A burden of rare copy number variants in obsessive-compulsive disorder.

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2248 deeply phenotyped OCD cases and 3608 unaffected controls from Sweden and Norway. Cases carry an elevated burden of CNVs ≥30 kb in size (OR = 1.12, P = 1.77 × 10-3). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02-0.11, P = 2.58 × 10-3). This signal was largely driven by CNVs overlapping protein-coding regions (OR = 1.19, P = 3.08 × 10-4), particularly deletions impacting loss-of-function intolerant genes (pLI >0.995, OR = 4.12, P = 2.54 × 10-5). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60 × 10-3). In cases where sufficient clinical data were available (n = 1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P < 0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P = 0.02). The results demonstrate a contribution of rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.

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

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

General somatic health and lifestyle habits in individuals with obsessive- compulsive disorder: an international survey.

BACKGROUND: Obsessive-compulsive disorder (OCD) has been associated with a broad range of health-related issues. Unhealthy lifestyle habits such as physical inactivity, an unhealthy diet, smoking, and alcohol consumption are hypothesized to contribute to this association. However, the lifestyle habits of individuals with OCD have been scarcely investigated. In this international survey, we explored the physical health and lifestyle habits of adults with a self-reported diagnosis of OCD. METHODS: An online global survey available in seven languages was disseminated through interest organizations and social media between July 2021 and March 2022. The survey included questions relating to socio-demographic variables and clinical characteristics (including OCD symptom severity - as measured with the 12-item self-report scale Obsessive-Compulsive Inventory [OCI-12] - and psychotropic medication), physical health, and lifestyle habits. Frequencies and percentages, or means and standard deviations, as appropriate, were calculated. Subgroup analyses by OCD symptom severity, gender, and age group were performed. RESULTS: A total of 496 individuals with OCD completed the survey and were included in the analyses (mean age = 36.0 years, SD = 12.5, range 18-79; 78.8% women). Most participants were from Europe (n = 245, 49.4%) and North America (n = 187, 37.7%). OCD symptom severity scores were on the moderate range (OCI-12 mean score = 21.2, SD = 9.1). A majority (n = 354, 71.4%) reported having comorbid somatic health issues, mainly allergies, gastrointestinal conditions, and cardiometabolic conditions. Nearly half of the sample (n = 236, 47.6%) reported a body mass index ≥ 25, corresponding to at least overweight. A significant proportion of the participants reported low physical activity (n = 271, 55.0%), unhealthy dietary habits (n = 182, 36.7%), risk consumption of alcohol (n = 111, 22.3%), and non-restorative sleep (n = 268, 54.0%). Subgroup analyses showed overall similar results across groups, with some exceptions. CONCLUSIONS: In this sample, individuals with OCD self-reported a range of health-related issues and a number of unhealthy lifestyle behaviors, most prominently a lack of physical activity. Interventions aimed at modifying unhealthy lifestyles to prevent or improve health conditions beyond the psychiatric symptoms should be considered.

Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: A preliminary investigation.

Individuals with severe and treatment-resistant obsessive-compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS-treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD. As such, we have begun to collect DNA from trOCD cases who qualify for DBS, and here we report results from whole exome sequencing and microarray genotyping of our first five cases. All participants had previously received DBS in the bed nucleus of stria terminalis (BNST), with two patients responding to the surgery and one showing a partial response. Our analyses focused on gene-disruptive rare variants (GDRVs; rare, predicted-deleterious single-nucleotide variants or copy number variants overlapping protein-coding genes). Three of the five cases carried a GDRV, including a missense variant in the ion transporter domain of KCNB1, a deletion at 15q11.2, and a duplication at 15q26.1. The KCNB1 variant (hg19 chr20-47991077-C-T, NM_004975.3:c.1020G>A, p.Met340Ile) causes substitution of methionine for isoleucine in the trans-membrane region of neuronal potassium voltage-gated ion channel KV2.1. This KCNB1 substitution (Met340Ile) is located in a highly constrained region of the protein where other rare missense variants have previously been associated with neurodevelopmental disorders. The patient carrying the Met340Ile variant responded to DBS, which suggests that genetic factors could potentially be predictors of treatment response in DBS for OCD. In sum, we have established a protocol for recruiting and genomically characterizing trOCD cases. Preliminary results suggest that this will be an informative strategy for finding risk genes in OCD.

Maternal suicide attempts and deaths in the first year after cesarean delivery.

BACKGROUND: Cesarean delivery (CD) has been associated with postpartum psychiatric disorders, but less is known about the risk of suicidal behaviors. We estimated the incidence and risk of suicide attempts and deaths during the first postpartum year in mothers who delivered via CD v. vaginally. METHOD: All deliveries in Sweden between 1973 and 2012 were identified. The mothers were followed since delivery for 12 months or until the date of one of the outcomes (i.e. suicide attempt or death by suicide), death by other causes or emigration. Associations were estimated using Cox proportional hazards regression models. RESULTS: Of 4 016 789 identified deliveries, 514 113 (12.8%) were CDs and 3 502 676 (87.2%) were vaginal deliveries. During the 12-month follow-up, 504 (0.098%) suicide attempts were observed in the CD group and 2240 (0.064%) in the vaginal delivery group (risk difference: 0.034%), while 11 (0.0037%) deaths by suicide were registered in the CD group and 109 (0.0029%) in the vaginal delivery group (risk difference: 0.008%). Compared to vaginal delivery, CD was associated with an increased risk of suicide attempts [hazard ratio (HR) 1.46; 95% CI 1.32-1.60], but not of deaths by suicide (HR 1.44; 95% CI 0.88-2.36). CONCLUSIONS: Maternal suicidal behaviors during the first postpartum year were uncommon in Sweden. Compared to vaginal delivery, CD was associated with a small increased risk of suicide attempts, but not death by suicide. Improved understanding of the association between CD and maternal suicidal behaviors may promote more appropriate measures to improve maternal mental well-being and further reduce suicidal risks.

Executive functioning in body dysmorphic disorder and obsessive-compulsive disorder.

OBJECTIVE: To assess executive functions (EFs) in patients with body dysmorphic disorder (BDD) and obsessive-compulsive disorder (OCD) compared with healthy controls. METHODS: Adults diagnosed with BDD (n = 26) or OCD (n = 29) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and healthy controls (n = 28) underwent validated and computerized neuropsychological tests, spatial working memory (SWM), intra-extra-dimensional set shifting (IED), and stop signal task (SST), from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Test performance was compared between groups, and correlated with standardized symptom severity of BDD and OCD. Significance level was set to P < .05. RESULTS: There were no statistically significant between-group differences on key outcome measures in SWM, IED, or SST. There was a weak positive correlation between symptom severity and test errors on SWM and IED in both OCD and BDD groups; increased clinical severity was associated with more errors in these tests. Furthermore, there was a negative correlation between symptom severity and SST in the BDD group. CONCLUSIONS: Patients with BDD or OCD did not differ from healthy control subjects in terms of test performance; however, there were several statistically significant correlations between symptom severity and performance in those with BDD or OCD. More studies on EFs in BDD and OCD are required to elucidate if there are differences in EFs between these two disorders.

Psychometric and structural properties of the Karolinska Exhaustion Disorder Scale: a 1,072-patient study.

OBJECTIVE: Exhaustion disorder is a stress-related diagnosis that was introduced in 2005 to the Swedish version of the International Statistical Classification of Diseases and Related Health Problems, 10th edition (ICD-10). The Karolinska Exhaustion Disorder Scale (KEDS) was developed to assess exhaustion disorder symptomatology. While the KEDS is intended to reflect a single construct and be used based on its total score, the instrument's characteristics have received limited attention. This study investigated the KEDS's psychometric and structural properties in a large clinical sample. METHODS: The study relied on data from 1,072 patients diagnosed with exhaustion disorder that were included in two clinical trials in Sweden. We investigated the dimensionality, homogeneity, and reliability of the KEDS using advanced statistical techniques, including exploratory structural equation modeling (ESEM) bifactor analysis. RESULTS: A one-factor confirmatory analytic model exhibited a poor fit, suggesting at least a degree of multidimensionality. The ESEM bifactor analysis found the general factor to explain about 72% of the common variance extracted, with an omega hierarchical coefficient of 0.680. Thus, the ESEM bifactor analysis did not clearly support the scale's essential unidimensionality. A homogeneity analysis revealed a scale-level H of only 0.296, suggesting that KEDS's total scores do not accurately rank individuals on the latent continuum assumed to underlie the measure. The KEDS's reliability was modest, signaling considerable measurement error. CONCLUSION: Findings reveal important limitations to the KEDS with possible implications for the status of exhaustion disorder as a nosological category. TRIAL REGISTRATION: This study was pre-registered on Open Science Framework (osf.io) on April 24, 2022 ( https://osf.io/p34sq/ ).

In search of environmental risk factors for obsessive-compulsive disorder: study protocol for the OCDTWIN project.

BACKGROUND: The causes of obsessive-compulsive disorder (OCD) remain unknown. Gene-searching efforts are well underway, but the identification of environmental risk factors is at least as important and should be a priority because some of them may be amenable to prevention or early intervention strategies. Genetically informative studies, particularly those employing the discordant monozygotic (MZ) twin design, are ideally suited to study environmental risk factors. This protocol paper describes the study rationale, aims, and methods of OCDTWIN, an open cohort of MZ twin pairs who are discordant for the diagnosis of OCD. METHODS: OCDTWIN has two broad aims. In Aim 1, we are recruiting MZ twin pairs from across Sweden, conducting thorough clinical assessments, and building a biobank of biological specimens, including blood, saliva, urine, stool, hair, nails, and multimodal brain imaging. A wealth of early life exposures (e.g., perinatal variables, health-related information, psychosocial stressors) are available through linkage with the nationwide registers and the Swedish Twin Registry. Blood spots stored in the Swedish phenylketonuria (PKU) biobank will be available to extract DNA, proteins, and metabolites, providing an invaluable source of biomaterial taken at birth. In Aim 2, we will perform within-pair comparisons of discordant MZ twins, which will allow us to isolate unique environmental risk factors that are in the causal pathway to OCD, while strictly controlling for genetic and early shared environmental influences. To date (May 2023), 43 pairs of twins (21 discordant for OCD) have been recruited. DISCUSSION: OCDTWIN hopes to generate unique insights into environmental risk factors that are in the causal pathway to OCD, some of which have the potential of being actionable targets.

An online self-guided cognitive intervention for unwanted intrusive thoughts about harming infants in new parents: initial randomised controlled trial with mediation analysis.

Approximately one-fifth of new parents struggle with unwanted intrusive thoughts (UITs) about intentionally harming their child. This study evaluated the initial efficacy, feasibility and acceptability of a novel online self-guided cognitive intervention for new parents with distressing UITs. Self-recruited parents (N = 43, 93% female, age 23-43 years) of children 0-3 years reporting daily distressing and impairing UITs were randomized to the 8-week self-guided online cognitive intervention or to waiting-list. The primary outcome was change on the Parental Thoughts and Behaviour Checklist (PTBC) from baseline to week 8 (post-intervention). The PTBC and negative appraisals (mediator) were assessed at baseline, weekly, post-intervention and at the 1-month follow-up. Results showed that the intervention led to statistically significant reductions in distress and impairment associated with UITs at post-intervention (controlled between-group d = 0.99, 95% CI 0.56 to 1.43), which were maintained at the 1-month follow-up (controlled between-group d = 0.90, 95% CI 0.41 to 1.39). The intervention was deemed to be feasible and acceptable by the participants. Change in negative appraisals mediated reductions in UITs but the model was sensitive to mediator-outcome confounders. We conclude that this novel online self-guided cognitive intervention can potentially reduce the distress and impairment associated with UITs in new parents. Large-scale trials are warranted.Abbreviations: UITs: Unwanted Intrusive Thoughts PTBC: Parental Thoughts and Behaviour Checklist.

The association between body dysmorphic symptoms and suicidality among adolescents and young adults: a genetically informative study.

BACKGROUND: Previous research indicates that body dysmorphic disorder (BDD) is associated with risk of suicidality. However, studies have relied on small and/or specialist samples and largely focussed on adults, despite these difficulties commonly emerging in youth. Furthermore, the aetiology of the relationship remains unknown. METHODS: Two independent twin samples were identified through the Child and Adolescent Twin Study in Sweden, at ages 18 (N = 6027) and 24 (N = 3454). Participants completed a self-report measure of BDD symptom severity. Young people and parents completed items assessing suicidal ideation/behaviours. Logistic regression models tested the association of suicidality outcomes with: (a) probable BDD, classified using an empirically derived cut-off; and (b) continuous scores of BDD symptoms. Bivariate genetic models examined the aetiology of the association between BDD symptoms and suicidality at both ages. RESULTS: Suicidal ideation and behaviours were common among those with probable BDD at both ages. BDD symptoms, measured continuously, were linked with all aspects of suicidality, and associations generally remained significant after adjusting for depressive and anxiety symptoms. Genetic factors accounted for most of the covariance between BDD symptoms and suicidality (72.9 and 77.7% at ages 18 and 24, respectively), but with significant non-shared environmental influences (27.1 and 22.3% at ages 18 and 24, respectively). CONCLUSIONS: BDD symptoms are associated with a substantial risk of suicidal ideation and behaviours in late adolescence and early adulthood. This relationship is largely explained by common genetic liability, but non-shared environmental effects are also significant and could provide opportunities for prevention among those at high-risk.

Familial risk and heritability of diagnosed borderline personality disorder: a register study of the Swedish population.

Family and twin studies of Borderline Personality Disorder (BPD) have found familial aggregation and genetic propensity for BPD, but estimates vary widely. Large-scale family studies of clinically diagnosed BPD are lacking. Therefore, we performed a total-population study estimating the familial aggregation and heritability of clinically diagnosed BPD. We followed 1,851,755 individuals born 1973-1993 in linked Swedish national registries. BPD-diagnosis was ascertained between 1997 and 2013, 11,665 received a BPD-diagnosis. We identified relatives and estimated sex and birth year adjusted hazard ratios, i.e., the rate of BPD-diagnoses in relatives to individuals with BPD-diagnosis compared to individuals with unaffected relatives, and used structural equation modeling to estimate heritability. The familial association decreased along with genetic relatedness. The hazard ratio was 11.5 (95% confidence interval (CI) = 1.6-83.8) for monozygotic twins; 7.4 (95% CI = 1.0-55.3) for dizygotic twins; 4.7 (95% CI = 3.9-5.6) for full siblings; 2.1 (95% CI = 1.5-3.0) for maternal half-siblings; 1.3 (95% CI = 0.9-2.1) for paternal half-siblings; 1.7 (95% CI = 1.4-2.0) for cousins whose parents were full siblings; 1.1 (95% CI = 0.7-1.8) for cousins whose parents were maternal half-siblings; and 1.9 (95% CI = 1.2-2.9) for cousins whose parents were paternal half-siblings. Heritability was estimated at 46% (95% CI = 39-53), and the remaining variance was explained by individually unique environmental factors. Our findings pave the way for further research into specific genetic variants, unique environmental factors implicated, and their interplay in risk for BPD.

Do borderline personality disorder and attention-deficit/hyperactivity disorder co-aggregate in families? A population-based study of 2 million Swedes.

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.

Genetic and environmental sources of familial coaggregation of obsessive-compulsive disorder and suicidal behavior: a population-based birth cohort and family study.

Obsessive-compulsive disorder (OCD) is associated with high risk of suicide. It is yet unknown whether OCD and suicidal behaviors coaggregate in families and, if so, what are the mechanisms underlying this coaggregation. In a population-based birth cohort and family study, we linked individuals born in Sweden in 1967-2003 (n = 3,594,181) to their parents, siblings, and cousins, and collected register-based diagnoses of OCD, suicide attempts, and deaths by suicide and followed them until December 31, 2013. We also applied quantitative genetic modeling to estimate the contribution of genetic and environmental factors to the familial coaggregation of OCD and suicidal behavior. An elevated risk of suicide attempts was observed across all relatives of individuals with OCD, increasing proportionally to the degree of genetic relatedness, with odds ratios (OR) ranging from 1.56 (95% confidence interval (CI) 1.49-1.63) in parents to 1.11 (95% CI 1.07-1.16) in cousins. The risk of death by suicide also increased alongside narrowing genetic distance, but was only significant in parents (OR 1.55; 95% CI 1.40-1.72) and full siblings (OR 1.80; 95% CI 1.43-2.26) of individuals with OCD. Familial coaggregation of OCD and suicide attempts was explained by additive genetic factors (60.7%) and non-shared environment (40.4%), with negligible contribution of shared environment. Similarly, familial coaggregation with death by suicide was attributed to additive genetics (65.8%) and nonshared environment (34.2%). Collectively, these observations indicate that OCD and suicidal behaviors coaggregate in families largely due to genetic factors. The contribution of unique environment is also considerable, providing opportunities to target high-risk groups for prevention and treatment.

A population-based family clustering study of tic-related obsessive-compulsive disorder.

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 < 0.0001). These differences remained when the groups were matched by age at first OCD diagnosis and after various sensitivity analyses. The observed familial patterns of OCD in relation to tics were not seen in relation to other neuropsychiatric comorbidities. Tic-related OCD is a particularly familial subtype of OCD. The results have important implications for ongoing gene-searching efforts.

Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy.

Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.

Does Size Matter? Genital Self-Image, Genital Size, Pornography Use and Openness Toward Cosmetic Genital Surgery in 3503 Swedish Men and Women.

BACKGROUND: Dissatisfaction with the appearance and size of one's genitalia is a common issue, and the use of cosmetic genital surgery is increasing among people with normal genitalia. AIM: This cross-sectional study aimed to investigate the distribution of genital self-image in a large sample of males and females, and whether selected factors could predict genital self-image. METHODS: Three thousand five hundred three anonymous participants completed online questionnaires. Multiple linear regressions were used to identify the association between genital self-image and genital size (length of penis or protrusion of labia minora), consumption of sexually explicit material (SEM), sexual activity, avoidance and safety seeking behaviors, openness toward genital cosmetic surgery and age. OUTCOMES: Total scores on the Female and Male Genital Self Image Scale were used as the main outcome measures. RESULTS: Overall, 3.6% of females and 5.5% of males had a severely low genital self-image (defined as 2 SD below the mean) and 33.8% of all individuals reported dissatisfaction with the appearance of their genitalia, with 13.7% of females and 11.3% of males considering undergoing cosmetic genital surgery. Mean protrusion of labia minora and stretched flaccid penis length in the population was estimated to 0.76 cm (95% CI 0.63-0.89 cm) and 12.5 cm (95% CI 12.33-12.76 cm), respectively. A higher genital self-image score was predicted by having a larger penis or less protruding labia minora, but not by the degree of SEM consumption, although 93.6% of males and 57.5% of females had consumed SEM in the past three months. The degree of avoidance and safety seeking behaviors, sexual activity, and openness toward genital cosmetic surgery predicted a low genital self-image. Being older was associated with a better genital self-image in females. CLINICAL IMPLICATIONS: The results show that a psychological intervention may be needed as an alternative to cosmetic genital surgery for people who are dissatisfied with the appearance of their genitals. STRENGTHS AND LIMITATIONS: This is one of few available studies investigating the association between actual genital size and genital dissatisfaction. The vast sample size and high response rate are also strengths. Limitations include the cross-sectional design, and possible bias in the study sample due to self-selection. CONCLUSION: Overall, a low genital self-image and dissatisfaction with one's genitalia is relatively common and is influenced not only by genital size, but also behaviors performed to alleviate worry about one's genitals. Hustad IB, Malmqvist K, Ivanova E, et al. Does Size Matter? Genital Self-Image, Genital Size, Pornography Use and Openness Toward Cosmetic Genital Surgery in 3503 Swedish Men and Women. J Sex Med 2022;19:1378-1386.

Operational Definitions of Treatment Response and Remission in Obsessive-Compulsive Disorder Capture Meaningful Improvements in Everyday Life.

INTRODUCTION: The operational definitions of treatment response, partial response, and remission in obsessive-compulsive disorder (OCD) are widely used in clinical trials and regular practice. However, the clinimetric sensitivity of these definitions, that is, whether they identify patients that experience meaningful changes in their everyday life, remains unexplored. OBJECTIVE: The objective was to examine the clinimetric sensitivity of the operational definitions of treatment response, partial response, and remission in children and adults with OCD. METHODS: Pre- and post-treatment data from five clinical trials and three cohort studies of children and adults with OCD (n = 1,528; 55.3% children, 61.1% female) were pooled. We compared (1) responders, partial responders, and non-responders and (2) remitters and non-remitters on self-reported OCD symptoms, clinician-rated general functioning, and self-reported quality of life. Remission was also evaluated against post-treatment diagnostic interviews. RESULTS: Responders and remitters experienced large improvements across validators. Responders had greater improvements than partial responders and non-responders on self-reported OCD symptoms (Cohen's d 0.65-1.13), clinician-rated functioning (Cohen's d 0.53-1.03), and self-reported quality of life (Cohen's d 0.63-0.73). Few meaningful differences emerged between partial responders and non-responders. Remitters had better outcomes across most validators than non-remitters. Remission criteria corresponded well with absence of post-treatment diagnosis (sensitivity/specificity: 93%/83%). Using both the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Clinical Global Impression Scale yielded more conservative results and more robust changes across validators, compared to only using the Y-BOCS. CONCLUSIONS: The current definitions of treatment response and remission capture meaningful improvements in the everyday life of individuals with OCD, whereas the concept of partial response has dubious clinimetric sensitivity.

Hit-and-run: a Swedish nationwide cohort study of serious transport accidents and convictions due to traffic offenses in obsessive-compulsive disorder.

PURPOSE: Individuals with obsessive-compulsive disorder (OCD) often report driving-related obsessions, such as fears of causing accidents, but the risk of transport accidents in OCD is unknown. We investigated whether individuals with OCD have an increased risk of serious transport accidents and convictions due to traffic offenses and explored the role of psychiatric comorbidities. METHODS: We included all individuals ≥ 18 years living in Sweden between 1997 and 2013 (N = 5,760,734). A total of 23,126 individuals had a diagnosis of OCD in the National Patient Register. We also identified 16,607 families with full siblings discordant for OCD. Cox proportional hazards regression models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of three outcomes in individuals with OCD, compared to unexposed individuals and their unexposed full siblings: injuries or deaths due to transport accidents, injuries or deaths due to motor vehicle accidents, and convictions related to traffic offenses. Psychiatric comorbidities were systematically adjusted for. RESULTS: Women, but not men, with OCD had a marginally increased risk of serious transport accidents (adjusted HR = 1.20 [95% CI 1.13-1.28]) and motor vehicle accidents (adjusted HR = 1.20 [95% CI 1.09-1.31]), compared to unaffected individuals. Neither women nor men with OCD had a significantly increased risk of convictions. The sibling comparisons showed no significant associations. When psychiatric comorbidities were adjusted for, several observed associations became non-significant or inversed (HRs and 95% CIs below one). CONCLUSION: The risks of serious transport accidents and driving-related criminal convictions in OCD are negligible and heavily influenced by psychiatric comorbidity.

Implementing therapist-guided internet-delivered cognitive behaviour therapy for obsessive-compulsive disorder in the UK's IAPT programme: A pilot trial.

OBJECTIVES: Digital therapies such as internet-delivered cognitive behaviour therapy (ICBT) can improve treatment access for patients with common mental disorders, but are rarely used in the Improving Access to Psychological Therapies (IAPT) programme in the United Kingdom. The objective of this study was to evaluate an evidence-based ICBT intervention for obsessive-compulsive disorder (OCD-NET) in three IAPT services in an open trial. METHODS: Consecutively referred patients with a primary diagnosis of OCD (n = 474) were offered OCD-NET. Symptoms of OCD, depression, anxiety, and level of functioning were measured weekly throughout treatment. RESULTS: In the full intention to treat sample (n = 474), the intervention was associated with large reductions in self-reported OCD symptoms (d = 1.77), anxiety (d = 1.55) and depression (d = 0.8), as well as improvements in functional impairment (d = 0.51 to 0.72). Further, 35% of participants were in recovery at their last assessment, 25% achieved reliable improvement and 15% met criteria for both recovery and improvement. Among participants completing at least 4 modules (n = 261), corresponding to an adequate 'dose' of treatment, the rates of recovery (44%), reliable improvement (34%) and reliable recovery (21%) were higher. A majority of participants were satisfied with the online treatment and found the online materials helpful. CONCLUSIONS: OCD-NET is an effective treatment when delivered in regular care within the IAPT system. Challenges associated with implementing ICBT in regular health care are discussed.

Initial evaluation of a therapist-supported online cognitive therapy self-help for patients with taboo obsessions.

OBJECTIVES: The current study evaluated the feasibility of an internet-delivered cognitive therapy (I-CT) in a self-help format with minimal therapist support for patients with obsessive-compulsive disorder (OCD) with primary taboo obsessions. Specifically, the aims were to investigate (1) whether participants were able to grasp and apply the internet-delivered cognitive framework to their own situation; (2) whether they had clinically meaningful reductions of OCD symptom severity; and (3) whether reduced negative appraisals (hypothesized mechanism of change in CT) preceded reductions in OCD symptom severity. METHOD: Nineteen OCD patients with primary taboo obsessions, recruited from an OCD clinic or self-referrals, received the I-CT intervention for 10 weeks. I-CT did not contain any systematic exposure or response prevention. RESULTS: Adherence and engagement with the intervention was high. Most participants (n = 13, 68%) understood and successfully applied the cognitive model to their own situation. Within-group analyses showed large reductions in OCD symptom severity at post-treatment (bootstrapped within group d = 1.67 [95% CI; 0.67 to 2.66]) measured with the Yale-Brown Obsessive-Compulsive Scale. The gains were maintained at the 6-month follow-up. Post-hoc analyses revealed that the large reductions in OCD symptom severity were driven by the participants who understood the cognitive model. Reductions in negative appraisals predicted subsequent reductions in OCD symptom severity during treatment. CONCLUSION: It is possible to adapt a purely cognitive intervention to a digital guided self-help format and to achieve both cognitive change and meaningful symptom reduction. The results require confirmation in a randomized clinical trial.