Evaluating changes in functioning and psychological distress in visitors of the @ease youth mental health walk-in centres.

BACKGROUND: Highly accessible youth initiatives worldwide aim to prevent worsening of mental health problems, but research into outcomes over time is scarce. AIMS: This study aimed to evaluate outcomes and support use in 12- to 15-year-old visitors of the @ease mental health walk-in centres, a Dutch initiative offering free counselling by trained and supervised peers. METHOD: Data of 754 visitors, collected 2018-2022, included psychological distress (Clinical Outcomes in Routine Evaluation 10 (CORE-10)), social and occupational functioning (Social and Occupational Functioning Assessment Scale (SOFAS)), school absenteeism and support use, analysed with change indicators (first to last visit), and mixed models (first three visits). RESULTS: Among return visitors, 50.5% were female, 79.4% were in tertiary education and 36.9% were born outside of The Netherlands (one-time visitors: 64.7%, 72.9% and 41.3%, respectively). Moreover, 29.9% of return visitors presented with suicidal ideations, 97.1% had clinical psychological distress levels, and 64.1% of the latter had no support in the previous 3 months (one-time visitors: 27.2%, 90.7% and 71.1%, respectively). From visit 1 to 3, psychological distress decreased (ß = -3.79, 95% CI -5.41 to -2.18; P < 0.001) and social and occupational functioning improved (ß = 3.93, 95% CI 0.51-7.36; P = 0.025). Over an average 3.9 visits, 39.6% improved reliably and 28.0% improved clinically significantly on the SOFAS, which was 28.4% and 8.8%, respectively, on the CORE-10, where 43.2% improved in clinical category. Counselling satisfaction was rated 4.5/5. CONCLUSIONS: Reductions in psychological distress, improvements in functioning and high counselling satisfaction were found among @ease visitors, forming a basis for future research with a control group.

Endocannabinoid levels in plasma and neurotransmitters in the brain: a preliminary report on patients with a psychotic disorder and healthy individuals.

BACKGROUND: Interactions between the endocannabinoid system (ECS) and neurotransmitter systems might mediate the risk of developing a schizophrenia spectrum disorder (SSD). Consequently, we investigated in patients with SSD and healthy controls (HC) the relations between (1) plasma concentrations of two prototypical endocannabinoids (N-arachidonoylethanolamine [anandamide] and 2-arachidonoylglycerol [2-AG]) and (2) striatal dopamine synthesis capacity (DSC), and glutamate and y-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC). As anandamide and 2-AG might reduce the activity of these neurotransmitters, we hypothesized negative correlations between their plasma levels and the abovementioned neurotransmitters in both groups. METHODS: Blood samples were obtained from 18 patients and 16 HC to measure anandamide and 2-AG plasma concentrations. For all subjects, we acquired proton magnetic resonance spectroscopy scans to assess Glx (i.e. glutamate plus glutamine) and GABA + (i.e. GABA plus macromolecules) concentrations in the ACC. Ten patients and 14 HC also underwent [18F]F-DOPA positron emission tomography for assessment of striatal DSC. Multiple linear regression analyses were used to investigate the relations between the outcome measures. RESULTS: A negative association between 2-AG plasma concentration and ACC Glx concentration was found in patients (p = 0.008). We found no evidence of other significant relationships between 2-AG or anandamide plasma concentrations and dopaminergic, glutamatergic, or GABAergic measures in either group. CONCLUSIONS: Our preliminary results suggest an association between peripheral 2-AG and ACC Glx levels in patients.

Hearing loss and history of otolaryngological conditions in adults with microdeletion 22q11.2.

Previous studies have shown that the 22q11.2 microdeletion, associated with 22q11.2 deletion syndrome (22q11.2DS), conveys an increased risk of chronic otitis media, and hearing loss at young age. This study reports on hearing loss and history of otolaryngological conditions in adults with 22q11.2DS. We conducted a retrospective study of 60 adults with 22q11.2DS (41.7% male) at median age 25 (range 16-74) years who had visited an otolaryngologist and audiologist for routine assessment at a 22q11.2 expert center. Demographic, genetic, audiometric, and otolaryngological data were systematically extracted from the medical files. Regression analysis was used to evaluate the effect of age, sex, full-scale intelligence quotient, and history of chronic otitis media on the severity of hearing loss. Hearing loss, mostly high-frequency sensorineural, was found in 78.3% of adults. Higher age and history of chronic otitis media were associated with more severe hearing loss. Otolaryngological conditions with possible treatment implications included chronic otitis media (56.7%), globus pharyngeus (18.3%), balance problems (16.7%), and obstructive sleep apnea (8.3%). The results suggest that  in 22q11.2DS, high-frequency hearing loss appears to be common from a young adult age, and often unrecognized. Therefore, we recommend periodic audiometric screening in all adults, including high-frequency ranges.

The Effects of a Digital, Transdiagnostic, Clinically and Peer-Moderated Treatment Platform for Young People With Emerging Mental Health Complaints: Repeated Measures Within-Subjects Study.

BACKGROUND: To address the growing prevalence of youth mental health problems, early intervention is crucial to minimize individual, societal, and economic impacts. Indicative prevention aims to target emerging mental health complaints before the onset of a full-blown disorder. When intervening at this early stage, individuals are more responsive to treatment, resulting in cost-effective outcomes. The Moderated Online Social Therapy platform, which was successfully implemented and proven effective in Australia, is a digital, peer- and clinically moderated treatment platform designed for young people. The Netherlands was the first country outside Australia to implement this platform, under the name Engage Young People Early (ENYOY). It has the potential to reduce the likelihood of young people developing serious mental health disorders. OBJECTIVE: This study aims to investigate the effects on young people using the ENYOY-platform in relation to psychological distress, psychosocial functioning, and positive health parameters. METHODS: Dutch-speaking young people with emerging mental health complaints (N=131) participated in the ENYOY-platform for 6 months in a repeated measures within-subjects study. Psychological distress, psychosocial functioning, and positive health parameters were assessed at baseline and 3, 6, and 12 months. Repeated measures ANOVA was conducted and adjusted for age, sex, therapy, and community activity. The Reliable Change Index and Clinically Significant Index were computed to compare the baseline with the 6- and 12-month measurements. The missing data rate was 22.54% and the dropout rate 62.6% (82/131). RESULTS: The primary analysis (77/131, 58.8%) showed that psychological distress decreased and psychosocial functioning improved over time with large effect sizes (P<.001 in both cases; ηp2=0.239 and 0.318, respectively) independent of age (P=.76 for psychological distress and P=.48 for psychosocial functioning), sex (P=.24 and P=.88, respectively), therapy activity (P=.49 and P=.80, respectively), or community activity (P=.59 and P=.48, respectively). Similarly, secondary analyses (51/131, 38.9%) showed significant effects of time on the quality of life, well-being, and meaningfulness positive health parameters (P<.05; ηp2=0.062, 0.140, and 0.121, respectively). Improvements in all outcome measures were found between baseline and 3 and 6 months (P≤.001-.01; d=0.23-0.62) and sustained at follow-up (P=.18-.97; d=0.01-0.16). The Reliable Change Index indicated psychological distress improvements in 38% (39/102) of cases, no change in 54.9% (56/102) of cases, and worsening in 5.9% (6/102) of cases. Regarding psychosocial functioning, the percentages were 50% (51/102), 43.1% (44/102), and 6.9% (7/102), respectively. The Clinically Significant Index demonstrated clinically significant changes in 75.5% (77/102) of cases for distress and 89.2% (91/102) for functioning. CONCLUSIONS: This trial demonstrated that the ENYOY-platform holds promise as a transdiagnostic intervention for addressing emerging mental health complaints among young people in the Netherlands and laid the groundwork for further clinical research. It would be of great relevance to expand the population on and service delivery of the platform. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12888-021-03315-x.

The association between clinical, sociodemographic, familial, and environmental factors and treatment resistance in schizophrenia: A machine-learning-based approach.

BACKGROUND: Prediction of treatment resistance in schizophrenia (TRS) would be helpful to reduce the duration of ineffective treatment and avoid delays in clozapine initiation. We applied machine learning to identify clinical, sociodemographic, familial, and environmental variables that are associated with TRS and could potentially predict TRS in the future. STUDY DESIGN: Baseline and follow-up data on trait(-like) variables from the Genetic Risk and Outcome of Psychosis (GROUP) study were used. For the main analysis, we selected patients with non-affective psychotic disorders who met TRS (n = 200) or antipsychotic-responsive criteria (n = 423) throughout the study. For a sensitivity analysis, we only selected patients who met TRS (n = 76) or antipsychotic-responsive criteria (n = 123) at follow-up but not at baseline. Random forest models were trained to predict TRS in both datasets. SHapley Additive exPlanation values were used to examine the variables' contributions to the prediction. STUDY RESULTS: Premorbid functioning, age at onset, and educational degree were most consistently associated with TRS across both analyses. Marital status, current household, intelligence quotient, number of moves, and family loading score for substance abuse also consistently contributed to the prediction of TRS in the main or sensitivity analysis. The diagnostic performance of our models was modest (area under the curve: 0.66-0.69). CONCLUSIONS: We demonstrate that various clinical, sociodemographic, familial, and environmental variables are associated with TRS. Our models only showed modest performance in predicting TRS. Prospective large multi-centre studies are needed to validate our findings and investigate whether the model's performance can be improved by adding data from different modalities.

@ease peer-to-peer youth walk-in centres in The Netherlands: A protocol for evaluating longitudinal outcomes, follow-up results and cost-of-illness.

AIM: Innovative youth mental health services around the globe vigorously work on increasing highly needed mental health care accessibility but their service users and care effectiveness have rarely been studied. The Dutch youth walk-in centres of @ease opened in 2018, with currently 11 locations at which free anonymous peer-to-peer counselling is offered to young people aged 12-25. The aim of this protocol is to outline the to-be-conducted research at @ease. METHODS: Three studies are outlined: (1) an outcome evaluation of @ease visits using hierarchical mixed model analyses and change calculations, (2) a cost-of-illness study using calculations for costs of truancy and care usage among these help-seeking young people, with regression analyses for risk group identification, and (3) a follow-up evaluation at three, six and 12 months to assess long-term effects after ending @ease visits. Data provided by young people include demographics, parental mental illness, truancy, past treatment, psychological distress (CORE-10) and health-related quality of life (EQ-5D-5L). Social and occupational functioning (SOFAS), suicidal ideation and need for referral are rated by the counsellors. Questionnaires are filled out at the end of every visit and at follow-up via e-mail or text, provided permission is given. DISCUSSION: Research regarding the visitors and effectiveness of the @ease services is fully original. It offers unique insights into the mental wellbeing and cost-of-illness of young people who may otherwise remain unseen while suffering from a high disease burden. The upcoming studies shed light on this unseen group, inform policy and practice and direct future research.

Updated clinical practice recommendations for managing adults with 22q11.2 deletion syndrome.

This review aimed to update the clinical practice guidelines for managing adults with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society recruited expert clinicians worldwide to revise the original clinical practice guidelines for adults in a stepwise process according to best practices: (1) a systematic literature search (1992-2021), (2) study selection and synthesis by clinical experts from 8 countries, covering 24 subspecialties, and (3) formulation of consensus recommendations based on the literature and further shaped by patient advocate survey results. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text review, with 2318 meeting inclusion criteria (clinical care relevance to 22q11.2DS) including 894 with potential relevance to adults. The evidence base remains limited. Thus multidisciplinary recommendations represent statements of current best practice for this evolving field, informed by the available literature. These recommendations provide guidance for the recognition, evaluation, surveillance, and management of the many emerging and chronic 22q11.2DS-associated multisystem morbidities relevant to adults. The recommendations also address key genetic counseling and psychosocial considerations for the increasing numbers of adults with this complex condition.

The substantia nigra in the pathology of schizophrenia: A review on post-mortem and molecular imaging findings.

Dysregulation of striatal dopamine is considered to be an important driver of pathophysiological processes in schizophrenia. Despite being one of the main origins of dopaminergic input to the striatum, the (dys)functioning of the substantia nigra (SN) has been relatively understudied in schizophrenia. Hence, this paper aims to review different molecular aspects of nigral functioning in patients with schizophrenia compared to healthy controls by integrating post-mortem and molecular imaging studies. We found evidence for hyperdopaminergic functioning in the SN of patients with schizophrenia (i.e. increased AADC activity in antipsychotic-free/-naïve patients and elevated neuromelanin accumulation). Reduced GABAergic inhibition (i.e. decreased density of GABAergic synapses, lower VGAT mRNA levels and lower mRNA levels for GABAA receptor subunits), excessive glutamatergic excitation (i.e. increased NR1 and Glur5 mRNA levels and a reduced number of astrocytes), and several other disturbances implicating the SN (i.e. immune functioning and copper concentrations) could potentially underlie this nigral hyperactivity and associated striatal hyperdopaminergic functioning in schizophrenia. These results highlight the importance of the SN in schizophrenia pathology and suggest that some aspects of molecular functioning in the SN could potentially be used as treatment targets or biomarkers.

Does baseline EEG activity differ in the transition to or from a chronic pain state? A longitudinal study.

BACKGROUND AND AIM: Identifying EEG brain markers might yield better mechanistic insights into how chronic pain develops and could be treated. An existing longitudinal EEG study gave us the opportunity to determine whether the development of pain is accompanied by less alpha power-ie, a "relaxed" brain state-and vice versa. METHODS: Five-minute resting EEG with the eyes open was measured 2 times in 95 subjects at T0 (baseline) and T1 (6 months later). Based on the Short-Form Health Survey and Brief Pain Inventory questionnaire, subjects were divided into 4 groups: staying pain-free (n = 44), developing chronic pain (n = 8), becoming pain-free (n = 15), and ongoing chronic pain (n = 28). The EEG data of 14 electrodes were analyzed by multilevel regression. RESULTS: The group that developed chronic pain demonstrated less power in the lower-frequency bands over time during the resting state EEG, whereas the transition to a pain-free state had the opposite pattern. Thus, the a priori hypothesis was confirmed. CONCLUSIONS: Transitions in pain states are linked to a change in baseline EEG activity. Future research is needed to replicate these results in a larger study sample and in targeted clinical populations. Furthermore, these results might be beneficial in optimizing neurofeedback algorithms for the treatment of chronic pain.

Parkinsonism in Genetic Neurodevelopmental Disorders: A Systematic Review.

Background: With advances in clinical genetic testing, associations between genetic neurodevelopmental disorders and parkinsonism are increasingly recognized. In this review, we aimed to provide a comprehensive overview of reports on parkinsonism in genetic neurodevelopmental disorders and summarize findings related to genetic diagnosis, clinical features and proposed disease mechanisms. Methods: A systematic literature review was conducted in PubMed and Embase on June 15, 2021. Search terms for parkinsonism and genetic neurodevelopmental disorders, using generic terms and the Human Phenotype Ontology, were combined. Study characteristics and descriptive data were extracted from the articles using a modified version of the Cochrane Consumers and Communication Review Group's data extraction template. The protocol was registered in PROSPERO (CRD42020191035). Results: The literature search yielded 208 reports for data-extraction, describing 69 genetic disorders in 422 patients. The five most reported from most to least frequent were: 22q11.2 deletion syndrome, beta-propeller protein-associated neurodegeneration, Down syndrome, cerebrotendinous xanthomatosis, and Rett syndrome. Notable findings were an almost equal male to female ratio, an early median age of motor onset (26 years old) and rigidity being more common than rest tremor. Results of dopaminergic imaging and response to antiparkinsonian medication often supported the neurodegenerative nature of parkinsonism. Moreover, neuropathology results showed neuronal loss in the majority of cases. Proposed disease mechanisms included aberrant mitochondrial function and disruptions in neurotransmitter metabolism, endosomal trafficking, and the autophagic-lysosomal and ubiquitin-proteasome system. Conclusion: Parkinsonism has been reported in many GNDs. Findings from this study may provide clues for further research and improve management of patients with GNDs and/or parkinsonism.

Resting-state functional connectivity in adults with 47,XXX: a 7 Tesla MRI study.

Triple X syndrome is a sex chromosomal aneuploidy characterized by the presence of a supernumerary X chromosome, resulting in a karyotype of 47,XXX in affected females. It has been associated with a variable cognitive, behavioral, and psychiatric phenotype, but little is known about its effects on brain function. We therefore conducted 7 T resting-state functional magnetic resonance imaging and compared data of 19 adult individuals with 47,XXX and 21 age-matched healthy control women using independent component analysis and dual regression. Additionally, we examined potential relationships between social cognition and social functioning scores, and IQ, and mean functional connectivity values. The 47,XXX group showed significantly increased functional connectivity of the fronto-parietal resting-state network with the right postcentral gyrus. Resting-state functional connectivity (rsFC) variability was not associated with IQ and social cognition and social functioning deficits in the participants with 47,XXX. We thus observed an effect of a supernumerary X chromosome in adult women on fronto-parietal rsFC. These findings provide additional insight into the role of the X chromosome on functional connectivity of the brain. Further research is needed to understand the clinical implications of altered rsFC in 47,XXX.

Triple X syndrome: Psychiatric disorders and impaired social functioning as a risk factor.

BACKGROUND: Women with triple X syndrome (TXS) have an extra X chromosome. TXS appeared to be associated with psychiatric disorders in biased or underpowered studies. AIM: This study aims to describe the prevalence of psychiatric disorders in adults with TXS in a relatively large and less biased group of participants. METHOD: In this cross-sectional study, data were collected from 34 women with TXS (mean age = 32.9; s.d. = 13.1) and 31 controls (mean age = 34.9; s.d. = 13.7). Psychiatric disorders were assessed using the MINI International Neuropsychiatric Interview (MINI) and the adult behavior checklist (ABCL). Trait and state anxiety were assessed using the State-Trait Anxiety Inventory. RESULTS: In the TXS group, MINI results showed a higher prevalence of major depressive episodes (43.3%), psychotic disorders (29.4%), and suicidality (23.5%). Only 50% of the TXS group earned a normal score for the total syndrome score using the ABCL. In addition, levels of trait anxiety were higher in the TXS group. Only three women in each group received psychotropic medication. Impaired social functioning appeared to represent a major risk factor in TXS as regards psychotic, affective disorders, trait anxiety, and low self-esteem. CONCLUSIONS: Women with TXS are vulnerable to developing psychiatric disorders, and women with both TXS and impaired social functioning are even more vulnerable.

The Relationships between Dopaminergic, Glutamatergic, and Cognitive Functioning in 22q11.2 Deletion Syndrome: A Cross-Sectional, Multimodal 1H-MRS and 18F-Fallypride PET Study.

BACKGROUND: Individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk of developing psychosis and cognitive impairments, which may be related to dopaminergic and glutamatergic abnormalities. Therefore, in this exploratory study, we examined the association between dopaminergic and glutamatergic functioning in 22q11DS. Additionally, the associations between glutamatergic functioning and brain volumes in 22q11DS and healthy controls (HC), as well as those between dopaminergic and cognitive functioning in 22q11DS, were also examined. METHODS: In this cross-sectional, multimodal imaging study, glutamate, glutamine, and their combined concentration (Glx) were assessed in the anterior cingulate cortex (ACC) and striatum in 17 22q11DS patients and 20 HC using 7T proton magnetic resonance spectroscopy. Ten 22q11DS patients also underwent 18F-fallypride positron emission tomography to measure dopamine D2/3 receptor (D2/3R) availability in the ACC and striatum. Cognitive performance was assessed with the Cambridge Neuropsychological Test Automated Battery. RESULTS: No significant associations were found between ACC or striatal (1) glutamate, glutamine, or Glx concentrations and (2) D2/3R availability. In HC but not in 22q11DS patients, we found a significant relationship between ACC volume and ACC glutamate, glutamine, and Glx concentration. In addition, some aspects of cognitive functioning were significantly associated with D2/3R availability in 22q11DS. However, none of the associations remained significant after Bonferroni correction. CONCLUSIONS: Although our results did not reach statistical significance, our findings suggest an association between glutamatergic functioning and brain volume in HC but not in 22q11DS. Additionally, D2/3R availability seems to be related to cognitive functioning in 22q11DS. Studies in larger samples are needed to further elucidate our findings.

Post-traumatic stress in adults with 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is associated with an elevated genetic risk of several psychiatric disorders. However, the prevalence of post-traumatic stress disorder (PTSD) in individuals with 22q11.2DS has been reported to be only 0.9%; this is lower than that of the general population (3.9%). We explored the occurrence of PTSD and traumatic events in a Dutch cohort of 112 adults with 22q11.2DS, and found PTSD in 8.0%, traumatic events in 20.5% and trauma-focused treatment in 17.9% of patients. Our novel findings suggest that PTSD may be underdiagnosed in individuals with 22q11.2DS. Clinicians and other caregivers should be alert to trauma in this population in order to enable treatment and minimise psychiatric burden.

Dopaminergic alterations in populations at increased risk for psychosis: A systematic review of imaging findings.

Alterations of the dopaminergic system may be important neurobiological correlates of vulnerability and transition to psychosis. We systematically reviewed the evidence for dopaminergic alterations demonstrated by in-vivo imaging studies in humans at increased risk of developing psychosis, covering clinical, genetic, and environmental high-risk groups. All 63 included studies utilized Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), or neuromelanin-sensitive Magnetic Resonance Imaging (NM-MRI) methods to collect data concerning the dopaminergic system during rest and/or following pharmacological, behavioural, or cognitive challenges. The current evidence highlights that 1) striatal dopamine D2/3 receptor availability is unaltered in all three high-risk groups compared with healthy individuals; 2) striatal dopamine synthesis capacity (sDSC) is increased in some clinical and genetic high-risk individuals relative to controls (e.g. people that meet clinical criteria for being at ultra-high risk of developing psychosis and individuals with 22q11.2 deletion syndrome), while sDSC is decreased in cannabis-using environmental high-risk individuals. It seems likely that all three high-risk groups can be stratified into multiple subgroups, with varying risks to develop psychosis, transition rates, and underlying neurobiology. The present results support the hypothesis that dopaminergic abnormalities occur before high-risk individuals develop psychosis.

Altered subcortical and cortical brain morphology in adult women with 47,XXX: a 7-Tesla magnetic resonance imaging study.

BACKGROUND: Triple X syndrome (47,XXX) is a relatively common sex chromosomal aneuploidy characterized by the presence of a supernumerary X chromosome in females and has been associated with a variable cognitive, behavioural and psychiatric phenotype. 47,XXX may serve as a suitable model for studying the effect of genetic architecture on brain morphology. Previous studies have shown alterations in brain structure in 47,XXX particularly in childhood and adolescence. In this study, we examined subcortical and cortical brain morphology in adult women with 47,XXX using ultra-high field 7T MRI. Given previous evidence of impaired social functioning and emotion recognition in adults with 47,XXX, we also investigated the relationship of these functions with brain morphology. METHODS: Twenty-one adult women with 47,XXX and 22 age- and sex-matched healthy controls were included. Structural T1-weighted images were acquired using a 7-Tesla magnetic resonance scanner. Measures of subcortical brain volumes, cortical surface area and thickness, and cortical folding were obtained and compared between the groups using general linear models. Additionally, we examined potential relationships between brain outcome measures and social functioning and social cognition in 47,XXX using correlation analyses. RESULTS: Adults with 47,XXX showed lower volumes of the thalamus, caudate, putamen, hippocampus, nucleus accumbens and pallidum, and larger lateral ventricle volumes. Lower surface area was found in the superior frontal gyrus and superior temporal gyrus in 47,XXX participants compared to healthy controls. Altered cortical thickness and cortical folding were not present in 47,XXX. Cortical thickness was associated with social cognition in 47,XXX. CONCLUSIONS: Results suggest that a supernumerary X chromosome in females affects subcortical and lateral ventricle volumes, and cortical surface area in adulthood. 47,XXX may serve as a suitable model for studying genetic influences on structural brain morphology across developmental stages in order to understand neurobiological mechanisms underlying cognitive and behavioural impairments.

Ocular findings in 22q11.2 deletion syndrome: A systematic literature review and results of a Dutch multicenter study.

The 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disorder with an estimated prevalence of 1:3000 live births. Manifestations show a marked variability in expression and include speech- and language delay, intellectual disability, and neuropsychiatric disorders. We aim to provide an overview of ocular findings in 22q11.2DS in order to optimize recommendations for ophthalmic screening. We combined results from a systematic literature review with results from a multicenter cross-sectional study of patients with 22q11.2DS who were assessed by an ophthalmologist. Our systematic literature search yielded four articles, describing 270 patients. We included 132 patients in our cross-sectional study (median age 8.9 [range 0-56] years). Most reported ocular findings were retinal vascular tortuosity (32%-78%), posterior embryotoxon (22%-50%), eye lid hooding (20%-67%), strabismus (12%-36%), amblyopia (2%-11%), ptosis (4%-6%), and refractive errors, of which hyperopia (6%-48%) and astigmatism (3%-23%) were most common. Visual acuity was (near) normal in most patients (91%-94%). Refractive errors, strabismus, and amblyopia are treatable conditions that are frequently present in patients with 22q11.2DS and should be corrected at an early stage. Therefore, in 22q11.2DS, we recommend ophthalmic and orthoptic screening at the age of 3 years or at diagnosis, and a low-threshold referral in adults.

Cohort profile: demographic and clinical characteristics of the MILESTONE longitudinal cohort of young people approaching the upper age limit of their child mental health care service in Europe.

PURPOSE: The presence of distinct child and adolescent mental health services (CAMHS) and adult mental health services (AMHS) impacts continuity of mental health treatment for young people. However, we do not know the extent of discontinuity of care in Europe nor the effects of discontinuity on the mental health of young people. Current research is limited, as the majority of existing studies are retrospective, based on small samples or used non-standardised information from medical records. The MILESTONE prospective cohort study aims to examine associations between service use, mental health and other outcomes over 24 months, using information from self, parent and clinician reports. PARTICIPANTS: Seven hundred sixty-three young people from 39 CAMHS in 8 European countries, their parents and CAMHS clinicians who completed interviews and online questionnaires and were followed up for 2 years after reaching the upper age limit of the CAMHS they receive treatment at. FINDINGS TO DATE: This cohort profile describes the baseline characteristics of the MILESTONE cohort. The mental health of young people reaching the upper age limit of their CAMHS varied greatly in type and severity: 32.8% of young people reported clinical levels of self-reported problems and 18.6% were rated to be 'markedly ill', 'severely ill' or 'among the most extremely ill' by their clinician. Fifty-seven per cent of young people reported psychotropic medication use in the previous half year. FUTURE PLANS: Analysis of longitudinal data from the MILESTONE cohort will be used to assess relationships between the demographic and clinical characteristics of young people reaching the upper age limit of their CAMHS and the type of care the young person uses over the next 2 years, such as whether the young person transitions to AMHS. At 2 years follow-up, the mental health outcomes of young people following different care pathways will be compared. TRIAL REGISTRATION NUMBER: NCT03013595.

Social functioning and emotion recognition in adults with triple X syndrome.

BACKGROUND: Triple X syndrome (TXS) is caused by aneuploidy of the X chromosome and is associated with impaired social functioning in children; however, its effect on social functioning and emotion recognition in adults is poorly understood. AIMS: The aim of this study was to investigate social functioning and emotion recognition in adults with TXS. METHOD: This cross-sectional cohort study was designed to compare social functioning and emotion recognition between adults with TXS (n = 34) and an age-matched control group (n = 31). Social functioning was assessed with the Adult Behavior Checklist and Social Responsiveness Scale for Adults. Emotion recognition was assessed with the Emotion Recognition Task in the Cambridge Neuropsychological Test Automated Battery. Differences were analysed by Mann-Whitney U-test. RESULTS: Compared with controls, women with TXS scored higher on the Adult Behavior Checklist, including the Withdrawn scale (P < 0.001, effect size 0.4) and Thought Problems scale (P < 0.001, effect size 0.4); and higher on the Social Responsiveness Scale for Adults, indicating impaired social functioning (P < 0.001, effect size 0.5). In addition, women with TXS performed worse on the Emotion Recognition Task, particularly with respect to recognising sadness (P < 0.005, effect size 0.4), fear (P < 0.01, effect size 0.4) and disgust (P < 0.02, effect size 0.3). CONCLUSIONS: Our findings indicate that adults with TXS have a higher prevalence of impaired social functioning and emotion recognition. These results highlight the relevance of sex chromosome aneuploidy as a potential model for studying disorders characterised by social impairments such as autism spectrum disorder, particularly among women.

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.