Search

Background Validated clinical prediction models of short-term remission in psychosis are lacking. Our aim was to develop a clinical prediction model aimed at predicting 4−6-week remission following a first episode of psychosis. Method Baseline clinical data from the Athens First Episode Research Study was used to develop a Support Vector Machine prediction model of 4-week symptom remission in first-episode psychosis patients using repeated nested cross-validation. This model was further tested to predict 6-week remission in a sample of two independent, consecutive Danish first-episode cohorts. Results Of the 179 participants in Athens, 120 were male with an average age of 25.8 years and average duration of untreated psychosis of 32.8 weeks. 62.9% were antipsychotic-naïve. Fifty-seven percent attained remission after 4 weeks. In the Danish cohort, 31% attained remission. Eleven clinical scale items were selected in the Athens 4-week remission cohort. These included the Duration of Untreated Psychosis, Personal and Social Performance Scale, Global Assessment of Functioning and eight items from the Positive and Negative Syndrome Scale. This model significantly predicted 4-week remission status (area under the receiver operator characteristic curve (ROC-AUC) = 71.45, P < .0001). It also predicted 6-week remission status in the Danish cohort (ROC-AUC = 67.74, P < .0001), demonstrating reliability. Conclusions Using items from common and validated clinical scales, our model significantly predicted early remission in patients with first-episode psychosis. Although replicated in an independent cohort, forward testing between machine learning models and clinicians’ assessment should be undertaken to evaluate the possible utility as a routine clinical tool.

Validated clinical prediction models of short-term remission in psychosis are lacking. Our aim was to develop a clinical prediction model aimed at predicting 4-6-week remission following a first episode of psychosis.Baseline clinical data from the Athens First Episode Research Study was used to develop a Support Vector Machine prediction model of 4-week symptom remission in first-episode psychosis patients using repeated nested cross-validation. This model was further tested to predict 6-week remission in a sample of two independent, consecutive Danish first-episode cohorts.Of the 179 participants in Athens, 120 were male with an average age of 25.8 years and average duration of untreated psychosis of 32.8 weeks. 62.9% were antipsychotic-naïve. Fifty-seven percent attained remission after 4 weeks. In the Danish cohort, 31% attained remission. Eleven clinical scale items were selected in the Athens 4-week remission cohort. These included the Duration of Untreated Psychosis, Personal and Social Performance Scale, Global Assessment of Functioning and eight items from the Positive and Negative Syndrome Scale. This model significantly predicted 4-week remission status (area under the receiver operator characteristic curve (ROC-AUC) = 71.45, P.0001). It also predicted 6-week remission status in the Danish cohort (ROC-AUC = 67.74, P.0001), demonstrating reliability.Using items from common and validated clinical scales, our model significantly predicted early remission in patients with first-episode psychosis. Although replicated in an independent cohort, forward testing between machine learning models and clinicians' assessment should be undertaken to evaluate the possible utility as a routine clinical tool.

AIMS Athens First-Episode Psychosis (FEP) Research study, aims to explore the potential associations between multiple genetic, environmental and neurometabolic risk factors of psychotic disorders, through the clinical management of FEP patients with minimal exposure (

Background.Premorbid adjustment (PA) abnormalities in psychotic disorders are associated with an earlier age at onset (AAO) and unfavorable clinical outcomes, including treatment resistance. Prior family studies suggest that familial liability, likely reflecting increased genetic risk, and socioeconomic status (SES) contribute to premorbid maladjustment. However, their joint effect possibly indicating gene–environment interaction has not been evaluated.Methods.We examined whether family history of psychosis (FHP) and parental SES may predict PA and AAO in unrelated cases with first-episode psychosis (n= 108) and schizophrenia (n= 104). Premorbid academic and social functioning domains during childhood and early adolescence were retrospectively assessed. Regression analyses were performed to investigate main effects of FHP and parental SES, as well as their interaction. The relationships between PA, AAO, and response to antipsychotic medication were also explored.Results.Positive FHP associated with academic PA difficulties and importantly interacted with parental SES to moderate social PA during childhood (interactionp= 0.024). Positive FHP and parental SES did not predict differences in AAO. Nevertheless, an earlier AAO was observed among cases with worse social PA in childhood (β= −0.20;p= 0.005) and early adolescence (β= −0.19;p= 0.007). Further, confirming evidence emerged for an association between deficient childhood social PA and poor treatment response (p= 0.04).Conclusions.Familial risk for psychosis may interact with parental socioeconomic position influencing social PA in childhood. In addition, this study supports the link between social PA deviations, early psychosis onset, and treatment resistance, which highlights premorbid social functioning as a promising clinical indicator.

Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Liability to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published GWAS in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected (“Concordant”) direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants demonstrating the counterintuitive (“Discordant”) relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education and/or schizophrenia at p−8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs, and many of these have been validated by larger, more recent single-phenotype GWAS. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms: early neurodevelopmental pathways that characterize concordant allelic variation, and adulthood synaptic pruning pathways that were linked to the paradoxical positive genetic association between education and schizophrenia. Further, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia, but also to the broader biological dimensions that are implicated in both general health outcomes and psychiatric illness.

Genome-wide association studies have led to the development of polygenic score (PS) predictors that explain increasing proportions of the variance in human complex traits. In parallel, progress in preimplantation genetic testing now allows genome-wide genotyping of embryos generated viain vitrofertilization (IVF). Jointly, these developments suggest the possibility of screening embryos for polygenic traits such as height or cognitive function. There are clear ethical, legal, and societal concerns regarding such a procedure, but these cannot be properly discussed in the absence of data on the expected outcomes of screening. Here, we use theory, simulations, and real data to evaluate the potential gain of PS-based embryo selection, defined as the expected difference in trait value between the top-scoring embryo and an average, unselected embryo. We observe that the gain increases very slowly with the number of embryos, but more rapidly with increased variance explained by the PS. Given currently available polygenic predictors and typical IVF yields, the average gain due to selection would be ≈2.5cm if selecting for height, and ≈2.5 IQ (intelligence quotient) points if selecting for cognitive function. These mean values are accompanied by wide confidence intervals; in real data drawn from nuclear families with up to 20 offspring each, we observe that the offspring with the highest PS for height was the tallest only in 25% of the families. We discuss prospects and limitations of PS-based embryo selection for the foreseeable future.

Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome‐wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow‐up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome‐wide single‐nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta‐analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC‐SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation‐based analysis revealed an excess of strongly associated loci among GWAS top‐ranked signals for verbal working memory (WM) and antisaccade intra‐subject reaction time variability (empirical P

Genetic variability within the ZNF804A gene has been recently found to be associated with schizophrenia and bipolar disorder, although the pathways by which this gene may confer risk remain largely unknown. We set out to investigate whether common ZNF804A variants affect psychosis-related intermediate phenotypes such as cognitive performance dependent on prefrontal and frontotemporal brain function, schizotypal traits, and attenuated psychotic experiences in a large young male population. Association analyses were performed using all 4 available self-rated schizotypy questionnaires and cognitive data retrospectively drawn from the Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS). DNA samples from 1507 healthy young men undergoing induction to military training were genotyped for 4 previously studied polymorphic markers in the ZNF804A gene locus. Single-marker analysis revealed significant associations between 2 recently identified candidate schizophrenia susceptibility variants (rs1344706 and rs7597593) and a refined positive schizotypy phenotype characterized primarily by self-rated paranoia/ideas of reference. Nominal associations were noted with all positive, but not negative, schizotypy related factors. ZNF804A genotype effect on paranoia was confirmed at the haplotype level. No significant associations were noted with central indexes of sustained attention or working memory performance. In this study, ZNF804A variation was associated with a population-based self-rated schizotypy phenotype previously suggested to preferentially reflect genetic liability to psychosis and defined by a tendency to misinterpret otherwise neutral social cues and perceptual experiences in one's immediate environment, as personally relevant and significant information. This suggests a novel route by which schizophrenia-implicated ZNF804A genetic variation may confer risk to clinical psychosis at the general population level.

Objective Alterations in glutamate homeostasis and Kv1.3 voltage-gated potassium channel function have been independently associated with T cell dysfunction, whereas selective blockade of Kv1.3 channels inhibits T cell activation and improves T cell–mediated manifestations in animal models of autoimmunity. Because low extracellular glutamate concentrations enhance the activity of this channel in normal T cells ex vivo, we undertook this study to examine serum glutamate concentrations and Kv1.3 channel activity in patients with systemic lupus erythematosus (SLE). Methods We used high-performance liquid chromatography for glutamate measurements, and we used the whole-cell patch-clamp technique for electrophysiologic studies performed in freshly isolated, noncultured peripheral T cells. Results Mean ± SD serum concentrations of glutamate were lower in patients with either clinically quiescent SLE (77 ± 27 μM [n = 18]) or active SLE (61 ± 36 μM [n = 16]) than in healthy controls (166 ± 64 μM [n = 24]) (both P < 0.0001). The intrinsic gating properties of the Kv1.3 channels in lupus T cells were found to be comparable with those in healthy control–derived T cells. Notably, electrophysiologic data from SLE patient–derived T cells exposed to extracellular glutamate concentrations similar to their respective serum levels (50 μM) demonstrated Kv1.3 current responses enhanced by almost 20% (P < 0.01) compared with those subsequently obtained from the same cell in the presence of glutamate concentrations within control serum levels (200 μM). Conclusion Based on the key role of Kv1.3 channel activity in lymphocyte physiology, an enhancing in vivo effect of low serum glutamate concentrations on the functional activity of this channel may contribute to lupus T cell hyperactivity. Studies to further elucidate Kv1.3 responses in SLE, as well as the possible pathogenetic role of this unsuspected metabolic abnormality, may have therapeutic implications for SLE patients.

Independent genome-wide association studies have implicated a common single nucleotide polymorphism within the ANK3 gene (rs10994336) in bipolar disorder (BD) susceptibility, thus establishing rs10994336 marker as a strong candidate predisposing genetic factor for BD. Furthermore, recent findings demonstrate that this variant impacts on cognitive functioning in BD patients, their unaffected relatives, and healthy controls by influencing sustained attention. Here, we aimed to replicate this finding in a large population-based sample of healthy young adults (n=1808). Sustained attention was evaluated using the Continuous Performance Test as in the original study and working memory was assessed with the n-back task. Individuals carrying the BD risk T-allele showed significantly reduced sensitivity in target detection, increased errors of commission, and atypical response latency variability. In addition, we confirmed the lack of an association between the rs10994336 variant and working memory, as well as general intellectual ability, suggesting a specific effect on the Continuous Performance Test performance.

The response to psychosocial stress is influenced by both psychosocial factors and genetic vulnerability. The most investigated gene in gene × environment studies in abnormal response to environmental stressors is the one coding for the serotonin transporter (SLC6A4). Variability within this gene has been associated with functional brain differences, personality dimensions, reactivity to stress and risk for various psychopathological conditions. In the present study, we set out to investigate the association of common genetic variants within SLC6A4 with state psychopathology in a community sample homogeneously exposed to stress, thus inquiring about potential genetic differences in stress sensitivity. One thousand eight hundred seventy-five young conscripts were evaluated for psychopathological distress with the 90-item Symptoms Checklist Revised in their first 2 weeks of admission to obligatory military service. Of these, 1594 were genotyped for the biallelic ins/del polymorphism (5-HTTLPR S/L) within the promoter region of SLC6A4, as well as the variation within the 'long' 5-HTTLPR allele (rs25531A/G). Homozygous for the 5-HTTLPR S allele reported significantly higher scores for paranoid ideation as compared with L-allele carriers. Slight effects on other subscales were observed, but were not significant after correction for multiple testing. Despite limitations linked to the evaluation of psychopathology by a single general scale and multiple comparisons, the present study support a role of SLC6A4 in modulating abnormal responses to environmental stress. In particular, variation within this gene may confer risk for paranoid/defensive reactions under conditions of environmental stress associated with military induction.

Background While association studies on schizophrenia show conflicting results regarding the importance of the regulator of the G-protein signaling 4 (RGS4) gene, recent work suggests that RGS4 may impact on the structural and functional integrity of the prefrontal cortex. We aimed to study associations of common RGS4 variants with prefrontal dependent cognitive performance and schizotypy endophenotypes at the population level. Methods Four RGS4 single nucleotide polymorphisms (SNP1 [rs10917670], SNP4 [rs951436], SNP7 [rs951439], and SNP18 [rs2661319]) and their haplotypes were selected. Their associations with self-rated schizotypy (SPQ), vigilance, verbal, spatial working memory and antisaccade eye performance were tested with regressions in a representative population of 2,243 young male military conscripts. Results SNP4 was associated with negative schizotypy (higher SPQ negative factor for common T allele, p = 0.009; p = 0.031 for differences across genotypes) and a similar trend was seen also for common A allele of SNP18 (p = 0.039 for allele-load model; but p = 0.12 for genotype differences). Haplotype analyses showed a similar pattern with a dose-response for the most common haplotype (GGGG) on the negative schizotypy score with or without adjustment for age, IQ and their interaction (p = 0.011 and p = 0.024, respectively). There was no clear evidence for any association of the RGS4 variants with cognitive endophenotypes, except for an isolated effect of SNP18 on antisaccade error rate (p = 0.028 for allele-load model). Conclusion Common RGS4 variants were associated with negative schizotypal personality traits amongst a large cohort of young healthy individuals. In accordance with recent findings, this may suggest that RGS4 variants impact on the functional integrity of the prefrontal cortex, thus increasing susceptibility for psychotic spectrum disorders.