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Background: Velo-cardio-facial syndrome (VCFS) is associated with deletions in the qll band of chromosome 22, learning disability and psychosis, but the neurobiological basis is poorly understood.Aims: To investigate brain anatomy in adults with VCFS.Method: Magnetic resonance imaging was used to study 10 patients with VCFS and 13 matched controls. We carried out three analyses: qualitative; traced regional brain volume; and measurement of grey and white matter volume.Results: The subjects with VCFS had: a high prevalence of white matter hyperintensities and abnormalities of the septum pellucidum; a significantly smaller volume of cerebellum; and widespread differences in white matter bilaterally and regional specific differences in grey matter in the left cerebellum, insula, and frontal and right temporal lobes.Conclusions: Deletion at chromosome 22q11 is associated with brain abnormalities that are most likely neurodevelopmental and may partially explain the high prevalence of learning disability and psychiatric disorder in VCFS. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented discussing the possible link between carbamazepine (CBZ) and neuroleptic malignant syndrome in which CBZ may play a role by acting on the sodium and potassium channels.

Abstract: Variation in estrogen level is reported by some to affect brain maturation and memory. The neurobiological basis for this may include modulation of the serotonergic system. No neuroimaging studies have directly examined the effect of extended estrogen therapy (ET), on the 5-HT2A receptor in human brain. We investigated the effect of long-term ET on cortical 5-HT2A receptor availability in postmenopausal women. In a cross-sectional study, we compared cortical 5-HT2A receptor availability in 17 postmenopausal ERT-naive women and 17 long-term oophorectomised estrogen-users, age- and IQ-matched using single photon emission tomography and the selective 5-HT2A receptor ligand 123I-5-I-R91150. Also, we used the Revised Wechsler Memory Scale to relate memory function to 5-HT2A receptor availability. Never-users had significantly higher 5-HT2A receptor availability than estrogen-users in hippocampus (1.17 vs. 1.11, respectively, p =0.02), although this did not remain significant after correction for multiple comparisons. Hippocampal 5-HT2A receptor availability correlated negatively with verbal and general memory and delayed recall (r =−0.45, p =0.01; r =−0.40, p =0.02; r =−0.36, p =0.04). Right superior temporal 5-HT2A receptor availability correlated negatively with verbal memory (r =−0.36, p =0.04). In estrogen-users, receptor availability correlated negatively with verbal and general memory (r =−0.70, p =0.002; r =−0.69, p =0.002); and in never-users, receptor availability negatively correlated with attention and concentration (r =−0.54, p =0.02). Long-term ET may be associated with lower 5-HT2A receptor availability in hippocampus. This may reflect increased activity within the serotonergic pathway leading to down-regulation of post-synaptic receptor. Also, increased availability of the 5-HT2A receptor in hippocampus is associated with poorer memory function. [Copyright &y& Elsevier]

Several multivariate prognostic models have been published to predict outcomes in patients with first episode psychosis (FEP), but it remains unclear whether those predictions generalize to independent populations. Using a subset of demographic and clinical baseline predictors, we aimed to develop and externally validate different models predicting functional outcome after a FEP in the context of a schizophrenia-spectrum disorder (FES), based on a previously published cross-validation and machine learning pipeline. A crossover validation approach was adopted in two large, international cohorts (EUFEST, n = 338, and the PSYSCAN FES cohort, n = 226). Scores on the Global Assessment of Functioning scale (GAF) at 12 month follow-up were dichotomized to differentiate between poor (GAF current < 65) and good outcome (GAF current ≥ 65). Pooled non-linear support vector machine (SVM) classifiers trained on the separate cohorts identified patients with a poor outcome with cross-validated balanced accuracies (BAC) of 65-66%, but BAC dropped substantially when the models were applied to patients from a different FES cohort (BAC = 50-56%). A leave-site-out analysis on the merged sample yielded better performance (BAC = 72%), highlighting the effect of combining data from different study designs to overcome calibration issues and improve model transportability. In conclusion, our results indicate that validation of prediction models in an independent sample is essential in assessing the true value of the model. Future external validation studies, as well as attempts to harmonize data collection across studies, are recommended., (© 2024. The Author(s).)

Objective: To investigate the relation between the use of Touch Screen Devices (TSDs), such as smartphones and tablets, and interference suppression as assessed by the Bivalent Shape Task (BST) in 5-11-year-old children., Methods: Thirty-eight children from a Dutch primary school were included. Interference suppression was measured in the incongruent level of the BST. TSD use was measured by a standardized interview. The dataset was analyzed using multilevel analysis because of its nested structure., Results: Children with moderate to high TSD use showed a longer reaction time (RT) as age progresses in the incongruent level ( T  = 2.40, p  = .017), compared to children with no to low TSD use. Furthermore, an interaction between TSD use, age, gender, and the incongruent level demonstrated an increased RT in boys with moderate to high TSD use compared to boys with no to low TSD use as age increases ( T  = -2.23, p  = .026)., Conclusion: The RT in response of interfering stimuli seems to be negatively influenced by TSD use as age progresses in children aged 5-11. Moreover, a gender-specific effect could be observed. Given the potential impact of these findings, more research would be helpful to further explore causal mechanisms.

In patients with psychosis, rates of tobacco smoking and childhood trauma are significantly higher compared to the general population. Childhood trauma has been proposed as a risk factor for tobacco smoking. However, little is known about the relationship between childhood trauma and smoking in psychosis. In a subsample of the Genetic Risk and Outcome of Psychosis study (760 patients with psychosis, 991 unaffected siblings, and 491 healthy controls), tobacco smoking was assessed using the Composite International Diagnostic Interview and childhood trauma was measured with the Childhood Trauma Questionnaire. Logistic regression models were used to assess associations between trauma and smoking, while correcting for confounders. Positive associations were found between total trauma, abuse, and neglect, and an increased risk for smoking in patients, while correcting for age and gender (OR trauma 1.77, 95% CI 1.30-2.42, p < 0.001; OR abuse 1.69, 95% CI 1.23-2.31, p = 0.001; OR neglect 1.48, 95% CI 1.08-2.02, p = 0.014). In controls, total trauma and abuse were positively associated with smoking, while correcting for age and gender (OR trauma 2.40, 95% CI 1.49-3.88, p < 0.001; OR abuse 2.02, 96% CI 1.23-3.32, p = 0.006). All associations lost their significance after controlling for additional covariates and multiple testing. Findings suggest that the association between childhood trauma and tobacco smoking can be mainly explained by confounders (gender, cannabis use, and education) in patients with psychosis. These identified aspects should be acknowledged in tobacco cessation programs., (© 2024. The Author(s).)

There is no multi-country/multi-language study testing a-priori multivariable associations between non-modifiable/modifiable factors and validated wellbeing/multidimensional mental health outcomes before/during the COVID-19 pandemic. Moreover, studies during COVID-19 pandemic generally do not report on representative/weighted non-probability samples. The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is a multi-country/multi-language survey conducting multivariable/LASSO-regularized regression models and network analyses to identify modifiable/non-modifiable factors associated with wellbeing (WHO-5)/composite psychopathology (P-score) change. It enrolled general population-representative/weighted-non-probability samples (26/04/2020-19/06/2022). Participants included 121,066 adults (age=42±15.9 years, females=64 %, representative sample=29 %) WHO-5/P-score worsened (SMD=0.53/SMD=0.74), especially initially during the pandemic. We identified 15 modifiable/nine non-modifiable risk and 13 modifiable/three non-modifiable protective factors for WHO-5, 16 modifiable/11 non-modifiable risk and 10 modifiable/six non-modifiable protective factors for P-score. The 12 shared risk/protective factors with highest centrality (network-analysis) were, for non-modifiable factors, country income, ethnicity, age, gender, education, mental disorder history, COVID-19-related restrictions, urbanicity, physical disorder history, household room numbers and green space, and socioeconomic status. For modifiable factors, we identified medications, learning, internet, pet-ownership, working and religion as coping strategies, plus pre-pandemic levels of stress, fear, TV, social media or reading time, and COVID-19 information. In multivariable models, for WHO-5, additional non-modifiable factors with |B|>1 were income loss, COVID-19 deaths. For modifiable factors we identified pre-pandemic levels of social functioning, hobbies, frustration and loneliness, and social interactions as coping strategy. For P-scores, additional non-modifiable/modifiable factors were income loss, pre-pandemic infection fear, and social interactions as coping strategy. COH-FIT identified vulnerable sub-populations and actionable individual/environmental factors to protect well-being/mental health during crisis times. Results inform public health policies, and clinical practice., Competing Interests: Conflict of interest Conflict of interest statements of all authors are detailed in eTable 12., (Copyright © 2024. Published by Elsevier B.V.)

Competing Interests: Declaration of interests PDM is a founding director, patron, and former founding board member of headspace. He is the executive director of Orygen, Australia's National Centre of Excellence in Youth Mental Health and lead agency for five headspace centres across northwest Melbourne. He is a past President of the International Association for Youth Mental Health, and a past President of the IEPA; Early Intervention in Mental Health and of the Schizophrenia International Research Society. S-JB has provided paid expert witness work for UK charities and legal organisations. She is the author of two books related to the brain, education, and learning, for which she receives royalties. She gives talks in schools in the state and private sector, at education conferences, for education organisations, and for other public, private, and third sector organisations (some talks are remunerated). She is a member of the Rethinking Assessment group, the Steering Committee of the Cambridge Centre of Science Policy, the Technical Advisory Group for the UK Government Department of Education's Education and Outcomes Panel-C Study, the Singapore Government National Research Foundation Scientific Advisory Board, and the Singapore Government Human Potential Scientific Advisory Board. She was a member of the Times Education Commission (2021–22). IBH has received honoraria for consultancy and educational activities from Janssen Cilag. He was a member of the Clinical Advisory Group for the evaluation of the Better Access to Psychiatrists, Psychologists and General Practitioners through the Medicare Benefits Schedule initiative, and is a member of Mental Health Reform Advisory Committee (Department of Health). He is the Chief Scientific Advisor to and a 3·2% equity shareholder in InnoWell, which aims to transform mental health services through the use of innovative technologies. FAEA has received honoraria for consultancy from Grand Challenges Canada and is a past member of the World Economic Forum's Global Future Council on Mental Health. AMC is a director of headspace, Australia's National Youth Mental Health Foundation, and the National Education Alliance for Borderline Personality Disorder. AD is the Academic Secretary for the Royal College of Psychiatrists’ Faculty of Child and Adolescent Psychiatry, a research advisory group member of the UK National Society for the Prevention of Cruelty to Children, a member of the UK Trauma Council, and an evidence panel member of the Early Intervention Foundation. TF's research group receives funding for consultancy to Place2Be, a third sector organisation that provides mental health training, support, and interventions to schools across the UK. JH is executive director of Youth Wellness Hubs Ontario and receives funding from Graham Boeckh Foundation and other donors through the Centre for Addiction and Mental Health Foundation. AJ is a trustee of the Samaritans and MQ. She has received fees for lecturing from the Scottish Association of Mental Health. She is an advisory board member of Our Future Health, UK. FK-L's work is the subject of publishing contracts with multiple companies in the EU, Magellan, Cobalt Therapeutics in the USA, and the National Health Service in the UK. Although she has received no remuneration to date, she might receive royalties in the future. She is a non-executive director of Orygen. CK is the founder of Wida, a digital mental health platform. He has received consulting fees from the UN Children's Fund. He has received grants from MQ: Transforming Mental Health in the UK, the Royal Academy of Engineering in the UK, the National Institutes of Health in the USA, the Medical Research Council in the UK, and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul in Brazil. DR is a Chief Scientific Advisor to headspace, Australia's National Youth Mental Health Foundation. JT receives book royalties from Simon and Schuster, legal consulting fees from Bergman and Little and the Attorney General's office of the State of Tennessee, and honoraria for speaking engagements. EK is the immediate past President of the IEPA: Early Intervention in Mental Health, and during the period of the Commission was the President elect and President. All other authors declare no competing interests.

Objectives: Ecological momentary interventions (EMI) are digital mobile health interventions administered in an individual's daily life to improve mental health by tailoring intervention components to person and context. Experience sampling via ecological momentary assessments (EMA) furthermore provides dynamic contextual information on an individual's mental health state. We propose a personalized data-driven generic framework to select and evaluate EMI based on EMA., Methods: We analyze EMA/EMI time-series from 10 individuals, published in a previous study. The EMA consist of multivariate psychological Likert scales. The EMI are mental health trainings presented on a smartphone. We model EMA as linear dynamical systems (DS) and EMI as perturbations. Using concepts from network control theory, we propose and evaluate three personalized data-driven intervention delivery strategies. Moreover, we study putative change mechanisms in response to interventions., Results: We identify promising intervention delivery strategies that outperform empirical strategies in simulation. We pinpoint interventions with a high positive impact on the network, at low energetic costs. Although mechanisms differ between individuals - demanding personalized solutions - the proposed strategies are generic and applicable to various real-world settings., Conclusions: Combined with knowledge from mental health experts, DS and control algorithms may provide powerful data-driven and personalized intervention delivery and evaluation strategies., (© 2024 The Author(s). International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

Background: Research on the pharmacogenetic influence of hepatic CYP450 enzyme 2D6 ( CYP2D6 ) on metabolism of drugs for psychosis and associated outcome has been inconclusive. Some results suggest increased risk of adverse reactions in poor and intermediate metabolizers, while others find no relationship. However, retrospective designs may fail to account for the long-term pharmacological treatment of patients. Previous studies found that clinicians adapted risperidone dose successfully without knowledge of patient CYP2D6 phenotype., Aim: Here, we aimed to replicate the results of those studies in a Dutch cohort of patients with psychosis ( N  = 418) on pharmacological treatment., Method: We compared chlorpromazine-equivalent dose between CYP2D6 metabolizer phenotypes and investigated which factors were associated with dosage. This was repeated in two smaller subsets; patients prescribed pharmacogenetics-actionable drugs according to published guidelines, and risperidone-only as done previously., Results: We found no relationship between chlorpromazine-equivalent dose and phenotype in any sample (complete sample: p  = 0.3, actionable-subset: p  = 0.82, risperidone-only: p  = 0.34). Only clozapine dose was weakly associated with CYP2D6 phenotype ( p  = 0.03)., Conclusion: Clinicians were thus not intuitively adapting dose to CYP2D6 activity in this sample, nor was CYP2D6 activity associated with prescribed dose. Although the previous studies could not be replicated, this study may provide support for existing and future pharmacogenetic research., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RvW has served/serves as an expert/received compensation from Lundbeck, Illumina, Benecke, PsyFar, Baxter, Chipsoft, NVvP, KNMP, KNMG, and WPA.

Background: Pharmacogenetics is considered a promising avenue for improving treatment outcomes, yet evidence arguing for the use of pharmacogenetics in the treatment of psychotic disorders is mixed and clinical usefulness is under debate. Many patients with psychosis use multiple medications, which can alter the metabolic capacity of CYP enzymes, a process called phenoconversion. In clinical studies, treatment outcomes of drugs for psychosis management may have been influenced by phenoconversion., Aim: Here we evaluate the impact and predictive value of CYP2D6 phenoconversion in patients with psychotic disorders under pharmacological treatment., Method: Phenoconversion-corrected phenotype was determined by accounting for inhibitor strength. Phenoconversion-corrected and genotype-predicted phenotypes were compared in association with side effects, subjective well-being and symptom severity., Results: Phenoconversion led to a large increase in poor metabolizers (PMs; 17-82, 16% of sample), due to concomitant use of the serotonin reuptake inhibitors fluoxetine and paroxetine. Neither CYP2D6-predicted nor phenoconversion-corrected phenotype was robustly associated with outcome measures. Risperidone, however, was most affected by the CYP2D6 genotype., Conclusion: Polypharmacy and phenoconversion were prevalent and accounted for a significant increase in PMs. CYP2D6 may play a limited role in side effects, symptoms and well-being measures. However, due to the high frequency of occurrence, phenoconversion should be considered in future clinical trials., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Introduction: Managing body weight in patients with antipsychotic-induced weight gain (AIWG) is challenging. Besides lifestyle interventions, pharmacological interventions may contribute to weight loss. This systematic review and meta-analysis evaluated the effect on weight loss and adverse effects of glucagon-like peptide-1 (GLP-1) agonists in patients with AIWG., Materials and Methods: Following PRISMA guidelines, we performed a meta-analysis of blinded and open-label randomised controlled trials (RCTs), non-randomised controlled trials and cohort studies that evaluated treatment with GLP-1 in patients with AIWG, regardless of psychiatric diagnosis. PubMed, Embase, PsycINFO and Cochrane Library databases were searched. Primary outcome measures were changes in body weight and BMI. Secondary outcomes were changes in adverse effects and severity of psychopathology due to GLP-1 agonists., Results: Only data for exenatide and liraglutide could be included, that is, five RCTs and one cohort study. For exenatide the mean weight loss was -2.48 kg (95% Confidence Interval (CI) -5.12 to +0.64; p = 0.07), for liraglutide the mean weight loss was -4.70 kg (95% CI -4.85 to -4.56; p < 0.001). The mean change in BMI was -0.82 (95% CI -1.56 to -0.09; p = 0.03) in the exenatide groups and -1.52 (95% CI -1.83 to -1.22; p < 0.001) in the liraglutide groups. Exenatide and liraglutide did not adversely affect psychopathology. The most common adverse events were nausea, vomiting, and diarrhoea., Conclusion: The GLP-1 agonists exenatide and liraglutide are promising drugs for inducing weight loss in patients with AIWG. The adverse effects are acceptable, and the addition of GLP-1 does not increase the severity of psychopathology. However, more research is needed., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function., (© 2024. The Author(s).)

Youth are at elevated risk of becoming victims of sexual exploitation, which has a detrimental impact on their physical and psychological well-being. Understanding factors associated with sexual exploitation is key for prevention efforts and adequate and timely treatment. This systematic review sheds more light on this by providing an overview of both risk and protective factors for sexual exploitation in male and female youth from a cross-cultural perspective. In all, 65 studies were selected meeting the inclusion criteria: qualitative or quantitative peer-reviewed studies in English, Dutch, or German with findings on risk and protective factors associated with sexual exploitation in youth aged up to 24 years. Results show that there are common risk factors in male and female youth worldwide (e.g., adverse childhood experiences, lack of a social network, substance use, and running away). Positive and supportive relationships are an important protective factor in mitigating the risk of sexual exploitation. Geographic differences were found. In non-Western continents, more environmental factors (e.g., economic vulnerabilities, residential instability) were cited. Research in countries outside the United States is limited and protective factors and males are underexamined. To fully understand vulnerabilities in youth, their interactions, and possible gender differences and to address the needs of diverse populations, more insight should be gained into the broader range of risk and protective factors worldwide. This systematic review has made a valuable contribution to this by providing practice, policy, and research guidance in the establishment of more targeted prevention efforts, adequate treatment, and areas to address in future research., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Sexually exploited young men are prevalent, yet underrepresented in clinical practice, policy and research. There are multiple barriers that often prevent young men to disclose and to seek or receive support, such as gender norms, limited awareness of victimization and feelings of guilt and shame., Objective: By gaining more insight into the background characteristics of young men who experienced sexual exploitation and their needs, this study aims to raise awareness and to better inform policymakers, care- and educational professionals on adequate prevention and intervention efforts., Methods: Twenty-six young men (age 14-32) who experienced sexual exploitation or other forms of sexual violence in their youth or were at high-risk, participated in this qualitative study that was conducted in The Netherlands. By means of semi-structured interviews and case-file analyses, data was collected to identify risk and protective factors in their life-course and support needs., Results: Several vulnerabilities (e.g. previous experiences of abuse and neglect, household dysfunction, social rejection, running away, substance use) and a lack of positive and supportive relationships led young men into high-risk situations. Among these were involvement in pay dates, criminality and having to survive from day to day, which contributed to victimization. Prevailing gender norms and experiences of stigmatization were often a barrier to express vulnerabilities and to disclose victimization. There was a wide variety in support needs, including peer-to-peer support, therapy, support with day-to-day practices and anonymous support., Conclusions: These results will contribute to adequate prevention and trauma-informed intervention strategies that meet the unique needs of young men at risk for, or victim of sexual exploitation., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Psychotic experiences (PEs) and social isolation (SI) seem related during early stages of psychosis, but the temporal dynamics between the two are not clear. Literature so far suggests a self-perpetuating cycle wherein momentary increases in PEs lead to social withdrawal, which, subsequently, triggers PEs at a next point in time, especially when SI is associated with increased distress. The current study investigated the daily-life temporal associations between SI and PEs, as well as the role of SI-related and general affective distress in individuals at clinical high risk (CHR) for psychosis., Methods: We used experience sampling methodology in a sample of 137 CHR participants. We analyzed the association between SI, PEs, and distress using time-lagged linear mixed-effects models., Results: SI did not predict next-moment fluctuations in PEs, or vice versa . Furthermore, although SI-related distress was not predictive of subsequent PEs, general affective distress during SI was a robust predictor of next-moment PEs., Conclusions: Our results suggest that SI and PEs are not directly related on a moment-to-moment level, but a negative emotional state when alone does contribute to the risk of PEs. These findings highlight the role of affective wellbeing during early-stage psychosis development.

Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3-8) for risperidone literature and 5 for aripiprazole (range: 4-6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

International studies measuring wellbeing/multidimensional mental health before/ during the COVID-19 pandemic, including representative samples for >2 years, identifying risk groups and coping strategies are lacking. COH-FIT is an online, international, anonymous survey measuring changes in well-being (WHO-5) and a composite psychopathology P-score, and their associations with COVID-19 deaths/restrictions, 12 a-priori defined risk individual/cumulative factors, and coping strategies during COVID-19 pandemic (26/04/2020-26/06/2022) in 30 languages (representative, weighted non-representative, adults). T-test, χ 2 , penalized cubic splines, linear regression, correlation analyses were conducted. Analyzing 121,066/142,364 initiated surveys, WHO-5/P-score worsened intra-pandemic by 11.1±21.1/13.2±17.9 points (effect size d=0.50/0.60) (comparable results in representative/weighted non-probability samples). Persons with WHO-5 scores indicative of depression screening (<50, 13% to 32%) and major depression (<29, 3% to 12%) significantly increased. WHO-5 worsened from those with mental disorders, female sex, COVID-19-related loss, low-income country location, physical disorders, healthcare worker occupations, large city location, COVID-19 infection, unemployment, first-generation immigration, to age=18-29 with a cumulative effect. Similar findings emerged for P-score. Changes were significantly but minimally related to COVID-19 deaths, returning to near-pre-pandemic values after >2 years. The most subjectively effective coping strategies were exercise and walking, internet use, social contacts. Identified risk groups, coping strategies and outcome trajectories can inform global public health strategies., Competing Interests: Declaration of competing interest Conflict of interest statements of all authors are detailed in eTable 8., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Resilience is a broad and dynamic concept that can be seen as being constituted by the combination of internal factors, for example, temperament profiles, and external factors, for example, social support. This paper aimed to identify temperament profiles in help-seeking youth exposed to adverse childhood experiences, and to investigate whether temperament (putative internal protective factor) interacts with social schemas (as proxy for the putative external protective factor social support) such that their combination is associated with (a) reduced mental health problems and (b) attenuated decrease in positive affect following daily life stressors., Methods: Self-report questionnaires were used to measure temperament, social schemas and mental health problems. The experience sampling method was used to assess stress and positive affect (i.e., stress-sensitivity as a potential daily life resilience mechanism). Temperament profiles were identified by latent profile analysis and regression analyses were used to examine (interaction) effects., Results: In 138 subjects, three temperament profiles were identified, that is, a moderate, volatile and persevering profile, of which the latter was negatively associated with mental health problems. Neither mental health problems nor stress sensitivity were found to be affected by the interaction between temperament and social schemas. However, positive social schemas were found to be independently associated with reduced mental health problems (b = -4.41; p = <.001) and reduced stress sensitivity (b = .10, p = .044)., Conclusions: Findings are relevant for both practice and research, and contribute to improving our understanding of putative protective factor in the development of mental ill-health, thereby further unravelling the construct of resilience., (© 2024 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Background: Worldwide, the division between Child and Adolescent Mental Health Services (CAMHS) and Adult Mental Health Services (AMHS) has frequently resulted in fragmented care with an unprepared, non-gradual transition. To improve continuity of care and other service transition experiences, service user input is essential. However, such previous qualitative studies are from a decade ago or focused on one mental disorder or country. The aim of the present study was to learn from service users' transition experiences and suggested improvements., Methods: Semi-structured interviews were held with young people aged 18-24 and/or parents/caregivers in the United Kingdom, Ireland, the Netherlands and Croatia. Inclusion was based on the experience of specialist mental health care before and after turning 18. Thematic analysis of transcribed and translated interview transcripts was performed using ATLAS.ti 9., Results: Main themes of service user experiences included abrupt changes in responsibilities, various barriers and a lack of preparation, communication and ongoing care. Young people expressed a great need for continuity of care. Their suggestions to improve transitional care included early and adequate preparation, joint working, improved communication from and between services, overlapping services, staying at CAMHS for longer and designated youth mental health teams., Conclusions: Young people who experienced care before and after turning 18 suggested either altering the age limits of services or ensuring early preparation and communication regarding the transition and finding AHMS. This communication should include general changes when turning 18. Further considerations include increasing collaboration and overlap between CAMHS and AMHS.

Objective: The Bivalent Shape Task (BST) tests the ability to suppress interfering information. The purpose of this study was to assess some psychometric properties of the BST in 5-11-year-old children, using multilevel analysis., Methods: The present study was initiated in a Dutch primary school in October 2019. The BST was administered as part of a larger neuropsychological assessment. The outbreak of Covid-19 and the subsequential lockdown in the Netherlands led to a premature termination of the study in March 2020. Data of 38 children were available. This dataset was analyzed and labeled as pilot., Results: Significant main effects of age, time components, levels, correct answer, and several interactions were found on the reaction time in the predicted direction. Random effects could also be modeled. A final statistical combination model is described., Conclusion: Despite the small study sample, it seems to be justified to conclude that the BST is a potentially valuable instrument to test interference suppression in 5-11-year-old children. In the analysis of the BST, multilevel analysis has proven to be very rewarding. Since the present study only examined a small part of reliability and validity aspects, further psychometric research is desired.

Background: We examined the course of illness over a 12-month period in a large, international multi-center cohort of people with a first-episode schizophrenia spectrum disorder (FES) in a naturalistic, prospective study (PSYSCAN)., Method: Patients with a first episode of schizophrenia, schizoaffective disorder (depressive type) or schizophreniform disorder were recruited at 16 institutions in Europe, Israel and Australia. Participants (N = 304) received clinical treatment as usual throughout the study., Results: The mean age of the cohort was 24.3 years (SD = 5.6), and 67 % were male. At baseline, participants presented with a range of intensities of psychotic symptoms, 80 % were taking antipsychotic medication, 68 % were receiving psychological treatment, with 46.5 % in symptomatic remission. The mean duration of untreated psychosis was 6.2 months (SD = 17.0). After one year, 67 % were in symptomatic remission and 61 % were in functional remission, but 31 % had been readmitted to hospital at some time after baseline. In the cohort as a whole, depressive symptoms remained stable over the follow-up period. In patients with a current depressive episode at baseline, depressive symptoms slightly improved. Alcohol, tobacco and cannabis were the most commonly used substances, with daily users of cannabis ranging between 9 and 11 % throughout the follow-up period., Conclusions: This study provides valuable insight into the early course of a broad range of clinical and functional aspects of illness in FES patients in routine clinical practice., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. Dr. Glenthøj has been the leader of a Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) (January 2009 – December 2021), which was partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations. All grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them. She has no other conflicts to disclose. Dr. Sachs has been a consultant to or has received honoraria from Angelini, Janssen Cilag, Lundbeck, Mylan, Recordati. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) ( N  = 135), Clinical High Risk (CHR) ( N  = 233), and First Episode Psychosis (FEP) ( N  = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52-0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18-0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82-0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design., Competing Interests: The following conflicts of interest are declared: Robert A. McCutcheon has received speaker/consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and co-directs a company that designs digital resources to support treatment of mental illness. Gemma Modinos has received consultancy fees from Boehringer Ingelheim for work unrelated to this study. Silvana Galderisi received advisory board/consultant fees, or honoraria/expenses from the following drug companies: Angelini, Boehringer Ingelheim, Gedeon Richter-Recordati, Innova Pharma-Recordati Group, Janssen, Lundbeck, Otsuka, Recordati Pharmaceuticals, Rovi Pharma and Sunovion Pharmaceuticals outside the submitted work., (© 2024 Published by Elsevier Inc.)

Importance: Targeting low self-esteem in youth exposed to childhood adversity is a promising strategy for preventing adult mental disorders. Ecological momentary interventions (EMIs) allow for the delivery of youth-friendly, adaptive interventions for improving self-esteem, but robust trial-based evidence is pending., Objective: To examine the efficacy of SELFIE, a novel transdiagnostic, blended EMI for improving self-esteem plus care as usual (CAU) compared with CAU only., Design, Setting, and Participants: This was a 2-arm, parallel-group, assessor-blinded, randomized clinical trial conducted from December 2018 to December 2022. The study took place at Dutch secondary mental health services and within the general population and included youth (aged 12-26 years) with low self-esteem (Rosenberg Self-Esteem Scale [RSES] <26) exposed to childhood adversity., Interventions: A novel blended EMI (3 face-to-face sessions, email contacts, app-based, adaptive EMI) plus CAU or CAU only., Main Outcomes and Measures: The primary outcome was RSES self-esteem at postintervention and 6-month follow-up. Secondary outcomes included positive and negative self-esteem, schematic self-beliefs, momentary self-esteem and affect, general psychopathology, quality of life, observer-rated symptoms, and functioning., Results: A total of 174 participants (mean [SD] age, 20.7 [3.1] years; 154 female [89%]) were included in the intention-to-treat sample, who were primarily exposed to childhood emotional abuse or neglect, verbal or indirect bullying, and/or parental conflict. At postintervention, 153 participants (87.9%) and, at follow-up, 140 participants (80.5%), provided primary outcome data. RSES self-esteem was, on average, higher in the experimental condition (blended EMI + CAU) than in the control condition (CAU) across both postintervention and follow-up as a primary outcome (B = 2.32; 95% CI, 1.14-3.50; P < .001; Cohen d-type effect size [hereafter, Cohen d] = 0.54). Small to moderate effect sizes were observed suggestive of beneficial effects on positive (B = 3.85; 95% CI, 1.83-5.88; P < .001; Cohen d = 0.53) and negative (B = -3.78; 95% CI, -6.59 to -0.98; P = .008; Cohen d = -0.38) self-esteem, positive (B = 1.58; 95% CI, 0.41-2.75; P = .008; Cohen d = 0.38) and negative (B = -1.71; 95% CI, -2.93 to -0.48; P = .006; Cohen d = -0.39) schematic self-beliefs, momentary self-esteem (B = 0.29; 95% CI, 0.01-0.57; P = .04; Cohen d = 0.24), momentary positive affect (B = 0.23; 95% CI, 0.01-0.45; P = .04; Cohen d = 0.20), momentary negative affect (B = -0.33; 95% CI, -0.59 to -0.03, P = .01, Cohen d = -0.27), general psychopathology (B = -17.62; 95% CI, -33.03 to -2.21; P = .03; Cohen d = -0.34), and quality of life (B = 1.16; 95% CI, 0.18-2.13; P = .02; Cohen d = 0.33) across postintervention and follow-up. No beneficial effects on symptoms and functioning were observed., Conclusions and Relevance: A transdiagnostic, blended EMI demonstrated efficacy on the primary outcome of self-esteem and signaled beneficial effects on several secondary outcomes. Further work should focus on implementing this novel EMI in routine public mental health provision., Trial Registration: Dutch Trial Register Identifier:NL7129(NTR7475).

(1) Background Pharmacological treatment for psychiatric disorders has shown to only be effective in about one-third of patients, as it is associated with frequent treatment failure, often because of side effects, and a long process of trial-and-error pharmacotherapy until an effective and tolerable treatment is found. This notion emphasizes the urgency for a personalized medicine approach in psychiatry. (2) Methods This prospective patient- and rater-blinded, randomized, controlled study will investigate the effect of dose-adjustment of antidepressants escitalopram and sertraline or antipsychotics risperidone and aripiprazole according to the latest state-of-the-art international dosing recommendations for CYP2C19 and CYP2D6 metabolizer status in patients with mood, anxiety, and psychotic disorders. A total sample of N = 2500 will be recruited at nine sites in seven countries (expected drop-out rate of 30%). Patients will be randomized to a pharmacogenetic group or a dosing-as-usual group and treated over a 24-week period with four study visits. The primary outcome is personal recovery using the Recovery Assessment Scale as assessed by the patient (RAS-DS), with secondary outcomes including clinical effects (response or symptomatic remission), side effects, general well-being, digital phenotyping, and psychosocial functioning. (3) Conclusions This is, to our knowledge, the first international, multi-center, non-industry-sponsored randomized controlled trial (RCT) that may provide insights into the effectiveness and utility of implementing pharmacogenetic-guided treatment of psychiatric disorders, and as such, results will be incorporated in already available dosing guidelines.

Background: In the future, clinicians might use information about neurobiological processes, obtained through imaging techniques, to guide personalized prevention and intervention strategies for psychosis and related disorders. However, this requires more knowledge about these individuals&rsquo; brain function., Aim: To advance the current knowledge on neurobiological processes in patients with schizophrenia spectrum disorders (SSD) and individuals at increased risk of these disorders., Method: We conducted a systematic review to address dopaminergic alterations in individuals at increased risk of SSD. Additionally, we acquired PET and MRI scans in patients with SSD and controls to obtain information about neurotransmitters, such as dopamine., Results: Striatal dopamine synthesis capacity was altered in individuals at increased risk of developing SSD compared to controls. In healthy volunteers, the concentration of neuromelanin, a breakdown product of dopamine, in the substantia nigra was negatively associated with striatal dopamine synthesis capacity. This was not the case for patients with SSD., Conclusion: We report differences in neurobiological processes and their interrelationships between patients with psychotic and related disorders and controls. This information may help predict psychosis susceptibility and treatment effectiveness in the future. Our findings can therefore contribute to the development of personalized treatments and better counselling of the patient.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Social cognitive impairment is a recognized feature of psychotic disorders. However, potential age-related differences in social cognitive impairment have rarely been studied., Study Design: Data came from 905 individuals with a psychotic disorder, 966 unaffected siblings, and 544 never-psychotic controls aged 18-55 who participated in the Genetic Risk and Outcome of Psychosis (GROUP) study. Multilevel linear models were fitted to study group main effects and the interaction between group and age on emotion perception and processing (EPP; degraded facial affect recognition) and theory of mind (ToM; hinting task) performance. Age-related differences in the association between socio-demographic and clinical factors, and EPP and ToM were also explored., Study Results: Across groups, EPP performance was associated with age (β = -0.02, z = -7.60, 95% CI: -0.02, -0.01, P < .001), with older participants performing worse than younger ones. A significant group-by-age interaction on ToM (X2(2) = 13.15, P = .001) indicated that older patients performed better than younger ones, while no age-related difference in performance was apparent among siblings and controls. In patients, the association between negative symptoms and ToM was stronger for younger than older patients (z = 2.16, P = .03)., Conclusions: The findings point to different age-related performance patterns on tests of 2 key social cognitive domains. ToM performance was better in older individuals, although this effect was only observed for patients. EPP was less accurate in older compared with younger individuals. These findings have implications with respect to when social cognitive training should be offered to patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Hypothesis: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes., Study Design: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score., Study Results: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores., Conclusions: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Suicide is a leading cause of death in individuals with psychotic disorders. Risk factors for suicidality across the psychosis vulnerability spectrum are insufficiently known., Methods: For patients (n = 830), siblings (n = 664) and controls (n = 444), suicidality was assessed by the use of a clinical interview. Multilevel modelling was used to investigate risk factors of suicidality. Lastly, risk factor × familial risk interaction effects were examined., Results: Multivariable models revealed a significant relation between suicidality and depressive symptoms across all three groups, and childhood trauma in patients and siblings. The association between suicidality and psychotic-like experiences is more pronounced in siblings compared to controls., Conclusion: Across the psychosis vulnerability spectrum, depressive symptoms and childhood trauma have been associated with suicidality. Clinicians should pay attention to suicidality in individuals at high familial risk for psychosis with psychotic-like experiences., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: 22q11.2 Deletion Syndrome (22q11DS) is a genetic disorder characterized by the deletion of adjacent genes at a location specified as q11.2 of chromosome 22, resulting in an array of clinical phenotypes including autistic spectrum disorder, schizophrenia, congenital heart defects, and immune deficiency. Many characteristics of the disorder are known, such as the phenotypic variability of the disease and the biological processes associated with it; however, the exact and systemic molecular mechanisms between the deleted area and its resulting clinical phenotypic expression, for example that of neuropsychiatric diseases, are not yet fully understood., Results: Using previously published transcriptomics data (GEO:GSE59216), we constructed two datasets: one set compares 22q11DS patients experiencing neuropsychiatric diseases versus healthy controls, and the other set 22q11DS patients without neuropsychiatric diseases versus healthy controls. We modified and applied the pathway interaction method, originally proposed by Kelder et al. (2011), on a network created using the WikiPathways pathway repository and the STRING protein-protein interaction database. We identified genes and biological processes that were exclusively associated with the development of neuropsychiatric diseases among the 22q11DS patients. Compared with the 22q11DS patients without neuropsychiatric diseases, patients experiencing neuropsychiatric diseases showed significant overrepresentation of regulated genes involving the natural killer cell function and the PI3K/Akt signalling pathway, with affected genes being closely associated with downregulation of CRK like proto-oncogene adaptor protein. Both the pathway interaction and the pathway overrepresentation analysis observed the disruption of the same biological processes, even though the exact lists of genes collected by the two methods were different., Conclusions: Using the pathway interaction method, we were able to detect a molecular network that could possibly explain the development of neuropsychiatric diseases among the 22q11DS patients. This way, our method was able to complement the pathway overrepresentation analysis, by filling the knowledge gaps on how the affected pathways are linked to the original deletion on chromosome 22. We expect our pathway interaction method could be used for problems with similar contexts, where complex genetic mechanisms need to be identified to explain the resulting phenotypic plasticity., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD., (© 2023. The Author(s).)

Background: Treatment-resistant depression (TRD) is a substantial public health burden, but current treatments have limited effectiveness. The aim was to investigate the safety and potential antidepressant effects of the serotonergic psychedelic drug 5-MeO-DMT in a vaporized formulation (GH001) in adult patients with TRD., Methods: The Phase 1 part ( n  = 8) of the trial investigated two single dose levels of GH001 (12 mg, 18 mg) with a primary endpoint of safety, and the Phase 2 part ( n  = 8) investigated an individualized dosing regimen (IDR) with up to three increasing doses of GH001 (6 mg, 12 mg, and 18 mg) within a single day, with a primary endpoint of efficacy, as assessed by the proportion of patients in remission (MADRS ≤ 10) on day 7., Results: Administration of GH001 via inhalation was well tolerated. The proportion of patients in remission (MADRS ≤ 10) at day 7 was 2/4 (50%) and 1/4 (25%) in the 12 mg and 18 mg groups of Phase 1, respectively, and 7/8 (87.5%) in the IDR group of Phase 2, meeting its primary endpoint ( p  < 0.0001). All remissions were observed from day 1, with 6/10 remissions observed from 2 h. The mean MADRS change from baseline to day 7 was -21.0 (-65%) and - 12.5 (-40%) for the 12 and 18 mg groups, respectively, and - 24.4 (-76%) for the IDR., Conclusion: Administration of GH001 to a cohort of 16 patients with TRD was well tolerated and provided potent and ultra-rapid antidepressant effects. Individualized dosing with up to three doses of GH001 on a single day was superior to single dose administration. Clinical Trial registration : Clinicaltrials.gov Identifier NCT04698603., Competing Interests: JRe and JRa are scientific consultants to GH Research. TT is an employee and shareholder of GH Research. The authors declare that this study received funding from GH Research. The funder had the following involvement in the study: study design, data analysis and preparation of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Reckweg, van Leeuwen, Henquet, van Amelsvoort, Theunissen, Mason, Paci, Terwey and Ramaekers.)

Personal recovery transcends illness and is a unifying human experience. Core elements in personal recovery are hope, meaning, and rebuilding oneself. Here we aim to investigate whether factors associated with personal recovery in patients with non-affective psychosis, unaffected siblings and healthy controls are similar. We investigated the association between personal recovery and resilience, social support, socio-demographic and illness-related variables in 580 patients, 630 siblings, and 351 healthy controls who participated in the Genetic Risk and Outcome of Psychosis (GROUP) study. Bi-variate associations between personal recovery and individual variables were assessed and multiple linear regression analyses were performed to estimate the proportion of variance in personal recovery that could be accounted for by the predictors and to investigate which predictors independently added to the model. Positive self was significantly and independently associated with personal recovery in all three groups. Pro-active action taking also seems to be important. Social functioning significantly contributed to explained variance in patients and siblings. Regarding illness-related factors, depressive symptoms had impact on personal recovery in both patients and siblings, whereas positive symptoms only did in siblings. The findings imply that not only personal recovery itself, but also some associated factors are universally human and suit us all. This means that patients and non-patients share supportive factors of personal recovery which may help to reach mutual understanding. Recovery-oriented practices and mental health services might be more effective when focusing also on improving self-image, functional coping styles and generating social interaction, next to the reduction of affective symptoms., Competing Interests: Declaration of competing interest The authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Dopaminergic dysregulation is one of the leading hypotheses for the pathoetiology underlying psychotic disorders such as schizophrenia. Molecular imaging studies have shown increased striatal dopamine synthesis capacity (DSC) in schizophrenia and people in the prodrome of psychosis. However, it is unclear if genetic risk for psychosis is associated with altered DSC. To investigate this, we recruited healthy controls and two antipsychotic naive groups of individuals with copy number variants, one with a genetic deletion at chromosome 22q11.2, and the other with a duplication at the same locus, who are at increased and decreased risk for psychosis, respectively. Fifty-nine individuals (21 with 22q11.2 deletion, 12 with the reciprocal duplication and 26 healthy controls) received clinical measures and [18F]-DOPA PET imaging to index striatal Ki cer . There was an inverse linear effect of copy number variant number on striatal Ki cer value (B = -1.2 × 10 -3 , SE = 2 × 10 -4 , p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Ki cer was significantly higher in the 22q11.2 deletion group compared to the healthy control (p < 0.001, Cohen's d = 1.44) and 22q11.2 duplication (p < 0.001, Cohen's d = 2) groups. Moreover, Ki cer was positively correlated with the severity of psychosis-risk symptoms (B = 730.5, SE = 310.2, p < 0.05) and increased over time in the subject who went on to develop psychosis, but was not associated with anxiety or depressive symptoms. Our findings suggest that genetic risk for psychosis is associated with dopaminergic dysfunction and identify dopamine synthesis as a potential target for treatment or prevention of psychosis in 22q11.2 deletion carriers., (© 2021. The Author(s).)