Differential Methylation Pattern of Schizophrenia Candidate Genes in Tetrahydrocannabinol-Consuming Treatment-Resistant Schizophrenic Patients Compared to Non-Consumer Patients and Healthy Controls.

BACKGROUND: Patients suffering from schizophrenic psychosis show reduced synaptic connectivity compared to healthy individuals. Furthermore, the use of cannabis often precedes the onset of schizophrenic psychosis. Therefore, we investigated whether consumption of cannabis has an impact on the methylation pattern of schizophrenia candidate genes concerned with the development and preservation of synapses and synaptic function. METHODS: Fifty blood samples of outpatients affected by treatment-resistant schizophrenic psychosis were collected in the outpatient department of Ch Ste Anne/INSERM (Paris, France). Extracted DNA was sent to the LMN/MHH (Hanover, Germany) where DNA samples were bisulfite converted. The methylation patterns of the promoter region of neuregulin 1 (NRG1), neurexin (NRXN1), disrupted in schizophrenia 1 (DISC1), and microtubule-associated-protein tau (MAPT) were then analysed by sequencing according to Sanger. RESULTS: In NRXN1 the group of non-consumer patients showed a methylation rate slightly lower than controls. In patients with preliminary use of tetrahydrocannabinol (THC) the NRXN1 promoter turned out to be methylated almost two times higher than in non-consumer patients. In MAPT, non-consumer patients showed a significant lower mean methylation rate in comparison to controls. In THC-consuming patients the difference compared with controls became less. NRG1 and DISC1 showed no significant differences between groups, whereas DISC1 appeared to be not methylated at all. CONCLUSION: In MAPT and NRXN1 mean methylation rates were lower in non-consumer patients compared with controls, which seems to be a compensatory mechanism. With consumption of THC, mean methylation rates were increased: in the case of MAPT compared with controls, and in NRXN1 even significantly beyond that. Methylation of NRG1 and DISC1 seems not to be affected by the psychiatric disorder or by consumption of THC.

Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?

Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry.

Alpha-lipoic acid in the treatment of psychiatric and neurological disorders: a systematic review.

Despite the existence of many preclinical studies, scientific evidence is lacking on the clinical use of alpha-lipoic acid (ALA) for central nervous system disorders. Therefore, we aimed at revising the literature concerning the use of ALA for the treatment of psychiatric and neurological conditions and to point out what is missing for the introduction of this antioxidant to this purpose. For this systematic review we performed a search using PubMed and SCOPUS databases with the following keywords: "alpha-Lipoic Acid AND central nervous system OR psychiatric disorders OR neurological disorders OR mood disorders OR anxiety OR psychosis OR Alzheimer OR Parkinson OR stroke". The total number of references found after automatically and manually excluding duplicates was 1061. After primary and secondary screening 32 articles were selected. Regarding psychiatric disorders, the studies of ALA in schizophrenia are advanced being ALA administration related to the improvement of schizophrenia symptoms and side effects of antipsychotic medication. In neurological disorders, ALA as a supplement was effective in the prevention of Alzheimer disease progression. For stroke, the use of the supplement ALAnerv® (containing 300 mg ALA) presented important results, since it was observed a reversal of clinical parameters and oxidative imbalance in these patients. For other neurological conditions, such as encephalopathy, multiple sclerosis, traumatic brain injury, mitochondrial disorders and migraine, the results are still preliminary. Overall, there is a need of well-designed clinical trials to enhance the clinical evidences of ALA effects for the treatment of neurological and psychiatric conditions.

Naltrexone in the Treatment of Broadly Defined Behavioral Addictions: A Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Broadly defined behavioral addiction is a conceptual framework including behaviors characterized by loss of control and continuation despite significant negative consequences. Broadly defined behavioral addictions share many similarities with substance use disorders. As naltrexone is one of the most studied treatment for substance use disorders, we conducted a meta-analysis of randomized placebo-controlled trials (RCT) assessing the effectiveness of naltrexone in the treatment of broadly defined behavioral addictions. METHOD: We conducted a literature search and selection, up to January 1, 2017, according to previously set inclusion criteria. The selected trials underwent a quality assessment before data extraction and statistical analysis, which used fixed and random effects models. Standardized mean differences (SMD) were calculated using Hedge's adjusted g. RESULTS: A total of 6 RCTs (n = 356) were included. Of these, 3 assessed naltrexone effectiveness in the treatment of pathological gambling, and 3 tested its benefits in broadly defined behavioral addictions other than pathological gambling (kleptomania, trichotillomania, and impulsive compulsive disorders). The meta-analysis of the whole sample resulted in a statistically significant score improvement under naltrexone versus placebo (fixed effect model: SMD = -0.27, 95% CI [-0.51 to -0.03], z = 2.23; p = 0.025). CONCLUSION: The results of our meta-analysis suggest a beneficial effect of naltrexone in the treatment of broadly defined behavioral addictions.

Longitudinal MicroRNA Signature of Conversion to Psychosis.

BACKGROUND AND HYPOTHESIS: The emergence of psychosis in ultra-high-risk subjects (UHR) is influenced by gene-environment interactions that rely on epigenetic mechanisms such as microRNAs. However, whether they can be relevant pathophysiological biomarkers of psychosis' onset remains unknown. STUDY DESIGN: We present a longitudinal study of microRNA expression, measured in plasma by high-throughput sequencing at baseline and follow-up, in a prospective cohort of 81 UHR, 35 of whom developed psychosis at follow-up (converters). We combined supervised machine learning and differential graph analysis to assess the relative weighted contribution of each microRNA variation to the difference in outcome and identify outcome-specific networks. We then applied univariate models to the resulting microRNA variations common to both strategies, to interpret them as a function of demographic and clinical covariates. STUDY RESULTS: We identified 207 microRNA variations that significantly contributed to the classification. The differential network analysis found 276 network-specific correlations of microRNA variations. The combination of both strategies identified 25 microRNAs, whose gene targets were overrepresented in cognition and schizophrenia genome-wide association studies findings. Interpretable univariate models further supported the relevance of miR-150-5p and miR-3191-5p variations in psychosis onset, independent of age, sex, cannabis use, and medication. CONCLUSIONS: In this first longitudinal study of microRNA variation during conversion to psychosis, we combined 2 methodologically independent data-driven strategies to identify a dynamic epigenetic signature of the emergence of psychosis that is pathophysiologically relevant.

Membrane Lipids in Ultra-High-Risk Patients: Potential Predictive Biomarkers of Conversion to Psychosis.

Alterations in membrane lipids are reported in schizophrenia. However, no conclusion can be drawn regarding the extended and predictive value of these alterations in persons at ultra-high risk of psychosis (UHR). Recent studies suggested that sterols' impact on psychiatric disorders was underestimated. Here, we simultaneously explored sterols, fatty acids (FA), and phospholipids (PL) in UHR persons for the first time. We analysed erythrocyte membrane lipids in 61 UHR persons, including 29 who later converted to psychosis (UHR-C) and 32 who did not (UHC-NC). We used gas chromatography for FA and liquid chromatography tandem with mass spectrometry for sterols and phospholipids. Among UHR individuals, elevated baseline membrane linoleic acid level was associated with conversion to psychosis (26.1% vs. 60.5%, p = 0.02). Combining sterols, FA, and PL membrane composition improved the prediction of psychosis onset (AUC = 0.73). This is the first report showing that membrane sterol participates, with other membrane lipids, in modulating the risk of psychosis. It suggests that membrane lipids could be used as biomarkers for personalised medicine in UHR patients.

Is baclofen a revolutionary medication in alcohol addiction management? Review and recent updates.

Baclofen, a γ-aminobutyric acid (GABA)-B receptor agonist, represents a promising drug in alcohol addiction management. Animal models have shown its action at various stages of the process of alcohol addiction. Moreover, initial open and randomized controlled trials have shown the efficacy of 30 mg/day baclofen on alcohol craving, intake, and relapse prevention. It may also decrease alcohol withdrawal symptoms. However, these initial studies were conducted by the same Italian team; 2 American studies, using a different methodology, did not confirm these effects. Following recent reports by an alcohol-dependent French physician who treated himself with high doses (120-270 mg/day), claiming prolonged suppression of alcohol craving and absence of dependence symptoms, baclofen has since received wide media exposure in France where it has been called "the treatment for alcoholism." An open-label French study supports these findings. In addition, baclofen seems to be particularly interesting because of its safety and tolerance, even in patients with cirrhosis. Thus, baclofen should benefit from further studies of its biobehavioral mechanisms, dose-response effect, and indications in various alcoholic patient profiles.

Methylation pattern and mRNA expression of synapse-relevant genes in the MAM model of schizophrenia in the time-course of adolescence.

Schizophrenia is highly heritable and aggregating in families, but genetics alone does not exclusively explain the pathogenesis. Many risk factors, including childhood trauma, viral infections, migration, and the use of cannabis, are associated with schizophrenia. Adolescence seems to be the critical period where symptoms of the disease manifest. This work focuses on studying an epigenetic regulatory mechanism (the role of DNA methylation) and its interaction with mRNA expression during development, with a particular emphasis on adolescence. The presumptions regarding the role of aberrant neurodevelopment in schizophrenia were tested in the Methyl-Azoxy-Methanol (MAM) animal model. MAM treatment induces neurodevelopmental disruptions and behavioral deficits in off-springs of the treated animals reminiscent of those observed in schizophrenia and is thus considered a promising model for studying this pathology. On a gestational day-17, adult pregnant rats were treated with the antimitotic agent MAM. Experimental animals were divided into groups and subgroups according to substance treatment (MAM and vehicle agent [Sham]) and age of analysis (pre-adolescent and post-adolescent). Methylation and mRNA expression analysis of four candidate genes, which are often implicated in schizophrenia, with special emphasis on the Dopamine hypothesis i.e., Dopamine receptor D2 (Drd2), and the "co-factors" Disrupted in schizophrenia 1 (DISC1), Synaptophysin (Syp), and Dystrobrevin-binding protein 1 (Dtnbp1), was performed in the Gyrus cingulum (CING) and prefrontal cortex (PFC). Data were analyzed to observe the effect of substance treatment between groups and the impact of adolescence within-group. We found reduced pre-adolescent expression levels of Drd2 in both brain areas under the application of MAM. The "co-factor genes" did not show high deviations in mRNA expression levels but high alterations of methylation rates under the application of MAM (up to ~20%), which diminished in the further time course, reaching a comparable level like in Sham control animals after adolescence. The pre-adolescent reduction in DRD2 expression might be interpreted as downregulation of the receptor due to hyperdopaminergic signaling from the ventral tegmental area (VTA), eventually even to both investigated brain regions. The notable alterations of methylation rates in the three analyzed co-factor genes might be interpreted as attempt to compensate for the altered dopaminergic neurotransmission.

A polymorphism in the glutamate metabotropic receptor 7 is associated with cognitive deficits in the early phases of psychosis.

Schizophrenia is an illness characterized by positive symptoms, negative symptoms, and cognitive impairments. Cognitive impairments occur before the onset of psychosis and could reflect glutamatergic dysregulation. Thus, identifying associations between genetic variations in genes coding for glutamatergic receptors and cognitive impairment in schizophrenia may help in understanding the basis of these deficits and in identifying potential drug targets. In a discovery cohort of 144 first-episode of psychosis patients (FEP), we genotyped 58 candidate Single Nucleotide Polymorphisms (SNPs) located in NMDA and metabotropic glutamatergic receptors. These SNPs were selected according to the results from the Psychiatric Genomic Consortium and were tested for association with intellectual quotient (IQ) as assessed with the Wechsler Intelligence Scales. For replication, we used the ICAAR cohort including 121 ultra-high-risk patients (UHR) with the same cognitive assessment. A polymorphism located in GRM7, rs1396409, was significantly associated with performance IQ in the discovery cohort of FEP. This association was replicated in the UHR cohort. This polymorphism is also associated with total IQ and verbal IQ in the merged dataset, with a predominant effect on the arithmetic subtest. The rs1396409 polymorphism is significantly associated with cognitive impairment during the onset of psychosis. This genetic association highlights the possible impact of glutamatergic genes in cognitive deficits in the early phases of psychosis and enforces the interest for new therapeutic interventions targeting the glutamatergic pathway.

Neuropsychological endophenotypes in attention-deficit/hyperactivity disorder: a review of genetic association studies.

As a relatively large body of research has been published up to now, it may be informative to explore whether the use of endophenotypes has produced consistent findings in attention-deficit hyperactivity disorder (ADHD). We reviewed the results of genetic studies investigating associations between putative susceptibility genes for ADHD and neuropsychological traits relevant for this disorder. A PubMed database search identified 47 studies. Most of them (n = 36) examined a single candidate gene, while seven studies examined two or three genes and only four studies examined 10 genes or more. The most investigated genes were DRD4, DAT1, COMT, MAOA, and DBH. Regarding DRD4, association of high reaction time variability with the 7-R allele absence appears to be the most consistent result. Speed of processing, set shifting, and cognitive impulsiveness were less frequently investigated, but seem to be altered in the 7-R allele carriers. Regarding DAT1, majority of studies reported negative results indicating that this gene may have a modulating effect rather than direct influence on cognitive functioning. The other genes were investigated in fewer studies, and the reported findings need to be replicated. The principal methodological issues that could represent confounding factors and may explain conflicting results are discussed.

Self-perceived cognitive functioning does not correlate with objective measures of cognition in schizophrenia.

BACKGROUND: Growing interest in the study of self-perceived cognitive deficits in schizophrenia has been recently observed. The authors validated in a previous study the Subjective Scale To Investigate Cognition into Schizophrenia Tunisian Arabic Version (SSTICS_tun_arab), a self-questionnaire established to collect cognitive complaints in patients with schizophrenia. OBJECTIVE: The aim of the present study was to explore the relationship between the SSTICS_tun_arab scores and objective cognitive performances. METHODS: One hundred four patients with schizophrenia spectrum disorders were administered measures of the Positive and Negative Syndrome Scale, the Global Assessment Functioning Scale, and the Calgary Depression Scale as well as measures of the SSTICS_tun_arab and a cognitive battery. RESULTS: No correlations were found between objective neuropsychologic performances and scores of the SSTICS_tun_arab. CONCLUSIONS: Our findings support the hypothesis of independence of self-perceived cognitive functioning from objective neuropsychologic deficits in schizophrenia. They also suggest that insight of mental illness seems to be not a unitary concept but more likely to be divided in different aspects including cognitive insight.

CNR1 gene polymorphisms in addictive disorders: a systematic review and a meta-analysis.

The aim of the present work was to systematically review all association studies of cannabis receptor 1 (CNR1) polymorphisms with dependence syndrome and to perform a meta-analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the 'high risk' versus 'low risk' alleles in cases with dependence versus controls. Studies were analyzed by random-effects meta-analysis using pooled OR. Eleven full text articles met our eligibility criteria and nine meta-analyses were performed on three polymorphisms of CNR1: rs1049353, rs806379 and the AAT repeat. Of these, only the AAT polymorphism showed a significant association with illicit substance dependence but only in the Caucasian population samples and using a risk allele definition of ≥ 16 repeats. Our analysis showed a small effect size (OR = 1.55, P = 0.045), with strong heterogeneity (Q = 19.87, P < 0.01 with I² = 85%). In line with the polygenic model, our meta-analysis supports a minor implication for CNR1 AAT polymorphism in illicit substance dependence vulnerability. Further studies in well-phenotyped samples and using more polymorphisms are needed to conclude on the actual influence of cannabinoid receptor polymorphisms.

Association of inflammation genes with alcohol dependence/abuse: a systematic review and a meta-analysis.

The aim of the present work was to systematically review all association studies of inflammation genes with alcohol dependence/alcohol abuse (AD/AA) and to perform a meta-analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the 'high-risk' versus 'low-risk' alleles in AD/AA cases versus controls. Data reported in at least three published studies were available for four genetic polymorphisms [TNF-α-238 (rs361525, G/A); TNF-α-308 (rs1800629, G/A); IL-1RA (VNTR [86 bp]n); IL-10-592 (rs1800896, C/A)]. In total, nine meta-analyses were performed. Of these, only the TNF-α-238 polymorphism showed a significant association with AD/AA (OR=1.36, 95% CI: 1.05-1.76). This risk remained significant and increased slightly when we considered only patients with advanced alcohol-related liver disease (AALD) (OR=1.5, 95% CI: 1.13-1.98) but not when we considered only patients without AALD (OR=1.08, 95% CI: 0.5-2.35). Sensitivity analysis showed that this genetic association is derived from the AALD phenotype rather than from AD. Our approach is limited by our phenotype definition; some studies included chronic heavy drinkers (minimal daily consumption of 80 g for a minimal duration of 10 years) but without a standardized psychiatric assessment.

Influence of polygenic risk scores for schizophrenia and resilience on the cognition of individuals at-risk for psychosis.

Cognitive impairment is a core feature of schizophrenia which precedes the onset of full psychotic symptoms, even in the ultra-high-risk stage (UHR). Polygenic risk scores (PRS) can be computed for many psychiatric disorders and phenotyping traits, including scores for resilience. We explored the correlations between several PRS and neurocognition in UHR individuals. We included 107 UHR individuals; 29.9% of them converted to psychosis (UHR-C) while 57.0% did not (UHR-NC) during the 1-year follow-up. Cognitive performances were assessed with the Wechsler Adult Intelligence Scale estimating the Intelligence Quotient (IQ), the Trail Making Test, the verbal fluency, the Stroop test, and the Wisconsin card sorting test. Linear regression models were used to test their association with the PRS for schizophrenia, bipolar disorder, major depression, ADHD, cross-disorders, cognitive performance, intelligence, education attainment, and resilience to schizophrenia. UHR-C had a lower IQ than UHR-NC. The PRS for schizophrenia negatively correlated with IQ, while the PRS for cognitive performance and for resilience positively correlated with IQ. PRS for schizophrenia showed a significant correlation with working memory and processing speed indices. PRS for schizophrenia showed a higher effect on IQ in UHR-NC, and UHR-NC with high PRS for schizophrenia had a similar IQ as UHR-C. Conversely, UHR-C with a high PRS for resilience performed as well as UHR-NC. Our findings suggest that cognitive deficits may predate the onset of psychosis. The genetic architecture of schizophrenia seems to impacts the cognition in UHR-NC. Cognition is also mediated by PRS for resilience.

Confirmation for a delayed inhibition of return by systematic sampling in schizophrenia.

Inhibition of return (IOR) is a phenomenon thought to reflect a mechanism to protect the organism from redirecting attention to previously scanned insignificant locations. A number of studies reported altered IOR in schizophrenia patients with a reduction of its amplitude. However, incomplete sampling of stimulus onset asynchronies (SOAs) makes data on IOR time course incomplete. We examined 14 stabilized young patients with recent onset schizophrenia and 16 healthy controls matched for gender, age, and years of education. Schizophrenia patients (13 males, 1 female) had a mean age of 26.3+/-5.8 years and a mean number of years of study of 9.6+/-3.6. Their illness had a mean duration of 147 weeks. Patients displayed moderate overall slow reaction times (387 ms) in comparison with controls (322 ms). Onset of IOR was found to be delayed in schizophrenia patients appearing between 700 and 800 ms following the cue onset while it appeared at 300 ms in controls. In patients, IOR was constant up to 1100 ms; however, its amplitude was weak with an average of 6 ms. Validity effects (overall and at each SOA value) were uncorrelated to age, years of study, duration of illness, or total or subscale scores on the Positive and Negative Syndrome Scale.

[How to manage adult attention deficit hyperactivity disorder in patients with substance use disorders?] / Comment prendre en charge le trouble déficit de l'attention/ hyperactivité de l'adulte en addictologie ?

How to manage adult attention deficit hyperactivity disorder in patients with substance use disorders? Adult attention deficit hyperactivity disorder (ADHD) frequently occurs with anxiety disorders, mood disorders and above all addictive comorbidities. Its evaluation must be systematic during an addictology consultation. ADHD is a neurodevelopmental disorder characterized by a complex clinical picture combining cognitive, affective and behavioral dimensions that frequently underlies addictive disorder. Substance misuse frequently begins as an over-the-counter medication. The multidimensional diagnostic approach makes it possible to detect these complex interactions. The motivational therapeutic approach involving the comorbidity issue is crucial to support the patient in his change towards a control of his addictions.

Comment prendre en charge le trouble déficit de l'attention/ hyperactivité de l'adulte en addictologie ? Le trouble déficit de l'attention/hyperactivité de l'adulte se présente fréquemment a vec des comorbidités anxieuses, thymiques et surtout addictives. Qu'il soit connu dès l'enfance ou non, traité ou non, son exploration doit être systématique en consultation d'addictologie. Pathologie développementale à l'expression clinique complexe mêlant les dimensions cognitive, affective et comportementale, ce trouble constitue un facteur de risque significatif pour les troubles addictifs. La prise de substances correspond fréquemment à des stratégies d'automédication. L'approche diagnostique multidimensionnelle permet de détecter ces interactions parfois complexes. L'approche thérapeutique motivationnelle et la prise en compte de cette comorbidité permettent d'accompagner le patient dans son changement vers un contrôle de ses addictions.

Reliability and correlation of mixture cell correction in methylomic and transcriptomic blood data.

OBJECTIVES: The number of DNA methylome and RNA transcriptome studies is growing, but investigators have to consider the cell type composition of tissues used. In blood samples, the data reflect the picture of a mixture of different cells. Specialized algorithms can address the cell-type heterogeneity issue. We tested if these corrections are correlated between two heterogeneous datasets. RESULTS: We used methylome and transcriptome datasets derived from a cohort of ten individuals whose blood was sampled at two different timepoints. We examined how the cell composition derived from these omics correlated with each other using "CIBERSORT" for the transcriptome and "estimateCellCounts function" in R for the methylome. The correlation coefficients between the two omic datasets ranged from 0.45 to 0.81 but correlations were minimal between two different timepoints. Our results suggest that a posteriori correction of a mixture of cells present in blood samples is reliable. Using an omic dataset to correct a second dataset for relative fractions of cells appears to be applicable, but only when the samples are simultaneously collected. This could be beneficial when there are difficulties to control the cell types in the second dataset, even when the sample size is limited.

Stress, Cortisol and NR3C1 in At-Risk Individuals for Psychosis: A Mendelian Randomization Study.

INTRODUCTION: The emergence of psychosis in at-risk individuals results from interactions between genetic vulnerability and environmental factors, possibly involving dysregulation of the hypothalamic-pituitary-adrenal axis. Hypercorticism was indeed described in schizophrenia and ultra-high-risk states, but its association with clinical outcome has yet to be demonstrated. The impact of stress through cortisol may vary depending on the expression level of genes related to the stress pathway. METHODS: To test this hypothesis, we selected NR3C1, the gene encoding the glucocorticoid receptor, and modeled through logistic regression how its peripheral expression could explain some of the risk of psychosis, independently of peripheral cortisol levels, in a French longitudinal prospective cohort of 133 at-risk individuals, adjusted for sex, age, cannabis, and antipsychotic medication intake. We then performed a genome-wide association analysis, stratified by sex (55 females and 78 males), to identify NR3C1 expression quantitative trait loci to be used as instrumental variables in a Mendelian randomization framework. RESULTS: NR3C1 expression was significantly associated with a higher risk of conversion to psychosis (OR = 2.03, p = 0.03), independently of any other factor. Cortisol was not associated with outcome nor correlated with NR3C1. In the female subgroup, rs6849528 was associated both with NR3C1 mRNA levels (p = 0.015, Effect-Size = 2.7) and conversion (OR = 8.24, p = 0.03). CONCLUSIONS: For the same level of cortisol, NR3C1 expression increases psychotic risk, independently of sex, age, cannabis, and antipsychotic intake. In females, Mendelian randomization confirmed NR3C1's effect on outcome to be unbiased by any environmental confounder.