In vitro study methodologies to investigate genetic aspects and effects of drugs used in attention-deficit hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children and adolescents, with up to 5% affected worldwide. Twin and family studies on ADHD show its high familiality with heritability estimated around 70%, but, to date, no specific polymorphism or gene was found to be specifically affected. Psychostimulants (amphetamine, methylphenidate) and non-psychostimulants (atomoxetine) are used successfully in ADHD therapy, but many of their mechanisms of action and their adverse effects are not yet fully understood. Therefore, both genetic findings and therapeutic interventions should be further investigated. One easy platform for such studies is in vitro analyses, which encompass neuronal cell culture studies, transfections of genetic constructs, binding and electrophysiology analyses. In this review, different methods will be referred in particular to ADHD findings, and new techniques will be mentioned for future studies of drug or genetic effects in vitr

Family Relationships in Selective Mutism-A Comparison Group Study of Children and Adolescents

Selective mutism (SM) mostly develops early in childhood and this has led to interest into whether there could be differences in relationships in families with SM compared to a control group without SM. Currently, there are merely few empirical studies examining family relationships in SM. A sample of 28 children and adolescents with SM was compared to 33 controls without SM. The groups were investigated using self-report questionnaires (Selective Mutism Questionnaire, Child-Parent Relationship Test—Child Version) for the assessment of SM and family relationships. Children with SM did not report a significantly different relationship to their mothers compared with the control group without SM. However, the scores in respect to the relationship to their fathers were significantly lower in cohesion, identification and autonomy compared with children without SM. Relationships in families with SM should be considered more in therapy

Betrayed by the nervous system: a comparison group study to investigate the 'unsafe world' model of selective mutism

The study presented in the following verifies some assumptions of the novel 'unsafe world' model of selective mutism (SM). According to this model, SM is a stress reaction to situations erroneously experienced via cognition without awareness as 'unsafe'. It assumes a high sensitivity to unsafety, whereby the nervous system triggers dissociation or freeze mode at relatively low thresholds. We examine whether there is a correlation between SM, sensory-processing sensitivity and dissociation. We compared a sample of 28 children and adolescents with SM (mean age 12.66 years; 18 females) to 33 controls without SM (mean age 12.45 years; 21 females). Both groups were compared using a medical history sheet, the 'Selective Mutism Questionnaire' (SMQ), a 'Checklist for Speaking Behaviour' (CheckS), the 'Highly Sensitive Person Scale' (HSPS), the 'Child Dissociative Checklist' (CDC), the 'Adolescent Dissociative Experience Scale' (A-DES) and the 'Social Phobia and Anxiety Inventory for Children' (SPAIK). Appropriate parametric and non-parametric tests were conducted to examine differences between groups. The results indicate that sensory-processing sensitivity was significantly higher in the group of children and adolescents with SM [X2(1) = 7.224, p = 0.0007; d = 1.092]. Furthermore, dissociative symptoms were more common in children and adolescents with SM than in controls [F(1, 33) = 13.004, p = 0.001; d = 0.986]. The results indicate that sensory-processing sensitivity and dissociation are important factors of SM that may hold important implications for the treatment. TRIAL REGISTRATION: This study is registered with the ClinicalTrials.gov number NCT04233905

Association study in siblings and case-controls of serotonin- and oxytocin-related genes with high functioning autism

BACKGROUND Autism spectrum disorder (ASD) is heritable and neurodevelopmental with unknown causes. The serotonergic and oxytocinergic systems are of interest in autism for several reasons: (i) Both systems are implicated in social behavior, and abnormal levels of serotonin and oxytocin have been found in people with ASD; (ii) treatment with selective serotonin reuptake inhibitors and oxytocin can yield improvements; and (iii) previous association studies have linked the serotonin transporter (SERT; SLC6A4), serotonin receptor 2A (HTR2A), and oxytocin receptor (OXTR) genes with ASD. We examined their association with high functioning autism (HFA) including siblings and their interaction. METHODS In this association study with HFA children (IQ > 80), siblings, and controls, participants were genotyped for four single nucleotide polymorphisms (SNPs) in OXTR (rs2301261, rs53576, rs2254298, rs2268494) and one in HTR2A (rs6311) as well as the triallelic HTTLPR (SERT polymorphism). RESULTS We identified a nominal significant association with HFA for the HTTLPR s allele (consisting of S and LG alleles) (p = .040; odds ratio (OR) = 1.697, 95% CI 1.191-2.204)). Four polymorphisms (HTTLPR, HTR2A rs6311, OXTR rs2254298 and rs53576) in combination conferred nominal significant risk for HFA with a genetic score of ≥4 (OR = 2.09, 95% CI 1.05-4.18, p = .037). The resulting area under the receiver operating characteristic curve was 0.595 (p = .033). CONCLUSIONS Our findings, combined with those of previous reports, indicate that ASD, in particular HFA, is polygenetic rather than monogenetic and involves the serotonergic and oxytocin pathways, probably in combination with other factors

The Impact of the COVID-19 Pandemic on Young Adults’ Mental Health in Switzerland: A Longitudinal Cohort Study from 2018 to 2021

Most of the studies that examine the effect of the COVID-19 pandemic on mental health have been restricted to pandemic mental health data alone. The aim of the current study was to estimate the pandemic’s effect on young Swiss adults’ mental health by comparing pandemic to pre-pandemic mental health. Longitudinal data of 1175 young Swiss adults who participated in the S-YESMH study in 2018 and were followed-up in 2020 and 2021 were analyzed. The study outcomes were self-reported symptoms of depression, generalized anxiety disorder (GAD), attention-deficit/hyperactivity disorder (ADHD), thoughts about death or self-harm, and risky single-occasion drinking (RSOD). Generalized estimation equations, logistic regression and statistical mediation analysis were used to analyze the data. Evidence was found of increased depression, GAD, and ADHD among young women and increased depression among young men, resulting from the COVID-19 pandemic. Uncertainty about the future predicted young women’s depression and anxiety in 2021. COVID-19 stress in 2021 fully mediated the effect of COVID-19 stress in 2020 on depression and GAD in 2021. Young Swiss women’s and men’s mental health appears to have been adversely affected by the COVID-19 pandemic, especially during the second pandemic year. Uncertainty about the future and stress becoming chronic in 2021 likely explain some of the adverse effects

The validity of conduct disorder symptom profiles in high-risk male youth.

Conduct disorder (CD) is a heterogeneous pattern of rule-breaking and aggressive symptoms. Until now it has been unclear whether valid, clinically useful symptom profiles can be defined for populations in youth at high-risk of CD. Interview-based psychiatric disorders, CD symptoms and officially recorded offences were assessed in boys from a detention facility and a forensic psychiatric hospital (N = 281; age 11.2-21.3 years). We used latent class analyses (LCA) to examine CD subtypes and their relationships with comorbid psychiatric disorders, suicidality, and criminal recidivism. LCA revealed five CD subtypes: no CD, mild aggressive CD, mild covert CD, moderate CD, and severe CD. The severe and, to a lesser degree, the moderate CD subtype were related to comorbid attention deficit hyperactivity disorder, substance use disorder, affective disorder, and suicidality. Time to violent criminal re-offending was predicted by severe CD (OR 5.98, CI 2.5-13.80) and moderate CD (OR 4.18, CI 1.89-9.21), but not by any other CD subtype in multivariate Cox regressions (controlling for age, low socioeconomic status and foreign nationality). These results confirm the existence of different CD symptom profiles in a high-risk group. Additional variable-oriented analyses with CD symptom count and aggressive/rule-breaking CD-dimensions further supported a dimensional view and a dose-response relationship of CD and criminal recidivism. Classifying high-risk young people according to the number of aggressive and rule-breaking CD symptoms is of major clinical importance and may provide information about risk of violent recidivism

Concordance of attachment representations in preschool siblings assessed by the attachment story completion task

Several studies have indicated only a modest concordance of attachment security in siblings in infancy. Until now, very little was known about the concordance of siblings’ attachment security beyond infancy, as assessed by the attachment story completion task. This cross-sectional study aims to examine the concordance of attachment representations of 38 first-born (4–7 years) and 38 second-born (3–5 years) siblings living in middle-class two-parent families. Personality factors and the level of parenting stress of the biological mothers (30–43 years) were analysed in relation to children’s attachment security. The results indicate a 43 % secure-insecure concordance rate between siblings’ attachment representations. Sibling’s gender correspondence, age differences and differences in parenting stress were not related to attachment concordance whereas gender of the first-born child was related to attachment concordance. The results also indicate that older children more frequently had secure attachment representations compared to younger children and that attachment insecurity was associated with greater negative impacts of life events, lower maternal life satisfaction and higher parenting stress. Our study indicates that siblings’ attachment representations may lack concordance even when siblings are assessed by the same method at the same time. If maternal and environmental factors are able to explain a substantial amount of variance in the attachment security of individual children, non-shared environmental factors might be underestimated when studying siblings’ attachment representations. The significant effect of age on children’s attachment representations found in this study suggests the need for future research on the stability of attachment representations during the preschool years

Improved Generation of Induced Pluripotent Stem Cells From Hair Derived Keratinocytes – A Tool to Study Neurodevelopmental Disorders as ADHD

In the last decade, there is an increasing application of induced pluripotent stem cells (iPSCs) for disease modeling. The iPSC technology enables the study of patient-specific neuronal cell lines in vitro to evaluate dysfunction at the cellular level and identify the responsible genetic factors. This approach might be particularly valuable for filling the gap of knowledge at the cellular and molecular levels underlying the pathophysiology of various neurodevelopmental and/or psychiatric disorders, such as attention-deficit hyperactivity disorder (ADHD). However, the invasiveness of skin biopsy or blood withdrawal might represent a major impediment in such protected population. Using hair derived keratinocytes as starting somatic cells circumvents this problem as sample collections can be performed non-invasively. Here we describe an improved, convenient, standardized and effective method to culture and reprogram hair derived keratinocytes from three healthy controls and one ADHD patient into iPSCs, which in turn will be used to generate differentiated neuronal cells. All the cell types were maintained in highly defined, serum-free conditions and showed expression of the respective key marker genes, assessed by both immunocytochemistry and qRT-PCR. The described in vitro personalized neuronal model has its advantage in modeling neurodevelopmental trajectories since it can recapitulate key processes of brain development at the cellular and molecular level and is intended to be used as for example studying ADHD etiopathology

Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders