The Challenge of Examining Social Determinants of Health in People Living With Tourette Syndrome.

BACKGROUND: To examine the association between race, ethnicity, and parental educational attainment on tic-related outcomes among Tourette Syndrome (TS) participants in the Tourette Association of America International Consortium for Genetics (TAAICG) database. METHODS: 723 participants in the TAAICG dataset aged ≤21 years were included. The relationships between tic-related outcomes and race and ethnicity were examined using linear and logistic regressions. Parametric and nonparametric tests were performed to examine the association between parental educational attainment and tic-related outcomes. RESULTS: Race and ethnicity were collapsed as non-Hispanic white (N=566, 88.0%) versus Other (N=77, 12.0%). Tic symptom onset was earlier by 1.1 years (P < 0.0001) and TS diagnosis age was earlier by 0.9 years (P = 0.0045) in the Other group (versus non-Hispanic white). Sex and parental education as covariates did not contribute to the differences observed in TS diagnosis age. There were no significant group differences observed across the tic-related outcomes in parental education variable. CONCLUSIONS: Our study was limited by the low number of nonwhite or Hispanic individuals in the cohort. Racial and ethnic minoritized groups experienced an earlier age of TS diagnosis than non-Hispanic white individuals. Tic severity did not differ between the two groups, and parental educational attainment did not affect tic-related outcomes. There remain significant disparities and gaps in knowledge regarding TS and associated comorbid conditions. Our study suggests the need for more proactive steps to engage individuals with tic disorders from all racial and ethnic minoritized groups to participate in research studies.

High persistence and low treatment rates of metabolic syndrome in patients with mood and anxiety disorders: A naturalistic follow-up study.

BACKGROUND: Patients with affective and anxiety disorders are at risk of metabolic syndrome (MetS) and, consequently, cardiovascular disease and premature death. In this study, the course and treatment of MetS was investigated using longitudinal data from a naturalistic sample of affective- and anxiety-disordered outpatients (Monitoring Outcome of psychiatric PHARmacotherapy [MOPHAR]). METHODS: Demographics, clinical characteristics, medication use, and MetS components were obtained for n = 2098 patients at baseline and, in a FU-subsample of n = 507 patients, after a median follow-up (FU) of 11 months. Furthermore, pharmacological treatment rates of MetS were investigated at baseline and FU. Finally, demographic and clinical determinants of change in MetS (component) scores were investigated. RESULTS: At baseline, 34.6 % of n = 2098 patients had MetS, 41.4 % of whom received treatment. Of patients with persisting MetS, 46.1 % received treatment for one (or more) MetS component(s) at baseline, and 56.6 % received treatment at FU. Treatment rates of solely elevated blood pressure and reduced HDL-cholesterol did significantly, but modestly, improve. Higher age, male sex, smoking behavior, low education, diabetes, and depressive versus anxiety disorder were predictors of worse outcome at FU on at least one MetS component. LIMITATIONS: We did not have data on lifestyle interventions as a form of treatment, which might partly have explained the observed low pharmacotherapeutic treatment rates. CONCLUSION: MetS (components) show high persistence rates in affective- and anxiety-disordered patients, and are, despite adequate monitoring, undertreated over time. This indicates that adherence and implementation of monitoring protocols should be crucially improved in psychiatric outpatients in secondary care.

Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population.

While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13-38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10-5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33-43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

Sex Differences in People with Tourette Syndrome and Persistent Motor or Vocal Tic Disorder in the Tourette Association of America International Consortium for Genetics Database.

Background and Objective: Tourette Syndrome (TS) and Persistent Motor or Vocal Tic Disorders (PMVT) are more prevalent in males (vs. females). Females with TS may have a delay in diagnosis, and more complex tic features (vs. males). With respect to comorbidities, obsessive-compulsive disorder (OCD) is more prevalent in females; attention-deficit hyperactivity disorder (ADHD) is more prevalent in males. Less is known about sex differences in PMVT. This study analyzes sex differences in outcomes among individuals with TS and PMVT in the Tourette Association of America International Consortium for Genetics dataset (TAAICG). Design/Methods: Data from 2403 individuals (N=2109 TS; N=294 PMVT) from the TAAICG were analyzed to explore the relationship between sex and TS or PMVT outcomes: age at tic onset; age at diagnosis; time-to-diagnosis; tic severity; and comorbidity rates. Regression models were adjusted for age and family relationships to examine the impact of sex on outcomes. Results: Females with TS (25.5% of the sample) had a later age of symptom onset (6.5±2.8 vs. 6.0±2.7; p=0.001), later age at diagnosis (13.3±11.2 vs. 10.7±8.1; p=0.0001), and a longer time-to-diagnosis [3 (1,7) vs. 2 (1,5), p=0.01] than males. The total Yale-Global Tic Severity Scale (YGTSS) was lower in females with TS (28.4±9.1 vs. 30.7±8.7); p<0.0001); OCD was slightly more prevalent in females (55% vs. 48.7%; p=0.01) although OCD severity did not differ by sex; ADHD was more prevalent in males (55.7% vs 38.9%; p<0.001). Females with TS had 0.46 lower odds of being diagnosed with TS (p<0.00001). Females with PMVT (42.9% of the sample) had an earlier age of symptom onset (7.9±3.3 vs. 8.9±3.7; p=0.05). Motor or vocal tic severity (YGTSS) was not significantly different. OCD, but not ADHD, was more prevalent in females (OCD: 41.9% vs. 22.2%; p<0.001: ADHD:16.5% vs 21.0%; p=0.4). Conclusion: Females with TS are less likely to be formally diagnosed and have a later age of symptom onset, later age at diagnosis, longer time-to-diagnosis, higher prevalence of OCD, and lower prevalence of ADHD (vs. males). Females with PMVT have an earlier age of symptom onset, higher prevalence of OCD, but similar ADHD prevalence rates (vs. males). Females with TS and PMVT may be clinically different than males with TS. Future research is needed to understand differences longitudinally in TS and PMVT.

Sleep disorders in a naturalistic cohort of Dutch psychiatric outpatients: prevalence rates and associations with psychopathology symptom severity and well-being.

Sleep problems are very common in individuals with a mental disorder. Given the abundant evidence indicating the negative impact of disturbed sleep on mental health outcome, insight into the prevalence of all types of sleep disorders in specific mental disorders and neurodevelopmental conditions is of practical importance. Therefore, we estimated the prevalence of six types of sleep disorders with the Holland Sleep Disorders Questionnaire in an overall mental health sample (n = 1082) and separately for different mental and neurodevelopmental conditions. Furthermore, associations between specific sleep disorders, psychopathology and well-being were studied. The impact of the total number of sleep disorders on these associations was examined. Overall, 46.2% of all participants scored above the cut-off for having a sleep disorder. Specifically, 26.8% scored on insomnia, 12.1% on sleep breathing disorders, 9.7% on hypersomnia, 13.7% on circadian rhythm sleep-wake disorders, 11.2% on parasomnia, and 17.9% on sleep-related movement disorders. Most sleep disorders were associated with greater severity of psychopathology and lower well-being. These associations got stronger with an increasing number of sleep disorders. Our study revealed higher suspected prevalence of most sleep disorders in a mental disorder sample compared to the general population. Moreover, the presence of sleep disorder(s) was strongly associated with symptom severity and reduced well-being. These findings extend the notion that early detection and treatment of sleep disorders in mental health populations is essential for psychiatric outcome.

Working Mechanisms of Exposure and Response Prevention in the Treatment of Tourette Syndrome and Tic Disorders Revisited: No Evidence for within-Session Habituation to Premonitory Urges.

BACKGROUND: Exposure and response prevention (ERP) has been shown to be an effective treatment for Tourette syndrome (TS) and chronic tic disorders (CTD). ERP is based on voluntary tic suppression in combination with prolonged exposure to premonitory urges preceding tics. A prevailing hypothesis of the working mechanism underlying ERP in tics is habituation to the premonitory urges as a result of prolonged exposure. However, results so far are equivocal. This study aims to further explore the relation between urges and ERP in tics, by investigating the course of premonitory urges during ERP sessions. METHODS: Using a data-driven approach, within-session habituation to premonitory urge intensity was investigated. In total, 29 TS patients rated urge intensity at seven timepoints during ten 1 h ERP sessions. RESULTS/CONCLUSIONS: Latent growth modeling showed an increase in urge intensity during the first 15 min of each session followed by a plateau in the remaining 45 min of the session. This does not support the idea of within-session habituation to premonitory urges as a working mechanism of ERP. Other potential underlying working mechanisms are discussed and should be tested in future research.

Pharmacogenetics of Long-Term Outcomes of Schizophrenia Spectrum Disorders: The Functional Role of CYP2D6 and CYP2C19.

Schizophrenia spectrum disorders (SSD) are complex mental disorders, and while treatment with antipsychotics is important, many patients do not respond or develop serious side effects. Genetic variation has been shown to play a considerable role in determining an individual's response to antipsychotic medication. However, previous pharmacogenetic (PGx) studies have been limited by small sample sizes, lack of consensus regarding relevant genetic variants, and cross-sectional designs. The current study aimed to investigate the association between PGx variants and long-term clinical outcomes in 691 patients of European ancestry with SSD. Using evidence from the literature on candidate genes involved in antipsychotic pharmacodynamics, we created a polygenic risk score (PRS) to investigate its association with clinical outcomes. We also created PRS using core variants of psychotropic drug metabolism enzymes CYP2D6 and CYP2C19. Furthermore, the CYP2D6 and CYP2C19 functional activity scores were calculated to determine the relationship between metabolism and clinical outcomes. We found no association for PGx PRSs and clinical outcomes; however, an association was found with CYP2D6 activity scores by the traditional method. Higher CYP2D6 metabolism was associated with high positive and high cognitive impairment groups relative to low symptom severity groups. These findings highlight the need to test PGx efficacy with different symptom domains. More evidence is needed before pharmacogenetic variation can contribute to personalized treatment plans.

Cardiovascular risk assessment methods yield unequal risk predictions: a large cross-sectional study in psychiatric secondary care outpatients.

BACKGROUND: Patients with a mental illness are more likely to develop, and die from, cardiovascular diseases (CVD), necessitating optimal CVD-risk (CVR)-assessment to enable early detection and treatment. Whereas psychiatrists use the metabolic syndrome (MetS)-concept to estimate CVR, GPs use absolute risk-models. Additionally, two PRIMROSE-models have been specifically designed for patients with severe mental illness. We aimed to assess the agreement in risk-outcomes between these CVR-methods. METHODS: To compare risk-outcomes across the various CVR-methods, we used somatic information of psychiatric outpatients from the PHAMOUS-, and MOPHAR-database, aged 40-70 years, free of past or current CVD and diabetes. We investigated: (1) the degree-of-agreement between categorical assessments (i.e. MetS-status vs. binary risk-categories); (2) non-parametric correlations between the number of MetS-criteria and absolute risks; and (3) strength-of-agreement between absolute risks. RESULTS: Seven thousand twenty-nine measurements of 3509 PHAMOUS-patients, and 748 measurements of 748 MOPHAR-patients, were included. There was systematic disagreement between the categorical CVR-assessments (all p < 0.036). Only MetS-status versus binary Framingham-assessment had a fair strength-of-agreement (κ = 0.23-0.28). The number of MetS-criteria and Framingham-scores, as well as MetS-criteria and PRIMROSE lipid-scores, showed a moderate-strong correlation (τ = 0.25-0.34). Finally, only the continuous PRIMROSE desk and lipid-outcomes showed moderate strength-of-agreement (ρ = 0.91). CONCLUSIONS: The varying methods for CVR-assessment yield unequal risk predictions, and, consequently, carry the risk of significant disparities regarding treatment initiation in psychiatric patients. Considering the significantly increased health-risks in psychiatric patients, CVR-models should be recalibrated to the psychiatric population from adolescence onwards, and uniformly implemented by health care providers. TRIAL REGISTRATION: The MOPHAR research has been prospectively registered with the Netherlands Trial Register on 19th of November 2014 (NL4779).

Anxiolytic effects of endocannabinoid enhancing compounds: A systematic review and meta-analysis.

The endocannabinoid system is a promising candidate for anxiolytic therapy, but translation to the clinic has been lagging. We meta-analyzed the evidence for anxiety-reduction by compounds that facilitate endocannabinoid signaling in humans and animals. To identify areas of specific potential, effects of moderators were assessed. Literature was searched in Pubmed and Embase up to May 2021. A placebo/vehicle-control group was required and in human studies, randomization. We excluded studies that co-administered other substances. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. We conducted three-level random effects meta-analyses and explored sources of heterogeneity using Bayesian regularized meta-regression (BRMA). The systematic review yielded 134 studies. We analyzed 120 studies (114 animal, 6 human) that investigated cannabidiol (CBD, 61), URB597 (39), PF-3845 (6) and AM404 (14). Pooled effects on conditioned and unconditioned anxiety in animals (with the exception of URB597 on unconditioned anxiety) and on experimentally induced anxiety in humans favored the investigational drugs over placebo/vehicle. Publication year was negatively associated with effects of CBD on unconditioned anxiety. Compared to approach avoidance tests, tests of repetitive-compulsive behavior were associated with larger effects of CBD and URB597, and the social interaction test with smaller effects of URB597. Larger effects of CBD on unconditioned anxiety were observed when anxiety pre-existed. Studies reported few side effects at therapeutic doses. The evidence quality was low with indications of publication bias. More clinical trials are needed to translate the overall positive results to clinical applications.

Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome.

BACKGROUND: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. METHODS: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. RESULTS: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. CONCLUSIONS: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

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.

Psychiatric manifestations of inborn errors of metabolism: A systematic review.

Inborn errors of metabolism (IEMs) are characterized by deficits in metabolic enzymes as a result of an inherited disease, leading to the accumulation or decreased excretion of proteins, carbohydrates and lipids. Although IEMs are often diagnosed during childhood, adolescent and adult onset variants may be accompanied by less somatic and more psychiatric manifestations, which often hampers recognition by psychiatrists of the distinction between a primary and secondary psychiatric disorder. To help clinicians in the diagnostic process, we aimed to provide an overview of psychiatric manifestations in IEMs. Our literature search yielded 4380 records in total, of which 88 studies were included in the qualitative synthesis. Reported psychiatric disorders in adolescent and adult IEMs included depression, anxiety disorder, psychosis, attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder and obsessive-compulsive disorder as assessed by semi-structured diagnostic interviews and validated questionnaires. A diagnostic screener and multidisciplinary IEM clinics are proposed to help clinicians during the diagnostic process, to prevent diagnostic delay and to raise awareness of the psychiatric manifestations among IEMs.

Meta-analysis of genome-wide association studies of hoarding symptoms in 27,537 individuals.

Hoarding Disorder (HD) is a mental disorder characterized by persistent difficulties discarding or parting with possessions, often resulting in cluttered living spaces, distress, and impairment. Its etiology is largely unknown, but twin studies suggest that it is moderately heritable. In this study, we pooled phenotypic and genomic data from seven international cohorts (N = 27,537 individuals) and conducted a genome wide association study (GWAS) meta-analysis of parent- or self-reported hoarding symptoms (HS). We followed up the results with gene-based and gene-set analyses, as well as leave-one-out HS polygenic risk score (PRS) analyses. To examine a possible genetic association between hoarding symptoms and other phenotypes we conducted cross-trait PRS analyses. Though we did not report any genome-wide significant SNPs, we report heritability estimates for the twin-cohorts between 26-48%, and a SNP-heritability of 11% for an unrelated sub-cohort. Cross-trait PRS analyses showed that the genetic risk for schizophrenia and autism spectrum disorder were significantly associated with hoarding symptoms. We also found suggestive evidence for an association with educational attainment. There were no significant associations with other phenotypes previously linked to HD, such as obsessive-compulsive disorder, depression, anxiety, or attention-deficit hyperactivity disorder. To conclude, we found that HS are heritable, confirming and extending previous twin studies but we had limited power to detect any genome-wide significant loci. Much larger samples will be needed to further extend these findings and reach a "gene discovery zone". To move the field forward, future research should not only include genetic analyses of quantitative hoarding traits in larger samples, but also in samples of individuals meeting strict diagnostic criteria for HD, and more ethnically diverse samples.

Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration-effect relations using the IB-de-risk tool.

BACKGROUND: Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Dosing guidelines to inform future human studies are however lacking. AIM: We aimed to predict the therapeutic window for anxiety-reducing effects of CBD in humans based on preclinical models. METHODS: We conducted two systematic searches in PubMed and Embase up to August 2021, into pharmacokinetic (PK) and pharmacodynamic (PD) data of systemic CBD exposure in humans and animals, which includes anxiety-reducing and potential side effects. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. A control group was an inclusion criterion in outcome studies. In human outcome studies, randomisation was required. We excluded studies that co-administered other substances. We used the IB-de-risk tool for a translational integration of outcomes. RESULTS: We synthesised data from 87 studies. For most observations (70.3%), CBD had no effect on anxiety outcomes. There was no identifiable relation between anxiety outcomes and drug levels across species. In all species (humans, mice, rats), anxiety-reducing effects seemed to be clustered in certain concentration ranges, which differed between species. DISCUSSION: A straightforward dosing recommendation was not possible, given variable concentration-effect relations across species, and no consistent linear effect of CBD on anxiety reduction. Currently, these results raise questions about the broad use as a drug for anxiety. Meta-analytic studies are needed to quantitatively investigate drug efficacy, including aspects of anxiety symptomatology. Acute and (sub)chronic dosing studies with integrated PK and PD outcomes are required for substantiated dose recommendations.

Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration.

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.

Let's talk about grief: Protocol of a study on the recognition and psychoeducation of prolonged grief disorder in outpatients with common mental disorders.

Background: Recognition that the loss of a loved one may result in prolonged grief disorder (PGD) has gained broad attention recently. PGD may disturb daily functioning to such a degree that mental health treatment is required. Because PGD symptoms often resemble symptoms of common mental disorders (CMD) such as anxiety, depressive, and post-traumatic stress disorder, clinicians may not consider a PGD diagnosis. Moreover, cultural varieties in expression of PGD may complicate recognition. This study explores the prevalence of PGD among both natives and refugees with anxiety, depressive, or trauma- and/or stressor-related disorders as well as clinicians' awareness and knowledge of PGD symptoms. In addition, a psychoeducation module on PGD symptoms is developed through patient expert collaboration. Methods: Prevalence of PGD symptoms is investigated among 50 participants who are referred to outpatient clinics for anxiety, depression, or post-traumatic stress, using the Traumatic Grief Inventory-Self Report Plus (TGI-SR+) and the Bereavement and Grief-Cultural Formulation Interview (BG-CFI). Clinicians will be interviewed on knowledge (gaps) with respect to PGD symptoms. Finally, focus groups with patient experts are held to develop a psychoeducation module tailored to the patients' needs, norms and values. Results: This study will show prevalence of PGD among patients who are referred for anxiety, depression, and post-traumatic stress, awareness and knowledge of clinicians on PGD symptoms, and will offer patient expert informed psychoeducation. Discussion: Research on prevalence and recognition of PGD is vital. Study results of the prevalence of PGD will be compared to previous studies. Recognition of PGD as distinct disorder from CMDs requires clinicians' awareness of symptoms related to the loss of a loved one. Thereby, clinicians need to take cultural aspects related to death, bereavement and mourning into consideration. Ethics and dissemination: The study protocol will be carried out in accordance with relevant guidelines and regulations. Exploratory research to assess the prevalence of PGD in patients suffering from CMDs will facilitate adequate diagnosis by increasing clinician's awareness of PGD symptoms. Tailored PGD psychoeducation, co-created by culturally diverse patient experts and clinicians will be made publicly available.

Effectiveness of 'Tackle Your Tics', a brief, intensive group-based exposure therapy programme for children with tic disorders: study protocol of a randomised controlled trial.

INTRODUCTION: This paper outlines the study protocol for the Dutch Tackle Your Tics study in youth with tic disorders. Tourette syndrome and chronic tic disorders are prevalent neurodevelopmental disorders, placing considerable burden on youth and their families. Behavioural treatment is the first-line, evidence-based intervention for tic disorders, but tic reduction and availability remain relatively low. Patient associations stress the need for more accessible high-quality treatments, also focusing on improving quality of life. Therefore, the brief, intensive group-based treatment Tackle Your Tics was developed. METHODS AND ANALYSIS: Tackle Your Tics is a 4-day intensive and comprehensive group-based intervention for children and adolescents (9-17 years) with Tourette syndrome or a chronic tic disorder. The programme encompasses exposure and response prevention treatment and additional supporting components (coping strategies, relaxation exercises and parent support). To study the effectiveness of Tackle Your Tics and identify predictors/moderators at baseline, a single-blinded randomised controlled trial (n=104) is conducted, comparing Tackle Your Tics (n=52) with a waiting list condition lasting 3 months (n=52). Assessments are performed at similar time points for both groups: at baseline, after 4 weeks, and at 3 and 6 months of follow-up, on tic severity, quality of life and other psychosocial variables. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the medical ethical committee of the Amsterdam Medical Centre (METC nr NL66340.018.18, v3 June 2020). Findings will be presented on national and international conferences, peer-reviewed scientific journals, patient organisation meetings and public media. Patient representatives are fully integrated as part of the research team. If Tackle Your Tics proves to be effective, it can expand evidence-based treatment possibilities for children and adolescents with tic disorders. Identifying the psychosocial predictors/moderators for the effectiveness of this intervention can provide personalised treatment advice in the future. TRIAL REGISTRATION NUMBER: NL8052.

Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial.

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid- and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (ß = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (ß = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens.

Cognitive and Experienced Flexibility in Patients With Anorexia Nervosa and Obsessive Compulsive Disorder.

Objective: Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) share a neuropsychological profile characterized by cognitive inflexibility as evident in set-shifting problems, and by strong detail focus. Clinically, both patient groups display a strong rigidity which may be explained by these neurocognitive difficulties. Cognitive inflexibility may hinder treatment uptake and help explain suboptimal treatment outcomes in both AN and OCD. This is the first study to compare clinical AN and OCD groups andto examine similarities and differences in cognitive flexibility. Specifically, this study aims to investigate neuropsychological outcomes and self-reported difficulties in both clinical groups and a control group, and explore associations between the different flexibility outcomes and illness. Method: Two hundred participants (61 AN, 72 OCD and 67 HC) performed neuropsychological tasks on set-shifting abilities (Trail Making Task, Stroop color-word interference, Intradimensional-Extradimensional shift task), detail focus (Group Embedded Figures Test) and self-reported set-shifting abilities and attention to detail (DFlex). Results: Similarities between patient groups were found in terms of reduced set-shifting ability on the Trail Making Task and detail focus. Moreover, both patient groups self-reported more set-shifting problems but a less strong detail focus than HC, which in turn were not related to neuropsychological task outcomes in either of the groups. In both patient groups longer illness duration was associated to longer reaction times in the switching tasks and for both groups symptom severity was associated to higher experienced inflexibility and attention to detail. Conclusion: Cognitive inflexibility processes are largely similar in patients with AN and OCD. Both patient groups report inflexibility, yet this is unrelated to neuropsychological outcomes. Illness duration seems to contribute to poorer set-shifting and higher illness severity is linked to more experienced inflexibility. Findings highlight the need for entangling different domains of cognitive flexibility and detail focus and examining self-report measures for a cohesive understanding of clinically relevant flexibility weaknesses in AN and OCD.