Do classic psychedelics increase the risk of seizures? A scoping review.

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.

Increasing prevalence of self-harm, suicidal behavior and suicidal ideation throughout a three-year period in the context of COVID-19 pandemic in Spain.

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.

Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk.

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 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 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-including those 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.

Mapping gray and white matter volume abnormalities in early-onset psychosis: an ENIGMA multicenter voxel-based morphometry study.

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.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Obsessive-Compulsive Spectrum Symptoms Are Associated With Functional Impairment in Children and Adolescents With Psychosis Risk Syndrome: The CAPRIS Study.

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.

Age-related change in cortical thickness in adolescents at clinical high risk for psychosis: a longitudinal study.

Progression to psychosis has been associated with increased cortical thinning in the frontal, temporal and parietal lobes in individuals at clinical high risk for the disorder (CHR-P). The timing and spatial extent of these changes are thought to be influenced by age. However, most evidence so far stems from adult samples. Longitudinal studies are essential to understanding the neuroanatomical changes associated to transition to psychosis during adolescence, and their relationship with age. We conducted a longitudinal, multisite study including adolescents at CHR-P and healthy controls (HC), aged 10-17 years. Structural images were acquired at baseline and at 18-month follow-up. Images were processed with the longitudinal pipeline in FreeSurfer. We used a longitudinal two-stage model to compute the regional cortical thickness (CT) change, and analyze between-group differences controlling for age, sex and scan, and corrected for multiple comparisons. Linear regression was used to study the effect of age at baseline. A total of 103 individuals (49 CHR-P and 54 HC) were included in the analysis. During follow-up, the 13 CHR-P participants who transitioned to psychosis exhibited greater CT decrease over time in the right parietal cortex compared to those who did not transition to psychosis and to HC. Age at baseline correlated with longitudinal changes in CT, with younger individuals showing greater cortical thinning in this region. The emergence of psychosis during early adolescence may have an impact on typical neuromaturational processes. This study provides new insights on the cortical changes taking place prior to illness onset.

Anxiety and depression played a central role in the COVID-19 mental distress: A network analysis.

INTRODUCTION: Psychological, socio-demographics, and clinical factors play an important role in patients with COVID-19, but their relationship is complex. The network approach might be used to disentangle complex interactions in different systems. Using data from a multicentre, cross-sectional, survey among patients with COVID-19 in Spain (July-November 2020), we investigated the network structure of mental disorders symptoms, social support, and psychological resilience, and changes in network structures according to the presence of a pre-existing mental disorder or hospitalization for COVID-19. METHODS: Subjects completed a survey to evaluate sociodemographic characteristics, COVID-19 infection status, resilience, social support, and symptoms of depression, anxiety disorders, post-traumatic stress disorder, panic attacks, and substance use disorder. 2084 patients with COVID-19 were included in the analysis. Network analysis was conducted to evaluate network and bridge centrality, and the network properties were compared between COVID-19 patients with and without a history of lifetime mental disorder, and between hospitalized and non-hospitalized patients. LIMITATIONS: Generalization of our findings may be difficult since differences in network connectivity may exist in different populations or samples. RESULTS: Anxiety and depression showed high centrality in patients with COVID-19 and anxiety showed the highest bridge influence in the network. Resilience and social support showed a low influence on mental disorder symptoms. Global network estimations show no statistically significant changes between patients with and without pre-existing mental disorders or between hospitalized and non-hospitalized patients. CONCLUSIONS: Anxiety might be a key treatment target in patients with COVID-19 since its treatment might prevent other mental health adverse outcomes.

Normative modeling of brain morphometry in Clinical High-Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in the majority of individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high-risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design Setting and Participants: Clinical, IQ and FreeSurfer-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1,340 CHR-P individuals [47.09% female; mean age: 20.75 (4.74) years] and 1,237 healthy individuals [44.70% female; mean age: 22.32 (4.95) years] from 29 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. Main Outcomes and Measures: For each regional morphometric measure, z-scores were computed that index the degree of deviation from the normative means of that measure in a healthy reference population (N=37,407). Average deviation scores (ADS) for CT, SA, SV, and globally across all measures (G) were generated by averaging the respective regional z-scores. Regression analyses were used to quantify the association of deviation scores with clinical severity and cognition and two-proportion z-tests to identify case-control differences in the proportion of individuals with infranormal (z<-1.96) or supranormal (z>1.96) scores. Results: CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z-scores, and all ADS vales. The proportion of CHR-P individuals with infranormal or supranormal values in any metric was low (<12%) and similar to that of healthy individuals. CHR-P individuals who converted to psychosis compared to those who did not convert had a higher percentage of infranormal values in temporal regions (5-7% vs 0.9-1.4%). In the CHR-P group, only the ADSSA showed significant but weak associations (|ß|<0.09; PFDR<0.05) with positive symptoms and IQ. Conclusions and Relevance: The study findings challenge the usefulness of macroscale neuromorphometric measures as diagnostic biomarkers of psychosis risk and suggest that such measures do not provide an adequate explanation for psychosis risk.

Longitudinal Changes in Cortical Surface Area Associated With Transition to Psychosis in Adolescents at Clinical High Risk for the Disease.

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.

What Role for Long-Acting Injectable Antipsychotics in Managing Schizophrenia Spectrum Disorders in Children and Adolescents? A Systematic Review.

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.

Upward trends in eating disorders, self-harm, and suicide attempt emergency admissions in female adolescents after COVID-19 lockdown.

INTRODUCTION: Increased mental health problems have been reported in children and adolescents related to the COVID-19 lockdown and its immediate aftermath, especially among adolescent females. However, the longer-term impact of persistent quarantine measures and social restrictions on this population is yet to be further explored. MATERIALS AND METHODS: We compared the number of children/adolescents admissions to the psychiatric emergency department (ED) of Hospital Clínic de Barcelona during the COVID-19 lockdown and the following year with the numbers of admissions the year before lockdown, adjusting for variations in the population. We also conducted separate analyses by gender, age group, and diagnostic categories. Finally, we also repeated the analyses considering the cumulated deficit/excess since the start of the lockdown. Statistical significance was estimated using binomial tests with Bonferroni correction. RESULTS: A total of 2425 admissions were recorded. Globally, admission rates decreased during the lockdown (46%) and progressively increased during the one-year aftermath (43% by spring 2021). This increase was particularly high in adolescent females (85%) while unclear in children and/or males. The main diagnostic categories involved were anxiety, depressive, and eating disorders, as well as self-harm behavior, suicidal ideation, and suicide attempts. The increase in eating disorders, self-harm behavior, and suicide attempts admissions in female adolescents remained statistically significant when considering the cumulated deficit/excess. CONCLUSIONS: We found increased ED admissions during the aftermath of the COVID-19 lockdown among adolescent females. We recommend strengthening the attention to this population to provide adequate specialized care and prevention strategies.

Psychopathology and mental health service use among youth in foster care admitted to a psychiatric inpatient unit: a 4-year retrospective controlled study.

Youth in foster care (FC) are at increased risk of poor psychosocial outcomes. The aim of this study was to assess psychopathology and mental health service use among youth living in FC who require psychiatric hospitalisation. All individuals admitted to our Children and Adolescent Inpatient Psychiatry Unit between 2014 and 2017 who were in FC were systematically reviewed. The control group was defined as all youth living with their immediate family and hospitalised in our unit throughout 2016. We identified 89 patients placed in FC and 247 controls. Socio-demographic and clinical data were retrospectively collected from computerised charts. A survival analysis of emergency department visits and readmission to the hospital was conducted. Compared to controls, the FC group presented significantly higher rates of conduct disorder (78.7% vs 14.6%; p < 0.001) and substance use disorder (49.4% vs 27.5%; p < 0.001), mainly cannabis use (34.8% vs 16.6%; p < 0.001); higher rates of comorbidity (96.6% vs 55.9%; p < 0.001) and mean number of comorbid diagnoses (3.3 ± 1.1 vs 2.3 ± 0.5; p < 0.001). The FC group had a higher number of emergency room visits before and after admission than controls. FC youth were also 2.77 times more likely to visit the emergency department after discharge, and in a shorter time period, than controls (p = 0.004). Disruptive behaviours, substance use disorder, and comorbid psychopathology were all more prevalent among FC youth than controls. Specific strategies are needed to optimize community mental health resources and address the increased use of emergency services by these youth before and after hospitalisation.

Radiological findings in brain MRI scans in youth with early-onset psychosis: A controlled study.

There is a lack of consensus on whether routine brain magnetic resonance imaging (MRI) should be recommended as part of the initial assessment in patients with psychosis. No study so far has qualitatively assessed brain MRI in patients with early-onset psychosis (EOP), in whom neurodevelopmental factors may play a stronger role. We aimed to determine the prevalence of brain MRI findings in patients with EOP compared to healthy controls, and assess whether these findings were clinically relevant. Retrospective clinical chart review of all patients with EOP in whom a brain MRI scan was acquired during admission to an inpatient child and adolescent psychiatry unit during January 2013-December 2017, compared to age and biologically assigned gender matched healthy controls. Between group analyses tested differences in rates of qualitatively abnormal MRI scans and changes in clinical management as a result of radiological findings. A total of 256 individuals were included (128 patients with EOP and 128 healthy controls). Patients with EOP presented with a significantly higher rate of abnormal MRI scans relative to healthy controls (21.9% vs 11.7%, p = .030; OR = 2.11, [95% CI:1.06-4.17]). Radiological findings in the EOP group triggered clinical referral for further evaluation or management more often than in the healthy control group (7.0% vs 1.6%, p = .030; OR = 4.76, [95% CI:1.01-22.50]). MRI scans in youth with EOP may be characterized by an increased number of radiological abnormalities than in controls. The rates of MRI findings requiring clinical referral suggests that routine MRI acquisition may need to be considered in patients with EOP.

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis.

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.

A systematic review and meta-analysis of structural and functional brain alterations in individuals with genetic and clinical high-risk for psychosis and bipolar disorder.

Neuroimaging findings in people at either genetic risk or at clinical high-risk for psychosis (CHR-P) or bipolar disorder (CHR-B) remain unclear. A meta-analytic review of whole-brain voxel-based morphometry (VBM) and functional magnetic resonance imaging (fMRI) studies in individuals with genetic risk or CHR-P or CHR-B and controls identified 94 datasets (N = 7942). Notwithstanding no significant findings were observed following adjustment for multiple comparisons, several findings were noted at a more liberal threshold. Subjects at genetic risk for schizophrenia or bipolar disorder or at CHR-P exhibited lower gray matter (GM) volumes in the gyrus rectus (Hedges' g = -0.19). Genetic risk for psychosis was associated with GM reductions in the right cerebellum and left amygdala. CHR-P was associated with decreased GM volumes in the frontal superior gyrus and hypoactivation in the right precuneus, the superior frontal gyrus and the right inferior frontal gyrus. Genetic and CHR-P were associated with small structural and functional alterations involving regions implicated in psychosis. Further neuroimaging studies in individuals with genetic or CHR-B are warranted.

Study Protocol-Coping With the Pandemics: What Works Best to Reduce Anxiety and Depressive Symptoms.

Background: The coronavirus disease 2019 (COVID-19) pandemic and lockdown might increase anxiety and depressive symptoms in most individuals. Health bodies recommend several coping behaviors to protect against such symptoms, but evidence on the relationship between these behaviors and symptoms mostly comes from cross-sectional studies in convenience samples. We will conduct a prospective longitudinal study of the associations between coping behaviors and subsequent anxiety and depressive symptoms during the COVID-19 pandemic in a representative sample of the Spanish general adult population. Methods: We will recruit 1,000 adult participants from all autonomous communities of Spain and with sex, age, and urbanicity distributions similar to those of their populations and assess anxiety and depressive symptoms and coping behaviors using fortnightly questionnaires and real-time methods (ecological momentary assessments) for 1 year. The fortnightly questionnaires will inquire about anxiety and depressive symptoms [General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9)] and the frequency of 10 potential coping behaviors (e.g., follow a routine) during the past 2 weeks. In addition, we will collect several variables that could confound or moderate these associations. These will include subjective well-being [International Positive and Negative Affect Schedule Short Form (I-PANAS-SF) and Satisfaction with Life Scale (SWLS)], obsessive-compulsive symptoms [Obsessive Compulsive Inventory-Revised (OCI-R)], personality and emotional intelligence [International Personality Item Pool (IPIP) and Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF)], sociodemographic factors (e.g., work status, housing-built environment), and COVID-19 pandemic-related variables (e.g., hospitalizations or limitations in social gatherings). Finally, to analyze the primary relationship between coping behaviors and subsequent anxiety and depressive symptoms, we will use autoregressive moving average (ARMA) models. Discussion: Based on the study results, we will develop evidence-based, clear, and specific recommendations on coping behaviors during the COVID-19 pandemic and lockdown. Such suggestions might eventually help health bodies or individuals to manage current or future pandemics.

Cortical gray matter reduction precedes transition to psychosis in individuals at clinical high-risk for psychosis: A voxel-based meta-analysis.

Gray matter and cortical thickness reductions have been documented in individuals at clinical high-risk for psychosis and may be more pronounced in those who transition to psychosis. However, these findings rely on small samples and are inconsistent across studies. In this review and meta-analysis we aimed to investigate neuroanatomical correlates of clinical high-risk for psychosis and potential predictors of transition, using a novel meta-analytic method (Seed-based d Mapping with Permutation of Subject Images) and cortical mask, combining data from surface-based and voxel-based morphometry studies. Individuals at clinical high-risk for psychosis who later transitioned to psychosis were compared to those who did not and to controls, and included three statistical maps. Overall, individuals at clinical high-risk for psychosis did not differ from controls, however, within the clinical high-risk for psychosis group, transition to psychosis was associated with less cortical gray matter in the right temporal lobe (Hedges' g = -0.377), anterior cingulate and paracingulate (Hedges' g = -0.391). These findings have the potential to help refine prognostic and etiopathological research in early psychosis.

Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group Mega-analysis.

Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk. Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). Design, Setting, and Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020. Main Outcomes and Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group). Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001). Conclusions and Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.

Theory of mind performance and prefrontal connectivity in adolescents at clinical high risk for psychosis.

Theory of mind(ToM) impairment is a key feature of psychotic disorders and has been documented in individuals at clinical high-risk for psychosis (CHR), suggesting that it may predate illness onset. However, no study to date has examined brain functional correlates of ToM in individuals at CHR during adolescence. The "Reading-the-Mind-in-the-Eyes" test was used to measure ToM performance in 50 CHR youth, 15 of whom transitioned to psychosis (CHR-t) at follow-up (12 ± 6 months) and 36 healthy volunteers. Resting-state functional MRI was acquired to evaluate functional connectivity within the default mode network. Group by age interaction revealed an age-positive association in ToM performance in healthy volunteers, which was not present in adolescents at CHR-t. Intrinsic functional connectivity in the medial prefrontal cortex was reduced in adolescents at CHR-t relative to those who did not transition and to healthy volunteers. Survival analyses revealed that participants at CHR with lower medial prefrontal cortex connectivity were at greatest risk of developing psychosis at follow-up. We demonstrate that lack of age-related maturation of ToM and reduced medial prefrontal cortex connectivity both precede the onset of psychosis during adolescence. Medial prefrontal cortex connectivity holds potential as a brain-based marker for the early identification of transition to psychosis.