A systematic review and meta-analysis of the association between maternal polycystic ovary syndrome and neuropsychiatric disorders in children

There is emerging evidence demonstrating an association between maternal polycystic ovary syndrome (PCOS) and autism spectrum disorder (ASD) in children, however, the cumulative effect of maternal PCOS on the development of ASD or other neuropsychiatry disorders (NPD) in children and separately for males and females has not been examined. We sought to systematically evaluate the influence of maternal PCOS on a wide range of NPD including ASD, attention deficit hyperactivity disorder (ADHD), chronic tic disorder (CDT), other behavior disorders, anxiety, depression, bipolar disorder, schizophrenia in children as well as in women of reproductive age only. We queried electronic databases including PubMed, EMBASE, and Google Scholar, until March 2021. We used DerSimonian and Laird (D-L) random effects method to compute pooled effect size in terms of odds ratio (OR). Nineteen studies (1667851 mothers, 2260622 children) were included in this study. Mothers with PCOS had an increased odds of children diagnosed with ASD (OR = 1.40, p < 0.001), ADHD (OR = 1.42, p < 0.001), CTD (OR = 1.44, p = 0.001), anxiety (OR = 1.33, p < 0.001), as well as other behavioral symptoms (OR = 1.45, p < 0.001) in the adjusted analysis. The association between maternal PCOS and ASD (OR: 1.43 vs. 1.66), ADHD (OR: 1.39 vs. 1.54), and CTD (OR: 1.42 vs. 1.51) was found to be significantly consistent between males and females, respectively. Our data do not suggest increased fetal testosterone exposure is associated with increased autistic traits in children. However, PCOS was significantly associated with increased odds of a wide range of NPD in women themselves. Maternal PCOS is a risk factor for various NPD with a similar extent in their children regardless of their underlying comorbidities. Managing PCOS is essential for women’s health as well as for their children’s health. More research is needed to determine the mechanisms and links between maternal PCOS and NPD in children.

Predicting Clinical Course from Subcortical Shape in Provisional Tic Disorder

The ongoing NewTics study examines children who have had tics for less than 9 months (NT group) - a population on which little research exists. Here, we further investigate relationships between subcortical shape and tic symptom outcomes. 138 children were assessed at baseline and a 12-month follow-up: 79 with NT, 27 tic-free healthy controls (HC), and 32 with chronic tic disorder or Tourette syndrome (TS), using T1-weighted MRI and total tic scores (TTS) from the Yale Global Tic Severity Scale to evaluate symptom change. Subcortical surface maps were generated using FreeSurfer-initialized large deformation diffeomorphic metric mapping, and linear regression models were constructed to correlate structural shapes with TTS while accounting for covariates, with relationships mapped onto structure surfaces. When compared to healthy controls, smaller mean volumes were found in the TS group for the caudate, nucleus accumbens, pallidum, and thalamus. NT had smaller mean volumes than controls in the caudate, pallidum, and thalamus. Surface maps illustrate distinct patterns of inward deformation (localized volume loss) in the TS group compared to NT children. In the NT group, a larger hippocampus at baseline significantly correlated with the worsening of tic symptoms at 12 months. Outward deformation in the hippocampus and inward deformation in the accumbens at baseline are also related to worsening tic symptoms at follow-up. Since the NT group has had tics only for a few months, we can rule out the possibility that these subcortical volume differences are caused by living with tics for years; they are more likely related to the cause of tics. These observations constitute some of the first prognostic biomarkers for tic disorders and suggest localized circuitry that may be associated with outcome of tic disorders.

EWAS of Monozygotic Twins Implicate a Role of mTOR Pathway in Pathogenesis of Tic Spectrum Disorder

Tic spectrum disorder (TSD) is an umbrella term which includes Gilles de la Tourette syndrome (GTS) and chronic tic disorder (CTD). They are considered highly heritable, yet the genetic components remain largely unknown. In this study we aimed to investigate disease-associated DNA methylation differences to identify genes and pathways which may be implicated in TSD aetiology. For this purpose, we performed an exploratory analysis of the genome-wide DNA methylation patterns in whole blood samples of 16 monozygotic twin pairs, of which eight were discordant and six concordant for TSD, while two pairs were asymptomatic. Although no sites reached genome-wide significance, we identified several sites and regions with a suggestive significance, which were located within or in the vicinity of genes with biological functions associated with neuropsychiatric disorders. The two top genes identified (TSC1 and CRYZ/TYW3) and the enriched pathways and components (phosphoinosides and PTEN pathways, and insulin receptor substrate binding) are related to, or have been associated with, the PI3K/AKT/mTOR pathway. Genes in this pathway have previously been associated with GTS, and mTOR signalling has been implicated in a range of neuropsychiatric disorders. It is thus possible that altered mTOR signalling plays a role in the complex pathogenesis of TSD.

WISC-IV performance of children with Chronic Tic Disorder, Obsessive–Compulsive Disorder and Attention-Deficit/Hyperactivity Disorder: results from a German clinical study

Background Chronic Tic Disorder (CTD), Obsessive–Compulsive Disorder (OCD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are complex neuropsychiatric disorders that frequently co-occur. The aim of this study was to examine WISC-IV performance of a clinical cohort of children with CTD, OCD and/or ADHD. Methods N = 185 children aged 6 to 17 years from Germany with CTD, OCD and/or ADHD were examined with the WISC-IV that comprises four index scores (VCI: Verbal Comprehension Index, PRI: Perceptual Reasoning Index, WMI: Working Memory Index, PSI: Processing Speed Index) and a Full Scale Intelligence Quotient (FSIQ). WISC-IV profiles of children with CTD-only, OCD-only, ADHD-only, CTD+ADHD, CTD+OCD and CTD+OCD+ADHD were compared with the WISC-IV norm (N = 1650, M = 100 and SD = 15) and among each other. Results Unpaired t-tests revealed that children with ADHD-only showed significant lower PSI scores, whereas children with CTD-only and OCD-only had significant higher VCI scores as compared to the German WISC-IV norm. One-way ANOVA revealed that children with ADHD-only showed significant lower WMI scores as compared to children with CTD+OCD. Conclusions We were able to confirm previous evidence on WISC-IV profiles in ADHD in a German clinical sample and contribute new findings on cognitive performance in children with (non-)comorbid CTD and OCD that have to be seen in light of the study’s limitations.

Pharmacological management of tourette's syndrome comorbid with obsessive-compulsive disorder in adult patients

AimsTourette's Syndrome (TS) is a neurodevelopmental disorder, which often presents in childhood and is hallmarked by motor and vocal tics. Obsessive-Compulsive Disorder (OCD) is a chronic neuropsychiatric condition characterised by intrusive thoughts and time-consuming repetitive behaviours. Research suggests that 15-20% of adult patients with TS will also meet the diagnostic criteria for OCD. Both illnesses appear to have neurobiological similarities but a differing course and clinical response to pharmacological treatments.Despite this, research into optimal management of adults with co-occurring TS or other tic disorders and OCD remains sparse. Comorbidities, are known to be poor predictor of response to selective serotonin reuptake inhibitors (SSRI) monotherapy in OCD and are often associated with treatment-refractory OCD. Similarly SSRI monotherapy in patients with OCD and comorbid TS can sometimes worsen motor tics (1 in 2000) and fail to improve OCD symptoms. In this review, we aim to evaluate evidence on the management of patients with co-occurring TS and OCD and address an important knowledge gap in clinical practice.MethodThis review was conducted in accordance with PRISMA Guidelines. We performed a search using PubMed, Cochrane Library and PsychINFO using the following Boolean Input “Tourettic-OCD” OR “tic-related OCD” OR ((OCD OR “obsessive-compulsive” OR “obsessive compulsive”) AND (Tourette OR “Tourette's” OR Tourettes OR tic))”. The search was conducted until January 2020. We then screened the articles of systematic reviews to extract additional studies from their reference lists.Result1888 studies were identified, of which 15 clinical trials were included in our systematic review. The presence of tics in patients with OCD are a major predictor for treatment-refractory OCD and a lack of improvement following monotherapy with SSRIs. Dual therapy with an SSRI and antipsychotics (particularly risperidone) are associated with improved outcomes in OCD patients with tics and TS patients with obsessive-compulsive symptoms. However, conjoint therapy with neuroleptics and SSRIs was only investigated when OCD burden was unsatisfactory following SSRI monotherapy.ConclusionThere are clinical implications when a patient with OCD also has a chronic tic disorder. The findings indicate the need for further research, particularly in the form of a larger cohort in randomised controlled trials, to determine when it is best to initiate patients with OCD and comorbid tic disorders on a dual antipsychotic-SSRI management strategy. Further evidence should also be done to determine other characteristics that predict an improvement to conjoint SSRI/neuroleptic therapy for effective symptom reduction.

Comorbid chronic tic disorder and tourette syndrome in children requiring inpatient mental health treatment

Objective: Children needing admission to an inpatient mental health unit often present with severe neuropsychiatric disorders characterised by complex psychopathology. We aimed to examine all admitted children with comorbid chronic tic disorder (CTD) and Tourette syndrome (TS) over a 10-year period and determine the clinical significance of these diagnoses. Method: A retrospective, naturalistic study was conducted, comparing children with and without CTD/TS in terms of co-morbid diagnoses, medication use, access to education, aggression contributing to the admission, duration of admission, functional outcomes and satisfaction with treatment. Data were analysed using Chi-square/Fisher’s exact test and t-test for categorical and continuous variables, respectively, and subsequently with unadjusted and adjusted linear and logistic regression analyses. Results: A relatively high proportion of children had co-morbid CTD/TS (19.7%). There was a significant association with co-morbid obsessive-compulsive disorder, intellectual disability and autism spectrum disorder but not attention deficit hyperactivity disorder. CTD/TS were associated with longer admissions even after adjustments for confounding but did not seem to be independently associated with other examined clinical characteristics. Conclusions: The prevalence of CTD/TS in children needing inpatient treatment is significant. In our sample, comorbid CTD/TS seem to represent a marker of overall symptom severity as evidenced by longer admissions.

Immunological Dysfunction in Tourette Syndrome and Related Disorders

Chronic tic disorder and Tourette syndrome are common childhood-onset neurological diseases. However, the pathophysiology underlying these disorders is unclear, and most studies have focused on the disinhibition of the corticostriatal–thalamocortical circuit. An autoimmune dysfunction has been proposed in the pathogenetic mechanism of Tourette syndrome and related neuropsychiatric disorders such as obsessive–compulsive disorder, autism, and attention-deficit/hyperactivity disorder. This is based on evidence from animal model studies and clinical findings. Herein, we review and give an update on the clinical characteristics, clinical evidence, and genetic studies in vitro as well as animal studies regarding immune dysfunction in Tourette syndrome.

Effectiveness of Behaviour Therapy for Children and Adolescents with Tourette Syndrome and Chronic Tic Disorder in a Naturalistic Setting

It is unclear if the results of randomised controlled trials (RCTs) of behaviour therapy (BT) for Tourette syndrome (TS) and chronic tic disorder (CTD) can be generalised to naturalistic clinical settings and are durable long-term. In this naturalistic study, 74 young people with TS/CTD received BT at a specialist clinic. Data were collected at baseline, post-treatment, and at 3-, 6-, and 12-month follow-ups. Measures included the Yale Global Tic Severity Scale (YGTSS) and the Clinical Global Impression-Improvement scale (CGI-I), amongst others. Tic severity and tic-related impairment improved after treatment, with large within-group effect sizes. At post-treatment, 57% of the participants were classified as treatment responders according to the CGI-I. Tic severity and tic-related impairment improved further through the follow-up, with 75% treatment responders at the 12-month follow-up. BT is an effective and durable treatment for young people with TS/CTD in a naturalistic specialist clinical setting, with comparable effects to RCTs.