A transdiagnostic prodrome for severe mental disorders: an electronic health record study.

Effective prevention of severe mental disorders (SMD), including non-psychotic unipolar mood disorders (UMD), non-psychotic bipolar mood disorders (BMD), and psychotic disorders (PSY), rely on accurate knowledge of the duration, first presentation, time course and transdiagnosticity of their prodromal stages. Here we present a retrospective, real-world, cohort study using electronic health records, adhering to RECORD guidelines. Natural language processing algorithms were used to extract monthly occurrences of 65 prodromal features (symptoms and substance use), grouped into eight prodromal clusters. The duration, first presentation, and transdiagnosticity of the prodrome were compared between SMD groups with one-way ANOVA, Cohen's f and d. The time course (mean occurrences) of prodromal clusters was compared between SMD groups with linear mixed-effects models. 26,975 individuals diagnosed with ICD-10 SMD were followed up for up to 12 years (UMD = 13,422; BMD = 2506; PSY = 11,047; median[IQR] age 39.8[23.7] years; 55% female; 52% white). The duration of the UMD prodrome (18[36] months) was shorter than BMD (26[35], d = 0.21) and PSY (24[38], d = 0.18). Most individuals presented with multiple first prodromal clusters, with the most common being non-specific ('other'; 88% UMD, 85% BMD, 78% PSY). The only first prodromal cluster that showed a medium-sized difference between the three SMD groups was positive symptoms (f = 0.30). Time course analysis showed an increase in prodromal cluster occurrences approaching SMD onset. Feature occurrence across the prodromal period showed small/negligible differences between SMD groups, suggesting that most features are transdiagnostic, except for positive symptoms (e.g. paranoia, f = 0.40). Taken together, our findings show minimal differences in the duration and first presentation of the SMD prodromes as recorded in secondary mental health care. All the prodromal clusters intensified as individuals approached SMD onset, and all the prodromal features other than positive symptoms are transdiagnostic. These results support proposals to develop transdiagnostic preventive services for affective and psychotic disorders detected in secondary mental healthcare.

Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

Prevalence and incidence of psychotic disorders in 22q11.2 deletion syndrome: a meta-analysis.

22q11.2 deletion syndrome (22q.11.2DS) might be one of the strongest genetic risk factors for psychosis, but robust estimates of prevalence and incidence of psychotic disorders in this condition are not available. To address this gap, we performed a multistep systematic PRISMA/MOOSE-compliant literature search of articles reporting prevalence (primary outcome) or incidence (secondary outcome) of psychotic disorders in 22q11.2DS samples (protocol: https://osf.io/w6hpg) using random-effects meta-analysis, subgroup analyses and meta-regressions. The pooled prevalence of psychotic disorders was 11.50% (95%CI:9.40-14.00%), largely schizophrenia (9.70%, 95%CI:6.50-14.20). Prevalence was significantly higher in samples with a mean age over 18 years, with both psychiatric and non-psychiatric comorbidities and recruited from healthcare services (compared to the community). Mean age was also significantly positively associated with prevalence in meta-regressions (p < 0.01). The pooled incidence of psychotic disorders was 10.60% (95%CI:6.60%-16.70%) at a mean follow-up time of 59.27 ± 40.55 months; meta-regressions were not significant. To our knowledge, this is the first comprehensive systematic review and meta-analysis of the prevalence and incidence of psychotic disorders in 22q11.2DS individuals. It demonstrates that around one in ten individuals with 22q11.2DS displays comorbid psychotic disorders, and around one in ten will develop psychosis in the following five years, indicating that preventive approaches should be implemented systematically in 22q11.2DS.

Beneath the surface: hyper-connectivity between caudate and salience regions in ADHD fMRI at rest.

Attention-Deficit/Hyperactivity Disorder (ADHD) comprises disturbances in attention, emotional regulation, and reward-related processes. In spite of the active efforts in researching neurofunctional correlates of these symptoms, how the activity of subcortical regions-such as basal ganglia-is related to ADHD has yet to be clarified. More specifically, how age may influence the critical changes observed in functional dynamics from childhood to adulthood remains relatively unexplored. We hence selected five core subcortical regions (amygdala, caudate, putamen, pallidum and hippocampus) as regions of interest from the previous literature, measuring their whole-brain voxel-wise rsFC in a sample of 95 ADHD and 90 neurotypical children and adolescents aged from 7 to 18. The only subcortical structure showing significant differences in rsFC was the caudate nucleus. Specifically, we measured increased rsFC with anterior cingulate and right insula, two mesolimbic regions pertaining to the Salience Network. The degree of hyper-rsFC positively correlated with ADHD symptomatology, and showed different patterns of evolution in ADHD vs neurotypical subjects. Finally, the rsFC scores allowed a fair discrimination of the ADHD group (Area Under the Curve ≥ 0.7). These findings shed further light on the fundamental role covered by subcortical structures in ADHD pathogenesis and neurodevelopment, providing new evidence to fill the gap between neurofunctional and clinical expressions of ADHD.

The noise in our brain: A systematic review and meta-analysis of neuroimaging and signal-detection studies on source monitoring in psychosis.

OBJECTIVES: Noisy thoughts or perceptions are characteristics of psychosis (PSY) and, they are deeply related to source monitoring (SM) - the ability to discriminate the origin of internal/external experiences. METHODS: This MOOSE, PRISMA-compliant meta-analysis compared SM performances in PSY compared to healthy controls (HC) focusing on signal-to-noise discrimination in order to: i) test whether neuroimaging procedures (fMRI/EEG) might be a group-specific source of noise for SM; ii) compare error- and accuracy-based indexes; iii) to meta-analyze signal-detection measures (i.e., discrimination index and response bias); iv) to determine the best index capturing SM deficits in psychosis. We conducted a 3-level meta-analysis for each aim to estimate pooled effect-sizes (Cohen's d). SM type, source discrimination and stimulus modality were used as meta-regressors. Heterogeneity (I2), publication bias (Egger's test) and multiple comparisons (Bonferroni correction) were considered. RESULTS: Sixteen neuroimaging, 44 error/accuracy-based behavioral and 7 signal-detection trials were included (2297 PSY, age range = 18.78-52.6; 1745 HC, age range = 21.1-53.3). The noise generated by neuroimaging procedures slightly influenced error, but not accuracy. Accuracy-based (d = -0.83), but not error-based, indexes showed significant and large SM impairments in PSY compared to HC. Overall SM performance differences between PSY and HC were larger in discrimination index (d = -0.65) and accuracy (d = -0.61), followed by response bias (d = -0.59, ns) and error-based (d = 0.35) indexes. CONCLUSION: Although both accuracy and discrimination indexes differentiate patients with PSY from HC, discrimination index is more reliable and may better capture the bi-directional nature of the internal/external source confusion.

Physical Health and Transition to Psychosis in People at Clinical High Risk.

BACKGROUND: The clinical high risk for psychosis (CHR-P) construct represents an opportunity for prevention and early intervention in young adults, but the relationship between risk for psychosis and physical health in these patients remains unclear. METHODS: We conducted a RECORD-compliant clinical register-based cohort study, selecting the long-term cumulative risk of developing a persistent psychotic disorder as the primary outcome. We investigated associations between primary outcome and physical health data with Electronic Health Records at the South London and Maudsley (SLaM) NHS Trust, UK (January 2013-October 2020). We performed survival analyses using Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models. RESULTS: The database included 137 CHR-P subjects; 21 CHR-P developed psychosis during follow-up, and the cumulative incidence of psychosis risk was 4.9% at 1 year and 56.3% at 7 years. Log-rank tests suggested that psychosis risk might change between different levels of nicotine and alcohol dependence. Kaplan-Meier curve analyses indicated that non-hazardous drinkers may have a lower psychosis risk than non-drinkers. In the Cox proportional hazard model, nicotine dependence presented a hazard ratio of 1.34 (95% CI: 1.1-1.64) (p = 0.01), indicating a 34% increase in psychosis risk for every additional point on the Fagerström Test for Nicotine Dependence. CONCLUSIONS: Our findings suggest that a comprehensive assessment of tobacco and alcohol use, diet, and physical activity in CHR-P subjects is key to understanding how physical health contributes to psychosis risk.

The lived experience of mental disorders in adolescents: a bottom-up review co-designed, co-conducted and co-written by experts by experience and academics.

We provide here the first bottom-up review of the lived experience of mental disorders in adolescents co-designed, co-conducted and co-written by experts by experience and academics. We screened first-person accounts within and outside the medical field, and discussed them in collaborative workshops involving numerous experts by experience - representing different genders, ethnic and cultural backgrounds, and continents - and their family members and carers. Subsequently, the material was enriched by phenomenologically informed perspectives and shared with all collaborators. The inner subjective experience of adolescents is described for mood disorders, psychotic disorders, attention-deficit/hyperactivity disorder, autism spectrum disorders, anxiety disorders, eating disorders, externalizing disorders, and self-harm behaviors. The recollection of individuals' past histories also indexes the prodromal (often transdiagnostic) features predating the psychiatric diagnosis. The experience of adolescents with mental disorders in the wider society is described with respect to their family, their school and peers, and the social and cultural context. Furthermore, their lived experience of mental health care is described with respect to receiving a diagnosis of mental disorder, accessing mental health support, receiving psychopharmacological treatment, receiving psychotherapy, experiencing peer support and mental health activism, and achieving recovery. These findings can impact clinical practice, research, and the whole society. We hope that this co-designed, co-conducted and co-written journey can help us maintain our commitment to protecting adolescents' fragile mental health, and can help them develop into a healthy, fulfilling and contributing adult life.

Physical Health in Clinical High Risk for Psychosis Individuals: A Cross-Sectional Study.

BACKGROUND: The clinical high risk for psychosis (CHR-P) phase represents an opportunity for prevention and early intervention in young adults, which also could focus on improving physical health trajectories. METHODS: We conducted a RECORD-compliant clinical register-based cohort study. The primary outcome was to describe the physical health of assessed CHR-P individuals, obtained via Electronic Health Records at the South London and Maudsley (SLaM) NHS Foundation Trust, UK (January 2013-October 2020). RESULTS: The final database included 194 CHR-P subjects (46% female). Mean age was 23.70 ± 5.12 years. Percentage of tobacco smokers was 41% (significantly higher than in the age-matched general population [24%]). We found that 49% of subjects who consumed alcohol had an AUDIT-C (Alcohol Use Disorder Identification Test) score above 5 (hazardous drinking), with an average score of 4.94 (significantly higher than in the general population [2.75]). Investigating diet revealed low fiber intake in most subjects and high saturated fat intake in 10% of the individuals. We found that 47% of CHR-P subjects met the UK recommended physical activity guidelines (significantly lower than in the general population [66%]). Physical parameters (e.g., weight, heart rate, blood pressure) were not significantly different from the general population. CONCLUSIONS: This evidence corroborates the need for monitoring physical health parameters in CHR-P subjects, to implement tailored interventions that target daily habits.

Prevalence of tobacco smoking in people at clinical high-risk for psychosis: Systematic review and meta-analysis.

Several hypotheses have been proposed to explain why individuals with psychosis consume more tobacco compared with the general population, but the reasons remain unclear. The phases predating the onset of psychosis could provide an interesting framework to clarify this association. The aim of this systematic review and meta-analysis is to provide an updated and comprehensive synthesis of the association between tobacco smoking and Clinical High Risk for Psychosis (CHRP) status. We performed a multistep systematic PRISMA/MOOSE-compliant electronic search for articles published from inception until October 1st, 2021. Web of Science was searched, complemented by a manual search of original articles reporting the outcome of tobacco consumption (defined as the number of individuals which were smoking tobacco at baseline) in a group of CHR-P patients versus healthy controls (HC). We employed quality assessment of the included studies with Newcastle Ottawa Scale (NOS). The effect size for the primary outcome was the odds ratio (OR) of smoking tobacco in CHR-P samples vs HC. We performed a random-effects model meta-analysis, assessment of heterogeneity with I2 index, sensitivity analyses excluding one study at a time for primary outcome, meta-regressions with four independent moderators (mean age, female ratio, sample size, NOS) and assessment of publication bias with funnel plot and Egger's test. We included 21 independent articles, totalling 2018 CHR-P individuals (mean age of 21.35 ± 2.91 years and average female ratio of 41 ± 7 %) and 1160 HC (mean age of 22.42 ± 3.70 years and average female ratio of 45 ± 11 %). The NOS score was 6.52 ± 1.25 (range from 0 to 9). The OR of smoking status was 2.22 (95%CI 1.74-2.84, p < 0.01). Heterogeneity (I2) was 24.09 (p = 0.16). Sensitivity analyses, removing one study at a time, revealed the robustness of our main finding. Meta-regressions did not reveal any significant association between the moderators and the main outcome. Visual inspection of the funnel plot and Egger's test did not reveal evident publication bias. Our main finding of an increased OR of smokers in the CHR-P individuals compared to healthy controls corroborates the accumulation of unhealthy lifestyles in this vulnerable group. This does not demonstrate any causal association between tobacco smoking and incidence of psychosis, which should be investigated in future prospective cohorts. In conclusion, the window of opportunity represented by CHR-P status should involve more efficient physical health screening and better investigating the aetiological impact of smoking in the development of psychosis.

Transdiagnostic risk of mental disorders in offspring of affected parents: a meta-analysis of family high-risk and registry studies.

The offspring of parents with mental disorders are at increased risk for developing mental disorders themselves. The risk to offspring may extend transdiagnostically to disorders other than those present in the parents. The literature on this topic is vast but mixed. To inform targeted prevention and genetic counseling, we performed a comprehensive, PRISMA 2020-compliant meta-analysis. We systematically searched the literature published up to September 2022 to retrieve original family high-risk and registry studies reporting on the risk of mental disorders in offspring of parents with any type of mental disorder. We performed random-effects meta-analyses of the relative risk (risk ratio, RR) and absolute risk (lifetime, up to the age at assessment) of mental disorders, defined according to the ICD or DSM. Cumulative incidence by offspring age was determined using meta-analytic Kaplan-Meier curves. We measured heterogeneity with the I2 statistic, and risk of bias with the Quality In Prognosis Studies (QUIPS) tool. Sensitivity analyses addressed the impact of study design (family high-risk vs. registry) and specific vs. transdiagnostic risks. Transdiagnosticity was appraised with the TRANSD criteria. We identified 211 independent studies that reported data on 3,172,115 offspring of parents with psychotic, bipolar, depressive, disruptive, attention-deficit/hyperactivity, anxiety, substance use, eating, obsessive-compulsive, and borderline personality disorders, and 20,428,575 control offspring. The RR and lifetime risk of developing any mental disorder were 3.0 and 55% in offspring of parents with anxiety disorders; 2.6 and 17% in offspring of those with psychosis; 2.1 and 55% in offspring of those with bipolar disorder; 1.9 and 51% in offspring of those with depressive disorders; and 1.5 and 38% in offspring of those with substance use disorders. The offspring's RR and lifetime risk of developing the same mental disorder diagnosed in their parent were 8.4 and 32% for attention-deficit/hyperactivity disorder; 5.8 and 8% for psychosis; 5.1 and 5% for bipolar disorder; 2.8 and 9% for substance use disorders; 2.3 and 14% for depressive disorders; 2.3 and 1% for eating disorders; and 2.2 and 31% for anxiety disorders. There were 37 significant transdiagnostic associations between parental mental disorders and the RR of developing a different mental disorder in the offspring. In offspring of parents with psychosis, bipolar and depressive disorder, the risk of the same disorder onset emerged at 16, 5 and 6 years, and cumulated to 3%, 19% and 24% by age 18; and to 8%, 36% and 46% by age 28. Heterogeneity ranged from 0 to 0.98, and 96% of studies were at high risk of bias. Sensitivity analyses restricted to prospective family high-risk studies confirmed the pattern of findings with similar RR, but with greater absolute risks compared to analyses of all study types. This study demonstrates at a global, meta-analytic level that offspring of affected parents have strongly elevated RR and lifetime risk of developing any mental disorder as well as the same mental disorder diagnosed in the parent. The transdiagnostic risks suggest that offspring of parents with a range of mental disorders should be considered as candidates for targeted primary prevention.

Mapping the implementation and challenges of clinical services for psychosis prevention in England.

Introduction: Indicated primary prevention of psychosis is recommended by NICE clinical guidelines, but implementation research on Clinical High Risk for Psychosis (CHR-P) services is limited. Methods: Electronic audit of CHR-P services in England, conducted between June and September 2021, addressing core implementation domains: service configuration, detection of at-risk individuals, prognostic assessment, clinical care, clinical research, and implementation challenges, complemented by comparative analyses across service model. Descriptive statistics, Fisher's exact test and Mann-Whitney U-tests were employed. Results: Twenty-four CHR-P clinical services (19 cities) were included. Most (83.3%) services were integrated within other mental health services; only 16.7% were standalone. Across 21 services, total yearly caseload of CHR-P individuals was 693 (average: 33; range: 4-115). Most services (56.5%) accepted individuals aged 14-35; the majority (95.7%) utilized the Comprehensive Assessment of At Risk Mental States (CAARMS). About 65% of services reported some provision of NICE-compliant interventions encompassing monitoring of mental state, cognitive-behavioral therapy (CBT), and family interventions. However, only 66.5 and 4.9% of CHR-P individuals actually received CBT and family interventions, respectively. Core implementation challenges included: recruitment of specialized professionals, lack of dedicated budget, and unmet training needs. Standalone services reported fewer implementation challenges, had larger caseloads (p = 0.047) and were more likely to engage with clinical research (p = 0.037) than integrated services. Discussion: While implementation of CHR-P services is observed in several parts of England, only standalone teams appear successful at detection of at-risk individuals. Compliance with NICE-prescribed interventions is limited across CHR-P services and unmet needs emerge for national training and investments.

A Pilot Study on Covid and Autism: Prevalence, Clinical Presentation and Vaccine Side Effects.

Background: Several neurobiological mechanisms have been proposed to support the hypothesis of a higher COVID-19 risk in individuals with autism spectrum disorder (ASD). However, no real-world data are available on this population. Methods: We compared the period prevalence (March-May 2020) and symptom presentation of COVID-19 infections between a sample of individuals with severe ASD (n = 36) and the staff personnel (n = 35) of two specialized centers. Anti-SARS-Cov-2 antibody positivity was used as a proxy of infection. Additionally, we evaluated vaccine side effects in the same groups. Results: No significant difference was found between the prevalence of COVID-19 positivity between autistic participants and staff personnel. Levels of antibodies against the spike protein and the receptor binding domain were not significantly different between autistic and staff participants. The level of antibodies against the N-terminal domain were higher in autistic individuals. There was a significant difference between the prevalence of symptomatic COVID-19 in autistic participants (9.1%) compared to staff personnel (92.3%). The most frequent side effect among autistic participants was light fever. Conclusions: The present study provides preliminary data on COVID-19 transmission and presentation in ASD. Our data do not support the hypothesis of a higher susceptibility and severity of COVID-19 in people with ASD.

Universal and Selective Interventions to Prevent Poor Mental Health Outcomes in Young People: Systematic Review and Meta-analysis.

BACKGROUND: Much is not known about the efficacy of interventions to prevent poor mental health outcomes in young people by targeting either the general population (universal prevention) or asymptomatic individuals with high risk of developing a mental disorder (selective prevention). METHODS: We conducted a PRISMA/MOOSE-compliant systematic review and meta-analysis of Web of Science to identify studies comparing post-test efficacy (effect size [ES]; Hedges' g) of universal or selective interventions for poor mental health outcomes versus control groups, in samples with mean age <35 years (PROSPERO: CRD42018102143). Measurements included random-effects models, I2 statistics, publication bias, meta-regression, sensitivity analyses, quality assessments, number needed to treat, and population impact number. RESULTS: 295 articles (447,206 individuals; mean age = 15.4) appraising 17 poor mental health outcomes were included. Compared to control conditions, universal and selective interventions improved (in descending magnitude order) interpersonal violence, general psychological distress, alcohol use, anxiety features, affective symptoms, other emotional and behavioral problems, consequences of alcohol use, posttraumatic stress disorder features, conduct problems, tobacco use, externalizing behaviors, attention-deficit/hyperactivity disorder features, and cannabis use, but not eating-related problems, impaired functioning, internalizing behavior, or sleep-related problems. Psychoeducation had the highest effect size for ADHD features, affective symptoms, and interpersonal violence. Psychotherapy had the highest effect size for anxiety features. CONCLUSION: Universal and selective preventive interventions for young individuals are feasible and can improve poor mental health outcomes.

What are we targeting when we treat autism spectrum disorder? A systematic review of 406 clinical trials.

The number of trials aimed at evaluating treatments for autism spectrum disorder has been increasing progressively. However, it is not clear which outcome measures should be used to assess their efficacy, especially for treatments which target core symptoms. The present review aimed to provide a comprehensive overview regarding the outcome measures used in clinical trials for people with autism spectrum disorder. We systematically searched the Web of KnowledgeSM database between 1980 and 2016 to identify published controlled trials investigating the efficacy of interventions in autism spectrum disorder. We included 406 trials in the final database, from which a total of 327 outcome measures were identified. Only seven scales were used in more than 5% of the studies, among which only three measured core symptoms (Autism Diagnostic Observation Schedule, Childhood Autism Rating Scale, and Social Responsiveness Scale). Of note, 69% of the tools were used in the literature only once. Our systematic review has shown that the evaluation of efficacy in intervention trials for autism spectrum disorder relies on heterogeneous and often non-specific tools for this condition. The fragmentation of tools may significantly hamper the comparisons between studies and thus the discovery of effective treatments for autism spectrum disorder. Greater consensus regarding the choice of these measures should be reached.

World/self ambivalence: A shared mechanism in different subsets of psychotic experiences? Linking symptoms with resting-state fMRI.

The psychosis spectrum comprises heterogeneous disorders characterized by both world-related and self-related symptoms. How these symptoms may arise with similar features in spite of the different aetiologies is yet an unsolved question. In behavior narrative review, we compare three conditions characterized by psychotic experiences (schizophrenia, substance-use disorder and sensory-deprivation) searching for links between their phenomenological features and the mechanisms underlying their onset. Clinically, psychotic experiences are characterized by the reciprocal contamination of world- and self-related contents, termed 'world/self ambivalence'. Neuroimaging evidence suggests that the imbalance between stimuli-, self-, and attention-related functional networks (visual/auditory, default-mode, and salience network respectively) assumes central relevance in all the conditions considered. Phenomenology and neurobiology were thus interrelated in light of the reviewed literature, identifying two key neuronal mechanisms which may lead to world/self ambivalence. First, psychotic experiences are associated with the relative dominance of one network over the other (default-mode over auditory/visual networks, or vice-versa), prompting an excess of internal or external pressure to the experienced ambivalence between world and self. Second, an altered salience network resting-state functional connectivity could generate a dysregulation of the attentive fluctuations from self- to world-related activity, thus blurring the boundary between the environment and oneself, labelled the 'world/self boundary'.

Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis.

BACKGROUND: Prenatal and perinatal insults are implicated in the aetiopathogenesis of psychotic disorders but the consistency and magnitude of their associations with psychosis have not been updated for nearly two decades. The aim of this systematic review and meta-analysis was to provide a comprehensive and up-to-date synthesis of the evidence on the association between prenatal or perinatal risk and protective factors and psychotic disorders. METHODS: In this systematic review and meta-analysis, we searched the Web of Science database for articles published up to July 20, 2019. We identified cohort and case-control studies examining the association (odds ratio [OR]) between prenatal and perinatal factors and any International Classification of Diseases (ICD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) non-organic psychotic disorder with a healthy comparison group. Other inclusion criteria were enough data available to do the analyses, and non-overlapping datasets. We excluded reviews, meta-analyses, abstracts or conference proceedings, and articles with overlapping datasets. Data were extracted according to EQUATOR and PRISMA guidelines. Extracted variables included first author, publication year, study type, sample size, type of psychotic diagnosis (non-affective psychoses or schizophrenia-spectrum disorders, affective psychoses) and diagnostic instrument (DSM or ICD and version), the risk or protective factor, and measure of association (primary outcome). We did random-effects pairwise meta-analyses, Q statistics, I2 index, sensitivity analyses, meta-regressions, and assessed study quality and publication bias. The study protocol was registered at PROSPERO, CRD42017079261. FINDINGS: 152 studies relating to 98 risk or protective factors were eligible for analysis. Significant risk factors were: maternal age younger than 20 years (OR 1·17) and 30-34 years (OR 1·05); paternal age younger than 20 years (OR 1·31) and older than 35 years (OR 1·28); any maternal (OR 4·60) or paternal (OR 2·73) psychopathology; maternal psychosis (OR 7·61) and affective disorder (OR 2·26); three or more pregnancies (OR 1·30); herpes simplex 2 (OR 1·35); maternal infections not otherwise specified (NOS; OR 1·27); suboptimal number of antenatal visits (OR 1·83); winter (OR 1·05) and winter to spring (OR 1·05) season of birth in the northern hemisphere; maternal stress NOS (OR 2·40); famine (OR 1·61); any famine or nutritional deficits in pregnancy (OR 1·40); maternal hypertension (OR 1·40); hypoxia (OR 1·63); ruptured (OR 1·86) and premature rupture (OR 2·29) of membranes; polyhydramnios (OR 3·05); definite obstetric complications NOS (OR 1·83); birthweights of less than 2000 g (OR 1·84), less than 2500 g (OR 1·53), or 2500-2999 g (OR 1·23); birth length less than 49 cm (OR 1·17); small for gestational age (OR 1·40); premature birth (OR 1·35), and congenital malformations (OR 2·35). Significant protective factors were maternal ages 20-24 years (OR 0·93) and 25-29 years (OR 0·92), nulliparity (OR 0·91), and birthweights 3500-3999 g (OR 0·90) or more than 4000 g (OR 0·86). The results were corrected for publication biases; sensitivity and meta-regression analyses confirmed the robustness of these findings for most factors. INTERPRETATION: Several prenatal and perinatal factors are associated with the later onset of psychosis. The updated knowledge emerging from this study could refine understanding of psychosis pathogenesis, enhance multivariable risk prediction, and inform preventive strategies. FUNDING: None.

Acute oxytocin effects in inferring others' beliefs and social emotions in people at clinical high risk for psychosis.

Social deficits are key hallmarks of the Clinical High Risk for Psychosis (CHR-P) state and of established psychotic disorders, and contribute to impaired social functioning, indicating a potential target for interventions. However, current treatments do not significantly ameliorate social impairments in CHR-P individuals. Given its critical role in social behaviour and cognition, the oxytocinergic (OT) system is a promising target for novel interventions in CHR-P subjects. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using functional magnetic resonance imaging (fMRI) on two occasions, once after 40IU self-administered intranasal OT and once after placebo. A modified version of the Sally-Anne task was used to assess brain activation during inferring others' beliefs and social emotions. The Reading the Mind in the Eyes Test was acquired prior to the first scan to test whether OT effects were moderated by baseline social-emotional abilities. OT did not modulate behavioural performances but reduced activation in the bilateral inferior frontal gyrus compared with placebo while inferring others' social emotions. Furthermore, the relationship between brain activation and task performance after OT administration was moderated by baseline social-emotional abilities. While task accuracy during inferring others' social emotion increased with decreasing activation in the left inferior frontal gyrus in CHR-P individuals with low social-emotional abilities, there was no such relationship in CHR-P individuals with high social-emotional abilities. Our findings may suggest that acute OT administration enhances neural efficiency in the inferior frontal gyrus during inferring others' social emotions in those CHR-P subjects with low baseline social-emotional abilities.

Universal and selective interventions to promote good mental health in young people: Systematic review and meta-analysis.

Promotion of good mental health in young people is important. Our aim was to evaluate the consistency and magnitude of the efficacy of universal/selective interventions to promote good mental health. A systematic PRISMA/RIGHT-compliant meta-analysis (PROSPERO: CRD42018088708) search of Web of Science until 04/31/2019 identified original studies comparing the efficacy of universal/selective interventions for good mental health vs a control group, in samples with a mean age <35 years. Meta-analytical random-effects model, heterogeneity statistics, assessment of publication bias, study quality and sensitivity analyses investigated the efficacy (Hedges' g=effect size, ES) of universal/selective interventions to promote 14 good mental health outcomes defined a-priori. 276 studies were included (total participants: 159,508, 79,142 interventions and 80,366 controls), mean age=15.0 (SD=7.4); female=56.0%. There was a significant overall improvement in 10/13 good mental health outcome categories that could be meta-analysed: compared to controls, interventions significantly improved (in descending order of magnitude) mental health literacy (ES=0.685, p<0.001), emotions (ES=0.541, p<0.001), self-perceptions and values (ES=0.49, p<0.001), quality of life (ES=0.457, p=0.001), cognitive skills (ES=0.428, p<0.001), social skills (ES=0.371, p<0.001), physical health (ES=0.285, p<0.001), sexual health (ES=0.257, p=0.017), academic/occupational performance (ES=0.211, p<0.001) and attitude towards mental disorders (ES=0.177, p=0.006). Psychoeducation was the most effective intervention for promoting mental health literacy (ES=0.774, p<0.001) and cognitive skills (ES=1.153, p=0.03). Physical therapy, exercise and relaxation were more effective than psychoeducation and psychotherapy for promoting physical health (ES=0.498, p<0.001). In conclusion, several universal/selective interventions can be effective to promote good mental health in young people. Future research should consolidate and extend these findings.

Prevalence and predictors of psychotropic medication use in adolescents and adults with autism spectrum disorder in Italy: A cross-sectional study.

Autism spectrum disorder (ASD) is a group of life-long neurodevelopmental conditions with a prevalence of 1.5% in developed countries. Beside core symptomatology, ASD people are frequently affected by psychiatric comorbidities and behavioral problems. To date, only risperidone and aripiprazole have been approved for the pharmacological treatment of ASD-associated irritability in children and adolescents, while no guidelines exist for adults. The present cross-sectional study examined the prevalence and predictors of psychotropic medication use in 195 autistic subjects, aged between 14 and 58, treated in two Italian tertiary care centers. 58.5% of the sample were taking at least one medication; one third of the sample were on polypharmacotherapy. Antipsychotics were prescribed to 40% of the sample. Nearly 30% of the sample were on anticonvulsants/mood stabilizers. Both antidepressants and benzodiazepines were prescribed to approximately 16% of the subjects. IQ, epilepsy and psychiatric comorbidities were regarded as independent predictors of both mono- and polypharmacotherapy, while severity of repetitive behaviors predicted only polypharmacotherapy. Our data highlighted that medications prescribed to adolescents and adults with ASD are heterogeneous and often rely only on clinicians' experience. Future research should investigate the effectiveness of psychotropic drugs in this specific population, to promote the development of appropriate treatment guidelines.