Cognitive reserve (CR) modulates the impact of neural alterations on clinical outcomes, yet its association with brain structure during youth remains unexplored. We aimed to investigate the relationship between CR and brain structure in young offspring of patients with schizophrenia or bipolar disorder, according to development of psychotic spectrum symptoms over time. 404 data acquisitions were analyzed from offspring of patients with schizophrenia or bipolar disorder, 43 offspring who developed psychotic spectrum symptoms over time (SzBpO-P), 94 offspring who did not (SzBpO-NP), and 80 community controls (CcO), re-assessed over a 12-year period (101 SzBpO-P, 181 SzBpO-NP, 122 CcO). Global and lobar volume, cortical surface area and thickness metrics were obtained from T1-weighted sequences acquired on a 3 Tesla MRI scanner and computed using FreeSurfer version 7.1. CR was calculated using a composite score including an estimated intelligence quotient, sociability, parental socioeconomic status, school performance, and developmental milestones. Multilevel mixed-effect logistic regression (categorical variables) or linear regression (continuous variables) models were conducted. A significant group-by-CR interaction was found for total intracranial volume (F = 7.770; p < 0.001), whereby the CcO and SzBpO-NP groups showed a positive association between CR and total intracranial volume, while this association was negative for SzBpO-P. No significant effects were observed in other brain structural metrics when adjusting for total intracranial volume. CR was differentially associated with total intracranial volume according to development of psychotic spectrum symptoms. These results may help identify youth at highest risk for severe mental health outcomes.

Cortical brain morphology in early-onset psychosis (EOP; age of onset < 19 years) is poorly understood, partly due to recruitment constraints linked to its low incidence. We pooled T1-weighted magnetic resonance imaging (MRI) data from 387 adolescents with EOP (mean age=16.1±1.5; 49.6% female) and 338 healthy controls (CTR; mean age=15.8±1.9, 54.4% female) from nine research sites worldwide. Using harmonized processing protocols with FreeSurfer, we extracted cortical brain metrics from 34 bilateral regions. Univariate regression analysis revealed widespread lower bilateral cortical thickness (left/right hemisphere: d=-0.36/-0.31), surface area (left/right: d=-0.42/-0.41), cortical volume (left/right: d=-0.58/-0.56), and Local Gyrification Index (LGI; left/right: d=-0.39/-0.52) in EOP relative to CTR. Subgroup analyses showed broader and more pronounced case-control differences in early-onset schizophrenia for area, volume, and LGI. We found no associations with antipsychotic medication use, illness duration, age of onset, or positive symptoms. Negative symptoms were related to smaller left lingual volumes (partial r=-0.21; p FDR =0.014) and antidepressant users had smaller area (d=-0.43; p FDR =0.034) and volume (d=-0.50; p FDR =0.003) of the right rostral anterior cingulate compared to non-users. Cortical alterations in EOP showed a similar pattern to those observed in prior studies on adults with schizophrenia (SCZ; r=0.62) and bipolar disorders (BD; r=0.61). However, surface area alterations were overall 1.5 times greater for EOP than adult SCZ and 4.6 times greater than adult BD. In the largest study of its kind, we observed an extensive pattern of cortical alterations in adolescents with psychotic disorders, highlighting the potential impact of aberrant neurodevelopment on cortical morphology in this clinical group.

The role of genetic factors shaping liability for psychosis remains unclear. Youth with first-episode, early-onset psychosis and youth at increased familial risk for psychosis show higher rates of co-occurring psychiatric diagnoses and cognitive difficulties than the general population. This study assessed polygenic scores (PGS) for psychiatric diagnoses, cognition and educational attainment in 414 youth: N = 69 cases with non-affective, early-onset psychosis (schizophrenia, schizophreniform and schizoaffective disorders), N = 62 cases with affective, early-onset psychoses (bipolar or depressive disorders with psychotic symptoms), N = 52 offspring of patients with schizophrenia, N = 94 offspring of patients with bipolar disorder, and N = 117 healthy controls. After quality control, PGS were calculated using the PRS-CS tool. Differences in PGS were examined by fitting binary logistic models. Sensitivity analyses ruled out effects of potential confounders. PGS for schizophrenia and bipolar disorder were higher in youth with non-affective, early-onset psychoses and offspring of patients with schizophrenia, and higher PGS scores for attention deficit hyperactivity disorder (ADHD) were found in youth with non-affective, early-onset psychoses and offspring of patients with bipolar disorder, relative to controls. PGS for cognition and educational attainment were lower in youth with non-affective, early-onset psychoses, compared with youth with affective, early-onset psychoses, offspring of bipolar disorder patients, and controls (all PFDR<0.05). Conclusion: These findings indicate shared and distinct genetic liability profiles influenced by patient and parental diagnoses. In addition to liability for schizophrenia and bipolar disorder, polygenic profiles for ADHD, cognition, and educational attainment may determine the genetic architecture of psychosis.

The Clinical High Risk (CHR) state for psychosis is consistently associated with widespread cortical thinning. However, the underlying mechanisms driving this neuroanatomical phenotype remain poorly understood. Here, we integrated the ENIGMA CHR Working Group's large pooled dataset (N = 1782 CHR, N = 1333 healthy controls) with an open-source PET molecular atlas to identify, for the first time, potential neurochemical drivers of cortical thinning associated with psychosis risk, transition, and its core symptoms. Using multilinear model analysis, we show that local chemoarchitecture significantly explains CT differences associated with CHR case-control status, the severity of negative symptoms, and future psychosis transition after excluding medication confounds. PET-based maps of dopamine, GABA, glutamate, serotonin, and norepinephrine consistently emerged as the strongest predictors of lower CT in CHR and psychosis transition (total dominance range: 62-69% and 58-87%, respectively), with contributions of monoamine systems being especially sensitive to medication exposure (8-23% change in dominance range). Negative symptom-associated cortical thinning was best explained by PET-based maps of dopamine, histamine, serotonin and opioid systems (total dominance range: 60-81%), with contributions of histamine being sensitive to medication exposure (9-19% change in dominance range). Combined, these results uniquely identify specific neurochemical systems - particularly monoaminergic, glutamatergic, and GABAergic pathways - as key molecular mechanisms associated with cortical thinning in people at high risk of developing psychosis.

Brain network architecture is anticipated to influence future grey matter loss in individuals at Clinical High Risk (CHR) for psychosis. However, existing studies on grey matter structural network properties in CHR are scarce and constrained by small sample sizes. Here, we examined network topology differences comparing a) CHR versus healthy controls (HC); b) CHR who transitioned to psychosis (CHR-T) versus those who did not (CHR-NT); and c) different subsyndromes. We included structural scans from 1842 CHR individuals and 1417 HC individuals from 31 sites within the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. At the global level, CHR individuals exhibited lower structural covariance (q < 0.001; Cohen’s d = 0.164) and less optimal structural network configuration than HC (lower global efficiency and clustering coefficient, d = 0.100,0.087, qs <= 0.027). Though no global difference between CHR-T and CHR-NT, network distinctiveness of the frontal and temporal surface area networks was higher in CHR-T than CHR-NT (d = 0.223,0.237) and HC (d = 0.208,0.219) (qs < 0.001). Network distinctiveness of the frontal cortical thickness network was lower in CHR-T (d = 0.218, q < 0.001) than CHR-NT and HC (d = 0.165, q < 0.001). Importantly, higher network distinctiveness was associated with worse positive symptoms in CHR-NT (frontal surface area, q = 0.008, R2 = 0.013) and at trend with worse negative symptoms in CHR-T (frontal thickness, q = 0.063, R2 = 0.049). Further, the brief intermittent psychotic syndrome subgroup showed more severe network alterations. Together, brain structural networks inform symptoms and the risk of transition to psychosis in CHR individuals.

Abnormalities in the concentration of brain metabolites have been found across neuropsychiatric conditions. This cross-sectional study set out to examine the relationship between levels of neurometabolites and age and sex -key modulators of brain function and structure-, continuously from childhood to early adulthood, in areas relevant to the study of psychiatric disorders. Magnetic resonance spectroscopy (¹H MRS) data was acquired in the dorsomedial prefrontal region (dmPF) and the medial temporal lobe (mTL) in 128 healthy individuals aged 7 to 34 years, 68.5 % females (ndmPF = 124; nmTL = 75). Absolute concentrations of glutamate (Glu), glutamate and glutamine (Glx), myo-inositol (mIns), N-acetyl-aspartate and N-acetyl-aspartyl-glutamate (tNAA), glycerophosphocholine and phosphocholine (tCho), and creatine and phosphocreatine (tCr) were determined, and tested for the effects of age, sex and their interaction. In the dmPF, there were linear, age-related decreases in Glu and Glx. The association between levels of both tNAA and tCr and age adjusted to a quadratic model, consisting of a positive association until ages 20.79 and 22.82, respectively, and a negative relationship thereafter. There was a significant effect of sex in the mTL, whereby concentrations of Glu, Glx and mIns were lower in females than in males. No age by sex interactions were detected. These findings highlight the importance of accounting for both linear and non-linear age-related effects and for the potential effect of sex when interpreting disease-related differences in ¹H MRS-quantified metabolites from childhood through to adulthood.

BACKGROUND:In vivo assessment of glutamatergic metabolites in patients with anti-NMDA receptor (anti-NMDAR) encephalitis compared with schizophrenia may help increase understanding of the pathophysiology of both conditions. METHODS:This 24-month prospective case-control study included participants ages 12 to 60 years with anti-NMDAR encephalitis during the post-acute stage and age- and sex-matched individuals with schizophrenia and healthy control participants (HCs). Single-voxel magnetic resonance spectroscopy was used to estimate brain concentrations of glutamatergic metabolites, myo-inositol, and N-acetylaspartate+N-acetylaspartylglutamate (tNAA) in the left dorsomedial prefrontal region (dmPF) and medial temporal lobe. The effect of group and time on metabolite levels and the relationship between metabolite levels and psychiatric and cognitive features were tested with multilevel linear mixed models. RESULTS:Thirty-two participants with anti-NMDAR encephalitis (84% women), 27 participants with schizophrenia (63% women), and 36 HCs (72% women) were included. In the dmPF, levels of glutamate and glutamate+glutamine were significantly lower in patients with anti-NMDAR encephalitis than in participants with schizophrenia (Cohen's d = -0.87 and d = -0.80, respectively) and HCs (d = -0.73 and d = -0.71). Myo-inositol levels were significantly higher in both participants with anti-NMDAR encephalitis (d = 0.91) and patients with schizophrenia (d = 1.07) than in HCs. Group differences remained stable over time. Metabolite levels were not associated with psychiatric or cognitive symptoms. CONCLUSIONS:This is the first report of hypoglutamatergia in the left dmPF in anti-NMDAR encephalitis and of increased levels of myo-inositol in both anti-NMDAR encephalitis and schizophrenia. The findings suggest persistent alterations in glutamatergic neurotransmission during the post-acute stage of anti-NMDAR encephalitis and overlapping neuroinflammatory processes between anti-NMDAR encephalitis and schizophrenia.

Introduction Regional gray matter (GM) alterations have been reported in early-onset psychosis (EOP, onset before age 18), but previous studies have yielded conflicting results, likely due to small sample sizes and the different brain regions examined. In this study, we conducted a whole brain voxel-based morphometry (VBM) analysis in a large sample of individuals with EOP, using the newly developed ENIGMA-VBM tool. Methods 15 independent cohorts from the ENIGMA-EOP working group participated in the study. The overall sample comprised T1-weighted MRI data from 482 individuals with EOP and 469 healthy controls. Each site performed the VBM analysis locally using the standardized ENIGMA-VBM tool. Statistical parametric T-maps were generated from each cohort and meta-analyzed to reveal voxel-wise differences between EOP and healthy controls as well as the individual-based association between GM volume and age of onset, chlorpromazine (CPZ) equivalent dose, and other clinical variables. Results Compared with healthy controls, individuals with EOP showed widespread lower GM volume encompassing most of the cortex, with the most marked effect in the left median cingulate (Hedges’ g = 0.55, p = 0.001 corrected), as well as small clusters of lower white matter (WM), whereas no regional GM or WM volumes were higher in EOP. Lower GM volume in the cerebellum, thalamus and left inferior parietal gyrus was associated with older age of onset. Deficits in GM in the left inferior frontal gyrus, right insula, right precentral gyrus and right superior frontal gyrus were also associated with higher CPZ equivalent doses. Conclusion EOP is associated with widespread reductions in cortical GM volume, while WM is affected to a smaller extent. GM volume alterations are associated with age of onset and CPZ equivalent dose but these effects are small compared to case-control differences. Mapping anatomical abnormalities in EOP may lead to a better understanding of the role of psychosis in brain development during childhood and adolescence.

The COVID-19 pandemic had a great impact on mental health both in the general population and in individuals with preexisting mental disorders. Lockdown, social restrictions, changes in daily habits and limited access to health services led to changes in consultations in mental health services. This study aimed to determine changing trends in psychiatric admissions by the inclusion of adult patients admitted to the Emergency Department (ED) of Hospital Clínic of Barcelona between 2019 and 2021. Acute admissions, social issues and psychiatric diagnoses were compared between years, seasons and considering the interaction between both years and seasons. A total of 13,677 individuals were included in the analysis. An overall reduction in consultations to the ED and a higher proportion of acute admissions was observed in 2020 in context of the COVID-19 outbreak. Increased prevalence of sleeping disorders and substance use disorders was found in 2020. Self-harming behavior, suicidal thoughts and suicidal behavior showed an increasing tendency over time, with their highest rates in 2021. Prevention and management strategies should be considered in order to address increasing needs in mental health care.

Introduction: Health institutions provide general recommendations to cope with global crises such as pandemics or geopolitical tensions. However, these recommendations are mainly based on cross-sectional evidence. The preregistered Repeated Assessment of Behaviors and Symptoms in the Population (RABSYPO) study sought to establish prospective longitudinal evidence from a cohort with a demographic distribution similar to that of the Spanish population to provide evidence for developing solid universal recommendations to reduce anxiety and depressive symptoms during times of uncertainty. Material and Methods: We first recruited via social networks a pool of Spanish individuals willing to participate and then randomly selected some within each stratum of age X gender X region X urbanicity to conduct a one-year-long bi-weekly online follow-up about the frequency of ten simple potential coping behaviors as well as anxiety (GAD-7) and depressive symptoms (PHQ-9). Mixed-effects autoregressive moving average models were used to analyze the relationship between past behaviors' frequency and subsequent symptom changes across the twenty-seven time points. Results: Among the 1049 who started the follow-up, 942 completed it and were included in the analyses. Avoiding excessive exposure to distressing news and maintaining a healthy/balanced diet, followed by spending time outdoors and physical exercise, were the coping behaviors most strongly associated with short and long-term reductions of anxiety and depressive symptoms. Engaging in relaxing activities and drinking water to hydrate were only associated with short-term symptom reductions. Socializing was associated with symptom reductions in the long term. Conclusions: This study provides compelling prospective evidence that adopting a set of simple coping behaviors is associated with small but significant reductions in anxiety and depressive symptoms during times of uncertainty. It also includes a layman's summary of this evidence to help develop general recommendations that serve as universal tools for enhancing mental health and well-being.

Seizures are a concerning adverse event frequently associated with the use of psychedelics, and hence, studies involving these substances tend to exclude patients with past history of epilepsy. This is especially relevant because epileptic seizures are markedly increased in the population suffering from mental disorders, and psychedelic assisted therapy is being researched as a promising treatment for several of them. To determine the extent of the current literature on the relationship between classic psychedelics and seizures, a scoping review was performed using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews). The search was conducted in PubMed, Web of Science, Google scholar, LILACS and Scielo, and both animal and human models were included. A total of 16 publications on humans, and 11 on animals, were found. The results are heterogeneous, but globally suggest that psychedelics may not increase the risk of seizures in healthy individuals or animals in the absence of other drugs. However, concomitant use of other substances or drugs, such as kambo or lithium, could increase the risk of seizures. Additionally, these conclusions are drawn from data lacking sufficient external validity, so they should be interpreted with caution. Future paths for research and a summary on possible neurobiological underpinnings that might clarify the relationship between classical psychedelics and seizures are also provided.

Background Regional gray matter volume (GMV) differences between individuals with mental disorders and comparison subjects may be confounded by co-occurring disorders. To disentangle the disorder-specific GMV correlates, we conducted a large-scale multi-disorder meta-analysis using a novel approach that explicitly models co-occurring disorders. Methods We systematically reviewed voxel-based morphometry studies indexed in PubMed and Scopus up to January 2023 comparing adults with major mental disorders (anorexia nervosa, schizophrenia-spectrum, anxiety, bipolar, major depressive, obsessive-compulsive, and post-traumatic stress disorders, plus attention-deficit/hyperactivity, autism spectrum, and borderline personality disorders) to comparison subjects. Two authors independently extracted data and assessed quality using the Newcastle-Ottawa Scale. We derived GMV correlates for each disorder using: a) a multi-disorder meta-analysis accounting for all co-occurring mental disorders simultaneously; b) separate standard meta-analyses for each disorder ignoring co-occurring disorders. We assessed the alterations’ extent, intensity (effect size), and specificity (inter-disorder correlations and transdiagnostic alterations) for both approaches. Results We included 433 studies (499 datasets) involving 19,718 patients and 16,441 comparison subjects (51% females, aged 20-67 years). We provide GMV correlate maps for each disorder using both approaches. The novel approach, which accounted for co-occurring disorders, produced GMV correlates that were more focal and disorder-specific (less correlated across disorders and fewer transdiagnostic abnormalities). Conclusions This work offers the most comprehensive atlas of GMV correlates across major mental disorders. Modeling co-occurring disorders yielded more specific correlates, supporting this approach’s validity. The atlas NIfTI maps are available online.

Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS + individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1,165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1,029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-includingthose from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS + from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS + in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

Objective: To compare clinical and functional variables among 3 groups of children and adolescents: subjects at clinical high risk for psychosis (CHR-P) who also have obsessive-compulsive symptoms (OCS), CHR-P patients without OCS, and healthy controls (HC).Methods: A total of 128 CHR-P patients and 98 HC between the ages of 10 and 17 years were recruited as part of a multicenter prospective longitudinal study conducted in Spain between January 1, 2011, and December 31, 2018, with diagnoses made for CHR-P using the Scale of Prodromal Symptoms (SOPS). Two groups were obtained based on Leyton Obsessional Inventory-Child Version (LOI-CV) scores: 64 CHR-P patients with OCS (OCS+) and 64 CHR-P patients without OCS (OCS-). Clinical variables were analyzed with a generalized linear model.Results: Overall, 128 CHR-P patients, 64 (50%) with OCS (mean ± SD age = 15.5 ± 1.4 years, 34.4% male), 64 CHR-P patients without OCS (mean ± SD age = 15.1 ± 1.9 years, 34.4% male), and 98 HC (mean ± SD age = 15.5 ± 1.5 years, 42.9% male), of whom 19 (19.5%) had OCS, were included. Generalized linear model analysis revealed significant differences between the groups. The OCS+ group showed more severe prodromal symptoms (P = .007), worse functioning at baseline (P = .044) and during the previous year (P = .004), and more dysmorphophobic symptoms (P < .001) compared to the OCS- group. OCS+ patients were also more frequently treated with antidepressants (P = .004) than were OCS- patients.Conclusions: In our sample, among children and adolescents with CHR-P, the prevalence of OCS was high (50%). OCS+ subjects had a more severe clinical and functional profile than OCS- subjects. Early detection and treatment of these symptoms can lead to better outcomes for these patients.

Background Long-acting injectable antipsychotics (LAIAs) are an efficacious and well-tolerated treatment in adults with schizophrenia spectrum disorders (SSD). However, there is less evidence for their use in children and adolescents. Objectives The aim of this systematic review was to summarize findings regarding the effectiveness and side effects of LAIA in children and adolescents with SSD. Methods Four databases (Web of Science, PubMed, MEDES, and Dialnet) were systematically searched for articles published between inception and 12 March, 2022, with the following inclusion criteria: (1) original articles or case reports; (2) providing data on efficacy/effectiveness or safety/tolerability of LAIA treatment in children and adolescents diagnosed with SSD (schizophrenia, schizoaffective disorder, schizophreniform disorder, non-affective psychotic disorder); (3) mean age of samples ≤ 18 years; and (4) written in English or Spanish. Exclusion criteria were review articles, clinical guides, expert consensus as well as posters or oral communication in conferences. The risk of bias was assessed using the ROBIS tool. Results From 847 articles found, 13 met the inclusion criteria. These included seven single case reports or case series, four retrospective chart reviews, a 24-week open-label trial, and one observational prospective study, covering a total of 119 adolescents (aged 12–17 years) with SSD. Almost all the articles described data on second-generation LAIA (53 patients on risperidone [once every other week], 33 on paliperidone palmitate [once monthly], 10 on aripiprazole [once monthly], and two on olanzapine pamoate [once monthly]). Twenty-one patients were reported to be only on first-generation LAIAs. Non-adherence was the main reason for starting an LAIA. In all of the studies, the use of LAIAs was associated with improvement in the patients’ symptoms. Conclusions There are few studies assessing the use of LAIAs in adolescents with SSD. Overall, these treatments have suggested good effectiveness and acceptable safety and tolerability. However, we found no studies examining their use in children aged < 12 years. The problems and benefits linked to this type of antipsychotic formulation in the child and adolescent population require further study, ideally with prospective, controlled designs.

Objective: Identifying biomarkers of transition to psychosis in individuals at clinical high risk for psychosis (CHR-P) is essential to understanding the mechanisms underlying the disease. Although cross-sectional abnormalities in cortical surface area (CSA) have been demonstrated in individuals at CHR-P who transition to psychosis (CHR-P-T) compared with those who do not (CHR-P-NT), how CSA longitudinally develops remains unclear, especially in younger individuals. We set out to compare CSA in adolescents at CHR-P and healthy controls (HC) over 2 points in time. Method: A longitudinal multicenter study was performed in adolescents at CHR-P in comparison to HC and according to transition to psychosis. Magnetic resonance imaging scans were acquired at baseline, at 18-month follow-up, or at the time of transition. Images were pre-processed and hemisphere and regional CSA were computed using FreeSurfer. Between-group analyses were performed with linear mixed-effects models. Results: A total of 313 scans (107 CHR-P and 102 HC) were included in the analysis. At 18 months, the rate of transition to psychosis in CHR-P was 23.4%. Adolescents at CHR-P-T presented greater age-related decrease in CSA in the left parietal and occipital lobes compared with HC, and in the bilateral parietal lobe and right frontal lobe relative to CHR-P-NT. These results were not influenced by antipsychotic treatment, cannabis use, or intelligence quotient (IQ). Conclusion: Adolescents at CHR-P that developed a psychotic disorder presented different developmental trajectories of CSA relative to those who did not. A relatively greater decrease in CSA in the parietal and frontal lobes may index clinical transition to psychosis in adolescents at CHR-P.