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Summary Background Exposure and Response Prevention (ERP) is a form of behavioural therapy for tics; however, its effectiveness remains uncertain. We aimed to evaluate the effectiveness of internet-delivered, therapist-supported, and parent-assisted ERP for treatment of tics in children and young people with Tourette syndrome or chronic tic disorder. Methods This multicentre, parallel group, single-blind, randomised controlled trial was conducted across two study sites in England. Participants were recruited via 16 patient identification centres, two study sites in England (Nottingham and London), or online self-referral. Eligible participants were aged 9–17 years, had Tourette syndrome or chronic tic disorder, had not received behavioural therapy for tics in the past 12 months or were about to start, and had a Yale Global Tic Severity Scale (YGTSS) Total Tic Severity Score (TTSS) of more than 15 or more than 10 if they had only motor or vocal tics. Patients were excluded if they had started or stopped medication for tics within the past 2 months; had current alcohol or substance dependence, psychosis, suicidality, anorexia nervosa, or suspected moderate to severe intellectual disability; or presented an immediate risk to self or others; or the parent or carer was unable to speak, read, or write in English. Eligible patients were randomly assigned (1:1) by masked outcome assessors to receive 10 weeks of online, remotely delivered, therapist-supported ERP or psychoeducation (active control). Outcome assessors, statisticians, health economists, the trial manager, and the chief investigator were masked to group allocation. Patients were not directly informed of their allocation, but this could be established from the content once treatment commenced and the patients were not, therefore, considered masked to treatment. The primary outcome was YGTSS-TTSS 3 months after randomisation, and analysis was done in all randomised patients for whom data were available for each timepoint and outcome. Safety analysis was by intention to treat. Longer term follow-up is ongoing. This trial is registered with ISRCTN (ISRCTN70758207) and ClinicalTrials.gov ( NCT03483493 ). Findings Between May 8, 2018, and Sept 30, 2019, we assessed 445 candidates for inclusion in the study. 221 potential participants were excluded (90 did not meet inclusion criteria, 84 declined to participate, and 47 unable to contact family). 224 participants were enrolled and randomly assigned to ERP (n=112) or psychoeducation (n=112). The enrolled patients were mostly male (n=177; 79%) and of White ethnicity (n=195; 87%). 11 patients were lost to follow-up 3 months after randomisation in the ERP group, compared with 12 patients in the psychoeducation group. Mean YGTSS-TTSS at 3 months after randomisation was 23·9 (SD 8·2) in the ERP group and 26·8 (7·3) in the psychoeducation group. The mean total decrease in YGTSS-TTSS at 3 months was 4·5 (16%, SD 1·1) in the ERP group versus 1·6 (6%, 1·0) in the psychoeducation group. The estimated mean difference in YGTSS-TTSS change between the groups adjusted for baseline and site was –2·29 points (95% CI –3·86 to –0·71) in favour of ERP, with an effect size of –0·31 (95% CI –0·52 to –0·10). Two serious adverse events occurred (one collapse and one tic attack), both in the psychoeducation group, neither of which were related to study treatment. Interpretation ERP is an effective behavioural therapy for tics. Remotely delivered, online ERP with minimal therapist contact time represents an efficient public mental health approach to improve access to behavioural therapy for tics in children and adolescents. Funding National Institute for Health Research and Health and Technology Assessment.

Background Little is known about the lived experiences of individuals with tic disorders when driving vehicles or trying to obtain a driving license. Objective To survey the driving-related experiences of adults with tic disorders. Methods A global survey was disseminated via social media, international patient organizations, and experts between April 27, 2020 and July 20, 2020. Results Participants were 228 adult individuals self-reporting a confirmed diagnosis of Tourette syndrome or chronic tic disorder. Of these, 183 (87.7%) had a driver's license. A minority (9%) reported that they had found it hard to pass the driving test. Tics only interfered with driving "a bit" (58.5%) or "not at all" (33%). A majority of participants reported being able to suppress their tics (39.5%) or that their tics are unchanged (28.5%) while driving. Nearly half of the participants (46.5%) had been involved in accidents, but only a negligible percentage (3.2%) considered that these were linked to the tics. Participants without a driver's license (n = 28, 12.3%) reported significantly more severe tics, compared to those with a license. The majority of these (60.7%) identified their tics as the main reason for not having a license and 64.3% said that they would like to receive support to obtain one. Conclusions The majority of surveyed participants with chronic tic disorders reported minimal difficulties with driving. However, a non-negligible minority of more severe cases struggle with driving or refrain from driving altogether and would benefit from additional support. The results have implications for clinicians and vehicle licensing agencies.

Little is known about the long-term prognosis of children with pediatric acute-onset neuropsychiatric syndrome (PANS). Out of the 46 eligible patients from the Karolinska PANS cohort, 34 consented to participate in a follow-up (median 3.3 years). Participants underwent a thorough clinical evaluation and were classified according to their clinical course. Resulting groups were compared on clinical characteristics and laboratory test results. We observed significant reductions in clinician-rated PANS symptom severity and improved general function. Two patients were classified as remitted, 20 as relapsing–remitting, and 12 as having a chronic-static/progressive course. The latter group had an earlier onset, greater impairment and received more pharmacological and psychological treatments. Although remission was rare, the majority of children with PANS were significantly improved over the follow-up period but a non-negligible minority of patients displayed a chronic-static/progressive course and required additional treatments. The proposed definitions of flare and clinical course may be useful in future clinical trials. Supplementary Information The online version of this article (10.1007/s10578-021-01135-4) contains supplementary material, which is available to authorized users.

Body dysmorphic disorder (BDD) often starts in childhood, with most cases developing symptoms before age 18. Yet, BDD research has primarily focused on adults. We report the clinical characteristics of the world’s largest cohort of carefully diagnosed youths with BDD and focus on previously unexplored sex and age differences. We systematically collected clinical data from 172 young people with BDD consecutively referred to 2 specialist pediatric obsessive–compulsive and related disorders outpatient clinics in Stockholm, Sweden and in London, England. A series of clinician-, self-, and parent-reported measures were administered. The cohort consisted of 136 girls, 32 boys, and 4 transgender individuals (age range 10–19 years). The mean severity of BDD symptoms was in the moderate to severe range, with more than one third presenting with severe symptoms and more than half showing poor or absent insight/delusional beliefs. We observed high rates of current psychiatric comorbidity (71.5%), past or current self-harm (52.1%), suicide attempts (11.0%), current desire for cosmetic procedures (53.7%), and complete school dropout (32.4%). Compared to boys, girls had significantly more severe self-reported BDD symptoms, depression, suicidal thoughts, and self-harm. Compared to the younger participants (14 or younger), older participants had significantly more severe compulsions and were more likely to report a desire for conducting cosmetic procedures. Adolescent BDD can be a severe and disabling disorder associated with significant risks and substantial functional impairment. The clinical presentation of the disorder is largely similar across sexes and age groups, indicating the importance of early detection and treatment. More research is needed specifically focusing on boys and pre-pubertal individuals with BDD.

Internet-delivered cognitive behaviour therapy (ICBT) is emerging as a powerful tool to fill the gap between demand and availability of evidence-based treatment for paediatric anxiety disorders. However, it is still unclear how to best implement it in routine clinical care. 123 children (8–12 years) with anxiety disorders underwent a 12-week ICBT programme with limited therapist support. Participants were assessed 3- and 12-month post-ICBT (3MFU and 12MFU, respectively). Non-remitters who still fulfilled diagnostic criteria for their principal anxiety disorder at 3MFU were offered additional manualised “face-to-face” (F2F) CBT. The aim of the study was to emulate a stepped-care model of health care delivery, where the long-term treatment gains of ICBT as well as the potential benefit of proving addition treatment to non-remitters of ICBT were evaluated. Remitters of ICBT (n = 73) continued to improve throughout the study period (pre-ICBT to 12MFU; Cohen’s d = 2.42). At 12MFU, 89% (n = 65) were free from their principal anxiety disorder. Of all the participants classed as non-remitters at 3MFU (n = 37), 48.6% (n = 18) accepted the offer to receive additional F2F CBT. These participants also improved with a large effect from pre-ICBT to 12MFU (Cohen’s d = 2.27), with the largest effect occurring during F2F CBT. At 12MFU, 83% (n = 15) were free from their principal anxiety disorders. The majority of non-remitters declining additional F2F CBT (63.2%; n = 12) did so due to already receiving treatment at their local CAMHS, prior to 3MFU. The effects of ICBT for anxiety disorders are durable at least up to 1 year after the end of treatment. Patients who fail to fully benefit from ICBT improved further with additional F2F sessions at our clinic, suggesting that it may be feasible to implement ICBT within a stepped-care model of health care delivery.

Objective: Obsessive-compulsive disorder (OCD) is a heterogeneous condition with well-established symptom dimensions across the lifespan. The objective of the present study was to use network analysis to investigate the internal structure of these dimensions in unselected schoolchildren and in children with OCD. Method: We estimated the network structure of OCD symptom dimensions in 6,991 schoolchildren and 704 children diagnosed with OCD from 18 sites across 6 countries. All participants completed the Obsessive-Compulsive Inventory−Child Version. Results: In both the school-based and clinic-based samples, the OCD dimensions formed an interconnected network with doubting/checking emerging as a highly central node, that is, having strong connections to other symptom dimensions in the network. The centrality of the doubting/checking dimension was consistent across countries, sexes, age groups, clinical status, and tic disorder comorbidity. Network differences were observed for age and sex in the school-based but not the clinic-based samples. Conclusion: The centrality of doubting/checking in the network structure of childhood OCD adds to classic and recent conceptualizations of the disorder in which the important role of doubt in disorder severity and maintenance is highlighted. The present results suggest that doubting/checking is a potentially important target for further research into the etiology and treatment of childhood OCD. Mr. Cervin has received funding from L.J. Boëthius Foundation, Lindhaga Foundation, Jerring Foundation, and Region Skåne that made possible the preparation of the present manuscript. Original data was collected in part by support from grants from the National Institute of Mental Health (NIMH) to Drs. Storch (1R01MH093381) and Geller (5R01MH093402).

Background Nonrandom mating has been shown for psychiatric diagnoses, with hypothesized—but not quantified—implications for offspring liability. This national cohort study enumerated the incidence of major psychiatric disorders among the offspring of parent pairs affected with schizophrenia (SCZ) and/or bipolar disorder (BIP) (i.e., dual-affected pairs). Methods Participants were all Swedish residents alive or born between 1968 and 2013 (n = 4,255,196 unique pairs and 8,343,951 offspring). Offspring with dual-affected, single-affected, and unaffected parents were followed (1973–2013) for incidence of broad psychiatric disorders. Primary outcomes included hazard ratio (HR) and cumulative incidence for SCZ and BIP in the offspring. Additional outcomes included any neuropsychiatric, anxiety, depressive, personality, or substance use disorders. Cumulative incidences of SCZ and BIP were used to inform heritability models for these disorders. Results Hazards were highest within disorder (e.g., offspring of dual-SCZ pairs had sharply raised hazards for SCZ [HR = 55.3]); however, they were significantly raised for all diagnoses (HR range = 2.89–11.84). Incidences were significantly higher for the majority of outcomes, with 43.4% to 48.5% diagnosed with “any” disorder over follow-up. Risks were retained, with modest attenuations, for the offspring of heterotypic pairs. The estimated heritability of liability for SCZ (h2 = 0.62, 95% confidence interval = 0.55–0.70) and BIP (h2 = 0.52, 95% confidence interval = 0.46–0.58) did not differ significantly from estimates derived from single-affected parents. Conclusions Risks for a broad spectrum of psychiatric diagnoses are significantly raised in the offspring of dual-affected parents, in line with expectations from a polygenic model of liability to disease risk. How these risks may contribute to population maintenance of these disorders is considered.

Background It is unclear how to best measure the complex symptom presentation of pediatric acute-onset neuropsychiatric syndrome (PANS). Methods Well-characterized participants of a 2–5 year follow-up study (n = 34; 56% male) underwent clinical evaluations and completed scales assessing global symptom severity, functional impairment and specific psychiatric symptoms. We explored inter-correlations between the measures and used intraclass correlation coefficients to evaluate the agreement between clinician-, parent- and child ratings of the same constructs. Results Ratings on symptom-specific measures varied largely between participants. Agreement between informants was excellent on functional scales, fair-to-moderate on global severity scales and mixed on symptom-specific scales. Clinician-rated global and functional measures had stronger inter-correlations with parent- and child-rated functional measures than with symptom-specific measures. Conclusions General instruments assessing global severity and functioning are well suited for the assessment and follow-up of PANS, but should be complemented by symptom-specific scales representative of core symptoms.

Background Insomnia is common in Tourette syndrome (TS) and chronic tic disorder (CTD), but precise prevalence estimates are lacking. Objective In this Swedish register-based cohort study, we estimated the prevalence of insomnia in TS/CTD and quantified the magnitude of this association, accounting for familial confounders and relevant somatic and psychiatric comorbidities. Methods Of 10,444,702 individuals living in Sweden during the period from 1997 to 2013, 5877 had a diagnosis of TS/CTD and were compared to unexposed individuals from the general population on the presence of insomnia using logistic regression models. Results Individuals with TS/CTD had a period prevalence of insomnia of 32.16%, compared to 13.70% of the unexposed population. This translated into a 6.7-fold increased likelihood of insomnia in TS/CTD (odds ratio adjusted [aOR] for sex, birth year, birth country, and somatic disorders = 6.74; 95% confidence interval [CI], 6.37-7.15). A full sibling comparison, designed to adjust for shared familial factors, attenuated the estimates (aOR = 5.41; 95% CI, 4.65-6.30). When individuals with attention-deficit/hyperactivity disorder (ADHD) and pervasive developmental disorders were excluded, the association was also attenuated, whereas exclusion of other psychiatric comorbidities had minimal impact. Having persistent TS/CTD, comorbid ADHD, and taking ADHD medication greatly increased the likelihood of insomnia. Conclusions Insomnia is significantly associated with TS/CTD, independently from somatic disorders, familial factors or psychiatric comorbidities, although familial factors, neurodevelopmental comorbidities, and ADHD/ADHD medication may explain part of the association. Insomnia should be routinely assessed and managed in TS/CTD, particularly in chronic patients and in those with comorbid ADHD. Other sleep disorders require further study. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

ObjectivesTo evaluate the cost-effectiveness of internet-delivered cognitive behaviour therapy for body dysmorphic disorder (BDD-NET).DesignSecondary cost-effectiveness analysis from a randomised controlled trial on BDD-NET versus online supportive psychotherapy.SettingAcademic medical centre.ParticipantsSelf-referred adult patients with a primary diagnosis of body dysmorphic disorder and a score of 20 or higher on the modified Yale-Brown obsessive compulsive scale (n = 94). Patients receiving concurrent psychotropic drug treatment were included if the dose had been stable for at least two months and remained unchanged during the trial.InterventionsParticipants received either BDD-NET (n = 47) or online supportive psychotherapy (n = 47) for 12 weeks.Primary and secondary outcome measuresThe primary outcome measures were cost-effectiveness and cost-utility from a societal perspective, using remission status from a diagnostic interview and quality-adjusted life years from EQ-5D, respectively. Secondary outcome measures were cost-effectiveness and cost-utility from a health care perspective and the clinic’s perspective.ResultsCompared to supportive psychotherapy, BDD-NET produced one additional remission for an average societal cost of $4132. The cost-utility analysis showed that BDD-NET generated one additional QALY to an average cost of $14319 from a societal perspective.ConclusionsBDD-NET is a cost-effective treatment for body dysmorphic disorder, compared to online supportive psychotherapy. The efficacy and cost-effectiveness of BDD-NET should be directly compared to face-to-face cognitive behaviour therapy.Trial registrationNCT02010619Strengths and limitations of this studyThis is the first cost-effectiveness evaluation of a novel internet-delivered treatment designed to increase access to cognitive behaviour therapy for patients with body dysmorphic disorderCost estimations were self-rated and might not capture all costs associated with treatmentThe self-referred participants were likely motivated to undergo treatment.

Background Treatment guidelines recommend behaviour therapy (BT) for patients with Tourette syndrome (TS) and chronic tic disorder (CTD). However, BT is rarely accessible due to limited availability of trained therapists and long travel distances to specialist clinics. Internet-delivered BT has the potential of overcoming these barriers through remote delivery of treatment with minimal therapist support. In the current protocol, we outline the design and methods of a randomised controlled trial (RCT) evaluating an internet-delivered BT programme referred to as BIP TIC. The trial’s primary objective is to determine the clinical efficacy of BIP TIC for reducing tic severity in young people with TS/CTD, compared with an active control intervention. Secondary objectives are to investigate the 12-month durability of the treatment effects and to perform a health economic evaluation of the intervention. Methods In this single-blind superiority RCT, 220 participants (9–17 years) with TS/CTD throughout Sweden will be randomised to 10–12 weeks of either therapist-supported internet-delivered BT based on exposure with response prevention (BIP TIC) or therapist-supported internet-delivered education. Data will be collected at baseline, 3 and 5 weeks into the treatment, at post-treatment, and 3, 6, and 12 months post-treatment. The primary endpoint is the 3-month follow-up. The primary outcome is tic severity as measured by the Yale Global Tic Severity Scale – Total Tic Severity Score. Treatment response is operationalised as scores of “Very much improved” or “Much improved” on the Clinical Global Impression – Improvement scale, administered at the primary endpoint. Outcome assessors will be blind to treatment condition at all assessment points. A health economic evaluation of BIP TIC will be performed, both in the short term (primary endpoint) and the long term (12-month follow-up). There are no planned interim analyses. Discussion Participant recruitment started on 26 April 2019 and finished on 9 April 2021. The total number of included participants was 221. The final participant is expected to reach the primary endpoint in September 2021 and the 12-month follow-up in June 2022. Data analysis for the primary objective will commence after the last participant reaches the primary endpoint. Trial registration ClinicalTrials.gov NCT03916055. Registered on 16 April 2019.

Pediatric body dysmorphic disorder (BDD) is challenging to treat. This study aimed to establish the prevalence of insomnia in youth with BDD and explore its impact on clinical outcomes. Sixty-six children and adolescents with BDD consecutively referred to a specialist clinic completed a range of clinical measures, including the Yale-Brown Obsessive–Compulsive Scale Modified for BDD-Adolescent Version (BDD-YBOCS-A), and the Insomnia Severity Index (ISI). Patients with clinical insomnia (ISI score ≥ 9) were compared to the rest of the sample on socio-demographic and clinical features. Fifty-six patients who received multimodal treatment were re-assessed post-treatment. A mixed-model ANOVA was performed to compare treatment outcomes between the insomnia vs. no insomnia groups, and Chi-squared tests were used to compare response and remission rates. According to the ISI, 48% of the sample qualified as having insomnia at baseline. These participants showed significantly higher self-reported BDD symptom severity, more depressive symptoms, and more functional impairment in daily activities. Patients with insomnia improved less on the BDD-YBOCS-A than those without insomnia, although the difference did not reach statistical significance. The rates of responders and remitters were lower in the insomnia group, compared to the non-insomnia group. Insomnia is prevalent in pediatric BDD, and is associated with more severe psychopathology and worse functioning in daily activities. Furthermore, youth experiencing BDD and insomnia may benefit from multimodal treatment to a lesser extent than those without insomnia. If these results are replicated in larger samples, treatment refinements for pediatric BDD could include specific modules to directly target insomnia. Electronic supplementary material The online version of this article (10.1007/s00787-019-01442-1) contains supplementary material, which is available to authorized users.

BackgroundThe number of clinical trials in body dysmorphic disorder (BDD) has steadily increased in recent years. As the number of studies grows, it is important to define the most empirically useful definitions for response and remission in order to enhance field-wide consistency and comparisons of treatment outcomes across studies. In this study, we aim to operationally define treatment response and remission in BDD.MethodWe pooled data from three randomized controlled trials of cognitive-behavior therapy (CBT) for BDD (combined n = 153) conducted at four academic sites in Sweden, the USA, and England. Using signal detection methods, we examined the Yale-Brown Obsessive Compulsive Scale modified for BDD (BDD–YBOCS) score that most reliably identified patients who responded to CBT and those who achieved remission from BDD symptoms at the end of treatment.ResultsA BDD–YBOCS reduction ⩾30% was most predictive of treatment response as defined by the Clinical Global Impression (CGI) – Improvement scale (sensitivity 0.89, specificity 0.91, 91% correctly classified). At post-treatment, a BDD–YBOCS score ⩽16 was the best predictor of full or partial symptom remission (sensitivity 0.85, specificity 0.99, 97% correctly classified), defined by the CGI – Severity scale.ConclusionBased on these results, we propose conceptual and operational definitions of response and full or partial remission in BDD. A consensus regarding these constructs will improve the interpretation and comparison of future clinical trials, as well as improve communication among researchers, clinicians, and patients. Further research is needed, especially regarding definitions of full remission, recovery, and relapse.

In the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), obsessive-compulsive disorder (OCD) included a new “tic-related” specifier. However, strong evidence supporting tic-related OCD as a distinct subtype of OCD is lacking. This study investigated whether, at the population level, tic-related OCD has a stronger familial load than non-tic-related OCD. From a cohort of individuals born in Sweden between 1967 and 2007 (n = 4,085,367; 1257 with tic-related OCD and 20,975 with non-tic-related OCD), we identified all twins, full siblings, maternal and paternal half siblings, and cousins. Sex- and birth year-adjusted hazard ratios (aHR) were calculated to estimate the risk of OCD in relatives of individuals with OCD with and without comorbid tics, compared with relatives of unaffected individuals. We found that OCD is a familial disorder, regardless of comorbid tic disorder status. However, the risk of OCD in relatives of individuals with tic-related OCD was considerably greater than the risk of OCD in relatives of individuals with non-tic-related OCD (e.g., risk for full siblings: aHR = 10.63 [95% CI, 7.92–14.27] and aHR = 4.52 [95% CI, 4.06–5.02], respectively; p value for the difference

Immune dysregulation due to chronic inflammation is a hypothesized risk factor underlying psychiatric disorders and suicidal behavior. Whether tonsillectomy and acute appendicitis used, respectively, as proxies for chronic and acute inflammation within the mucosa-associated lymphoid tissue (MALT) are associated with psychiatric disorders and suicidal behavior is currently unknown. A birth cohort study was conducted including 3,052,875 individuals born in Sweden between 1973 and 2003. We identified 210,686 individuals ever exposed to tonsillectomy and 86,928 individuals ever exposed to acute appendicitis, as well as 317,214 clusters of siblings discordant for tonsillectomy, and 160,079 sibling clusters discordant for acute appendicitis. Outcomes were an aggregate risk of ‘any psychiatric disorder’, ‘any suicidal behavior’, 12 individual psychiatric disorders, suicide attempts and deaths by suicide. Tonsillectomy was associated with increased odds of ‘any psychiatric disorder’ (adjusted odds ratio [aOR] = 1.39; 95% confidence interval (CI) = 1.38–1.41) and ‘any suicidal behavior’ (aOR = 1.41; 95% CI = 1.37–1.44), and most individual disorders. Acute appendicitis also increased the odds of ‘any psychiatric disorder’ and ‘any suicidal behavior’ (aOR = 1.23; 95% CI = 1.20–1.25, and aOR = 1.32; 95% CI = 1.28–1.37, respectively). Exposure to both tonsillectomy and appendicitis was associated with the highest odds of ‘any psychiatric disorder’ (aOR = 1.70; 95% CI = 1.59–1.82) and ‘any suicidal behavior’ (aOR = 1.90; 95% CI = 1.70–2.12). In sibling comparisons, the associations were attenuated but remained significant. We conclude that inflammation within the MALT, particularly when chronic, is robustly associated with a broad range of psychiatric disorders and suicidal behavior.

Obsessive–compulsive disorder and autism spectrum disorder commonly co-occur. Adapted cognitive behavior therapy for obsessive–compulsive disorder in adults with autism spectrum disorder has not previously been evaluated outside the United Kingdom. In this study, 19 adults with obsessive–compulsive disorder and autism spectrum disorder were treated using an adapted cognitive behavior therapy protocol that consisted of 20 sessions focused on exposure with response prevention. The primary outcome was the clinician-rated Yale–Brown Obsessive–Compulsive Scale. Participants were assessed up to 3 months after treatment. There were significant reductions on the Yale–Brown Obsessive–Compulsive Scale at post-treatment (d = 1.5), and improvements were sustained at follow-up (d = 1.2). Self-rated obsessive–compulsive disorder and depressive symptoms showed statistically significant reductions. Improvements in general functioning and quality of life were statistically non-significant. Three participants (16%) were responders at post-treatment and four (21%) were in remission from obsessive–compulsive disorder. At follow-up, three participants (16%) were responders and one (5%) was in full remission. Adapted cognitive behavior therapy for obsessive–compulsive disorder in adults with co-occurring autism spectrum disorder is associated with reductions in obsessive–compulsive symptoms and depressive symptoms. However, outcomes are modest; few patients were completely symptom free, and treatment engagement was low with few completed exposures and low adherence to homework assignments. We identify and discuss the need for further treatment refinement for this vulnerable group.

BackgroundMaternal polycystic ovary syndrome (PCOS) has been proposed as a model for investigating the role of prenatal androgen exposure in the development of neuropsychiatric disorders. However, women with PCOS are at higher risk of developing psychiatric conditions and previous studies are likely confounded by genetic influences.MethodsA Swedish nationwide register-based cohort study was conducted to disentangle the influence of prenatal androgen exposure from familial confounding in the association between maternal PCOS and offspring attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and Tourette's disorder and chronic tic disorders (TD/CTD). PCOS-exposed offspring (n = 21 280) were compared with unrelated PCOS-unexposed offspring (n = 200 816) and PCOS-unexposed cousins (n = 17 295). Associations were estimated with stratified Cox regression models.ResultsPCOS-exposed offspring had increased risk of being diagnosed with ADHD, ASD, and TD/CTD compared with unrelated PCOS-unexposed offspring. Associations were stronger in girls for ADHD and ASD but not TD/CTD [ADHD: adjusted hazard ratio (aHR) = 1.61 (95% confidence interval (CI) 1.31–1.99), ASD: aHR = 2.02 (95% CI 1.45–2.82)] than boys [ADHD: aHR = 1.37 (95% CI 1.19–1.57), ASD: aHR = 1.46 (95% CI 1.21–1.76)]. For ADHD and ASD, aHRs for girls were stronger when compared with PCOS-unexposed cousins, but slightly attenuated for boys.ConclusionsEstimates were similar when accounting for familial confounding (i.e. genetics and environmental factors shared by cousins) and stronger in girls for ADHD and ASD, potentially indicating a differential influence of prenatal androgen exposure v. genetic factors. These results strengthen evidence for a potential causal influence of prenatal androgen exposure on the development of male-predominant neuropsychiatric disorders in female offspring of women with PCOS.

BACKGROUNDWhether a patient benefits from psychotherapy or not is arguably a complex process and heterogeneous information extracted from process, genetic, demographic, and clinical data could contribute to the prediction of remission status after psychotherapy. This study applied supervised machine learning with such multi-modal baseline data to predict remission in patients with major depressive disorder (MDD) after completed psychotherapy.METHODSEight-hundred ninety-four genotyped adult patients (65.5% women, age range 18-75 years) diagnosed with MDD and treated with guided Internet-based Cognitive Behaviour Therapy (ICBT) at the Internet Psychiatry Clinic in Stockholm were included (2008-2016). Predictor variables from multiple domains were available: demographic, clinical, process (e.g. time to complete online questionnaires), and genetic (polygenic risk scores for depression, education and more). The outcome was remission status post ICBT (cut-off ≤10 on MADRS-S). Data were split into train (60%) and validation (40%) sets based on treatment start date. Predictor selection employed human domain knowledge followed by Recursive Feature Elimination. Model derivation was internally validated through repeated cross-validation resampling. The final random forest model was externally validated against a (i) null, (ii) logit, (iii) XGBoost, and (iv) blended meta-ensemble model on the hold-out validation set. Model transparency was explored through partial dependence and Local Interpretable Model-agnostic Explanations (LIME) analysis.RESULTSFeature selection retained 45 predictors representing all four predictor types. With unseen validation data, the final random forest model proved reasonably accurate at classifying post ICBT remission (Accuracy 0.656 [0.604, 0.705], P vs null model = 0.004; AUC 0.687 [0.631, 0.743]), slightly better vs logit (bootstrap D =1.730, P = 0.084) but not vs XGBoost (D = 0.463, P = 0.643). Transparency analysis showed model usage of all predictor types at both the group and individual patient level.CONCLUSIONA new, multi-modal classifier for predicting MDD remission status after ICBT treatment in routine psychiatric care was derived and empirically validated. The multi-modal approach to predicting remission may inform tailored treatment, and deserves further investigation.One-sentence SummaryPredicting remission of depression in adults after psychotherapy

Objective: The pathways from internalizing psychopathology to substance misuse remain largely unclear. We estimated associations between childhood internalizing problems and subsequent substance misuse in 2 family-based samples. We also investigated sex differences and the role of externalizing comorbidity. Method: We studied associations of childhood internalizing psychopathology with register-based substance misuse after age 13 years. Sample 1 included all individuals born in Sweden from 1984 to 2000 (N = 1,768,516). Depressive and anxiety disorders were included as register-based International Classification of Diseases Ninth Revision (ICD-9) or Tenth Revision (ICD-10) diagnoses before age 13. Sample 2 was a subsample within the population sample, the Child and Adolescent Twin Study in Sweden (CATSS) twin cohort (n = 12,408; born 1992-1998), with mood and anxiety problems assessed at age 9/12 by parents. In both samples, substance misuse was defined as an ICD-9/10 alcohol/drug use disorder or an alcohol/drug-related criminal conviction until December 2013. To account for familial effects, stratified analyses were conducted within siblings and twin pairs. Results: In the population sample, both depressive (hazard ratio [HR] = 2.75, 95% CI = 2.36-3.20) and anxiety disorders (HR = 1.52, 95% CI = 1.35-1.73) were associated with substance misuse. Childhood mood problems (HR = 2.28, 95% CI = 1.69-3.08) were associated with substance misuse in the CATSS sample. The associations were partially explained by familial factors, and comorbid externalizing disorders explained the associations in men but not in women. Conclusion: Childhood mood problems were associated with substance misuse, but familial factors shared by siblings partially explained the associations. The relationship of anxiety with substance misuse was complex and depended on measurement and the type of anxiety disorder. Internalizing problems may be especially important for substance misuse risk in women.

Background It remains unclear if individuals with Tourette syndrome (TS) or chronic tic disorder (CTD) have an elevated risk of subsequent substance misuse. Methods In this population-based cohort study, we investigated the association between ICD diagnoses of TS/CTD and substance misuse outcomes, accounting for psychiatric comorbidity and familial factors. The cohort included all individuals living in Sweden at any time between January 1, 1973, and December 31, 2013. Substance misuse outcomes were defined as an ICD code of substance use–related disorder or cause of death, or as a substance use–related criminal conviction in the nationwide registers. Results The cohort included 14,277,199 individuals, of whom 7832 had a TS/CTD diagnosis (76.3% men). TS/CTD was associated with an increased risk of any subsequent substance misuse outcomes (adjusted hazard ratio [aHR], 3.11; 95% confidence interval [CI], 2.94–3.29), including alcohol-related disorder (aHR, 3.45; 95% CI, 3.19–3.72), drug-related disorder (aHR, 6.84; 95% CI, 6.32–7.40), substance-related criminal convictions (aHR, 2.56; 95% CI, 2.36–2.77), and substance-related death (aHR, 2.54; 95% CI, 1.83–3.52). Excluding psychiatric comorbidities had little effect on the magnitude of the associations, with the exception of attention-deficit/hyperactivity disorder, which attenuated the risk of any substance misuse outcomes (aHR, 2.00; 95% CI, 1.82–2.19). The risk of any substance misuse outcomes in individuals with TS/CTD was substantially attenuated but remained significant when compared with their unaffected siblings (aHR, 1.74; 95% CI, 1.53–1.97). Conclusions TS/CTD were associated with various types of subsequent substance misuse outcomes, independently of psychiatric comorbidity and familial factors shared between siblings. Screening for drug and alcohol use should become part of the standard clinical routines, particularly in patients with comorbid attention-deficit/hyperactivity disorder.

This study aims to evaluate the preliminary efficacy and feasibility of ICBT for OCD in children with ASD, and benchmarking ICBT to specialized, regular care CBT.

Background It is unknown whether individuals with tic disorders are at increased risk for serious transport accidents. Objectives The aim of this study was to investigate the risk for injuries or death caused by transport and motor vehicle accidents in individuals with Tourette syndrome or chronic tic disorder. Methods This population‐based, sibling‐controlled cohort study included all individuals aged ≥18 years living in Sweden between 1997 and 2013 (N = 6,127,290). A total of 3449 individuals had a registered diagnosis of Tourette syndrome or chronic tic disorder in the Swedish National Patient Register. We also identified 2191 families with full siblings discordant for tic disorders. Cox proportional hazards regression modeling was used to estimate the risk for injuries or deaths as a result of transport accidents in individuals with a lifetime diagnosis of Tourette syndrome or chronic tic disorder compared with unexposed individuals and siblings. Results Individuals with tic disorders had a higher risk for transport injuries or death compared with the general population (adjusted hazard ratio, 1.50 [95% confidence interval: 1.33–1.69]) and their unaffected siblings (adjusted hazard ratio, 1.41 [95% confidence interval: 1.18–1.68]). The risks were similar across sexes. The exclusion of most psychiatric comorbidities did not alter the magnitude of the estimates. However, the risks were no longer significant after exclusion of individuals with comorbid attention deficit hyperactivity disorder. Conclusions The marginally increased risk for serious transport accidents in tic disorders is mainly driven by attention deficit hyperactivity disorder comorbidity. Improved detection and management of attention deficit hyperactivity disorder symptoms in this patient group are warranted. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Background: Behaviour therapy is an effective treatment in children and adolescents with tic disorders but is rarely available. Online delivery could widen access to therapy. We evaluated the efficacy of internet-delivered, therapist-supported and parent-assisted Exposure and Response Prevention (ERP) for tics. Methods: Multi-centre, parallel group, single-blind, randomised controlled trial. Eligible participants were aged 9-17 years with Tourette syndrome/chronic tic disorder, who had not received behaviour therapy for tics within 12 months, and had a Yale Global Tic Severity Scale (YGTSS) Total Tic Severity Score (TTSS) of >15, or >10 if motor or vocal tics only. Participants were recruited via 16 patient identification centres, two study sites, or online self-referral, and were randomised (1:1) by blinded outcome-assessors to receive either 10 weeks of ERP or psychoeducation (active control). The primary outcome was YGTSS-TTSS at 3 months’ post-randomisation, analysis was by intention-to-treat. The mean cost per patient for the intervention and health care costs were calculated. Registrations are ISRCTN (ISRCTN70758207) and ClinicalTrials.gov (NCT03483493). Findings: Between 8 th May 2018 and 30 th September 2019, 224 participants were enrolled; 112 to ERP and 112 to psychoeducation. The ERP intervention reduced YGTSS-TTSS by 2 . 29 points (95% CI: ‑3 . 86 to -0 . 71) compared to the psychoeducation group at 3 months, an effect that increased by 6 months post-randomisation (-2 . 64, 95% CI: -4 . 56 to -0 . 73). The average therapist time spent supporting the intervention was 2 . 5 hours. The additional cost per participant of the ERP intervention compared to psychoeducation was £159 (95% CI -£53 to £370). There were two unrelated serious adverse events, both in the psychoeducation group. Interpretation: Online-delivered, therapist-supported ERP therapy is clinically effective at reducing tics, with minimal therapist contact time. Online delivery could improve access to evidence-based treatment for tics in children and adolescents. Trial Registration: Registrations are ISRCTN (ISRCTN70758207) and ClinicalTrials.gov (NCT03483493). Funding: National Institute for Health Research, Health and Technology Assessment (HTA) Declaration of Interest: All authors have completed the ICMJE uniform disclosure from. Aside from receiving funding from NIHR to support their salaries CLH, LM, EBD, RJ, KK, BJB, CS, CM, ES, PA, TM, IS, JK, RH, MLN, AE, LRC, NK, SB, CG, EM declare no conflict of interests. CH declares he was Principal Investigator on a grant from the National Institute of Health Research (NIHR) Health Technology Assessment programme to conduct an Evidence Synthesis on the treatments for tics and Tourette syndrome in children and young people’ HTA Project:10/142/01. DM-C reports personal fees from Elsevier, personal fees from UpToDate Inc. outside the submitted work. Ethical Approval: Ethical and Health Research Authority (HRA) approval was received from North West Greater Manchester Research Ethics Committee on 23 March 2018 (ref.:18/NW/0079). The published trial protocol is available online15 and was approved by an independent trial steering committee (TSC) and data monitoring committee (DMC). Two substantial amendments were made and can be found in the appendix p1. The trial was prospectively registered with the ISRCTN (ISRCTN70758207) and ClinicalTrials.gov (NCT03483493).

The high comorbidity of Major Depressive Disorder (MDD), Anxiety Disorders (ANX), and Posttraumatic Stress Disorder (PTSD) has hindered the study of their structural neural correlates. The authors analyzed specific and common grey matter volume (GMV) characteristics by comparing them with healthy controls (HC). The meta-analysis of voxel-based morphometry (VBM) studies showed unique GMV diminutions for each disorder (p < 0.05, corrected) and less robust smaller GMV across diagnostics (p < 0.01, uncorrected). Pairwise comparison between the disorders showed GMV differences in MDD versus ANX and in ANX versus PTSD. These results endorse the hypothesis that unique clinical features characterizing MDD, ANX, and PTSD are also reflected by disorder specific GMV correlates.

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance. Recent genetic findings in TS have highlighted both numerous common variants with small effects and a few rare variants with moderate or large effects. Here we searched for genetic causes of TS in a large, densely-affected British pedigree using a systematic genomic approach. This pedigree spans six generations and includes 122 members, 85 of whom were individually interviewed, and 53 of whom were diagnosed as "cases" (consisting of 28 with definite or probable TS, 20 with chronic multiple tics [CMT], and five with obsessive-compulsive behaviors [OCB]). A total of 66 DNA samples were available (25 TS, 15 CMT, 4 OCB cases, and 22 unaffecteds) and all were genotyped using a dense single nucleotide polymorphism (SNP) array to identify shared segments, copy number variants (CNVs), and to calculate genetic risk scores. Eight cases were also whole genome sequenced to test whether any rare variants were shared identical by descent. While we did not identify any notable CNVs, single nucleotide variants, indels or repeat expansions of near-Mendelian effect, the most distinctive feature of this family proved to be an unusually high load of common risk alleles for TS. We found that cases within this family carried a higher load of TS common variant risk similar to that previously found in unrelated TS cases. Thus far, the strongest evidence from genetic data for contribution to TS risk in this family comes from multiple common risk variants rather than one or a few variants of strong effect.

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. Electronic supplementary material The online version of this article (10.1007/s10578-020-01098-y) contains supplementary material, which is available to authorized users.

Individuals with obsessive-compulsive disorder (OCD) may have an increased risk of cardiovascular disease (CVD), but evidence for specific types of CVD is limited. This population-based, sibling-controlled cohort study investigated the risk of specific CVD in individuals with OCD. Linking data from various Swedish population-based registers, we explored the risk of a range of CVD in a cohort of individuals diagnosed with OCD between 1973 and 2013 (n = 33,561), compared to matched (1:10) unaffected individuals (n = 335,610). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using conditional Cox proportional hazards regression models, adjusting for history of somatic diseases. To control for familial confounders, we analyzed 23,263 clusters of full siblings discordant for OCD. Individuals with psychiatric comorbidities were systematically excluded to assess the impact of these comorbidities. Over an average follow-up time of 27 years, OCD was associated with an increased risk of a broad range of CVD (adjusted HR [aHR] for any CVD = 1.25 [95% confidence interval [CI], 1.22–1.29]). These associations were strongest for the subtypes venous thrombo-embolism (aHR = 1.48 [95% CI, 1.38–1.58]) and heart failure (aHR = 1.37 [95% CI, 1.28–1.46]). When comparing OCD-exposed individuals with their non-exposed full siblings, results were largely similar. Exclusion of several groups of psychiatric comorbidities resulted in comparable results, albeit attenuated. Individuals with OCD have a moderately increased risk of CVD-related morbidity, independent from history of somatic diseases, familial confounders, and psychiatric comorbidities. The time may be ripe for the development and evaluation of lifestyle interventions to help reduce the risk of cardiovascular morbidity in OCD.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

A global survey of the perceived impact of the COVID-19 outbreak on the severity of tics in persons with Tourette syndrome (TS) or chronic tic disorder (CTD). V2 (edited after peer-review)

Current knowledge on the general somatic health and causes of death in Tourette syndrome and chronic tic disorder is very limited. Here, we review the available literature on the topic, while highlighting strengths and weaknesses of the studies conducted to date. These previous works have suggested associations between Tourette syndrome and chronic tic disorder and a range of health conditions, including autoimmune disorders, common allergies and respiratory diseases, sleep difficulties, and metabolic and cardiovascular outcomes. Additionally, the risk of mortality in tic disorders might be higher than that of the general population, but specific causes of death have rarely been studied, except for substance use-related deaths and suicide, which are significantly higher in individuals with Tourette syndrome and chronic tic disorder. Many of these emerging findings require replication and extension but, taken together, they suggest that that it might be sensible to monitor the general health and suicide risk of individuals with Tourette syndrome or chronic tic disorder across the lifespan. We suggest further avenues for research on this topic.

Background Previous attempts to identify predictors of treatment outcomes in body dysmorphic disorder (BDD) have yielded inconsistent findings. One way to increase precision and clinical utility could be to use machine learning methods, which can incorporate multiple non-linear associations in prediction models. Methods This study used a random forests machine learning approach to test if it is possible to reliably predict remission from BDD in a sample of 88 individuals that had received internet-delivered cognitive behavioral therapy for BDD. The random forest models were compared to traditional logistic regression analyses. Results Random forests correctly identified 78% of participants as remitters or non-remitters at post-treatment. The accuracy of prediction was lower in subsequent follow-ups (68, 66 and 61% correctly classified at 3-, 12- and 24-month follow-ups, respectively). Depressive symptoms, treatment credibility, working alliance, and initial severity of BDD were among the most important predictors at the beginning of treatment. By contrast, the logistic regression models did not identify consistent and strong predictors of remission from BDD. Conclusions The results provide initial support for the clinical utility of machine learning approaches in the prediction of outcomes of patients with BDD. Trial registration ClinicalTrials.gov ID: NCT02010619.

Determining response or remission status in body dysmorphic disorder (BDD) usually requires a lengthy interview with a trained clinician. This study sought to establish empirically derived cutoffs to define treatment response and remission in BDD using a brief self-report instrument, the Appearance Anxiety Inventory (AAI). Results from three clinical trials of BDD were pooled to create a sample of 123 individuals who had received cognitive-behavioral therapy for BDD, delivered via the Internet. The AAI was compared to gold-standard criteria for response and remission in BDD, based on the clinician-administered Yale–Brown Obsessive Compulsive Scale, modified for BDD (BDD-YBOCS), and evaluated using signal detection analysis. The results showed that a ≥ 40% reduction on the AAI best corresponded to treatment response, with a sensitivity of 0.71 and a specificity of 0.84. A score ≤ 13 at posttreatment was the optimal cutoff in determining full or partial remission from BDD, with a sensitivity of 0.75 and a specificity of 0.88. These findings provide benchmarks for using the AAI in BDD treatment evaluation when resource-intensive measures administered by clinicians are not feasible.

Background: This single-masked randomised controlled superiority trial evaluated the efficacy and cost-effectiveness of therapist guided internet-delivered cognitive behavioural therapy (ICBT) for social anxiety disorder (SAD) in youth compared with an active comparator, internet-delivered supportive therapy (ISUPPORT). Methods: Participants were 103 children and adolescents aged 10-17 years with a principal diagnosis of SAD, and their parents. Participants were randomly allocated to 10 weeks of ICBT (n=51) or ISUPPORT (n=52). Both interventions included three video call sessions with a therapist. The primary outcome measure was the Clinician Severity Rating (CSR), derived from the Anxiety Disorder Interview Schedule (ADIS-C), rated by masked clinicians post treatment and three months after the end of treatment (primary endpoint). Secondary outcomes included clinician-rated diagnostic status of SAD and global functioning, as well as child- and parent-reported social anxiety and comorbid depression. Findings: ICBT was significantly more efficacious than ISUPPORT in reducing the severity of SAD symptoms with a significant between-group effect size of d=0·66 (95% CI [0·27, 1·11]) at the 3-month follow-up. Similarly, most of the secondary outcome measures demonstrated moderate effect sizes favouring ICBT. The cost-effectiveness analyses indicated cost savings associated with ICBT compared to ISUPPORT. One suicide attempt was reported and managed in the ISUPPORT condition. No other serious adverse events were reported in either condition. Interpretation: ICBT is an efficacious and cost-effective intervention for children and adolescents with SAD. Implementation in clinical practice could markedly increase the availability of effective interventions for SAD. Trial Registration: The trial was registered at ClinicalTrials.gov with id NCT03247075 Funding: This work was funded by the Swedish Research Council for Health, Working Life and Welfare (Forte 2014-4052) and Region Stockholm (HNSV 14099). JH was supported by Region Stockholm (Dnr: K0173-2016; clinical postdoctoral appointment: 2017-2020). ES was supported by Region Stockholm (clinical research appointment; 2017-0605). Declaration of Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf. Dr. Mataix-Cols reports personal fees from Elsevier, personal fees from UpToDate, Inc., outside the submitted work. None of the other authors declare any conflict of interests. Ethics Approval Statement: The trial was approved by the Stockholm regional ethical review board (2017/1027-31/2).

Paediatric anxiety disorders are associated with substantial disability and long-term adverse consequences, but only a small proportion of affected children have access to evidence-based treatment. Internet-delivered cognitive behavioural therapy (ICBT) could help increase accessibility but needs further rigorous assessment. We aimed to assess the efficacy and cost-effectiveness of ICBT in the treatment of paediatric anxiety disorders.We did a single-blind randomised controlled trial in a clinical research unit within the Child and Adolescent Mental Health Services in Stockholm (Sweden). Eligible participants were children aged 8-12 years with a diagnosis of a principal anxiety disorder (seperation anxiety disorder, generalised anxiety disorder, specific phobia, social anxiety disorder, or panic disorder) of at least moderate severity. We randomly allocated participants (1:1) to ICBT or internet-delivered child-directed play, an active comparator aimed to improve parent-child relationships and increase a child's self-esteem without directly targeting anxiety. Block sizes for the randomisation varied between four and six and were generated using a computer random-number generator, and the allocation was concealed from the researchers by opaque sealed envelopes. Both treatment programmes comprised 12 modules presented over 12 weeks with weekly asynchronous online therapist support, and consisted of texts, films, illustrations, and exercises. The primary outcome was severity rating of the principal anxiety disorder 12-weeks post-treatment, via the Anxiety Disorder Interview Schedule for Diagnostic and Statistical Manual of Mental Disorders-IV (a rating of at least 4 corresponds to meeting the criteria for the principal diagnosis), assessed by clinicians masked to treatment allocation. All participants were included in the primary analysis (intention-to-treat). This trial is registered at ClinicalTrials.gov, number NCT02350257.Between March 11, 2015, and Oct 21, 2016, 131 participants were recruited and allocated to either ICBT (n=66) or internet-delivered child-directed play (n=65). The clinician-assessed severity rating of the principal anxiety disorder improved significantly after the 12-weeks treatment period for participants in both ICBT (within-group effect size 1·22, 95% CI 0·78-1·65) and the active control (0·72, 0·44-1·00) groups. However, greater improvement was seen with ICBT than with the active control (estimated mean difference 0·79, 95% CI 0·42-1·16, p=0·002; between-group effect size 0·77, 95% CI 0·40-1·15). 29 (48%) participants in the ICBT group no longer had their principal diagnosis, compared to nine (15%) in the active control group (odds ratio 5·41, 95% CI 2·26 to 12·90, p0·0001); the number needed to treat for ICBT to gain one additional participant in remission was three (95% CI 2·85 to 3·15). ICBT resulted in an average societal-cost saving of €493·05 (95% CI 477·17 to 508·92) per participant. No severe adverse events were reported.ICBT is an efficacious and cost-effective treatment for paediatric anxiety disorders that should be considered for implementation in routine clinical care.The Swedish Research Council for Health, Working Life and Welfare, and Stockholm County Council.

Large-scale family studies on the co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of clinically ascertained ADHD and BPD diagnoses using the entire Swedish population. In a register-based cohort design we included individuals born in Sweden 1979–2001, and identified their diagnoses during 1997–2013; in total, 2,113,902 individuals were included in the analyses. We obtained clinical diagnoses of ADHD and BPD from inpatient and outpatient care. Individuals with an ADHD diagnosis had an adjusted (for birth year, sex, and birth order) odds ratio (aOR) of 19.4 (95% confidence interval [95% CI] = 18.6–20.4) of also having a BPD diagnosis, compared to individuals not diagnosed with ADHD. Having a sibling with ADHD also increased the risk for BPD (monozygotic twins, aOR = 11.2, 95% CI = 3.0–42.2; full siblings, aOR = 2.8, 95% CI = 2.6–3.1; maternal half-siblings, aOR = 1.4, 95% CI = 1.2–1.7; paternal half-siblings, aOR = 1.5, 95% CI = 1.3–1.7). Cousins also had an increased risk. The strength of the association between ADHD and BPD was similar in females and males, and full siblings showed similar increased risks regardless of sex. Among both males and females, ADHD and BPD co-occur within individuals and co-aggregate in relatives; the pattern suggests shared genetic factors and no robust evidence for etiologic sex differences was found. Clinicians should be aware of increased risks for BPD in individuals with ADHD and their relatives, and vice versa.

The DSM-5 introduced a new chapter called obsessive-compulsive and related disorders (OCRDs), which includes four disorders along with obsessive-compulsive disorder (OCD): body dysmorphic disorder (BDD), hoarding disorder (HD), trichotillomania (hair pulling disorder) (TTM) and excoriation (skin picking) disorder (SPD). The DSM-5 OCRDs subworkgroup developed several short self-report scales for BDD, HD, TTM, and SPD that not only reflect the DSM-5 criteria, but also are consistent in content and structure and can be used by mental health professionals to generate dimensional severity scores for each disorder. The scales were initially validated in adult samples and is therefore unclear if these scales can be reliably used in younger populations. The aim of this study was to examine the psychometric properties of the DSM-5 OCRDs dimensional scales in a sample of 299 Spanish adolescents. The scales showed a one-dimensional structure, acceptable internal consistency (α = 0.69–0.89), convergent validity (rs=0.50–0.71), and significantly higher total values in individuals who indicated the presence of central symptoms of each disorder through diagnostic screening (Cohen's d = 0.65–1.59). The results provide support for further evaluation of these scales in clinical samples of adolescents with OCRDs.

BackgroundBody dysmorphic disorder (BDD) usually begins during adolescence but little is known about the prevalence, etiology, and patterns of comorbidity in this age group. We investigated the prevalence of BDD symptoms in adolescents and young adults. We also report on the relative importance of genetic and environmental influences on BDD symptoms, and the risk for co-existing psychopathology.MethodsPrevalence of BDD symptoms was determined by a validated cut-off on the Dysmorphic Concerns Questionnaire (DCQ) in three population-based twin cohorts at ages 15 (n = 6968), 18 (n = 3738), and 20–28 (n = 4671). Heritability analysis was performed using univariate model-fitting for the DCQ. The risk for co-existing psychopathology was expressed as odds ratios (OR).ResultsThe prevalence of clinically significant BDD symptoms was estimated to be between 1 and 2% in the different cohorts, with a significantly higher prevalence in females (1.3–3.3%) than in males (0.2–0.6%). The heritability of body dysmorphic concerns was estimated to be 49% (95% CI 38–54%) at age 15, 39% (95% CI 30–46) at age 18, and 37% (95% CI 29–42) at ages 20–28, with the remaining variance being due to non-shared environment. ORs for co-existing neuropsychiatric and alcohol-related problems ranged from 2.3 to 13.2.ConclusionsClinically significant BDD symptoms are relatively common in adolescence and young adulthood, particularly in females. The low occurrence of BDD symptoms in adolescent boys may indicate sex differences in age of onset and/or etiological mechanisms. BDD symptoms are moderately heritable in young people and associated with an increased risk for co-existing neuropsychiatric and alcohol-related problems.

Background The Online Remote Behavioral Intervention for Tics (ORBIT) study was a multicenter randomized controlled trial of a complex intervention that consisted of a web-based behavioral intervention for children and young people with tic disorders. In the first part of a two-stage process evaluation, we conducted a mixed methods study exploring the reach, dose, and fidelity of the intervention and contextual factors influencing engagement. Objective This study aims to explore the fidelity of delivery and contextual factors underpinning the ORBIT trial. Methods Baseline study data and intervention usage metrics from participants in the intervention arm were used as quantitative implementation data (N=112). The experiences of being in the intervention were explored through semistructured interviews with children (n=20) and parent participants (n=20), therapists (n=4), and referring clinicians (n=6). A principal component analysis was used to create a comprehensive, composite measure of children and young people’s engagement with the intervention. Engagement factor scores reflected relative uptake as assessed by a range of usage indices, including chapters accessed, number of pages visited, and number of log-ins. The engagement factor score was used as the dependent variable in a multiple linear regression analysis with various contextual variables as independent variables to assess if there were any significant predictors of engagement. Results The intervention was implemented with high fidelity, and participants deemed the intervention acceptable and satisfactory. The engagement was high, with child participants completing an average of 7.5 of 10 (SD 2.7) chapters, and 88.4% (99/112) of participants completed the minimum of the first four chapters—the predefined threshold effective dose. Compared with the total population of children with tic disorders, participants in the sample tended to have more educated parents and lived in more economically advantaged areas; however, socioeconomic factors were not related to engagement factor scores. Factors associated with higher engagement factor scores included participants enrolled at the London site versus the Nottingham site (P=.01), self-referred versus clinic referred (P=.04), higher parental engagement as evidenced by the number of parental chapters completed (n=111; ρ=0.73; P Conclusions Overall, the intervention had high fidelity of delivery and was evaluated positively by participants, although reach may have been constrained by the nature of the randomized controlled trial. Parental engagement and therapist time for parents were strong predictors of intervention implementation, which has important implications for designing and implementing digital therapeutic interventions in child and adolescent mental health services. International Registered Report Identifier (IRRID) RR2-10.1186/s13063-019-3974-3

The association between obsessive-compulsive disorder (OCD) and Tourette's/chronic tic disorders (TD/CTD) with autoimmune diseases (ADs) is uncertain. In this nationwide study, we sought to clarify the patterns of comorbidity and familial clustering of a broad range of ADs in individuals with OCD, individuals with TD/CTD and their biological relatives. From a birth cohort of 7 465 455 individuals born in Sweden between 1940 and 2007, we identified 30 082 OCD and 7279 TD/CTD cases in the National Patient Register and followed them up to 31 December 2013. The risk of 40 ADs was evaluated in individuals with OCD, individuals with TD/CTD and their first- (siblings, mothers, fathers), second- (half siblings) and third-degree (cousins) relatives, compared with population controls. Individuals with OCD and TD/CTD had increased comorbidity with any AD (43% and 36%, respectively) and many individual ADs. The risk of any AD and several individual ADs was consistently higher among first-degree relatives than among second- and third-degree relatives of OCD and TD/CTD probands. The risk of ADs was very similar in mothers, fathers and siblings of OCD probands, whereas it tended to be higher in mothers and fathers of TD/CTD probands (compared with siblings). The results suggest a familial link between ADs in general (that is, not limited to Streptococcus-related conditions) and both OCD and TD/CTD. Additional mother-specific factors, such as the placental transmission of antibodies, cannot be fully ruled out, particularly in TD/CTD.

Background Persons with neuropsychiatric disorders are at increased risk of suicide, but there is little data concerning Tourette’s and chronic tic disorders (TD/CTD). We aimed to quantify the risk of suicidal behavior in a large nationwide cohort of patients with TD/CTD, establish the contribution of psychiatric comorbidity to this risk, and identify predictors of suicide. Methods Using a validated algorithm, we identified 7736 TD/CTD cases in the Swedish National Patient Register during a 44-year period (1969–2013). Using a matched case-cohort design, patients were compared with general population control subjects (1:10 ratio). Risk of suicidal behavior was estimated using conditional logistic regressions. Predictors of suicidal behavior in the TD/CTD cohort were studied using Cox regression models. Results In unadjusted models, TD/CTD patients, compared with control subjects, had an increased risk of both dying by suicide (odds ratio: 4.39; 95% confidence interval [CI]: 2.89–6.67) and attempting suicide (odds ratio: 3.86; 95% CI: 3.50–4.26). After adjusting for psychiatric comorbidities, the risk was reduced but remained substantial. Persistence of tics beyond young adulthood and a previous suicide attempt were the strongest predictors of death by suicide in TD/CTD patients (hazard ratio: 11.39; 95% CI: 3.71–35.02, and hazard ratio: 5.65; 95% CI: 2.21–14.42, respectively). Conclusions TD/CTD are associated with substantial risk of suicide. Suicidal behavior should be monitored in these patients, particularly in those with persistent tics, history of suicide attempts, and psychiatric comorbidities. Preventive and intervention strategies aimed to reduce the suicidal risk in this group are warranted.

Adverse perinatal events may increase the risk of Tourette’s and chronic tic disorders (TD/CTD), but previous studies have been unable to control for unmeasured environmental and genetic confounding. We aimed to prospectively investigate potential perinatal risk factors for TD/CTD, taking unmeasured factors shared between full siblings into account. A population-based birth cohort, consisting of all singletons born in Sweden in 1973–2003, was followed until December 2013. A total of 3 026 861 individuals were identified, 5597 of which had a registered TD/CTD diagnosis. We then studied differentially exposed full siblings from 947 942 families; of these, 3563 families included siblings that were discordant for TD/CTD. Perinatal data were collected from the Medical Birth Register and TD/CTD diagnoses were collected from the National Patient Register, using a previously validated algorithm. In the fully adjusted models, impaired fetal growth, preterm birth, breech presentation and cesarean section were associated with a higher risk of TD/CTD, largely independent from shared family confounders and measured covariates. Maternal smoking during pregnancy was associated with risk of TD/CTD in a dose–response manner but the association was no longer statistically significant in the sibling comparison models or after the exclusion of comorbid attention-deficit/hyperactivity disorder. A dose–response relationship between the number of adverse perinatal events and increased risk for TD/CTD was also observed, with hazard ratios ranging from 1.41 (95% confidence interval (CI): 1.33–1.50) for one event to 2.42 (95% CI: 1.65–3.53) for five or more events. These results pave the way for future gene by environment interaction and epigenetic studies in TD/CTD.

Objective: structural brain imaging studies in obsessive compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta and mega-analyses of data from OCD sites worldwide. Method: T-1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. Results: the meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohen's d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. Conclusions: the results indicate different patterns of sub cortical abnormalities in pediatric and adult OCD patients. The patlidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful.

Contains fulltext : 174490.pdf (Publisher’s version ) (Open Access) Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response. 10 p.

Patients with Attention-Deficit/Hyperactivity Disorder (ADHD) and obsessive/compulsive disorder (OCD) share problems with sustained attention, and are proposed to share deficits in switching between default mode and task positive networks. The aim of this study was to investigate shared and disorder-specific brain activation abnormalities during sustained attention in the two disorders. Twenty boys with ADHD, 20 boys with OCD and 20 age-matched healthy controls aged between 12 and 18 years completed a functional magnetic resonance imaging (fMRI) version of a parametrically modulated sustained attention task with a progressively increasing sustained attention load. Performance and brain activation were compared between groups. Only ADHD patients were impaired in performance. Group by sustained attention load interaction effects showed that OCD patients had disorder-specific middle anterior cingulate underactivation relative to controls and ADHD patients, while ADHD patients showed disorder-specific underactivation in left dorsolateral prefrontal cortex/dorsal inferior frontal gyrus (IFG). ADHD and OCD patients shared left insula/ventral IFG underactivation and increased activation in posterior default mode network relative to controls, but had disorder-specific overactivation in anterior default mode regions, in dorsal anterior cingulate for ADHD and in anterior ventromedial prefrontal cortex for OCD. In sum, ADHD and OCD patients showed mostly disorder-specific patterns of brain abnormalities in both task positive salience/ventral attention networks with lateral frontal deficits in ADHD and middle ACC deficits in OCD, as well as in their deactivation patterns in medial frontal DMN regions. The findings suggest that attention performance in the two disorders is underpinned by disorder-specific activation patterns., Highlights • Sustained attention is associated with disorder-specific dysfunction in ADHD and OCD. • ADHD patients showed dorsolateral prefrontal and dorsal inferior frontal gyrus underactivation. • OCD patients showed underactivation in middle anterior cingulate cortex. • Patient groups had disorder-specific patterns of overactivation in default mode network. • ADHD and OCD patients shared left insula/ventral inferior frontal gyrus underactivation.

A high proportion of individuals with body dysmorphic disorder (BDD) undergo cosmetic treatments in an attempt to 'fix' perceived defect/s in their physical appearance. Despite the frequency with which such procedures are sought, few studies have prospectively examined the outcomes of cosmetic procedures in individuals with BDD. This article aims to critically review the literature and discuss the current debate that exists on outcomes of cosmetic treatment for individuals with BDD. An emerging literature suggests the majority of individuals with BDD have poor outcomes after cosmetic interventions; however, based on the current literature, it cannot be fully ruled out that certain individuals with mild BDD and localised appearance concerns may benefit from these interventions. Gaps in the current literature are highlighted, alongside recommendations for future research. Carefully conducted longitudinal studies with well-characterised patient populations are needed.

Publisher's version, Objective: To assess whether severe psychiatric reactions to trauma and other adversities are associated with subsequent risk of life threatening infections. Design: Population and sibling matched cohort study. Setting: Swedish population. Participants: 144 919 individuals with stress related disorders (post-traumatic stress disorder (PTSD), acute stress reaction, adjustment disorder, and other stress reactions) identified from 1987 to 2013 compared with 184 612 full siblings of individuals with a diagnosed stress related disorder and 1 449 190 matched individuals without such a diagnosis from the general population. Main outcome measures: A first inpatient or outpatient visit with a primary diagnosis of severe infections with high mortality rates (ie, sepsis, endocarditis, and meningitis or other central nervous system infections) from the Swedish National Patient Register, and deaths from these infections or infections of any origin from the Cause of Death Register. After controlling for multiple confounders, Cox models were used to estimate hazard ratios of these life threatening infections. Results: The average age at diagnosis of a stress related disorder was 37 years (55 541, 38.3% men). During a mean follow-up of eight years, the incidence of life threatening infections per 1000 person years was 2.9 in individuals with a stress related disorder, 1.7 in siblings without a diagnosis, and 1.3 in matched individuals without a diagnosis. Compared with full siblings without a diagnosis of a stress related disorder, individuals with such a diagnosis were at increased risk of life threatening infections (hazard ratio for any stress related disorder was 1.47 (95% confidence intervals1.37 to 1.58) and for PTSD was 1.92 (1.46 to 2.52)). Corresponding estimates in the population based analysis were similar (1.58 (1.51 to 1.65) for any stress related disorder, P=0.09 for difference between sibling and population based comparison, and 1.95 (1.66 to 2.28) for PTSD, P=0.92 for difference). Stress related disorders were associated with all studied life threatening infections, with the highest relative risk observed for meningitis (sibling based analysis 1.63 (1.23 to 2.16)) and endocarditis (1.57 (1.08 to 2.30)). Younger age at diagnosis of a stress related disorder and the presence of psychiatric comorbidity, especially substance use disorders, were associated with higher hazard ratios, whereas use of selective serotonin reuptake inhibitors in the first year after diagnosis of a stress related disorder was associated with attenuated hazard ratios. Conclusion: In the Swedish population, stress related disorders were associated with a subsequent risk of life threatening infections, after controlling for familial background and physical or psychiatric comorbidities., The study was supported by Grant of Excellence, Icelandic Research Fund (grant No 163362-051, UAV), and European Research Council (ERC) consolidator grant (StressGene, grant No 726413, UAV); the Karolinska Institutet (Senior Researcher Award and Strategic Research Area in Epidemiology, FF); the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework (grant No 340-2013-5867, CA); and the West China Hospital, Sichuan University (1.3.5 Project for Disciplines of Excellence, grant No ZYJC18010, HS). This funding source had no role in study design, data collection, data analysis, data interpretation, writing of the scientific article, or the decision to submit the paper for publication.

This systematic review and meta-analysis examines the association between birth by cesarean delivery and risk of neurodevelopmental and psychiatric disorders in the offspring compared with birth by vaginal delivery., Key Points Question Is birth by cesarean delivery associated with an increased risk of neurodevelopmental and psychiatric disorders in the offspring compared with birth by vaginal delivery? Findings In this systematic review and meta-analysis of 61 studies comprising more than 20 million deliveries, birth by cesarean delivery was significantly associated with autism spectrum disorder and attention-deficit/hyperactivity disorder. Meaning The findings suggest that understanding the potential mechanisms behind these associations is important, especially given the increase in cesarean delivery rates for nonmedical reasons., Importance Birth by cesarean delivery is increasing globally, particularly cesarean deliveries without medical indication. Children born via cesarean delivery may have an increased risk of negative health outcomes, but the evidence for psychiatric disorders is incomplete. Objective To evaluate the association between cesarean delivery and risk of neurodevelopmental and psychiatric disorders in the offspring. Data Sources Ovid MEDLINE, Embase, Web of Science, and PsycINFO were searched from inception to December 19, 2018. Search terms included all main mental disorders in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). Study Selection Two researchers independently selected observational studies that examined the association between cesarean delivery and neurodevelopmental and psychiatric disorders in the offspring. Data Extraction and Synthesis Two researchers independently extracted data according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines and assessed study quality using the Newcastle-Ottawa Scale. Random-effects meta-analyses were used to pool odds ratios (ORs) with 95% CIs for each outcome. Sensitivity and influence analyses tested the robustness of the results. Main Outcomes and Measures The ORs for the offspring with any neurodevelopmental or psychiatric disorder who were born via cesarean delivery compared with those were born via vaginal delivery. Results A total of 6953 articles were identified, of which 61 studies comprising 67 independent samples were included, totaling 20 607 935 deliveries. Compared with offspring born by vaginal delivery, offspring born via cesarean delivery had increased odds of autism spectrum disorders (OR, 1.33; 95% CI, 1.25-1.41; I2 = 69.5%) and attention-deficit/hyperactivity disorder (OR, 1.17; 95% CI, 1.07-1.26; I2 = 79.2%). Estimates were less precise for intellectual disabilities (OR, 1.83; 95% CI, 0.90-3.70; I2 = 88.2%), obsessive-compulsive disorder (OR, 1.49; 95% CI, 0.87-2.56; I2 = 67.3%), tic disorders (OR, 1.31; 95% CI, 0.98-1.76; I2 = 75.6%), and eating disorders (OR, 1.18; 95% CI, 0.96-1.47; I2 = 92.7%). No significant associations were found with depression/affective psychoses or nonaffective psychoses. Estimates were comparable for emergency and elective cesarean delivery. Study quality was high for 82% of the cohort studies and 50% of the case-control studies. Conclusions and Relevance The findings suggest that cesarean delivery births are associated with an increased risk of autism spectrum disorder and attention-deficit/hyperactivity disorder, irrespective of cesarean delivery modality, compared with vaginal delivery. Future studies on the mechanisms behind these associations appear to be warranted.

BackgroundCauses of the comorbidity of substance misuse with anxiety-related and depressive disorders (anxiety/depression) remain poorly known. We estimated associations of substance misuse and anxiety/depression in the general population and tested them while accounting for genetic and shared environmental factors.MethodsWe studied individuals born in Sweden 1968–1997 (n = 2 996 398) with follow-up in nationwide register data for 1997–2013. To account for familial effects, stratified analyses were conducted within siblings and twin pairs. Substance misuse was defined as ICD-10 alcohol or drug use disorder or an alcohol/drug-related criminal conviction. Three dimensions of ICD-10 anxiety and depressive disorders and a substance misuse dimension were identified through exploratory factor analysis.ResultsSubstance misuse was associated with a 4.5-fold (95% CI 4.50–4.58) elevated risk of lifetime generalized anxiety/depression, 4.7-fold (95% CI 4.63–4.82) elevated risk of panic disorder and agora/social phobia, and 2.9-fold elevated risk of phobias/OCD (95% CI 2.82–3.02) as compared to those without substance misuse. The associations were attenuated in within-family analyses but we found elevated risks in monozygotic twin pairs discordant for substance misuse as well as significant non-shared environmental correlations. The association between anxiety/depression and substance misuse was mainly driven by generalized anxiety/depression, whereas other anxiety/depression dimensions had minor or no independent associations with substance misuse.ConclusionsSubstance misuse and anxiety/depression are associated at the population level, and these associations are partially explained by familial liabilities. Our findings indicate a common genetic etiology but are also compatible with a potential partially causal relationship between substance misuse and anxiety/depression.

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a descriptive clinical entity defined by the abrupt onset of psychiatric and somatic symptoms leading to significant loss of function. Data on well-characterized PANS patients are limited, biomarkers have yet to be identified, and a solid evidence base to guide treatment is lacking. In this study, we present our experience of a systematic evaluation of the first 45 patients included in a Swedish cohort. Methods: During the period 2014–2018, our clinic received 100 referrals regarding suspected PANS. All patients underwent a standardized psychiatric/medical evaluation by a child/adolescent psychiatrist and a clinical psychologist or a nurse. Those with severe symptoms were also assessed by a pediatric neurologist and a pediatric rheumatologist. Laboratory tests were obtained at different time points in an attempt to capture an active disease state. Results: Of the 100 referrals, 45 met strict PANS criteria and consented to participate in a long-term follow-up study. The median age at intake was 7.2 years (range 3.0–13.1) and 56% were male. Ninety-three percent fulfilled both criteria for acute/atypical onset of PANS symptoms and having had an infection in relation to onset. Sixteen percent had an onset of an autoimmune or inflammatory disorder in temporal relation to the onset of PANS-related symptoms. The most common onset symptoms were obsessive-compulsive disorder (89%), anxiety (78%), and emotional lability (71%). Twenty-four percent had a preexisting autoimmune disease (AD) and 18% a preexisting psychiatric/neuropsychiatric diagnosis. Sixty-four percent of biological relatives had at least one psychiatric disorder and 76% at least one AD or inflammatory disorder. Complement activation (37%), leukopenia (20%), positive antinuclear antibodies (17%), and elevated thyroid antibodies (11%) were the most common laboratory findings. Conclusions: In our PANS cohort, there was a strong indication of an association with AD. Further work is needed to establish whether any of the potential biomarkers identified will be clinically useful. Long-term follow-up of these patients using the Swedish national registers will enable a deeper understanding of the course of this patient group.