclusionsCortical thinning is independent of gender, age, age of onset and duration of the illness and does not seem to significantly influence clinical and functional symptomatology. These findings support a primary neurodevelopment disorder affecting the normal cerebral cortex development in schizophrenia.

New models of interaction between genetic and environmental factors have been proposed to explain the pathogenesis of schizophrenia. The Val158Met polymorphism of the COMT (Catechol-O-Methyltransferase) gene, involved in dopamine regulation and related to negative symptoms, has been previously thought to interact with cannabis use in the modulation of risk of psychosis. The aim of the study was to explore the existence of an interaction between COMT genotype and cannabis use in early stages of psychosis and its effects on the age of onset in a representative group of first-episode psychosis patients. Age of onset, DUP (Duration of Untreated Psychosis) and cannabis use (regular user versus sporadic or non-user) were assessed in 169 Caucasian patients with a first-episode schizophrenia spectrum disorder. COMT polymorphism was typed using PCR of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with DUP and age of onset as dependent variables, cannabis and the COMT genotype as fixed factors, and gender as a covariate. The MANCOVA was significant for age of onset and DUP. Cannabis users had a significant earlier age of onset. Age of onset was later in the Met homozygote group (non-significant). The cannabis-COMT interaction showed a significant effect on both DUP and age of onset. Post hoc analyses showed that differences between genotypes were only present in the non-users' group. Based on these results, the use of cannabis could exert a modulator effect on the genotype, suppressing the delay effect for the age of onset in the case of the Met allele patients.

Evidence so far indicates that the consistent association between insular cortex abnormalities and schizophrenia is already present at early phases of the illness. In the present investigation we aimed to study the specificity of insular structural abnormalities in schizophrenia by using region-of-interest morphometry to assess insular cortex morphological characteristics in the same heterogeneous sample of schizophrenia-spectrum patients. The 225 subjects, comprising 82 schizophrenia patients, 36 schizophreniform disorder patients and 24 patients with nonschizophrenic non-affective psychoses, and 83 healthy individuals were investigated. Magnetic resonance imaging brain scans (1.5T) were obtained and images analysed to evaluate insular cortex morphometric variables. The main resulting measurements were for insular gray matter volume and cortical surface area. The contribution of sociodemographic and clinical characteristics was controlled. Patients with schizophrenia-spectrum disorders did not significantly differ from controls in the insular cortex morphometric variables evaluated (all P's>0.11). Clinical variables were not significantly related with insular morphological changes. Noteworthy is the fact that none of the group morphological measurements varied significantly by gender or hemisphere. Neither did we find significant differences when patients with schizophrenia and with other non-affective psychoses were compared. Contrary to our initial hypotheses, we were unable to demonstrate significant morphometric anomalies in a large and heterogeneous sample of patients with a first-episode of schizophrenia-spectrum disorders.

Impaired cognitive function has been identified as a core feature of schizophrenia. However, a significant proportion of patients do not show any cognitive deficits. The aim of this study was to assess if there were differences in white matter integrity between patients with and without cognitive impairment.A diffusion tensor imaging study and neurocognitive assessment were conducted in 49 patients with first-episode psychosis and 41 healthy comparison subjects. Subjects were assessed using the Continuous Performance Test, the Grooved Pegboard Test, the Rey Auditory Verbal Learning Test, and the Trail Making Test Part B. For each test, the patient sample was subdivided according to performance, with those scoring more than one standard deviation below the normative mean categorized as impaired. For each cognitive domain, white matter fractional anisotropy in deficit and nondeficit subgroups was compared using a voxel-based analysis. A nonparametric statistical method, controlling for multiple comparisons, was applied.Impairment on the Trail Making Test Part B was associated with reduced fractional anisotropy in the right/left anterior thalamic radiation and inferior fronto-occipital fasciculus, forceps minor, and left superior and inferior longitudinal fasciculi. Patients exhibiting Grooved Pegboard Test impairment showed reduced fractional anisotropy in the forceps minor, inferior fronto-occipital fasciculus, anterior thalamic radiation, and corticospinal and corticopontine tracts. Impaired performance on the Rey Auditory Verbal Learning Test and Continuous Performance Test was not associated with significant differences in fractional anisotropy.Deficits in executive and motor functioning in patients with first-episode psychosis are associated with reductions in white matter integrity in the major fasciculi that connect the frontal and temporal cortices as well as in pathways connecting cortical and subcortical regions. Their presence at the onset of illness, in minimally medicated patients, indicates that these findings are not attributable to effects of chronic illness or its treatment.

article i nfo There is substantial evidence suggesting that individual variability in antipsychotic treatment response could be genetically determined. Variations in several serotonin transporter (5-HTT) gene polymorphisms have been associated with antipsychotic response among chronic patients with schizophrenia, although their implication in early response among first-episode patients remains unclear. Two polymorphisms in the 5- HTTgene (a 44 bp insertion/deletion in the promoter region and the functional polymorphism rs25531) were genotyped in a sample of 147 drug-naive patients experiencing a first episode of a non-affective psychosis. Early (6 weeks) response to antipsychotic treatment with haloperidol, olanzapine or risperidone was assessed with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. No clear association was found between the rs25531 variant and treatment response. However, significant associations were observed between 5-HTT-LPR variants and early negative symptom response among first-episode patients with psychosis. Our results suggest a minor contribution to antipsychotic drug response of genetic alterations in the 5-HTT gene.

Evidence so far indicates the consistent association between brain structural abnormalities and schizophrenia already present at the early phases of the illness. This study investigates the specificity of brain structural abnormalities in schizophrenia by using region-of-interest method of volumetric analysis in a heterogeneous sample of schizophrenia spectrum patients at their first break of the illness. 225 subjects, comprising 82 schizophrenia patients, 36 schizophreniform disorder patients and 24 patients with non-schizophrenic non-affective psychoses, and 83 healthy individuals underwent a magnetic resonance imaging brain scan. Quantitative brain morphometric variables were assessed: cortical CSF, lateral ventricle, total brain tissue, white matter and cortical and subcortical gray matter volumes. The contribution of sociodemographic, cognitive and clinical characteristics was controlled. Compared with controls, schizophrenia (P=0.017) and schizophreniform disorder (P=0.023) patients showed an increase in cortical CSF volume. Schizophrenia patients had also markedly enlarged lateral ventricle volume compared to controls (P=0.026). The patients with non-schizophrenic non-affective psychoses did not significantly differ in lateral ventricle and cortical CSF volumes from controls. Compared with controls, schizophrenia and schizophreniform disorder patients demonstrated a significant decrease in total brain tissue (-1.30% and -1.12% respectively). Thalamic volume was reduced (-3.84%) in schizophrenia patients compared to controls (P=0.040). Clinical and cognitive variables were not significantly related with morphological changes. The brain changes found in patients with a first episode of schizophrenia spectrum disorders are robustly associated with the diagnoses of schizophrenia and schizophreniform disorder and are independent of relevant intervening variables.

Objective This study examined the main metabolic side effects induced by antipsychotic treatment in a cohort of first episode drug-naive subjects after the first year of treatment. Methods A randomized, open-label, prospective clinical trial was conducted. Participants were 164 consecutive subjects included in a first episode program and never treated with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone. The main outcome measures were changes at 1 year in fasting glucose parameters (glucose, insulin levels and insulin resistance index) and changes in fasting lipid parameters (total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol). Results 144 of the total sample were evaluated at 1 year. There was a statistically significant increase in the mean values of insulin levels, insulin resistance index, total cholesterol, LDL-cholesterol and triglycerides. No pathological values in fasting glucose plasma levels were found at baseline and there were no changes after 1 year. Weight gain was positively correlated with changes in insulin levels, insulin resistance index and triglyceride levels. We did not detect statistically significant differences between treatments in any of the parameters evaluated. Conclusions Fasting glycaemia and insulin concentrations at baseline do not support the hypothesis that schizophrenia is associated with an underlying abnormality in glucose metabolism. The changes in insulin and lipid parameters at 1 year seem to be related to the magnitude of weight gain. There were no significant differences between haloperidol, olanzapine and risperidone concerning metabolic adverse effects after the first year of treatment.

Objective Many studies have reported that cognitive ability may be predictive of the functional outcome for patients with schizophrenia. However, no study has prospectively examined these aspects in schizophrenia and bipolar disorders simultaneously. The present study attempted to analyze if neurocognition and clinical status predicts the real-life functioning for patients with schizophrenia or bipolar I disorder, using a longitudinal design. Method Forty-seven schizophrenic and 43 bipolar I outpatients were assessed twice with a neurocognitive battery (Executive Functions, Working Memory, Verbal Memory, Visual Memory, Visual-Motor Processing, Vigilance, Vocabulary and Motor Speed tasks), clinical scales (the Positive and Negative Symptom Scale, the Hamilton Rating Scale for Depression and the Clinician Administered Rating Scale for Mania) and functional outcome measures (the Global Assessment of Functioning Scale, the WHO's Disability Assessment Scale and occupational adaptation level) over a one-year follow-up period. The cognitive performance of the patients was compared, at baseline and one year later, with that of 25 healthy subjects. Results In schizophrenia patients, global functioning one year later was predicted by a composite neurocognitive score and three specific domain (verbal memory, motor speed, vocabulary). Symptoms appeared to explain less of the variance in functioning. In bipolar I patients, changes in the composite neurocognitive score over one year, deficits in the visual/motor processing domain, severity of symptoms (psychotic, excitatory and affective symptoms) and premorbid adjustment at the first assessment were the variables that better predicted functioning or disability changes over follow-up period. Conclusions Although the relationships between cognition, symptoms and functional capacity differ for schizophrenia or bipolar I patients, neuropsychological performance seems to be a principal longitudinal predictor of functioning in both disorders. Baseline neurocognition and cognitive changes over 12 months predicted changes in functioning over the same period, but only in bipolar I patients. These cognitive domains could be potential neurocognitive endophenotypes (endophenocognitypes) with regard to bipolar I disorder.

Aim: The aim of the study was to analyse the treated incidence of schizophrenia in Cantabria (Northern Spain) and the sociodemographic risk factors associated with the illness onset. Methods: Data were obtained from patients included in the Cantabria's Clinical Programme on First-Episode Psychosis (schizophrenia spectrum DSM-IV diagnosis) from 2001 to 2005, from the Cantabria first-episode schizophrenia study (carried out between 1988 and 1989) and from the 2001 Spanish census. Results: Annual incidence was 1.38 per 10 000 inhabitants in the risk-ageperiod. Identified risk factors were male gender (relative risk (RR): 1.61), age 15–25 years (RR: 3.48), unemployment (RR: 2.82), single status (RR: 5.88), low educational level (RR: 4.38), urban environment (RR: 1.62) and cannabis consumption (odds ratio: 12.83). The incidence in females was significantly lower than the one obtained 15 years ago. Conclusions: The reported factors suggest that underlying biological and social factors modulate the risk of psychosis. This balance operates differently in males and females.

Catechol-O-methyltransferase (COMT) Val158Met polymorphism has been identified as a potential etiologic factor in schizophrenia. It has been proposed that this polymorphism could be associated with specific clinical markers. The aim of the study was to evaluate the influence of COMT Val158Met polymorphism genotype in the phenotypic expression of first episode psychosis at onset. Age of onset, DUP, SANS, and SAPS (positive, disorganized, and negative dimensions) were studied in 169 Caucasian drug-naïve patients with a first-episode of non-affective psychosis. The COMT Val158Met polymorphism was typed using PCR amplification of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with COMT and gender as independent variables. Patients with Val/Val genotype had significantly higher levels of SANS negative dimension scores (F: 3.539; P = 0.031) and had a younger age of onset (F: 4.649; P = 0.011) than Met carriers. Our findings suggest that the Val allele is associated with onset phenotypic features related to a poor prognosis of the illness. These data would indicate that COMT genotype may have a role in the etiological model for schizophrenia and other psychotic disorders.

Background: Structural brain anomalies are present at early phases of psychosis. The objective was to examine the impact of Catechol-O-Methyltransferase (COMT) gene variations on brain morphology in first-episode non-affective psychosis. We hypothesized that the low activity-COMT (COMTL) allele would be associated with the presence of structural brain changes as assessed by quantitative magnetic resonance imaging (MRI). Methods: Fifty-two males and 23 females underwent COMT genotyping and MRI. Patients were categorized into three genetic subgroups: COMTH/H, COMTL/H and COMTL/L. MRI data were analyzed using BRAINS2. Global and lobar volumes of grey matter (GM) and cerebrospinal fluid (CSF) were compared among the three groups after controlling for total intracranial volume and age of illness onset. Results: COMTL carriers showed a significant enlargement of the lateral ventricles (F = 7.13, p = 0.009), right lateral ventricle (F = 5.99, p = 0.017) and left lateral ventricle (F = 6.22, p = 0.015). No other significant differences in any of the brain structures were found among subgroups. Conclusions: Our findings suggest that genetic variations of COMT can contribute to the enlargement of the lateral ventricles described in early phases of non-affective psychosis.

Choline acetyltransferase (ChAt) is extensively distributed throughout the CNS where, by catalyzing acetylcholine synthesis, it participates in modulating wide-ranging cholinergic-dependent functions including cognitive performance, sleep, arousal, movement, and visual information processing. Recently, compelling evidence has mounted implicating ChAt in schizophrenia. In particular, studies have identified significant reductions in ChAt activity in the nucleus accumbens and pontine tegmentum of such patients, which furthermore correlate significantly with measures of cognitive performance in the disorder. Similarly, elevated levels of choline, the acetylcholine precursor, have been identified among patients, implicating altered ChAt activity in these individuals. We sought to investigate the potential contribution of three ChAt gene polymorphisms in schizophrenia, and uncovered evidence for significant association between one of these, rs1880676G/A, and disease susceptibility among Basque individuals (genotypewise χ2 = 20.7, P = 0.00003; allelewise χ2 = 10.1, P = 0.002). A similar trend for association with susceptibility was observed for a second SNP, rs3810950G/A, (genotypwise χ2 = 6.4, P = 0.05; allelewise χ2 = 3.75, P = 0.05). Evidence was also uncovered for a potential influence of these polymorphisms on olanzapine treatment outcome among Spanish patients (F-statistic = 5.02, P = 0.03; F-statistic = 6.53, P = 0.02 respectively), and on improvements in positive symptoms in the case of rs3810950 (F-statistic = 5.3, P = 0.03) and general psychopathology in the case of rs1880676 and rs3810950 (F-statistic = 5.24, P = 0.03; F-statistic = 5.31, P = 0.03 respectively) during therapy. While more comprehensive studies are warranted to determine the precise contribution of ChAt mediated mechanisms in schizophrenia, our findings tentatively implicate a genetic influence of ChAt in the disorder's susceptibility and treatment. © 2007 Wiley-Liss, Inc.

Background Animal models have implicated the α 1 -adrenergic subtypes in cognitive functions relevant to schizophrenia, but no consensus exists with regard to the status of noradrenergic receptor populations in psychiatric patients. We focused on one α 1 -adrenergic subtype, the α 1A -adrenergic receptor, and proposed that genetic variants within the regulatory region of this gene (ADRA1A) alter the expression of this receptor, influencing susceptibility toward schizophrenia. Methods This study examined this proposal by testing the hypothesis that single nucleotide polymorphisms (SNPs) in the promoter region of the α 1A -adrenergic gene were associated with schizophrenia by performing case–control association analysis on SNPs found in a 5′ upstream region, which included the putative promoter region and 5′ untranslated region. Our sample consisted of 103 schizophrenia and 14 schizoaffective disorder patients and 176 control subjects. All recruits were from a Spanish population isolate of Basque origin that is characterized by low heterogeneity, which was selected with the intent that it might facilitate the identification of disease-related polymorphisms. Results A total of eight SNPs (−9625 G/A, −7255 A/G, −6274 C/T, −4884 A/G, −4155 C/G, −2760 A/C, −1873 G/A, and −563 C/T) were confirmed at a rare allele frequency of >5%. Association with schizophrenia and schizoaffective disorder was found for the −563 C/T SNP ( p = .0005 for allele and p = .007 for genotype, Bonferroni corrected) and −9625 G/A SNP ( p = .02 for allele and p = .03 for genotype, Bonferroni corrected). Significant differences in the 54 haplotypes formed by these eight SNPs were also found between patients and control subjects ( p = .008, Bonferroni corrected). Conclusions Because of the strength of these results and the location of these SNPs in the regulatory region of this gene, functional studies investigating the possible influence of these SNPs on receptor expression levels in schizophrenia are warranted.

A growing amount of evidence suggests that schizotypy is a dimensional construct probably consisting of three factors (i.e. cognitive-perceptual, interpersonal, disorganised). This study aimed to ascertain, using a Spanish version of the Schizotypal Personality Questionnaire-Brief (SPQ-B), the factor structure of schizotypy and its relation with sex and age in a nonclinical population. A sample of 443 undergraduate students at the University of Barcelona (Spain) completed the Spanish version of the SPQ-B. Factor analysis resulted in three substantive symptom dimensions: cognitive-perceptual, interpersonal, and disorganised. Age was negatively correlated both with the total score and with the three factors. Analyses of covariance (ANCOVA), entering age as a covariate, revealed sex differences, with higher scores for males in the total score, interpersonal factor, and disorganised factor, and higher scores for females in the cognitive-perceptual factor. The implications of our findings are discussed both regarding sex differences and the influence of age in the expression of schizotypal traits.