Cortical dysplasia and autistic trait severity in children with Tuberous Sclerosis Complex: a clinical epidemiological study.

Tuberous Sclerosis Complex (TSC) is characterized by a high prevalence of autism spectrum disorders (ASD). Little is known about the relation between cortical dysplasia and ASD severity in TSC. We assessed ASD severity (using the Autism Diagnostic Observation Scale), tuber and radial migration line (RML) count and location, and cognitive functioning in 52 children with TSC and performed regression and mediation analyses. Tuber and RML count were strongly positively related to ASD severity. However, when correcting for cognitive functioning, the majority of associations became insignificant and only total tuber count remained associated to the severity of restricted/repetitive behaviors. Occipital RML count remained associated with overall ASD severity, and social communication/interaction deficit severity specifically. This study shows the important explanatory role of cognitive functioning in the association between cortical dysplasia and ASD severity, and the relevance of separately studying the two ASD subdomains.

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.

Autism Spectrum Disorder Symptom Profiles in Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex and Neurofibromatosis Type 1.

Studying Autism Spectrum Disorder (ASD) heterogeneity in biologically homogeneous samples may increase our knowledge of ASD etiology. Fragile X syndrome (FXS), Angelman syndrome (AS), Tuberous Sclerosis Complex (TSC), and Neurofibromatosis type 1 (NF1) are monogenic disorders with high a prevalence of ASD symptomatology. This study aimed to identify ASD symptom profiles in a large group of children and adolescents (0;9-28 years) with FXS, AS, TSC, and NF1. Data on ASD symptomatology (Autism Diagnostic Observation Scale (ADOS-2) & Social Responsiveness Scale (SRS-2)) were collected from children and adolescents with FXS (n = 54), AS (n = 93), TSC (n = 112), and NF1 (n = 278). To identify groups of individuals with similar ASD profiles, we performed two latent profile analyses. We identified a four-profile model based on the ADOS-2, with a (1) 'Non-spectrum symptom profile', (2) 'Social Affect symptom profile', (3)'Restricted/Repetitive Behaviors symptom profile', and (4)'ASD symptom profile'. We also identified a four-profile model based on the SRS, with a (1)'Non-clinical symptom profile', (2)'Mild symptom profile', (3)'Moderate symptom profile', and (4)'Severe symptom profile'. Although each syndrome group exhibited varying degrees of severity, they also displayed heterogeneity in the profiles in which they were classified. We found distinct ASD symptom profiles in a population consisting of children and adolescents with FXS, AS, TSC, and NF1. Our study highlights the importance of a personalized approach to the identification and management of ASD symptoms in rare genetic syndromes. Future studies should aim to include more domains of functioning and investigate the stability of latent profiles over time.

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.

Autism Symptoms in Children and Young Adults With Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex, and Neurofibromatosis Type 1: A Cross-Syndrome Comparison.

Objective: The etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogeneity and heterogeneity in symptoms across individuals. This study compares ASD symptomatology between monogenetic syndromes with a high ASD prevalence, in order to reveal syndrome specific vulnerabilities and to clarify how genetic variations affect ASD symptom presentation. Methods: We assessed ASD symptom severity in children and young adults (aged 0-28 years) with Fragile X Syndrome (FXS, n = 60), Angelman Syndrome (AS, n = 91), Neurofibromatosis Type 1 (NF1, n = 279) and Tuberous Sclerosis Complex (TSC, n = 110), using the Autism Diagnostic Observation Schedule and Social Responsiveness Scale. Assessments were part of routine clinical care at the ENCORE expertise center in Rotterdam, the Netherlands. First, we compared the syndrome groups on the ASD classification prevalence and ASD severity scores. Then, we compared individuals in our syndrome groups with an ASD classification to a non-syndromic ASD group (nsASD, n = 335), on both ASD severity scores and ASD symptom profiles. Severity scores were compared using MANCOVAs with IQ and gender as covariates. Results: Overall, ASD severity scores were highest for the FXS group and lowest for the NF1 group. Compared to nsASD, individuals with an ASD classification in our syndrome groups showed less problems on the instruments' social domains. We found a relative strength in the AS group on the social cognition, communication and motivation domains and a relative challenge in creativity; a relative strength of the NF1 group on the restricted interests and repetitive behavior scale; and a relative challenge in the FXS and TSC groups on the restricted interests and repetitive behavior domain. Conclusion: The syndrome-specific strengths and challenges we found provide a frame of reference to evaluate an individual's symptoms relative to the larger syndromic population and to guide treatment decisions. Our findings support the need for personalized care and a dimensional, symptom-based diagnostic approach, in contrast to a dichotomous ASD diagnosis used as a prerequisite for access to healthcare services. Similarities in ASD symptom profiles between AS and FXS, and between NF1 and TSC may reflect similarities in their neurobiology. Deep phenotyping studies are required to link neurobiological markers to ASD symptomatology.

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.

Transitional psychiatry in the Netherlands: Experiences and views of mental health professionals.

BACKGROUND: The majority of psychopathology emerges in late adolescence and continues into adulthood. Continuity of care must be guaranteed in this life phase. The current service configuration, with a distinction between child/adolescent and adult mental health services (CAMHS and AMHS), impedes continuity of care. AIM: To map professionals' experiences with and attitudes towards young people's transition from CAMHS to AMHS and the problems they encounter. METHODS: An online questionnaire distributed among professionals providing mental health care to young people (15-25 years old) with psychiatric disorders. RESULTS: Five hundred and eighteen professionals completed the questionnaire. Decision-making regarding transition is generally based on the professional's own deliberations. The preparation was limited to discussing changes with the adolescent and parents. Most transition-related problems are experienced in CAMHS, primarily with regard to collaboration with AMHS. Respondents report that the developmental age should be leading in the transition-decision making process and that developmentally appropriate services are important in bridging the gap. CONCLUSION: Professionals in CAMHS and AMHS experience problems in the preparation of, and the collaboration during transition. The problems are related to coordination, communication and rules and regulations. Professionals attach importance to improvement through an increase in flexibility and more specialist services for youth.

Developmental Trajectories of Anxiety and Depression Symptoms from Early to Middle Childhood: a Population-Based Cohort Study in the Netherlands.

Developmental patterns of anxiety and depression symptoms in early childhood have previously been related to anxiety and mood disorders in middle childhood. In the current study, trajectories of anxiety and depression symptoms (1.5-10 years) were related to children's broader psychosocial and school-related functioning at 10 years. We included a population-based sample of 7499 children, for whom primary caregivers reported anxiety and depression symptoms on the Child Behavior Checklist, at children's ages of 1.5, 3, 6, and 10. Growth Mixture Modeling identified four distinct, gender-invariant, trajectories of anxiety and depression symptoms: low (82.4%), increasing (7.4%), decreasing (6.0%), and increasing symptoms up to age 6 followed by a decrease to age 10 (preschool-limited, 4.2%). Children with a non-Dutch ethnicity had lower odds to be in the increasing trajectory and higher odds to be in the decreasing and pre-school limited trajectory. Also, low maternal education predicted the decreasing and pre-school limited trajectory. Higher levels of psychopathology during pregnancy for both mothers and fathers predicted the increasing, decreasing, and preschool-limited trajectory, compared to the low trajectory. At age 10, children in the increasing and preschool-limited trajectory had diminished psychosocial outcomes (friendship-quality and self-esteem) and worse school-related outcomes (school performance and school problems). This study adds to current knowledge by demonstrating that developmental patterns of anxiety and depression symptoms in early childhood are related to broader negative outcomes in middle childhood. Child and family factors could guide monitoring of anxiety and depression symptoms in the general population and provide targets for prevention programs.

Stress reactivity predicts symptom improvement in children with anxiety disorders.

BACKGROUND: We examined the longitudinal associations of autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis rest and reactivity measures with anxiety and depressive symptoms at one-year follow-up in children with anxiety disorders. METHODS: In a clinical sample of 152 children with a primary DSM-IV anxiety disorder, aged 8 to 12 years, anxiety and depressive symptoms were assessed with the Multidimensional Anxiety Scale for Children and the Children's Depression Inventory at pre-treatment baseline and one year later, after treatment with cognitive behavioral therapy. At baseline, children participated in a 70min stress task. Salivary cortisol was measured directly prior to and 20min post stress task. Skin conductance level (SCL), heart rate and high frequency heart rate variability (HRV) were continuously measured during rest and the stress task. To investigate if rest or reactivity measures predicted anxiety and depressive symptoms at one year follow-up, linear regression analyses were conducted for rest and reactivity measures of SCL, heart rate, HRV and cortisol separately. RESULTS: Higher SCL reactivity predicted less decrease of anxiety symptoms at one-year follow-up. Cortisol reactivity showed a weak association with depressive symptoms at one-year follow-up: lower cortisol reactivity predicted less decrease in depressive symptoms. LIMITATIONS: Only self-reported anxiety and depressive symptoms were used. However, all predictors were objective biological measures, hence there is no risk of shared method variance bias. CONCLUSIONS: These findings suggest that pre-treatment HPA and ANS responsiveness to stress are predictive biomarkers for a lack of symptom improvement in children with a clinical anxiety disorder.

Alterations in HPA-axis and autonomic nervous system functioning in childhood anxiety disorders point to a chronic stress hypothesis.

BACKGROUND: It is of debate whether or not childhood anxiety disorders (AD) can be captured by one taxonomic construct. This study examined whether perceived arousal (PA), autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis measures can distinguish children with different primary diagnoses of clinical anxiety disorders (AD) from each other, and from a general population reference group (GP). METHODS: The study sample consisted of 152 AD children (comparing separation anxiety disorder, generalized anxiety disorder, social phobia and specific phobia), aged 8- to 12-years, and 200 same-aged reference children. HPA-axis functioning was measured by a diurnal cortisol profile. ANS functioning was measured by continuous measures of skin conductance level in rest and during a mental arithmetic task and high frequency heart rate variability in rest. PA was assessed by a questionnaire. RESULTS: The AD sample showed lower high frequency heart rate variability during rest, heightened anticipatory PA, higher basal and reactive skin conductance levels and lower basal HPA-axis functioning compared to the GP sample. The existence of three or more clinical disorders, i.e. a high clinical 'load', was associated with lower basal HPA-axis functioning, higher skin conductance level and lower posttest PA. Specific phobia could be discerned from social phobia and separation anxiety disorder on higher skin conductance level. CONCLUSIONS: Our findings indicated that children with AD have specific psychophysiological characteristics, which resemble the psychophysiological characteristics of chronic stress. A high clinical 'load' is associated with an altered ANS and HPA-axis functioning. Overall, ANS and HPA-axis functioning relate to AD in general, accept for specific phobia.

Blunted HPA axis response to stress is related to a persistent Dysregulation Profile in youth.

The Child Behavior Checklist Dysregulation Profile (DP) in youth has been shown to be a predictor of psychopathology later in life. We examined the activity of the hypothalamic pituitary adrenal (HPA) axis in youth with remitted, new, persistent, and no DP. Data from 489 youth (47% boys) participating in a Dutch longitudinal general population study were included (Wave 1 mean age=11.5, Wave 2=14.2). Wave 2 diurnal cortisol patterns and levels in response to a laboratory stress paradigm were compared in youth with DP at Wave 1 only, Wave 2 only, both Waves, and neither Wave. Youth with the DP at Wave 2 only or at both time points showed blunted cortisol responses to stress relative to the other two groups. There were no group or sex differences in diurnal cortisol activity. More research is needed to determine how the association between DP symptoms and HPA axis functioning changes over time.

Perceived and physiological arousal during a stress task: can they differentiate between anxiety and depression?

BACKGROUND: Anxiety and depression might be two different valid constructs that often co-occur, or they could be different manifestations of the same underlying vulnerability. A theoretical framework to address this question is the tripartite model, by Clark and Watson, which hypothesizes that physiological hyperarousal (PH) is specific for anxiety. Knowledge about the relationship between PH, psychophysiological measures, perceived arousal, and anxiety would increase our understanding of the validity of the PH construct in this model. Our objective was to assess whether (a) hypothalamic-pituitary-adrenocortical (HPA) axis functioning, and (b) perceived arousal before, during and after stress can differentiate anxious from depressive children. METHODS: In a general population sample of 225 children aged 8-12 years, self-reported anxiety and depressive symptoms were assessed using the Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI). Perceived arousal was assessed using a self-report questionnaire before, during and after a stress task. Basal and reactive HPA-axis functioning were used as indices for psychophysiological arousal. RESULTS: Our data showed that the relation between perceived arousal and anxiety problems is stronger than the relation with depressive problems. Reactive HPA-axis functioning is reduced in children with depressive problems. CONCLUSIONS: Some evidence was found in support of the tripartite model. Our findings indicate that perceived arousal to a challenge might be a useful tool to assess the PH component of the tripartite model. Reactive HPA-axis functioning might be able to differentiate between anxiety and depressive problems in children in a general population sample, but effect sizes are small and replication is needed.