Predicting treatment resistance in schizophrenia patients: Machine learning highlights the role of early pathophysiologic features.

Detecting patients with a high-risk profile for treatment-resistant schizophrenia (TRS) can be beneficial for implementing individually adapted therapeutic strategies and better understanding the TRS etiology. The aim of this study was to explore, with machine learning methods, the impact of demographic and clinical patient characteristics on TRS prediction, for already established risk factors and unexplored ones. This was a retrospective study of 500 patients admitted during 2020 to the University Hospital Group for Paris Psychiatry. We hypothesized potential TRS risk factors. The selected features were coded into structured variables in a new dataset, by processing patients discharge summaries and medical narratives with natural-language processing methods. We compared three machine learning models (XGBoost, logistic elastic net regression, logistic regression without regularization) for predicting TRS outcome. We analysed feature impact on the models, suggesting the following factors as markers of a high-risk TRS profile: early age at first contact with psychiatry, antipsychotic treatment interruptions due to non-adherence, absence of positive symptoms at baseline, educational problems and adolescence mental disorders in the personal psychiatric history. Specifically, we found a significant association with TRS outcome for age at first contact with psychiatry and medication non-adherence. Our findings on TRS risk factors are consistent with the review of the literature and suggest potential in using early pathophysiologic features for TRS prediction. Results were encouraging with the use of natural-langage processing techniques to leverage raw data provided by discharge summaries, combined with machine leaning models. These findings are a promising step for helping clinicians adapt their guidelines to early detection of TRS.

Leriglitazone halts disease progression in adult patients with early cerebral adrenoleukodystrophy.

Cerebral adrenoleukodystrophy (CALD) is an X-linked rapidly progressive demyelinating disease leading to death usually within a few years. The standard of care is hematopoietic stem cell transplantation (HSCT), but many men are not eligible due to age, absence of a matched donor, or lesions of the corticospinal tracts (CST). Based on the ADVANCE study showing that leriglitazone decreases the occurrence of CALD, we treated 13 adult CALD patients (19-67 years of age) either not eligible to HSCT (n= 8) or awaiting HSCT (n= 5). Patients were monitored every 3 months with standardized neurological scores, plasma biomarkers and brain MRI comprising lesion volumetrics and diffusion tensor imaging. The disease stabilized clinically and radiologically in 10 patients with up to 2 years of follow-up. Five patients presented with gadolinium enhancing CST lesions that all turned gadolinium negative and, remarkably, regressed in four patients. Plasma neurofilament light chain levels stabilized in all 10 patients and correlated with lesion load. The two patients who continued to deteriorate were over 60 years of age with prominent cognitive impairment. One patient rapidly died from Covid19. These results suggest that leriglitazone can arrest disease progression in adults with early-stage CALD and may be an alternative treatment to HSCT.

Investigating the increased risk of schizophrenia and bipolar disorders in relatives of ADHD probands using colocalization analysis of common genetic variants.

BACKGROUND: Relatives of ADHD probands are known to be at increased risk of schizophrenia and bipolar disorder, suggesting shared genetic factors. In this study, we aim to identify shared common risk variants (i.e., Single-Nucleotide Polymorphisms, SNPs) between ADHD and schizophrenia, and between ADHD and bipolar disorder. METHODS: With the summary data from three GWAS, one on ADHD (20,183 cases with ADHD and 35,191 controls), another on schizophrenia (76,755 cases with schizophrenia and 243,649 controls) and another on bipolar disorder (41,917 cases with bipolar disorder and 371,549 controls), we used colocalization analysis to identify SNPs shared by ADHD and schizophrenia, and SNPs shared by ADHD and bipolar disorder. Functional genomic analyses were then conducted on these two sets of shared common genetic variants. RESULTS: We found that three of the 12 SNPs associated with ADHD colocalized with schizophrenia SNPs and one of the 12 SNPs associated with ADHD colocalized with bipolar disorder. Only 0.4% of the SNPs associated with schizophrenia (2 out of 431) and 2.3% of the SNPs associated with bipolar disorder (2 out of 86), colocalized with ADHD SNPs. Some genes mapped to these shared genetic variants (SCN2A and UNC5D) are involved in the development of the nervous system. CONCLUSIONS: Using colocalization analysis, the present study uncovers shared genetic variants associated with ADHD and schizophrenia as well as ADHD and bipolar disorder, and may at least partially explain the increased risk of schizophrenia and bipolar disorder in relatives of ADHD probands.

Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a multifactorial psychiatric illness affecting ∼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive. METHODS: In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies. FINDINGS: We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na+ conductance. Whole transcriptome sequencing in BD neurons revealed altered gene expression pathways related to glutamate transmission, alterations in cell signalling and ion transport/channel activity. We found altered Akt signalling as a potential therapeutic effect of Li in LR neurons from patients with BD, and that Akt activation mimics Li effect in LR neurons. Furthermore, the increased neural network activity observed in both LR & LNR neurons from patients with BD were reversed by AMP-activated protein kinase (AMPK) activation. INTERPRETATION: These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD. FUNDING: Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.

Maternal smoking during pregnancy and cortical structure in children with attention-deficit/hyperactivity disorder.

Maternal smoking during pregnancy (MSDP) is considered a risk factor for ADHD. While the mechanisms underlying this association are not well understood, MSDP may impact the developing brain in ways that lead to ADHD. Here, we investigated the effect of prenatal smoking exposure on cortical brain structures in children with ADHD using two methods of assessing prenatal exposure: maternal recall and epigenetic typing. Exposure groups were defined according to: (1) maternal recall (+MSDP: n = 24; -MSDP: n = 85) and (2) epigenetic markers (EM) (+EM: n = 14 -EM: n = 21). CIVET-1.1.12 and RMINC were used to acquire cortical brain measurements and perform statistical analyses, respectively. The vertex with highest significance was tested for association with Continuous Performance Test (CPT) dimensions. While no differences of brain structures were identified between +MSDP and -MSDP, +EM children (n = 10) had significantly smaller surface area in the right orbitofrontal cortex (ROFc), middle temporal cortex (RTc) and parahippocampal gyrus (RPHg) (15% FDR) compared to -EM children (n = 20). Cortical surface area in the RPHg significantly correlated with CPT commission errors T-scores. This study suggests that molecular markers may better define exposure to environmental risks, as compared to human recall.

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.

Neurophysiological explorations across the spectrum of psychosis, autism, and depression, during wakefulness and sleep: protocol of a prospective case-control transdiagnostic multimodal study (DEMETER).

BACKGROUND: Quantitative electroencephalography (EEG) analysis offers the opportunity to study high-level cognitive processes across psychiatric disorders. In particular, EEG microstates translate the temporal dynamics of neuronal networks throughout the brain. Their alteration may reflect transdiagnostic anomalies in neurophysiological functions that are impaired in mood, psychosis, and autism spectrum disorders, such as sensorimotor integration, speech, sleep, and sense of self. The main questions this study aims to answer are as follows: 1) Are EEG microstate anomalies associated with clinical and functional prognosis, both in resting conditions and during sleep, across psychiatric disorders? 2) Are EEG microstate anomalies associated with differences in sensorimotor integration, speech, sense of self, and sleep? 3) Can the dynamic of EEG microstates be modulated by a non-drug intervention such as light hypnosis? METHODS: This prospective cohort will include a population of adolescents and young adults, aged 15 to 30 years old, with ultra-high-risk of psychosis (UHR), first-episode psychosis (FEP), schizophrenia (SCZ), autism spectrum disorder (ASD), and major depressive disorder (MDD), as well as healthy controls (CTRL) (N = 21 × 6), who will be assessed at baseline and after one year of follow-up. Participants will undergo deep phenotyping based on psychopathology, neuropsychological assessments, 64-channel EEG recordings, and biological sampling at the two timepoints. At baseline, the EEG recording will also be coupled to a sensorimotor task and a recording of the characteristics of their speech (prosody and turn-taking), a one-night polysomnography, a self-reference effect task in virtual reality (only in UHR, FEP, and CTRL). An interventional ancillary study will involve only healthy controls, in order to assess whether light hypnosis can modify the EEG microstate architecture in a direction opposite to what is seen in disease. DISCUSSION: This transdiagnostic longitudinal case-control study will provide a multimodal neurophysiological assessment of clinical dimensions (sensorimotor integration, speech, sleep, and sense of self) that are disrupted across mood, psychosis, and autism spectrum disorders. It will further test the relevance of EEG microstates as dimensional functional biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT06045897.

Asynchronous neural maturation predicts transition to psychosis.

AIM: Neuroimaging-based machine-learning predictions of psychosis onset rely on the hypothesis that structural brain anomalies may reflect the underlying pathophysiology. Yet, current predictors remain difficult to interpret in light of brain structure. Here, we combined an advanced interpretable supervised algorithm and a model of neuroanatomical age to identify the level of brain maturation of the regions most predictive of psychosis. METHODS: We used the voxel-based morphometry of a healthy control dataset (N = 2024) and a prospective longitudinal UHR cohort (N = 82), of which 27 developed psychosis after one year. In UHR, psychosis was predicted at one year using Elastic-Net-Total-Variation (Enet-TV) penalties within a five-fold cross-validation, providing an interpretable map of distinct predictive regions. Using both the whole brain and each predictive region separately, a brain age predictor was then built and validated in 1605 controls, externally tested in 419 controls from an independent cohort, and applied in UHR. Brain age gaps were computed as the difference between chronological and predicted age, providing a proxy of whole-brain and regional brain maturation. RESULTS: Psychosis prediction was performant with 80 ± 4% of area-under-curve and 69 ± 5% of balanced accuracy (P < 0.001), and mainly leveraged volumetric increases in the ventromedial prefrontal cortex and decreases in the left precentral gyrus and the right orbitofrontal cortex. These regions were predicted to have delayed and accelerated maturational patterns, respectively. CONCLUSION: By combining an interpretable supervised model of conversion to psychosis with a brain age predictor, we showed that inter-regional asynchronous brain maturation underlines the predictive signature of psychosis.

Orbitofrontal sulcal patterns in catatonia.

BACKGROUND: Catatonia is a psychomotor syndrome frequently observed in disorders with neurodevelopmental impairments, including psychiatric disorders such as schizophrenia. The orbitofrontal cortex (OFC) has been repeatedly associated with catatonia. It presents with an important interindividual morphological variability, with three distinct H-shaped sulcal patterns, types I, II, and III, based on the continuity of the medial and lateral orbital sulci. Types II and III have been identified as neurodevelopmental risk factors for schizophrenia. The sulcal pattern of the OFC has never been investigated in catatonia despite the role of the OFC in the pathophysiology and the neurodevelopmental component of catatonia. METHODS: In this context, we performed a retrospective analysis of the OFC sulcal pattern in carefully selected homogeneous and matched subgroups of schizophrenia patients with catatonia (N = 58) or without catatonia (N = 65), and healthy controls (N = 82). RESULTS: Logistic regression analyses revealed a group effect on OFC sulcal pattern in the left (χ2 = 18.1; p < .001) and right (χ2 = 28.3; p < .001) hemispheres. Catatonia patients were found to have more type III and less type I in both hemispheres compared to healthy controls and more type III on the left hemisphere compared to schizophrenia patients without catatonia. CONCLUSION: Because the sulcal patterns are indirect markers of early brain development, our findings support a neurodevelopmental origin of catatonia and may shed light on the pathophysiology of this syndrome.

Correlation of the methylomic signature of smoking during pregnancy with clinical traits in ADHD.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent childhood disorder. Maternal smoking during pregnancy is a replicated environmental risk factor for this disorder. It is also a robust modifier of gene methylation during the prenatal developmental period. In this study, we sought to identify loci differentially methylated by maternal smoking during pregnancy and relate their methylation levels to various behavioural and physical outcomes relevant to ADHD. METHODS: We extracted DNA from blood samples from children diagnosed with ADHD and deeply phenotyped. Genome-wide DNA methylation was assessed using Infinium MethylationEPIC BeadChip. Maternal smoking during pregnancy was self-declared and assessed retrospectively. RESULTS: Our sample included 231 children with ADHD. Statistically significant differences in DNA methylation between children exposed or not to maternal smoking during pregnancy were detected in 3457 CpGs. We kept 30 CpGs with at least 5% of methylation difference between the 2 groups for further analysis. Six genes were associated with varied phenotypes of clinical relevance to ADHD. The levels of DNA methylation in RUNX1 were positively correlated with the CBCL scores, and DNA methylation in MYO1G correlated positively with the score at the Conners rating scale. Methylation level in a CpG located in GFI1 correlated with birthweight, a risk factor for ADHD. Differentially methylated regions were also identified and confirmed the association of RUNX1 methylation levels with the CBCL score. LIMITATIONS: The study has several limitations, including the retrospective recall with self-report of maternal smoking during pregnancy as well as the grouping of individuals of varying age and developmental stage and of both males and females. In addition, the correlation design prevents the building of causation models. CONCLUSION: This study provides evidence for the association between the level of methylation at specific loci and quantitative dimensions highly relevant for ADHD as well as birth weight, a measure that has already been associated with increased risk for ADHD. Our results provide further support to public health educational initiatives to stop maternal smoking during pregnancy.

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.

Lack of guidelines and translational knowledge is hindering the implementation of psychiatric genetic counseling and testing within Europe - A multi-professional survey study.

Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field. We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders. Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant. We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe.

Prevalence and factors associated with depression and suicidal ideation among French students in 2016: A national study.

Depression is one of the leading causes of morbidity worldwide and increases the risk of suicide. Students are known as a population at risk for depression. This study aimed to evaluate the prevalence of 12 months major depressive episode (MDE) and suicidal thoughts in French students and investigate associated factors. A questionnaire was sent by email to a representative sample of the French student population between April 28th and June 27th 2016. MDE was assessed using the Composite International Diagnostic Interview Short Form (CIDI-SF). The response rate was 18.7% (N= 18,875). Prevalence of 12 months MDE was 15.8%, and suicidal thoughts was 9%. Factors associated with MDE were being a woman, study field (law/eco, human/social sciences, and medical), having failed midterms exams or dropout, refusal or stop social scholarship, and subjective financial difficulties. Factors associated with suicidal thoughts were study field (human/social sciences), having failed midterms exams or dropout, and important subjective financial difficulties. The use of CIDI-SF allows comparison with the 2017 French national study, and showed more MDE in students than in the general population. This is the only national study on French students before COVID 19 pandemic.

Electroencephalography microstates imbalance across the spectrum of early psychosis, autism, and mood disorders.

BACKGROUND: Electroencephalography (EEG) microstates translate resting-state temporal dynamics of neuronal networks throughout the brain and could constitute possible markers of psychiatric disorders. We tested the hypothesis of an increased imbalance between a predominant self-referential mode (microstate C) and a decreased attentional mode (microstate D) in psychosis, mood, and autism spectrum disorders. METHODS: We retrospectively included 135 subjects from an early psychosis outpatient unit, with available eyes-closed resting-state 19 electrodes EEG. Individual-level then group-level modified K-means clustering in controls provided four microstate maps that were then backfitted to all groups. Differences between microstate parameters (occurrence, coverage, and mean duration) were computed between controls and each group, and between disease groups. RESULTS: Microstate class D parameters were systematically decreased in disease groups compared with controls, with an effect size increasing along the psychosis spectrum, but also in autism. There was no difference in class C. C/D ratios of mean duration were increased only in SCZ compared with controls. CONCLUSIONS: The decrease in microstate class D may be a marker of stage of psychosis, but it is not specific to it and may rather reflect a shared dimension along the schizophrenia-autism spectrum. C/D microstate imbalance may be more specific to schizophrenia.

Corrigendum: Prader-Willi syndrome: Symptoms and topiramate response in light of genetics.

[This corrects the article DOI: 10.3389/fnins.2023.1126970.].

Down syndrome regression disorder, a case series: Clinical characterization and therapeutic approaches.

Down syndrome (DS) is one of the most frequent genetic disorders and represents the first cause of intellectual disability of genetic origin. While the majority of patients with DS follow a harmonious evolution, an unusual neurodevelopmental regression may occur, distinct from that described in the context of autism spectrum disorders, called down syndrome regression disorder (DSRD). Based on four patients, two males and two females, with age range between 20 and 24, treated at the Reference Center for Rare Psychiatric Disorders of the GHU Paris Psychiatry and Neurosciences [Pôle hospitalo-universitaire d'Évaluation Prévention et Innovation Thérapeutique (PEPIT)], we describe this syndrome, discuss its etiologies and propose therapeutic strategies. DSRD often occurs in late adolescence. There is a sudden onset of language disorders, loss of autonomy and daily living skills, as well as behavioral symptoms such as depression, psychosis, or catatonia. These symptoms are non-specific and lead to an overlap with other diagnostic categories, thus complicating diagnosis. The etiologies of the syndrome are not clearly identified but certain predispositions of patients with trisomy 21 have suggested an underlying immune-mediated mechanism. Symptomatic therapeutic approaches (serotonergic antidepressants, atypical antipsychotics, benzodiazepines) were not effective, and generally associated with poor tolerance. Etiological treatments, including anti-inflammatory drugs and corticosteroids, led to partial or good recovery in the four cases. Early recognition of regressive symptoms and rapid implementation of adapted treatments are required to improve the quality of life of patients and their families.

Prader-Willi syndrome: Symptoms and topiramate response in light of genetics.

Introduction: Prader-Willi Syndrome (PWS) is a rare genetic condition, which affects one in 25,000 births and results in various phenotypes. It leads to a wide range of metabolic and endocrine disorders including growth delay, hypogonadism, narcolepsy, lack of satiety and compulsive eating, associated with mild to moderate cognitive impairment. Prognosis is especially determined by the complications of obesity (diabetes, cardiorespiratory diseases) and by severe behavioral disorders marked by impulsivity and compulsion. This heterogeneous clinical picture may lead to mis- or delayed diagnosis of comorbidities. Moreover, when diagnosis is made, treatment remains limited, with high interindividual differences in drug response. This may be due to the underlying genetic variability of the syndrome, which can involve several different genetic mutations, notably deletion or uniparental disomy (UPD) in a region of chromosome 15. Here, we propose to determine whether subjects with PWS differ for clinical phenotype and treatment response depending on the underlying genetic anomaly. Methods: We retrospectively included all 24 PWS patients who were referred to the Reference Center for Rare Psychiatric Disorders (GHU Paris Psychiatrie and Neurosciences) between November 2018 and July 2022, with either deletion (N = 8) or disomy (N = 16). The following socio-demographic and clinical characteristics were recorded: age, sex, psychiatric and non-psychiatric symptoms, the type of genetic defect, medication and treatment response to topiramate, which was evaluated in terms of eating compulsions and impulsive behaviors. We compared topiramate treatment doses and responses between PWS with deletion and those with disomy. Non-parametric tests were used with random permutations for p-value and bootstrap 95% confidence interval computations. Results: First, we found that disomy was associated with a more severe clinical phenotype than deletion. Second, we observed that topiramate was less effective and less tolerated in disomy, compared to deletion. Discussion: These results suggest that a pharmacogenomic-based approach may be relevant for the treatment of compulsions in PWS, thus highlighting the importance of personalized medicine for such complex heterogeneous disorders.

Abnormalities in one-carbon metabolism in young patients with psychosis.

Introduction: Folates, the main actors in one-carbon (C1) metabolism, are involved in synthesising monoamines and maintaining genomic stability. Previous studies support the association between C1 metabolism and schizophrenia. The main purpose of this study was to assess the prevalence of plasma folate, and/or vitamin B12 deficiencies and hyperhomocysteinemia in young patients with psychotic disorders. Methods: We included young inpatients (15-30 years old) with psychosis between 2014 and 2017 from Sainte-Anne Hospital in Paris. Plasma folate, vitamin B12 deficiency and homocysteinemia dosages were done at admission. Clinical data were extracted retrospectively, and patients diagnosed with a first-episode psychosis (FEP), schizophrenia, schizoaffective disorder, or persistent delusional disorder were retained for the analysis. Results: Among the 334 inpatients, 188 (56%) had C1 dosages available (135 males; 53 females). From the 188 patients, 32% had a C1 abnormality. This abnormality reached 38% of FEP patients. The most frequent abnormality was folate deficiency: 21% of all patients and 27% of FEP. Lower levels of folates were found in males compared to females (p = 0.02) and were correlated with more severe disorder, as assessed by Clinical Global Impression - Severity (CGI-S; p = 0.009). Antipsychotic dosage was positively associated with B12 levels (p = 0.013) and negatively with homocysteinemia (p = 0.034). Conclusion: One-carbon metabolism anomalies in young patients with psychotic disorders are highly prevalent, reaching almost half of the patients with FEP. Potential protective effects from females and antipsychotics have emerged. These results spotlight the need for new therapeutic prospects, such as folate supplementation, to achieve personalised medical approaches to the early stages of psychotic disorders.