The Association Between Trajectories of Self-reported Psychotic Experiences and Continuity of Mental Health Care in a Longitudinal Cohort of Adolescents and Young Adults.

BACKGROUND AND HYPOTHESIS: Young people (YP) with psychotic experiences (PE) have an increased risk of developing a psychiatric disorder. Therefore, knowledge on continuity of care from child and adolescent (CAMHS) to adult mental health services (AMHS) in relation to PE is important. Here, we investigated whether the self-reported trajectories of persistent PE were associated with likelihood of transition to AMHS and mental health outcomes. STUDY DESIGN: In this prospective cohort study, interviews and questionnaires were used to assess PE, mental health, and service use in 763 child and adolescent mental health service users reaching their service's upper age limit in 8 European countries. Trajectories of self-reported PE (3 items) from baseline to 24-month follow-up were determined using growth mixture modeling (GMM). Associations were assessed with auxiliary variables and using mixed models. Study results. At baseline, 56.7% of YP reported PE. GMM identified 5 trajectories over 24 months: medium increasing (5.2%), medium stable (11.7%), medium decreasing (6.5%), high decreasing (4.2%), and low stable (72.4%). PE trajectories were not associated with continuity of specialist care or transition to AMHS. Overall, YP with PE reported more mental health problems at baseline. Persistence of PE or an increase was associated with poorer outcomes at follow-up. CONCLUSIONS: PE are common among CAMHS users when reaching the upper age limit of CAMHS. Persistence or an increase of PE was associated with poorer mental health outcomes, poorer prognosis, and impaired functioning, but were less discriminative for continuity of care.

Medication adherence and persistence in children and adolescents with attention deficit hyperactivity disorder (ADHD): a systematic review and qualitative update.

Low medication-adherence and persistence may reduce the effectiveness of ADHD-medication. This preregistered systematic review (PROSPERO CRD42020218654) on medication-adherence and persistence in children and adolescents with ADHD focuses on clinically relevant questions and extends previous reviews by including additional studies. We included a total of n = 66 studies. There was a lack of consistency in the measurement of adherence/persistence between studies. Pooling the medication possession ratios (MPR) and using the most common adherence definition (MPR ≥ 80%) indicated that only 22.9% of participants had good adherence at 12-month follow-up. Treatment persistence on medication measured by treatment duration during a 12-month follow-up averaged 170 days (5.6 months). Our findings indicate that medication-adherence and persistence among youth with ADHD are generally poor and have not changed in recent years. Clinicians need to be aware that various factors may contribute to poor adherence/persistence and that long-acting stimulants and psychoeducational programs may help to improve adherence/persistence. However, the evidence to whether better adherence/persistence contributes to better long-term outcomes is limited and requires further research.

Co-Occurring Methylenetetrahydrofolate Reductase (MTHFR) rs1801133 and rs1801131 Genotypes as Associative Genetic Modifiers of Clinical Severity in Rett Syndrome.

AIM: Remethylation disorders such as 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency reduce the remethylation of homocysteine to methionine. The resulting hyperhomocysteinemia can lead to serious neurological consequences and multisystem toxicity. The role of MTHFR genotypes has not been investigated in patients with Rett Syndrome (RTT). In this study, we sought to assess the impact of co-occurring MTHFR genotypes on symptom profiles in RTT. METHOD: Using pharmacogenomic (PGx) testing, the MTHFR genetic polymorphisms rs1801133 (c.665C>T mutation) and rs1801131 (c.1286A>C mutation) were determined in 65 patients (18.7 years ± 12.1 [mean ± standard deviation]) with RTT as part of routine clinical care within the Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, a National and Specialist Child and Adolescent Mental Health Service (CAMHS) in the UK. The clinical severity of patients was assessed using the RTT-anchored Clinical Global Impression Scale (RTT-CGI). RESULTS: The clinical severity symptom distribution varied between the homozygous and heterozygous MTHFR rs1801133 and rs1801131 genotypes. Those with the homozygous genotype had a narrower spread of severity scores across several domains (language and communication, ambulation, hand-use and eye contact clinical domains). Patients with the homozygous genotype had statistically significantly greater CGI-Severity scores than individuals with a non-homozygous MTHFR genotype (Z = -2.44, p = 0.015). When comparing the ratings of moderately impaired (4), markedly impaired (5), severely impaired (6) and extremely impaired (7), individuals with the homozygous MTHFR genotype were more impaired than those with the non-homozygous MTHFR genotype (Z = -2.06, p = 0.039). There was no statistically significant difference in the number of prescribed anti-epileptic drugs between the genotypes. CONCLUSIONS: Our findings show that in those with a pathogenic RTT genetic variant, co-occurring homozygotic MTHFR rs1801133 and rs1801131 polymorphisms may act as associative genetic modifiers of clinical severity in a subset of patients. Profiling of rs1801133 and rs1801131 in RTT may therefore be useful, especially for high-risk patients who may be at the most risk from symptom deterioration.

Practitioner Review: Continuity of mental health care from childhood to adulthood for youths with ADHD - who, how and when?

Many youths with attention-deficit/hyperactivity disorder (ADHD) experience significant long-term impairment and may develop concurrent mental and somatic health difficulties as adults. This is associated with burden and costs for the individual and society which could be prevented through continued support in youth. Yet, only few young people transition to adult mental health services for ongoing care in different countries worldwide. We provide an overview on current transition practices, highlighting the gaps in knowledge and the barriers to effective service transitioning, while considering the large geographical variation in available guidelines and service provision. For ease of use, this review is organized in a question-and-answer format covering different aspects of the transition process and considering both service users' and clinicians' perspectives. Consensus is needed to identify those that require continued care, the optimal timing to arrange transition, and the most suitable services. Finally, we discuss cost-effectiveness of transition practices, consider examples of best practice, and propose recommendations on how to improve transitional care, including the importance of service users' input into transition planning.

Adaptation and validation of the On Your Own Feet - Transition Experiences Scale evaluating transitions to adult services among adolescent mental health service users in Europe.

PURPOSE: Experiences of young people transitioning from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS) have mostly been investigated qualitatively. This study adapts and validates the On Your Own Feet - Transition Experiences Scale (OYOF-TES) in a sample of CAMHS users in Europe and describes young people's and parents' experiences with transition and end of care at CAMHS. METHODS: The OYOF-TES was adapted to a mental health setting and translated. An End Of Care (OYOF-EOC) version (self- and parent-report) was developed. A total of 457 young people and 383 parents completed an OYOF-TES or OYOF-EOC. Psychometric properties and descriptives are presented. RESULTS: The Cronbach's alphas of the OYOF-TES and OYOF-EOC parent/self-report ranged from 0.92 to 0.94. The two-factor structure was confirmed. The mean overall satisfaction reported by young people was 6.15 (0-10; SD=2.92) for transition and 7.14 (0-10; SD=2.37) for care ending. However, 26.7%-36.4% of young people were unsatisfied. DISCUSSION: The OYOF-TES and OYOF-EOC can be used reliably in mental healthcare settings to capture young people's and parents' transition experiences. The majority of young people and parents was satisfied with the process of transition and care ending, yet a third of young people had negative experiences.

The efficacy of real versus sham external Trigeminal Nerve Stimulation (eTNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) over 4 weeks: a protocol for a multi-centre, double-blind, randomized, parallel-group, phase IIb study (ATTENS).

BACKGROUND: Attention Deficit/Hyperactivity Disorder (ADHD), if severe, is usually treated with stimulant or non-stimulant medication. However, users prefer non-drug treatments due to side effects. Alternative non-medication treatments have so far only shown modest effects. External trigeminal nerve stimulation (eTNS) is a minimal risk, non-invasive neuromodulation device, targeting the trigeminal system. It was approved for ADHD in 2019 by the USA Food and Drug administration (FDA) based on a small proof of concept randomised controlled trial (RCT) in 62 children with ADHD showing improvement of ADHD symptoms after 4 weeks of nightly real versus sham eTNS with minimal side effects. We present here the protocol of a larger confirmatory phase IIb study testing efficacy, longer-term persistency of effects and underlying mechanisms of action. METHODS: A confirmatory, sham-controlled, double-blind, parallel-arm, multi-centre phase IIb RCT of 4 weeks of eTNS in 150 youth with ADHD, recruited in London, Portsmouth, and Southampton, UK. Youth with ADHD will be randomized to either real or sham eTNS, applied nightly for 4 weeks. Primary outcome is the change in the investigator-administered parent rated ADHD rating scale. Secondary outcomes are other clinical and cognitive measures, objective hyperactivity and pupillometry measures, side effects, and maintenance of effects over 6 months. The mechanisms of action will be tested in a subgroup of 56 participants using magnetic resonance imaging (MRI) before and after the 4-week treatment. DISCUSSION: This multi-centre phase IIb RCT will confirm whether eTNS is effective in a larger age range of children and adolescents with ADHD, whether it improves cognition and other clinical measures, whether efficacy persists at 6 months and it will test underlying brain mechanisms. The results will establish whether eTNS is effective and safe as a novel non-pharmacological treatment for ADHD. TRIAL REGISTRATION: ISRCTN82129325 on 02/08/2021, https://doi.org/10.1186/ISRCTN82129325 .

Psychopharmacology in children and adolescents: unmet needs and opportunities.

Psychopharmacological treatment is an important component of the multimodal intervention approach to treating mental health conditions in children and adolescents. Currently, there are many unmet needs but also opportunities, alongside possible risks to consider, regarding the pharmacological treatment of mental health conditions in children and adolescents. In this Position Paper, we highlight and address these unmet needs and opportunities, including the perspectives of clinicians and researchers from the European College of Neuropsychopharmacology-Child and Adolescent Network, alongside those of experts by lived experience from national and international associations, via a survey involving 644 participants from 13 countries, and of regulators, through representation from the European Medicines Agency. We present and discuss the evidence base for medications currently used for mental disorders in children and adolescents, medications in the pipeline, opportunities in the development of novel medications, crucial priorities for the conduct of future clinical studies, challenges and opportunities in terms of the regulatory and legislative framework, and innovations in the way research is conducted, reported, and promoted.

Suicidality Treatment Occurring in Paediatrics (STOP) Medication Suicidality Side Effects Scale in young people in two cohorts across Europe.

OBJECTIVES: As part of the 'Suicidality: Treatment Occurring in Paediatrics (STOP)' study, we developed and performed psychometric validation of an electronic-clinical-outcome-assessment (eCOA), which included a patient-reported-outcome (ePRO), an observer-rated-outcome (eObsRO) for parents/carers and a clinician-reported-outcome (eClinRO) that allows identification and monitoring of medication-related suicidality (MRS) in adolescents. DESIGN: STOP: Prospective study: A two phase validation study to assess the impact of medication on suicidal ideations. SETTING: Six participating countries: Netherlands, UK, Germany, France, Spain and Italy that were part of the Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 261411. PARTICIPANTS: Cohort 1 consisted of 41 adolescent-completions, 50 parent-completions and 56 clinician-completions. Cohort 2 consisted of 244 adolescent-completions, 198 parent-completions and 240 clinician-completions from across the six countries. The scale was administered only to participants who have screened positive for the STOP-Suicidality Assessment Scale (STOP-SAS). RESULTS: A total of 24 items for the development of the STOP-Medication Suicidality Side Effects Scale (STOP-MS3) were identified and three versions (for patients, parents and clinicians) of the STOP-MS3 were developed and validated in two separate study cohorts comprising of adolescents, their parents and clinicians. Cronbach's α coefficients were above 0.85 for all domains. The inter-rater reliability of the STOP-MS3 was good and significant for the adolescent (ePRO), clinician (eClinRO) (r=0.613), parent (eObsRO) versions of the scale (r=0.394) and parent and clinician (r=0.347). Exploratory factor analysis identified a 3-factor model across 24 items for the adolescent and parent version of the scale: (1) Emotional Dysregulation, (2) Somatic Dysregulation and (3) Behavioural Dysregulation. For the clinician version, a 4-factor model defined the scale structure: (1) Somatic Dysregulation, (2) Emotional Dysregulation, (3) Behavioural Dysregulation and (4) Mood Dysregulation. CONCLUSION: These findings suggest that the STOP-MS3 scale, a web-based eCOA, allows identification and monitoring of MRS in the adolescent population and shows good reliability and validity.

Different whole-brain functional connectivity correlates of reactive-proactive aggression and callous-unemotional traits in children and adolescents with disruptive behaviors.

BACKGROUND: Disruptive behavior in children and adolescents can manifest as reactive aggression and proactive aggression and is modulated by callous-unemotional traits and other comorbidities. Neural correlates of these aggression dimensions or subtypes and comorbid symptoms remain largely unknown. This multi-center study investigated the relationship between resting state functional connectivity (rsFC) and aggression subtypes considering comorbidities. METHODS: The large sample of children and adolescents aged 8-18 years (n = 207; mean age = 13.30±2.60 years, 150 males) included 118 cases with disruptive behavior (80 with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptom scores were analyzed as covariates when assessing group differences and dimensional aggression effects on hypothesis-free global and local voxel-to-voxel whole-brain rsFC based on functional magnetic resonance imaging at 3 Tesla. RESULTS: Compared to controls, the cases demonstrated altered rsFC in frontal areas, when anxiety but not ADHD symptoms were controlled for. For cases, reactive and proactive aggression scores were related to global and local rsFC in the central gyrus and precuneus, regions linked to aggression-related impairments. Callous-unemotional trait severity was correlated with ICC in the inferior and middle temporal regions implicated in empathy, emotion, and reward processing. Most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety were controlled for. CONCLUSIONS: This study clarifies that hypothesis-free brain connectivity measures can disentangle distinct though overlapping dimensions of aggression in youths. Moreover, our results highlight the importance of considering comorbid symptoms to detect aggression-related rsFC alterations in youths.

Healthcare costs for young people transitioning the boundary between child/adolescent and adult mental health services in seven European countries: results from the MILESTONE study.

BACKGROUND: The boundary between services for children and adolescents and adults has been identified as problematic for young people with mental health problems. AIMS: To examine the use and cost of healthcare for young people engaged in mental healthcare before and after the child/adolescent and adult service boundary. METHOD: Data from 772 young people in seven European countries participating in the MILESTONE trial were analysed. We analysed and costed healthcare resources used in the 6-month period before and after the service boundary. RESULTS: The proportion of young people engaging with healthcare services fell substantially after crossing the service boundary (associated costs €7761 pre-boundary v. €3376 post-boundary). Pre-boundary, the main cost driver was in-patient care (approximately 50%), whereas post-boundary costs were more evenly spread between services; cost reductions were correlated with pre-boundary in-patient care. Severity was associated with substantially higher costs pre- and post-boundary, and those who were engaged specifically with mental health services after the service boundary accrued the greatest healthcare costs post-service boundary. CONCLUSIONS: Costs of healthcare are large in this population, but fall considerably after transition, particularly for those who were most severely ill. In part, this is likely to reflect improvement in the mental health of young people. However, qualitative evidence from the MILESTONE study suggests that lack of capacity in adult services and young people's disengagement with formal mental health services post-transition are contributing factors. Long-term data are needed to assess the adverse long-term effects on costs and health of this unmet need and disengagement.

Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders-Implications for Individuals with Rett Syndrome: A Systematic Review.

This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies, leukodystrophies, lysosomal storage disorders and retinal dystrophies and extrapolated the key clinical findings to individuals with Rett syndrome (RTT). The PRISMA guidelines were used to search six databases during the last decade, followed by a thematic analysis to identify the emerging themes. Thematic analysis across the different disorders revealed four themes: (I) Therapeutic time window of gene therapy; (II) Administration and dosing strategies for gene therapy; (III) Methods of gene therapeutics and (IV) Future areas of clinical interest. Our synthesis of information has further enriched the current clinical evidence base and can assist in optimising gene therapy and gene editing studies in individuals with RTT, but it would also benefit when applied to other disorders. The findings suggest that gene therapies have better outcomes when the brain is not the primary target. Across different disorders, early intervention appears to be more critical, and targeting the pre-symptomatic stage might prevent symptom pathology. Intervention at later stages of disease progression may benefit by helping to clinically stabilise patients and preventing disease-related symptoms from worsening. If gene therapy or editing has the desired outcome, older patients would need concerted rehabilitation efforts to reverse their impairments. The timing of intervention and the administration route would be critical parameters for successful outcomes of gene therapy/editing trials in individuals with RTT. Current approaches also need to overcome the challenges of MeCP2 dosing, genotoxicity, transduction efficiencies and biodistribution.

Beyond "Psychotropic": Repurposing Psychiatric Drugs for COVID-19, Alzheimer's Disease, and Cancer.

Importance: "Psychotropic" drugs have widespread reach and impact throughout the brain and body. Thus, many of these drugs could be repurposed for non-psychiatric indications of high public health impact.Observations: The selective serotonin reuptake inhibitor (SSRI) fluvoxamine was shown efficacious as a COVID-19 treatment based on randomized controlled trials (RCTs), and a benefit of other antidepressants has been posited based on observational and preclinical studies. In this review, we illuminate features of SSRIs and other psychiatric drugs that make them candidates to repurpose for non-psychiatric indications. We summarize research that led to fluvoxamine's use in COVID-19 and provide guidance on how to use it safely. We summarize studies suggestive of benefit of other antidepressants versus COVID-19 and long COVID. We also describe putative mechanisms of psychiatric drugs in treating long COVID, Alzheimer's disease, cancer, and other conditions.Conclusion and Relevance: There is a potentially great clinical and public health impact of psychotropic drug repurposing. Challenges exist to such repurposing efforts, but solutions exist for researchers, regulators, and funders that overcome these challenges.

The future of child and adolescent clinical psychopharmacology: A systematic review of phase 2, 3, or 4 randomized controlled trials of pharmacologic agents without regulatory approval or for unapproved indications.

We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010-08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes.

The importance of clinicians' and parents' awareness of suicidal behaviour in adolescents reaching the upper age limit of their mental health services in Europe.

BACKGROUND: To study clinicians' and parents' awareness of suicidal behaviour in adolescents reaching the upper age limit of their Child and Adolescent Mental Health Service (CAMHS) and its association with mental health indicators, transition recommendations and mental health service (MHS) use. METHODS: 763 CAMHS users from eight European countries were assessed using multi-informant and standardised assessment tools at baseline and nine months follow-up. Separate ANCOVA's and pairwise comparisons were conducted to assess whether clinicians' and parents' awareness of young people's suicidal behaviour were associated with mental health indicators, clinician's recommendations to continue treatment and MHS use at nine months follow-up. RESULTS: 53.5 % of clinicians and 56.9 % of parents were unaware of young people's self-reported suicidal behaviour at baseline. Compared to those whose clinicians/parents were aware, unawareness was associated with a 72-80 % lower proportion of being recommended to continue treatment. Self-reported mental health problems at baseline were comparable for young people whose clinicians and parents were aware and unaware of suicidal behaviour. Clinicians' and parents' unawareness were not associated with MHS use at follow-up. LIMITATIONS: Aspects of suicidal behaviour, such as suicide ideation, -plans and -attempts, could not be distinguished. Few young people transitioned to Adult Mental Health Services (AMHS), therefore power to study factors associated with AMHS use was limited. CONCLUSION: Clinicians and parents are often unaware of suicidal behaviour, which decreases the likelihood of a recommendation to continue treatment, but does not seem to affect young people's MHS use or their mental health problems.

Age-related brain deviations and aggression.

BACKGROUND: Disruptive behavior disorders (DBD) are heterogeneous at the clinical and the biological level. Therefore, the aims were to dissect the heterogeneous neurodevelopmental deviations of the affective brain circuitry and provide an integration of these differences across modalities. METHODS: We combined two novel approaches. First, normative modeling to map deviations from the typical age-related pattern at the level of the individual of (i) activity during emotion matching and (ii) of anatomical images derived from DBD cases (n = 77) and controls (n = 52) aged 8-18 years from the EU-funded Aggressotype and MATRICS consortia. Second, linked independent component analysis to integrate subject-specific deviations from both modalities. RESULTS: While cases exhibited on average a higher activity than would be expected for their age during face processing in regions such as the amygdala when compared to controls these positive deviations were widespread at the individual level. A multimodal integration of all functional and anatomical deviations explained 23% of the variance in the clinical DBD phenotype. Most notably, the top marker, encompassing the default mode network (DMN) and subcortical regions such as the amygdala and the striatum, was related to aggression across the whole sample. CONCLUSIONS: Overall increased age-related deviations in the amygdala in DBD suggest a maturational delay, which has to be further validated in future studies. Further, the integration of individual deviation patterns from multiple imaging modalities allowed to dissect some of the heterogeneity of DBD and identified the DMN, the striatum and the amygdala as neural signatures that were associated with aggression.

Systematic Review and Meta-analysis: Efficacy of Pharmacological Interventions for Irritability and Emotional Dysregulation in Autism Spectrum Disorder and Predictors of Response.

OBJECTIVE: Emotional dysregulation and irritability are common in individuals with autism spectrum disorder (ASD). We conducted the first meta-analysis assessing the efficacy of a broad range of pharmacological interventions for emotional dysregulation and irritability in ASD and predictors of response. METHOD: Following a preregistered protocol (PROSPERO: CRD42021235779), we systematically searched multiple databases until January 1, 2021. We included placebo-controlled randomized controlled trials (RCTs) and evaluated the efficacy of pharmacological interventions and predictors of response for emotional dysregulation and irritability. We assessed heterogeneity using Q statistics and publication bias. We conducted subanalyses and meta-regressions to identify predictors of response. The primary effect size was the standardized mean difference. Quality of studies was assessed using the Cochrane Risk of Bias Tool (RoB2). RESULTS: A total of 2,856 individuals with ASD in 45 studies were included, among which 26.7% of RCTs had a high risk of bias. Compared to placebo, antipsychotics (standardized mean difference = 1.028, 95% CI = 0.824-1.232) and medications used to treat attention-deficit/hyperactivity disorder (ADHD) (0.471, 0.061-0.881) were significantly better than placebo in improving emotional dysregulation and irritability, whereas evidence of efficacy was not found for other drug classes (p > .05). Within individual medications, evidence of efficacy was found for aripiprazole (1.179, 0.838-1.520) and risperidone (1.074, 0.818-1.331). Increased rates of comorbid epilepsy (ß = -0.049, p = .026) were associated with a lower efficacy. CONCLUSION: Some pharmacological interventions (particularly risperidone and aripiprazole) have proved efficacy for short-term treatment of emotional dysregulation and irritability in ASD and should be considered within a multimodal treatment plan, taking into account also the tolerability profile and families' preferences.

Emotion recognition profiles in clusters of youth based on levels of callous-unemotional traits and reactive and proactive aggression.

Youth with disruptive behavior showing high callous-unemotional (CU) traits and proactive aggression are often assumed to exhibit distinct impairments in emotion recognition from those showing mainly reactive aggression. Yet, reactive and proactive aggression and CU traits may co-occur to varying degrees across individuals. We aimed to investigate emotion recognition in more homogeneous clusters based on these three dimensions. In a sample of 243 youth (149 with disruptive behavior problems and 94 controls) aged 8-18 years, we used model-based clustering on self-report measures of CU traits and reactive and proactive aggression and compared the resulting clusters on emotion recognition (accuracy and response bias) and working memory. In addition to a Low and Low-Moderate symptom cluster, we identified two high CU clusters. The CU-Reactive cluster showed high reactive and low-to-medium proactive aggression; the CU-Mixed cluster showed high reactive and proactive aggression. Both CU clusters showed impaired fear recognition and working memory, whereas the CU-Reactive cluster also showed impaired recognition of disgust and sadness, partly explained by poor working memory, as well as a response bias for anger and happiness. Our results confirm the importance of CU traits as a core dimension along which youth with disruptive behavior may be characterized, yet challenge the view that high CU traits are closely linked to high proactive aggression per se. Notably, distinct neurocognitive processes may play a role in youth with high CU traits and reactive aggression with lower versus higher proactive aggression.

Leaving child and adolescent mental health services in the MILESTONE cohort: a longitudinal cohort study on young people's mental health indicators, care pathways, and outcomes in Europe.

BACKGROUND: The configuration of having separate mental health services by age, namely child and adolescent mental health services (CAMHS) and adult mental health services (AMHS), might be a barrier to continuity of care that adversely affects young people's mental health. However, no studies have investigated whether discontinuity of care in the transition period affects mental health. We aimed to discern the type of care young people receive after reaching the upper age limit of their CAMHS and examine differences in outcomes at 24-month follow-up between young people receiving different types of care. METHODS: To assess mental health in young people from 39 CAMHS in eight European countries (Belgium, Croatia, France, Germany, Italy, Ireland, the Netherlands, and the UK), we did a longitudinal cohort study. Eligible young people were CAMHS users up to 1 year younger than the upper age limit of their CAMHS or up to 3 months older, if they were still in CAMHS. Information on mental health service use, mental health problems (ie, using the Health of the Nation Outcome Scale for Children and Adolescents, Youth Self-Report and Adult Self-Report, DSM-5, and ICD-10), and sociodemographic characteristics were collected using self-reported, parent-reported, and clinician-reported interviews and questionnaires. Mixed models were applied to assess relationships between baseline characteristics, mental health service use, and outcomes. FINDINGS: The MILESTONE cohort included 763 young people. The participants were 60·0% female (n=458) and 40·0% male (n=305), 90·3% White (n=578), and had a mean age of 17·5 years (range 15·2-19·6 years). Over the 24-month follow-up period, 48 young people (6·3%) actively withdrew from the study. For young people, the higher their scores on the Health of the Nation Outcome Scale for Children and Adolescents (p=0·0009) and Youth Self-Report and Adult Self-Report (p=0·046), and who had a clinical classification of severe mental illness (p=0·0033), had suicidal thoughts or behaviours or self-harm (p=0·034), used psychotropic medication (p=0·0014), and had a self-reported or parent-reported need for continued treatment (p<0·0001) at baseline, were more likely to transition to AMHS or stay in CAMHS than to have care end. Overall, over the 24-month follow-up period, the mental health of young people improved, but 24·4% of young people reported an increase in problems calculated using the reliable change index, of whom 5·3% had a clinically relevant increase in problems. At 24-month follow-up, no differences in change in mental health problems since baseline were found between young people who used different types of care (CAMHS, AMHS, or no care). INTERPRETATION: Although approximately half of young people reaching the upper age limit of their CAMHS stop using mental health services, this was not associated with a deterioration in their mental health. Young people with the most severe mental health problems are more likely to receive continued care. If replicated, our findings suggest investments in improving transitional care for all CAMHS users might not be cost-effective in times of rising health-care costs, but might be better targeted at a subgroup of young people with increasing mental health problems who do not receive continued treatment. FUNDING: European Commission's 7th Framework Programme.

Lifestyle intervention in obese pregnancy and cardiac remodelling in 3-year olds: children of the UPBEAT RCT.

BACKGROUND/OBJECTIVES: Obesity in pregnancy has been associated with increased childhood cardiometabolic risk and reduced life expectancy. The UK UPBEAT multicentre randomised control trial was a lifestyle intervention of diet and physical activity in pregnant women with obesity. We hypothesised that the 3-year-old children of women with obesity would have heightened cardiovascular risk compared to children of normal BMI women, and that the UPBEAT intervention would mitigate this risk. SUBJECTS/METHODS: Children were recruited from one UPBEAT trial centre. Cardiovascular measures included blood pressure, echocardiographic assessment of cardiac function and dimensions, carotid intima-media thickness and heart rate variability (HRV) by electrocardiogram. RESULTS: Compared to offspring of normal BMI women (n = 51), children of women with obesity from the trial standard care arm (n = 39) had evidence of cardiac remodelling including increased interventricular septum (IVS; mean difference 0.04 cm; 95% CI: 0.018 to 0.067), posterior wall (PW; 0.03 cm; 0.006 to 0.062) and relative wall thicknesses (RWT; 0.03 cm; 0.01 to 0.05) following adjustment. Randomisation of women with obesity to the intervention arm (n = 31) prevented this cardiac remodelling (intervention effect; mean difference IVS -0.03 cm (-0.05 to -0.008); PW -0.03 cm (-0.05 to -0.01); RWT -0.02 cm (-0.04 to -0.005)). Children of women with obesity (standard care arm) compared to women of normal BMI also had elevated minimum heart rate (7 bpm; 1.41 to 13.34) evidence of early diastolic dysfunction (e prime) and increased sympathetic nerve activity index by HRV analysis. CONCLUSIONS: Maternal obesity was associated with left ventricular concentric remodelling in 3-year-old offspring. Absence of remodelling following the maternal intervention infers in utero origins of cardiac remodelling. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: The UPBEAT trial is registered with Current Controlled Trials, ISRCTN89971375.