Background Hypochondriasis, or health anxiety disorder, is associated with increased mortality, mainly from potentially preventable causes. Substance misuse is a well-known contributor to premature death, yet its relationship with hypochondriasis remains unclear. We assessed the risk of broadly defined substance-related problems in individuals diagnosed with hypochondriasis.Methods This Swedish register-based matched cohort study included 4,129 individuals diagnosed with hypochondriasis in specialist services between 1997 and 2020 and 41,290 demographically matched unexposed individuals. Stratified Cox proportional hazards models were fitted to estimate hazard ratios (HRs) for the association between hypochondriasis and substance-related problems - defined as alcohol and drug use disorders, dispensed medications for alcohol dependence and opioid use disorders, and alcohol- and drug-related accidental poisonings, deaths, and suspected criminal offenses. Models were adjusted for sociodemographic variables, parental substance-related problems, and personal psychiatric history.Results Substance-related problems were identified in 504 (12.2%) individuals with hypochondriasis and 1,924 (4.7%) matched unexposed individuals. After adjustment for sociodemographic and parental covariates, hypochondriasis was significantly associated with an increased risk of substance-related problems (HR, 2.55; 95% confidence interval [CI], 2.30-2.84). Similar results were observed in individuals without preexisting substance-related problems (HR, 2.85; 95% CI, 2.48-3.27). Further adjustment for psychiatric comorbidity, particularly anxiety and depression, reduced the risk estimates, but the associations remained statistically significant. In an additional analysis including primary care diagnoses of hypochondriasis (presumably reflecting less complex cases), the risk of substance-related problems remained elevated (HR, 1.61; 95% CI, 1.39-1.86).Conclusion Improved recognition of, and clinical awareness of substance misuse may help reduce long-term adverse outcomes in individuals with hypochondriasis.

Aims Social anxiety disorder (SAD) is one of the most common anxiety disorders and is associated with significant impairment and societal costs. The association between SAD and mortality remains poorly understood, partly because in epidemiological research it is rarely studied independently from other anxiety disorders. In this population-based matched cohort and sibling control study, we estimated the risk of all-cause and cause-specific mortality in individuals with SAD.Methods From a population of individuals born from 1932 and living in Sweden between 1997 and 2020, we identified all cases of SAD (Swedish ICD-10 code F40.1) in the National Patient Register. Each of these individuals was matched on sex, birth year and county of residence with 10 individuals who had never received a diagnosis. Mortality data were extracted from the Cause of Death Register. Risks were estimated using Cox proportional hazards regression models. Models adjusted for sociodemographic covariates and other lifetime psychiatric disorders. We also identified all clusters of full siblings and conducted within-sibling comparisons to account for unmeasured familial confounding.Results The matched cohort included 57,360 individuals with SAD and 573,600 unexposed individuals. During the follow-up, 2355 deaths were registered within the exposed cohort vs. 7800 deaths in the matched cohort (crude mortality rates, 5.25 and 1.73 per 1000 person-years, respectively). The full cohort was followed up for a mean of 7.87 years (standard deviation 5.23). In models adjusting for sociodemographic variables, individuals with SAD had a 2.24-fold increased hazard of all-cause mortality (95% confidence interval [CI], 2.13-2.35). The increased risk was observed for both natural (adjusted hazard ratio [HR], 1.62; 95% CI 1.52-1.72) and unnatural causes of death (HR, 4.18; 95% CI 3.82-4.58). The results were robust to additional adjustment for psychiatric comorbidities, but the magnitude of the associations was attenuated, particularly when adjusting for substance use disorders. In the sibling cohort, 39,993 individuals with SAD were compared with their 64,640 unaffected siblings. While the estimates were also attenuated, they remained statistically significant (HR for all-cause mortality, 1.40; 95% CI 1.36-1.45).Conclusions Individuals with SAD face an increased risk of mortality, attributable primarily to unnatural causes of death, such as suicide, but also to natural causes, even after adjusting for socioeconomic variables. Psychiatric comorbidities, particularly substance use disorders, and shared familial factors may also contribute to this excess death. Further study of underlying mechanisms may inform prevention and early intervention strategies to reduce mortality in this vulnerable population.

Background Obsessive-compulsive disorder (OCD) is associated with an increased risk of morbidity and mortality due to cardiometabolic disorders. Whether this association is driven by familial factors is unknown. This population-based family study explored the familial co-aggregation of OCD and cardiometabolic disorders.Methods We identified 6 049 717 individuals born in Sweden between 1950 and 2008, including 50 212 individuals with OCD, and followed them up to 2020. These individuals were linked to their mothers, fathers, full siblings, maternal and paternal half siblings, aunts, uncles and cousins. We estimated the risk of cardiovascular diseases (CVD) and metabolic disorders (including obesity, type 2 diabetes and hyperlipidaemia), comparing the relatives of probands with and without OCD. Cox proportional hazards regression models, incorporating time-varying exposures, estimated HRs.Results OCD was associated with an increased risk of CVD (HR 1.47; 95% CI 1.43 to 1.51), obesity (HR 1.69; 95% CI 1.63 to 1.74), type 2 diabetes (HR 2.01; 95% CI 1.90 to 2.12) and hyperlipidaemia (HR 1.42; 95% CI 1.33 to 1.52). The relatives of probands with OCD exhibited small increased risks of CVD (HRs from 1.01 to 1.11) and obesity (HRs from 1.03 to 1.20). Slightly increased risks for type 2 diabetes were observed in mothers (HR 1.11; 95% CI 1.07 to 1.15) and full siblings (HR 1.12; 95% CI 1.05 to 1.20), while for hyperlipidaemia it was only observed in mothers (HR 1.06; 95% CI 1.02 to 1.10).Conclusions Our results do not support a major contribution of familial factors to the association between OCD and cardiometabolic disorders, suggesting a more prominent role of unique environmental factors.

Trichotillomania is an understudied, underrecognized, and difficult-to-treat psychiatric disorder that affects about 1–2% of the population, predominantly women. This study aimed to characterize the sociodemographic and clinical characteristics of a Swedish cohort of individuals with a diagnosis of trichotillomania assigned in specialist services across the country. Through the Swedish National Patient Register, we identified all individuals with an ICD-10 diagnosis of trichotillomania between January 1st, 1997 and December 31st, 2020. The cohort included 1,234 individuals, with a median age at first diagnosis of 25 years (interquartile range, 16–35). Most individuals were female (85%) and single (82%). Most (79%) individuals had a comorbid psychiatric disorder diagnosed during the study period. Anxiety-related disorders (65%), depressive disorders (48%), and neurodevelopmental disorders (39%) were the most frequent co-occurring diagnoses. Most (72%) individuals were dispensed psychotropic medications during the period ranging from 12 months prior to and 12 months after the first trichotillomania diagnosis. Antidepressants (58%), hypnotics/sedatives (36%), and anxiolytics (31%) were the most frequently dispensed medications. Altogether, the characteristics of individuals diagnosed with trichotillomania in Swedish specialist services were similar to those reported in previous literature, opening the possibility of register-based research into this underdiagnosed and understudied condition.

Background:Trichotillomania is an understudied psychiatric disorder characterized by repeated hair-pulling resulting in hair loss. Little is known about the risk of problematic substance use in this patient group. In this nationwide matched cohort study, we investigated the association between trichotillomania and substance-related problems. Methods:We linked various nationwide administrative and clinical registers in Sweden. Among 12,015,664 individuals living in the country from January 1, 1997, to December 31, 2020, we identified 1136 individuals with an ICD-10 diagnosis of trichotillomania at age ≥10 years (86.4% female, median age at first diagnosis 23.8 years [interquartile range 13.3-34.9 years]) and matched them with 11,360 unaffected individuals. The outcome was broadly defined as substance-related problems (alcohol- and drug-related disorders, suspected criminal offenses, and deaths). Stratified Cox proportional hazards regression was used to determine hazard ratios (HRs) for the association between trichotillomania and any substance-related problems. Results:Over a mean follow-up period of 6 years, substance-related problems were recorded for 137 (12.1%) individuals with trichotillomania and 399 (3.5%) matched individuals (crude incidence rates per 1000 person-years of 21.6 and 5.6, respectively). After controlling for sociodemographic covariates and parental substance-related problems, trichotillomania was associated with an increased relative risk of substance-related problems (HR, 3.12; 95% CI, 2.53-3.85). Adjusting also for comorbid psychiatric history did not meaningfully change the findings. Conclusions:Individuals with trichotillomania had a 3-fold increased risk of substance-related problems compared with unaffected individuals. Future research should examine the mechanisms underlying this association and inform the clinical management of the dual diagnoses.

BACKGROUND:Despite considerable interest in the consequences of benzodiazepine and benzodiazepine-related Z-drug (BZDR) use, little is known about whether and how initiation of BZDR treatment relates to the development of alcohol- and drug-related problems. AIMS:This study aimed to examine the association of incident BZDR dispensing with subsequent alcohol- and drug-related problems. METHODS:This nationwide register-based study included demographically matched and co-twin control cohorts. Among all Swedish residents aged older than 10 years and BZDR-naïve by 2007, 960,430 BZDR-recipients with incident dispensation in 2007-2019 and without any recorded pre-existing substance-related conditions were identified and matched (1:1) to non-recipients from the general population. Twin BZDR-recipients (n = 12,048) were linked to 12,579 unexposed co-twins. Outcomes included alcohol and drug use disorders, poisoning, deaths, and related suspected criminal offences. Flexible parametric survival models estimated outcome risks across up to 14 years of follow-up. RESULTS:In the demographically matched cohort (60% women, median age at BZDR initiation 51 years), incidence rates in BZDR-recipients and non-recipients (per 1000 person-years) were 5.60 versus 2.79 for alcohol-related and 4.15 versus 1.23 for drug-related problems, respectively. In fully adjusted models, relative risks were increased for alcohol- and drug-related problems (adjusted hazard ratio (95% confidence interval): 1.56 (1.53-1.59) and 2.11 (2.05-2.17), respectively). The risks persisted within the co-twin comparison, different follow-ups, and all additional sensitivity analyses. CONCLUSIONS:BZDR initiation was associated with a small but robust increase in absolute and relative risks of developing alcohol- and drug-related problems. The findings contribute to evidence base for making decisions on BZDR treatment initiation.

The extent to which bullying victimization is associated with an increased risk of obsessive-compulsive disorder (OCD) has received little empirical attention. This longitudinal, population-based, genetically informative study examined whether self-reported bullying victimization at age 15 was associated with a clinical diagnosis of OCD in the Swedish National Patient Register and with self-reported obsessive-compulsive symptoms (OCS) at ages 18 and 24 in 16,030 twins from the Child and Adolescent Twin Study in Sweden. Using a discordant twin design, including monozygotic (MZ) and dizygotic (DZ) twins, each twin was compared with their co-twin, allowing a strict control of genetic and environmental confounding. At the population level, adjusting for birth year and sex, each standard deviation (SD) increase in bullying victimization was associated with a 32% increase in the odds of an OCD diagnosis (OR, 1.32; 95% CI, 1.21-1.44), of 0.13 SD in OCS at age 18 (beta, 0.13; 95% CI, 0.11-0.16), and of 0.11 SD in OCS at age 24 (beta, 0.11; 95% CI, 0.07-0.16). While associations tended to persist in the within DZ-twin comparison models, the estimates attenuated and were no longer statistically significant in the within MZ-twin comparisons. These results suggest that the association between bullying victimization and OCD/OCS is likely due to genetic confounding and therefore incompatible with a strong causal effect. Other mechanisms, such as evocative gene-environment correlations, are more plausible explanations for the observed associations.

Importance:Behavior therapy is a recommended intervention for Tourette syndrome (TS) and chronic tic disorder (CTD), but availability is limited and long-term effects are uncertain. Objective:To investigate the long-term efficacy and cost-effectiveness of therapist-supported, internet-delivered exposure and response prevention (ERP) vs psychoeducation for youths with TS or CTD. Design, Setting, And Participants:This 12-month controlled follow-up of a parallel group, superiority randomized clinical trial was conducted at a research clinic in Stockholm, Sweden, with nationwide recruitment. In total, 221 participants aged 9 to 17 years with TS or CTD were enrolled between April 26, 2019, and April 9, 2021, of whom 208 (94%) provided 12-month follow-up data. Final follow-up data were collected on June 29, 2022. Outcome assessors were masked to treatment allocation throughout the study. Interventions:A total of 111 participants were originally randomly allocated to 10 weeks of therapist-supported, internet-delivered ERP and 110 participants to therapist-supported, internet-delivered psychoeducation. Main Outcomes And Measures:The primary outcome was within-group change in tic severity, measured by the Total Tic Severity Score of the Yale Global Tic Severity Scale (YGTSS-TTSS), from the 3-month follow-up to the 12-month follow-up. Treatment response was defined as 1 (very much improved) or 2 (much improved) on the Clinical Global Impression-Improvement scale. Analyses were intention-to-treat and followed the plan prespecified in the published study protocol. A health economic evaluation was performed from 3 perspectives: health care organization (including direct costs for treatment provided in the study), health care sector (additionally including health care resource use outside of the study), and societal (additionally including costs beyond health care [eg, parent's absenteeism from work]). Results:In total, 221 participants were recruited (mean [SD] age, 12.1 [2.3] years; 152 [69%] male). According to the YGTSS-TTSS, there were no statistically significant changes in tic severity from the 3-month to the 12-month follow-up in either group (ERP coefficient, -0.52 [95% CI, -1.26 to 0.21]; P = .16; psychoeducation coefficient, 0.00 [95% CI, -0.78 to 0.78]; P > .99). A secondary analysis including all assessment points (baseline to 12-month follow-up) showed no statistically significant between-group difference in tic severity from baseline to the 12-month follow-up (coefficient, -0.38 [95% CI, -1.11 to 0.35]; P = .30). Treatment response rates were similar in both groups (55% in ERP and 50% in psychoeducation; odds ratio, 1.25 [95% CI, 0.73-2.16]; P = .42) at the 12-month follow-up. The health economic evaluation showed that, from a health care sector perspective, ERP produced more quality-adjusted life years (0.01 [95% CI, -0.01 to 0.03]) and lower costs (adjusted mean difference -$84.48 [95% CI, -$440.20 to $977.60]) than psychoeducation at the 12-month follow-up. From the health care organization and societal perspectives, ERP produced more quality-adjusted life years at higher costs, with 65% to 78% probability of ERP being cost-effective compared with psychoeducation when using a willingness-to-pay threshold of US $79 000. Conclusions And Relevance:There were no statistically significant changes in tic severity from the 3-month through to the 12-month follow-up in either group. The ERP intervention was not superior to psychoeducation at any time point. While ERP was not superior to psychoeducation alone in reducing tic severity at the end of the follow-up period, ERP is recommended for clinical implementation due to its likely cost-effectiveness and support from previous literature. Trial Registration:ClinicalTrials.gov Identifier: NCT03916055.

Objective To estimate the risk of all cause and cause specific mortality in people with obsessive-compulsive disorder (OCD) compared with matched unaffected people from the general population and with their unaffected siblings. Design Population based matched cohort and sibling cohort study. Setting Register linkage in Sweden. Participants Population based cohort including 61 378 people with OCD and 613 780 unaffected people matched (1:10) on sex, birth year, and county of residence; sibling cohort consisting of 34 085 people with OCD and 47 874 unaffected full siblings. Cohorts were followed up for a median time of 8.1 years during the period from 1 January 1973 to 31 December 2020. Main outcome measures All cause and cause specific mortality. Results 4787 people with OCD and 30 619 unaffected people died during the study period (crude mortality rate 8.1 and 5.1 per 1000 person years, respectively). In stratified Cox proportional hazards models adjusted for birth year, sex, county, migrant status (born in Sweden versus abroad), and sociodemographic variables (latest recorded education, civil status, and family income), people with OCD had an increased risk of all cause mortality (hazard ratio 1.82, 95% confidence interval 1.76 to 1.89) and mortality due to natural causes (1.31, 1.27 to 1.37) and unnatural causes (3.30, 3.05 to 3.57). Among the natural causes of death, those due to endocrine, nutritional, and metabolic diseases, mental and behavioural disorders, and diseases of the nervous, circulatory, respiratory, digestive, and genitourinary systems were higher in the OCD cohort. Conversely, the risk of death due to neoplasms was lower in the OCD cohort compared with the unaffected cohort. Among the unnatural causes, suicide showed the highest hazard ratio, followed by accidents. The results were robust to adjustment for psychiatric comorbidities and familial confounding. Conclusions Non-communicable diseases and external causes of death, including suicides and accidents, were major contributors to the risk of mortality in people with OCD. Better surveillance, prevention, and early intervention strategies should be implemented to reduce the risk of fatal outcomes in people with OCD.

BackgroundTourette syndrome (TS) and chronic tic disorder (CTD) may be associated with an increased risk of mortality, but specific causes of death are poorly understood.ObjectivesIn this matched cohort and sibling cohort study, we estimated the risk of all-cause and cause-specific mortality in individuals with TS/CTD, compared with unaffected matched individuals and unaffected full siblings.MethodsWe identified all individuals diagnosed with TS/CTD in the Swedish National Patient Register who were living in the country between 1973 and 2020 and matched them (1:10) to individuals without TS/CTD from the general population. We also identified their siblings without TS/CTD. All-cause and cause-specific mortality outcomes, based on the International Classification of Diseases codes, were extracted from the Cause of Death Register. Covariates included sociodemographic variables and psychiatric disorders. Risks of mortality were estimated using Cox proportional hazards regression models.ResultsWe included 10,280 individuals with TS/CTD and 102,800 matched individuals without TS/CTD. In adjusted models, individuals with TS/CTD had an 86% increased hazard of all-cause mortality (hazard ratio: 1.86, 95% confidence interval: 1.65-2.11). The increased risk was observed for both natural (particularly nervous, digestive, and respiratory system diseases) and unnatural causes of death (including suicides and accidents). The sibling comparison showed similar results, indicating that the associations were unlikely to be explained by familial confounding.ConclusionsIndividuals with TS/CTD are at increased risk of death due to both natural and unnatural causes. As some of these deaths are potentially preventable, greater focus on the somatic health of individuals with TS/CTD is warranted. (c) 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND: Body dysmorphic disorder (BDD) is thought to be associated with considerable suicide risk. This nationwide cohort study quantified the risks of intentional self-harm-including nonsuicidal self-injuries and suicide attempts-and death by suicide in BDD. METHODS: Individuals with a validated ICD-10 diagnosis of BDD in the Swedish National Patient Register, registered between January 1, 1997, and December 31, 2020, were matched with 10 unexposed individuals (i.e., without BDD) from the general population on birth year, sex, and county of residence. Conditional Poisson regression models estimated incidence rate ratios and 95% CIs for intentional self-harm. Stratified Cox proportional hazards models estimated hazard ratios and 95% CIs for death by suicide. Models adjusted for sociodemographic variables and lifetime psychiatric comorbidities. RESULTS: Among 2833 individuals with BDD and 28,330 unexposed matched individuals, 466 (16.45%) and 1071 (3.78%), respectively, had at least 1 record of intentional self-harm during the study period (incidence rate ratio = 3.37; 95% CI, 3.02-3.76). In the BDD group, about two-thirds (n = 314; 67%) had their first recorded self-harm event before their first BDD diagnosis. A total of 17 (0.60%) individuals with BDD and 27 (0.10%) unexposed individuals died by suicide (hazard ratio = 3.47; 95% CI, 1.76-6.85). All results remained robust to additional adjustment for lifetime psychiatric comorbidities. A higher proportion of individuals with BDD who died by suicide had at least 1 previous record of intentional self-harm compared with unexposed individuals (52.94% vs. 22.22%; p = .036). CONCLUSIONS: BDD was associated with a 3-fold increased risk of intentional self-harm and death by suicide.

Animal studies have suggested a link between benzodiazepine and related Z-drug (BZDR) use and immune dysfunction. Corresponding evidence in humans is limited and focuses mainly on pneumonia. This study aimed to assess the association of incident BZDR use with subsequent development of serious infections. This Swedish register-based study included a population-based demographically matched cohort, a co-twin control cohort, and an active comparator cohort. Out of 7,362,979 individuals aged below 65 years who were BZDR naïve by 2007, 713,896 BZDR recipients with incident dispensation of any BZDRs between 2007 and 2019 were 1:1 matched to 713,896 nonrecipients from the general population; 9197 BZDR recipients were compared with their 9298 unexposed co-twins/co-multiples; and 434,900 BZDR recipients were compared with 428,074 incident selective serotonin reuptake inhibitor (SSRI) recipients. The outcomes were identified by the first inpatient or specialist outpatient diagnosis of serious infections in the National Patient Register, or death from any infections recorded as the underlying cause in the Cause of Death Register. Cox proportional hazards regression models were fitted and controlled for multiple confounders, including familial confounding and confounding by indication. To study a possible dose–response association, the cumulative dosage of BZDRs dispensed during the follow-up was estimated for each BZDR recipient and modeled as a time-varying exposure with dose categories in tertiles [≤ 20 defined daily doses (DDDs), > 20 DDDs ≤ 65, and > 65 DDDs). The risk of infections was assessed in BZDR recipients within each category of the cumulative BZDR dosage compared to their demographically matched nonrecipients. In the demographically matched cohort (average age at incident BZDR use 42.8 years, 56.9

Importance Behavior therapy is a recommended intervention for Tourette syndrome (TS) and chronic tic disorder (CTD), but availability is limited and long-term effects are uncertain. Objective To investigate the long-term efficacy and cost-effectiveness of therapist-supported, internet-delivered exposure and response prevention (ERP) vs psychoeducation for youths with TS or CTD. Design, Setting, And Participants This 12-month controlled follow-up of a parallel group, superiority randomized clinical trial was conducted at a research clinic in Stockholm, Sweden, with nationwide recruitment. In total, 221 participants aged 9 to 17 years with TS or CTD were enrolled between April 26, 2019, and April 9, 2021, of whom 208 (94%) provided 12-month follow-up data. Final follow-up data were collected on June 29, 2022. Outcome assessors were masked to treatment allocation throughout the study. Interventions A total of 111 participants were originally randomly allocated to 10 weeks of therapist-supported, internet-delivered ERP and 110 participants to therapist-supported, internet-delivered psychoeducation. Main Outcomes And Measures The primary outcome was within-group change in tic severity, measured by the Total Tic Severity Score of the Yale Global Tic Severity Scale (YGTSS-TTSS), from the 3-month follow-up to the 12-month follow-up. Treatment response was defined as 1 (very much improved) or 2 (much improved) on the Clinical Global Impression-Improvement scale. Analyses were intention-to-treat and followed the plan prespecified in the published study protocol. A health economic evaluation was performed from 3 perspectives: health care organization (including direct costs for treatment provided in the study), health care sector (additionally including health care resource use outside of the study), and societal (additionally including costs beyond health care [eg, parent's absenteeism from work]). Results In total, 221 participants were recruited (mean [SD] age, 12.1 [2.3] years; 152 [69%] male). According to the YGTSS-TTSS, there were no statistically significant changes in tic severity from the 3-month to the 12-month follow-up in either group (ERP coefficient, -0.52 [95% CI, -1.26 to 0.21]; P = .16; psychoeducation coefficient, 0.00 [95% CI, -0.78 to 0.78]; P > .99). A secondary analysis including all assessment points (baseline to 12-month follow-up) showed no statistically significant between-group difference in tic severity from baseline to the 12-month follow-up (coefficient, -0.38 [95% CI, -1.11 to 0.35]; P = .30). Treatment response rates were similar in both groups (55% in ERP and 50% in psychoeducation; odds ratio, 1.25 [95% CI, 0.73-2.16]; P = .42) at the 12-month follow-up. The health economic evaluation showed that, from a health care sector perspective, ERP produced more quality-adjusted life years (0.01 [95% CI, -0.01 to 0.03]) and lower costs (adjusted mean difference -$84.48 [95% CI, -$440.20 to $977.60]) than psychoeducation at the 12-month follow-up. From the health care organization and societal perspectives, ERP produced more quality-adjusted life years at higher costs, with 65% to 78% probability of ERP being cost-effective compared with psychoeducation when using a willingness-to-pay threshold of US $79 000. Conclusions And Relevance There were no statistically significant changes in tic severity from the 3-month through to the 12-month follow-up in either group. The ERP intervention was not superior to psychoeducation at any time point. While ERP was not superior to psychoeducation alone in reducing tic severity at the end of the follow-up period, ERP is recommended for clinical implementation due to its likely cost-effectiveness and support from previous literature.

BACKGROUND: Postinfectious autoimmune processes are hypothesized to be causally related to both obsessive -compulsive disorder (OCD) and tic disorders, but current evidence is conflicting. This study examined whether prenatal maternal (and paternal, as an internal control) infections and early childhood infections in the offspring (i.e., during the first 3 years of life) were associated with a subsequent risk of OCD and Tourette syndrome or chronic tic disorder (TS/CTD).METHODS: Individuals exposed to any prenatal maternal infection (n = 16,743) and early childhood infection (n = 264,346) were identified from a population-based birth cohort consisting of 2,949,080 singletons born in Sweden between 1973 and 2003 and were followed through 2013. Cox proportional hazard regression models were used to estimate hazard ratios (HRs). Sibling analyses were performed to control for familial confounding.RESULTS: At the population level, and after adjusting for parental psychiatric history and autoimmune diseases, a significantly increased risk of OCD and TS/CTD was found in individuals exposed to prenatal maternal (but not paternal) infections (OCD: HR, 1.33; 95% CI, 1.12-1.57; TS/CTD: HR, 1.60; 95% CI, 1.23-2.09) and early childhood infections (OCD: HR, 1.19; 95% CI, 1.14-1.25; TS/CTD: HR, 1.34; 95% CI, 1.24-1.44). However, these associations were no longer significant in the sibling analyses.CONCLUSIONS: The results do not support the hypothesis that prenatal maternal or early-life infections play a direct causal role in the etiology of either OCD or TS/CTD. Instead, familial factors (e.g., genetic pleiotropy) may explain both the propensity to infections and the liability to OCD and TS/CTD.

BackgroundMany children with tic disorders outgrow their tics, but little is known about the proportion of individuals who will continue to require specialist services in adulthood and which variables are associated with tic persistence. ObjectivesThe aims were to estimate the proportion of individuals first diagnosed with tic disorders in childhood who continued to receive tic disorder diagnoses after age 18 years and to identify risk factors for persistence. MethodsIn this Swedish nationwide cohort study including 3761 individuals diagnosed with tic disorders in childhood, we calculated the proportion of individuals whose diagnoses persisted into adulthood. Minimally adjusted logistic regression models examined the associations between sociodemographic, clinical, and family variables and tic disorder persistence. A multivariable model was then fitted, including only variables that were statistically significant in the minimally adjusted models. ResultsSeven hundred and fifty-four (20%) children with tic disorders received a diagnosis of a chronic tic disorder in adulthood. Psychiatric comorbidity in childhood (particularly attention-deficit hyperactivity disorder, obsessive-compulsive disorder, pervasive developmental disorders, and anxiety disorders) and psychiatric disorders in first-degree relatives (particularly tic and anxiety disorders) were the strongest risk factors for persistence. We did not observe statistically significant associations with socioeconomic variables, perinatal complications, comorbid autoimmune diseases, or family history of autoimmune diseases. All statistically significant variables combined explained approximately 10% of the variance in tic disorder persistence (P < 0.0001). ConclusionsChildhood psychiatric comorbidities and family history of psychiatric disorders were the strongest risk factors associated with tic disorder persistence into adulthood. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

IMPORTANCE Maternal immune activation (MIA) leading to altered neurodevelopment in utero is a hypothesized risk factor for psychiatric outcomes in offspring. Primary antibody immunodeficiencies (PIDs) constitute a unique natural experiment to test the MIA hypothesis of mental disorders. OBJECTIVE To assess the association of maternal and paternal PIDs with psychiatric disorders and suicidal behavior in offspring. DESIGN, SETTING, AND PARTICIPANTS Cohort study of 4 294169 offspring of parents with and without PIDs living in Sweden at any time between 1973 and 2013. Data were extracted from Swedish nationwide health and administrative registers and were analyzed from May 5 to September 30, 2022. All individuals with diagnoses of PIDs identified between 1973 and 2013 from the National Patient Register were included. Offspring were included if born before 2003. Parent-offspring pairs in which both parents had a history of PIDs were excluded. EXPOSURES Lifetime records of parental PIDs according to the International Classification of Diseases, Eighth Revision (ICD-8); International Classification of Diseases, Ninth Revision (ICD-9); and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. MAIN OUTCOMES AND MEASURES Lifetime records of 10 psychiatric disorders and suicidal behavior identified using ICD-8, ICD-9, and ICD-10 diagnostic codes, including suicide attempts and death by suicide, among offspring. Covariates included sex, birth year, parental psychopathology, suicide attempts, and autoimmune diseases. Additional analyses excluded offspring with their own PIDs and autoimmune diseases. Poisson regression models were fitted separately for mothers and fathers to estimate incidence rate ratios (IRRs) and 95% CIs for the risk of psychiatric and suicidal behavior outcomes in the offspring of PID-exposed vs PID-unexposed mothers or fathers. RESULTS The cohort included 4294169 offspring (2 207 651 males [51.4%]) and 3 954 937 parents (1 987 972 females [50.3%]). A total of 7270 offspring (0.17%) had parents with PIDs, and 4 286 899 offspring had parents without PIDs. In fully adjusted models, offspring of mothers with PIDs had an increased risk of any psychiatric disorder, while no such risks were observed in offspring of fathers with PIDs (IRR, 1.17; 95% CI, 1.10-1.25 vs IRR, 1.03; 95% CI, 0.94-1.14; P < .001). Likewise, an increased risk of suicidal behavior was observed among offspring of mothers with PIDs but not offspring of fathers with PIDs (IRR, 1.20; 95% CI, 1.06-1.36 vs IRR, 1.10; 95% CI, 0.91-1.34; P = .01). For the offspring of mothers with PIDs, the risk of developing any psychiatric disorder was significantly higher for those with mothers with 6 of 10 individual disorders, with IRRs ranging from 1.15 (95% CI, 1.04-1.26) for anxiety and stress-related disorders and 1.15 (95% CI, 1.03-1.30) for substance use disorders to 1.71 (95% CI, 1.37-2.14) for bipolar disorders. Offspring of mothers with both PIDs and autoimmune diseases had the highest risk for any psychiatric disorder (IRR, 1.24; 95% CI, 1.11-1.38) and suicidal behavior (IRR, 1.44; 95% CI, 1.17-1.78). CONCLUSIONS AND RELEVANCE Findings of this cohort study suggest that maternal, but not paternal, PIDs were associated with a statistically significant increased risk of psychiatric disorders and suicidal behavior in the offspring, particularly when PIDs co-occur with autoimmune diseases. These findings align with the MIA hypothesis of mental disorders, but the precise mechanisms remain to be elucidated.

Purpose Despite being discouraged by guidelines, long-term use of benzodiazepines and related Z-drugs (BZDR) remains frequent in the real-world. An improved understanding of factors associated with the transition from new to long-term BZDR use and of temporal BZDR use trajectories is needed. We aimed to assess the proportion of long-term BZDR use (> 6 months) in incident BZDR-recipients across the lifespan; identify 5-year BZDR use trajectories; and explore individual characteristics (demographic, socioeconomic and clinical) and prescribing-related factors (pharmacological properties of the initial BZDR, prescriber’s healthcare level, and concurrent dispensing of other medications) associated with long-term BZDR use and distinct trajectories. Methods Our nationwide register-based cohort included all BZDR-recipients in Sweden with first dispensation in 2007–2013. Trajectories of BZDR use days per year were built using group-based trajectory modelling. Cox regression and multinomial logistic regression were fitted to assess the predictors of long-term BZDR use and trajectories’ membership. Results In 930,465 incident BZDR-recipients, long-term use increased with age (20.7%, 41.0%, and 57.4% in 0–17, 18–64, and ≥ 65-year-olds, respectively). Four BZDR use trajectories emerged, labelled ‘discontinued’, ‘decreasing’, ‘slow decreasing’ and ‘maintained’. The proportion of the ‘discontinued’ trajectory members was the largest in all ages, but reduced from 75.0% in the youths to 39.3% in the elderly, whereas the ‘maintained’ increased with age from 4.6% to 36.7%. Prescribing-related factors, in particular multiple BZDRs at initiation and concurrent dispensing of other medications, were associated with increased risks of long-term ( vs short-term) BZDR use and developing other trajectories ( vs ‘discontinued’) in all age groups. Conclusions The findings highlight the importance of raising awareness and providing support to prescribers to make evidence-based decisions on initiating and monitoring BZDR treatment across the lifespan.

Stable employment is consistently and strongly linked to key indicators of life quality and longevity, including physical and mental health, social integration, self-conception and self-fulfilment1. Involuntary exclusion, destabilization, or marginalization from the workforce has negative impacts across these same personal, social and economic domains. These effects may be further compounded by individual features (e.g., poor health, low education) or life stressors (e.g., low socioeconomic status, housing instability) associated with under- or un-employment2. Studies have highlighted a critical role for childhood adversity in influencing occupational trajectories. While the working definition has varied across investigations, there is a generally unified conception of “adversity” as encompassing both economic (e.g., low socioeconomic status) and emotional (e.g., chaotic environment) factors. In acknowledgement of its influence across these factors, it has been common for these definitions to include a measure of parental mental health. Despite this, the relationship of parental mental illness to intergenerational occupational outcomes remains poorly delineated. Previous work has focused primarily on proxy-behaviors associated with parental psychiatric health (e.g., alcohol/drug abuse), and on early-life features associated with future work opportunity (e.g., personality formation, educational attainment)3, 4. We are unaware of any work, to date, that has been powered to longitudinally dissect the relationship between established parental psychiatric diagnosis and objective occupational outcomes in offspring. Further, no work has considered the differential impact of parental diagnostic structure (e.g., mood vs. psychotic disorders; one vs. two affected parents) on these associations. Indeed, non-random mating is common in psychiatric populations5, 6, and likely to have a considerable impact on a range of offspring functional outcomes7. Here, we focused on the following questions: a) Is risk for receipt of disability pension and long-term unemployment increased among the offspring of persons with psychiatric disorders? b) Is this risk further increased if both biological parents have a psychiatric disorder? and c) What role do other individual (e.g., offspring's own mental health) and environmental (e.g., parent's level of education) factors have in this association? Ethical approval for this project was granted by the Regional Ethics Review Board in Stockholm, Sweden. Leveraging linkage of key Swedish national registers, we assembled a cohort of 2,010,587 offspring (from 1,198,151 parental pairs) born in Sweden from January 1, 1973 to December 31, 1993. Using offspring of psychiatrically unaffected parents as a reference (selected in an “uncleaned” manner8), we compared the risks of receiving disability pension and long-term unemployment in offspring of single-affected parents (mother or father) and dual-affected parents (both mother and father) with any of the following eleven major psychiatric disorders: attention deficit/hyperactivity disorder, autism spectrum disorder, Tourette's/chronic tic disorder, substance use disorders, generalized anxiety disorder, major depressive disorder, agoraphobia, social phobia, obsessive-compulsive disorder, schizophrenia and bipolar disorder. The disorders were then clustered into four operational groupings: neurodevelopmental disorders, substance use disorders, emotional disorders, and psychotic disorders (including schizophrenia and bipolar disorder). Within each disorder group, an exposure variable was created to distinguish dual-affected from single-affected pairs: for example, “dual-affected with psychotic disorders” indicates a pair in which both parents have schizophrenia or bipolar disorder (in any combination), while “single-affected with psychotic disorders” indicates a pair in which only one parent has a diagnosis within this disorder group. For offspring outcomes, we estimated the incidence risk ratio (IRR) for disability pension and long-term unemployment across exposure groups. Several covariates were integrated in our models, including key demographic characteristics (base model), with further adjustment for offspring somatic disorders and highest educational level. A fully-adjusted model further controlled for parent's highest educational level and his/her receipt of disability pension/long-term unemployment. Most covariates were defined over the full study period (e.g., full length of follow-up), with a minority adapted to capture impacts at salient timepoints. In sensitivity analyses, we explored the impact of offspring's own psychiatric health by excluding offspring with any of the above-mentioned disorders. We also re-ran the main analyses using a “cleaned” comparison group, in which neither parent had any of the eleven relevant lifetime psychiatric diagnoses. For each outcome, we fitted modified Poisson regression models with robust standard errors9, using person-years as the offset term to address different follow-up times among participants, and clustering by family identification number to account for non-independence of repeated observations within families. Compared to offspring of unaffected parents, individuals with one affected parent had a significantly increased risk of disability pension receipt, when accounting for demographic characteristics (IRR=1.88, 95% CI: 1.84-1.91, p<0.001; in 332,357 offspring of single-affected pairs vs. 1,641,244 offspring of unaffected pairs). The risk was doubled in offspring of dual-affected parents (IRR=2.84, 95% CI: 2.73-2.95, p<0.001; in 36,986 offspring of dual-affected pairs vs. 1,973,601 offspring of unaffected pairs). While all parental psychiatric disorders showed a significant association with offspring disability pension risk, the highest risk was observed in the offspring of parents affected with neurodevelopmental disorders (single-affected: IRR=3.36, 95% CI: 3.20-3.54, p<0.001; dual-affected: IRR=7.25, 95% CI: 5.68-9.26, p<0.001) and psychotic disorders (single-affected: IRR=2.11, 95% CI: 2.03-2.19, p<0.001; dual-affected: IRR=5.31, 95% CI: 4.33-6.52, p<0.001). Results were robust to further adjustment for offspring somatic disorders and education (single-affected with any disorders: IRR=1.73, 95% CI: 1.69-1.76, p<0.001; dual-affected with any disorders: IRR=2.38, 95% CI: 2.28-2.47, p<0.001) and for parental socioeconomic characteristics (IRR=1.40, 95% CI: 1.38-1.43, p<0.001; and IRR=1.60, 95% CI: 1.54-1.67, p<0.001, respectively). Results by parental disorder groups were also robust across models. Offspring with one affected parent had a significantly increased risk of unemployment, compared to offspring of unaffected parents (IRR=1.46, 95% CI: 1.45-1.48, p<0.001). This risk was markedly raised among offspring of dual-affected pairs (IRR=1.92, 95% CI: 1.87-1.96, p<0.001). Offspring of parents single- and dual-affected by neurodevelopmental and substance use disorders showed the highest unemployment burden across both the base model and the model controlling for offspring somatic disorders and education. The fully-adjusted model resulted in significant, but attenuated, risks among offspring: IRR=1.21, 95% CI: 1.20-1.23, p<0.001 (single-affected with any disorders) and IRR=1.34, 95% CI: 1.30-1.38, p<0.001 (dual-affected with any disorders). Corresponding results by parental disorder groups were also attenuated, though the majority of them retained significance. Repetition of analyses in a sub-cohort of offspring free from the diagnosis of interest produced comparable results for both outcomes. Likewise, the use of the “cleaned” comparison group in a sensitivity analysis did not alter the results. Taken together, these results indicate a consistent and profound association between psychiatric history of parents and labour market marginalization in their offspring, which is particularly striking in dual-affected families. Though our primary finding is one of global, relative occupational adversity among the children of all affected parents, variation was further observed by parental diagnosis, with children of families impacted by neurodevelopmental, psychotic and substance use disorders having increased risk for adverse occupational outcomes. Further work will be needed to gain nuanced insight into the mechanisms impeding labour market prospects in these populations, particularly given the limited impact of suspected determinant factors (e.g., child's own psychiatric health) on this association. Our findings suggest that such work should continue to extend consideration of differential risk dynamics by parent diagnosis and, particularly, parental diagnostic structure (e.g., single- vs. dual-affected families), in order to identify subgroups with particular need for preventive and early intervention strategies aimed to increase their chances of labour market participation.

Importance:The availability of behavior therapy for individuals with Tourette syndrome (TS) and chronic tic disorder (CTD) is limited. Objective:To determine the efficacy and cost-effectiveness of internet-delivered exposure and response prevention (ERP) for children and adolescents with TS or CTD. Design, Setting, and Participants:This single-masked, parallel group, superiority randomized clinical trial with nationwide recruitment was conducted at a research clinic in Stockholm, Sweden. Out of 615 individuals assessed for eligibility, 221 participants meeting diagnostic criteria for TS or CTD and aged 9 to 17 years were included in the study. Enrollment began in April 2019 and ended in April 2021. Data were analyzed between October 2021 and March 2022. Interventions:Participants were randomized to 10 weeks of therapist-supported internet-delivered ERP for tics (111 participants) or to therapist-supported internet-delivered education for tics (comparator group, 110 participants). Main Outcomes and Measures:The primary outcome was change in tic severity from baseline to the 3-month follow-up as measured by the Total Tic Severity Score of the Yale Global Tic Severity Scale (YGTSS-TTSS). YGTSS-TTSS assessors were masked to treatment allocation. Treatment response was operationalized as a score of 1 ("Very much improved") or 2 ("Much improved") on the Clinical Global Impression-Improvement scale. Results:Data loss was minimal, with 216 of 221 participants (97.7%) providing primary outcome data. Among randomized participants (152 [68.8%] boys; mean [SD] age, 12.1 [2.3] years), tic severity improved significantly, with a mean reduction of 6.08 points on the YGTSS-TTSS in the ERP group (mean [SD] at baseline, 22.25 [5.60]; at 3-month follow-up, 16.17 [6.82]) and 5.29 in the comparator (mean [SD] at baseline, 23.01 [5.92]; at 3-month follow-up, 17.72 [7.11]). Intention-to-treat analyses showed that the 2 groups improved similarly over time (interaction effect, -0.53; 95% CI, -1.28 to 0.22; P = .17). Significantly more participants were classified as treatment responders in the ERP group (51 of 108 [47.2%]) than in the comparator group (31 of 108 [28.7%]) at the 3-month follow-up (odds ratio, 2.22; 95% CI, 1.27 to 3.90). ERP resulted in more treatment responders at little additional cost compared with structured education. The incremental cost per quality-adjusted life-year gained was below the Swedish willingness-to-pay threshold, at which ERP had a 66% to 76% probability of being cost-effective. Conclusions and Relevance:Both interventions were associated with clinically meaningful improvements in tic severity, but ERP led to higher response rates at little additional cost. Trial Registration:ClinicalTrials.gov identifier: NCT03916055.