Janne Tidselbak Larsen

Importance: Severe anorexia nervosa (AN) carries substantial mortality risk, but its consequences associated with social and occupational functioning remain poorly characterized, limiting the development of targeted interventions to improve functioning, prevent and reduce long-term social disadvantage. Objective: To determine whether AN severity is associated with educational attainment, employment, income, and cohabitation status. Design: Cohort study following social and occupational outcomes across adulthood until age 55. Setting: Population-based. Participants: All individuals born in Denmark from 1963 to 1994, alive and residing in Denmark at age 30. The AN group had a first AN diagnosis between ages 10 and 25 years, excluding those who died or emigrated within 5 years. The comparison group had no AN diagnosis. Exposure: Illness severity of AN, measured by the AN Register-based Severity Index 5 years after the first AN diagnosis. Main Outcomes and Measures: Educational attainment was assessed at age 25 (upper secondary education) and at age 30/35 (highest completed education). Employment status, income deficiency, and cohabitation status were assessed annually from age 30 to 55. Results: Among 2,442,916 individuals, 9,465 were diagnosed with AN, of whom 1,996 (21.1%) were classified as severe AN cases. At age 25, individuals with severe AN had increased odds of non-completion of upper-secondary education compared to the general population (odds ratio [OR]=3.07; 95% confidence interval [CI]: 2.72-3.46), and those with less severe AN (OR=1.39; 95% CI: 1.29-1.50). At age 30, severe AN was associated with higher odds of unemployment (OR=3.42; 95% CI: 3.03-3.86), income deficiency (OR=3.84; 95% CI: 3.42-4.31), and living alone (OR=2.43; 95% CI: 2.17-2.71) compared to the less severe AN group. The risk of unemployment and income deficiency diverged across time: individuals with less severe AN gradually approached the general population, whereas those with severe AN diverged further over time. Within the AN cohort, severity differences persisted after adjustment for active AN diagnosis, with minimal attenuation. Conclusions and Relevance: Greater lifetime AN severity was associated with significantly poorer long-term social and occupational functioning outcomes, and these functional difficulties may persist beyond periods of active illness. This vulnerable group needs substantial support in these areas throughout the course of illness. Key points: Question: Is anorexia nervosa (AN) severity associated with long-term social and occupational functioning outcomes? Findings: In this population-based cohort study, greater AN severity was associated with poorer long-term functioning, including education, occupation, and cohabitation status, across adulthood. AN severity showed graded, dose-response-like relationships with those outcomes, and the gradient persisted regardless of whether individuals had active eating disorder diagnoses. Meaning: Individuals with severe AN show substantial social and occupational impairment, reflected in shorter education, weaker labour-market attachment, lower income, and greater likelihood of living alone, compared with the general population, with these disparities becoming more pronounced over time.

Importance: Anorexia nervosa (AN) is a severe psychiatric disorder with heterogeneous outcomes and elevated mortality. Characterizing severity trajectories may improve early risk stratification and targeted intervention. Objective: To identify AN severity trajectories using a register-based severity index (AN-RSI) and examine their associations with polygenic scores (PGS), preceding (prior to AN diagnosis) as well as subsequent (beyond 5 years post AN diagnosis) psychiatric and somatic disorders. Design: Population-based cohort study. Setting: Nationwide study in Denmark. Participants: Individuals born between 1963 and 2007 with diagnosed AN (N = 9534 individuals). Genetic data were available in a subsample (N = 5126). Exposures: Forty-one PGS indexing traits relevant to AN, and psychiatric and somatic disorders prior to AN diagnosis. Main Outcomes and Measures: AN-RSI trajectories, psychiatric, and somatic disorders beyond 5 years post AN diagnosis. Results: Three trajectories were identified: “low and stable” (32.6%), “medium and stable” (53.5%), and “high increasing” (14.0%). The “low and stable” group was used as the comparison group for all analyses. Each 1 standard deviation (SD) increase in AN PGS corresponded with 13% greater odds of following the “high increasing” trajectory. Increases in BMI and attention-deficit hyperactivity disorder (ADHD) PGS corresponded with 15% and 14% lower odds of following the “high increasing” trajectory, respectively. No preceding psychiatric or somatic disorders were significantly associated with trajectory membership. In contrast, subsequent psychiatric and somatic disorders were more likely in individuals following the “high increasing” trajectory with odds ratios ranging between 1.7 (ADHD) and 3.7 (psychoactive substance dependence) for psychiatric disorders and between 1.6 (poor fetal growth of child) and 4 (microcytic anemia) for somatic disorders. Conclusions and Relevance: Our findings demonstrate that individuals with AN follow distinct severity trajectories that are associated with differences in polygenic risk and post-diagnostic morbidity patterns but not with pre-diagnosis psychiatric or somatic morbidity. As the field progresses, incorporating PGS into comprehensive assessments at first presentation may aid in early identification, personalized intervention, and resource allocation for individuals at higher risk of developing a severe illness trajectory. Key points: Question: Do patients with anorexia nervosa follow distinct severity trajectories that are associated with specific genetic and morbidity risks? Findings: In this register-based study we identified three severity trajectories of anorexia nervosa. Those who followed the most severe illness trajectory had greater genetic liability to lower body weight and anorexia nervosa and were at greater risk for developing subsequent psychiatric and somatic disorders. Meaning: Illness severity trajectories in anorexia nervosa marked by genetic risk may assist in early identification and intervention for those at greatest risk of severe illness.

Objective: Anorexia nervosa (AN) is a severe psychiatric disorder with high morbidity and increased relative mortality compared to the general population. Involuntary treatment (IT) is implemented after exhausting voluntary treatment options. This study investigates mortality in patients with AN following IT, using IT as an indicator of patient vulnerability. Method: A register‐based cohort study including individuals diagnosed with AN (ICD‐10: F50.0, F50.1) from 2000 to 2016 at any Danish hospital and with an inpatient admission following their AN diagnosis. The exposure was the first instance of any IT event and categories of IT after AN. IT could be associated with AN or any other diagnosis. The outcome was mortality; all‐cause and divided into deaths from diseases and medical conditions, external causes, or suicide. Excess mortality was estimated as hazard ratios (HR) using Cox proportional hazards regression. The model was adjusted for sex, age at AN diagnosis, birth year, prior IT, self‐harm, and other psychiatric morbidities. Results: Over the study period 4425 individuals (93.3% female; mean age at diagnosis = 22, SD = 12) were included in the study. Of these, 821 individuals received IT (18.5%) and 206 individuals (4.7%) died. The HRs were elevated for all‐cause mortality (HR = 2.21, [95% CI: 1.54–3.17]), external causes (HR = 3.88, [95% CI: 1.94–7.77]), and suicide (HR = 5.30, [95% CI: 2.07–13.54]). The analysis of IT categories only showed an elevated HR for electroconvulsive therapy and somatic concerns (HR = 1.96, [95% CI: 1.04–3.67]). Discussion: Despite IT primarily being used to safeguard the life of the most vulnerable patients, mortality for those who received IT was elevated. The results indicate that this patient group requires sustained clinical attention.

Background: Severe anorexia nervosa (AN) represents a subgroup of individuals with AN with prolonged illness duration and poor prognosis. Previous research has reported increased medication use in AN, but prescription patterns in severe AN remain unexplored. Objectives: This study aimed to: (1) compare medication prescriptions between individuals with severe and less-severe AN; (2) explore the heterogeneity of prescription patterns among individuals with severe AN across different comorbidity profiles. Methods: Using Danish registers, this cohort study included 7654 individuals diagnosed with AN. We assigned cases to severe or less-severe groups based on their AN Register-based Severity Index scores. First, we examined trajectories of medication prescriptions and compared patterns between groups using logistic regression models. Second, common comorbidity profiles among individuals with severe AN were identified by latent class analysis for further between-group comparisons. Sensitivity analyses were conducted to test alternative definitions of severe AN. Findings: Compared with individuals with less-severe AN, those with severe AN were more likely to be prescribed various medications, including drugs targeting alimentary tract (OR 1.4, 95% CI 1.3 to 1.6), cardiovascular drugs (OR 1.1, 95% CI 1.0 to 1.3), analgesics (OR 1.2, 95% CI 1.1 to 1.3) and psychotropic drugs (OR 2.4, 95% CI 2.1 to 2.7). Notably, this pattern persisted even among individuals without diagnosed comorbidities. Within the severe group, five clusters with distinct comorbidity profiles emerged, and we consistently observed greater prescription rates than in the comorbidity-free cluster. Sensitivity analyses confirmed that our severity classification reliably distinguished severe from less-severe AN across multiple definitions. Conclusion: These findings indicate that severe AN is associated with substantially higher prevalence of prescribed medications, while specific comorbidity patterns further influence prescribing patterns. This diverse and prolonged pharmacological treatment in severe AN reflects the complexity of clinical management in this population. Clinical implications: Considering the widespread medication prescription in severe AN despite the lack of specific approved pharmacotherapy for the disorder, evidence-based treatment guidelines are urgently needed. Clinicians should recognise the substantial heterogeneity in severity and comorbidity burden within this population and develop comprehensive and specialised treatment strategies that evaluate risks and treatment needs across all individuals with AN, irrespective of comorbid conditions.

Background: Considering the high likelihood of chronicity, it is imperative to understand the risk factors and outcomes associated with severe anorexia nervosa (AN), for which Danish registers provide a unique opportunity. We developed a measure of AN severity adapted from clinical literature for use in register-based research. Methods: The study population included all Danish individuals born between 1963 and 2007 who were diagnosed with AN from 1969 to 2013. Using register data, we constructed the anorexia nervosa register-based severity index (AN-RSI), incorporating early or late illness onset, number of inpatient admissions and outpatient treatments, cumulative treatment length, and illness duration, each weighted based on clinical importance. Associations between AN-RSI scores, evaluated 5 years after first AN diagnosis, and mortality were estimated using survival analysis. Results: Among 9167 individuals diagnosed with AN, 132 died during follow-up: 17 from AN, 30 from suicide, and 85 from other causes. Higher AN-RSI scores were associated with increased rates of mortality from AN, somatic anorexia diagnosis, suicide, alcohol-related causes, and any cause. AN cases who scored in the top 20% of AN-RSI had especially high mortality rates. Furthermore, severe AN cases were also more likely to be in treatment in the next 5 years after severity was established. Conclusions: AN-RSI effectively captures mortality and long-term treatment in the absence of detailed patient records and is associated with later mortality in AN patients. AN-RSI could serve as a tool to examine epidemiological and genetic risk factors associated with AN course and outcomes.

Background Severe anorexia nervosa (AN) represents a subgroup of individuals with AN with prolonged illness duration and poor prognosis. Previous research has reported increased medication use in AN, but prescription patterns in severe AN remain unexplored. Methods Utilizing Danish registers, this cohort study included 7,654 individuals diagnosed with AN. We assigned cases to severe AN or less-severe AN groups based on their AN Register-based Severity Index scores. First, we examined trajectories of medication use and compared prescription patterns between groups using logistic regression models. Second, common comorbidity profiles among individuals with severe AN were identified by latent class analysis for further between-group comparisons. Sensitivity analyses were conducted to test alternative definitions of severe AN. Results Compared to individuals with less-severe AN, those with severe AN were more likely to be prescribed various medications, including drugs targeting the alimentary tract (OR = 1.44), cardiovascular drugs (OR = 1.12), analgesics (OR = 1.18), and psychotropic drugs (OR = 2.89). Notably, the severe AN group was prescribed medications even in the absence of diagnosed comorbidities and with significantly higher frequencies compared to those with less-severe AN. Within the severe group, five clusters with distinct comorbidity profiles emerged, and we observed an increased use of medication compared to the comorbidity-free cluster. Conclusion Our study highlights the higher medication use in individuals with severe AN and the association between medication use and comorbid conditions. These findings underscore the importance of comprehensive and specialized strategies for severe AN.

Objective: Anorexia nervosa (AN) and obsessive‐compulsive disorder (OCD) are highly comorbid; however, limited research has examined etiological pathways specific to individuals with AN developing OCD or individuals with OCD developing AN. This exploratory study aimed to identify factors influencing AN‐OCD comorbidity with a focus on the order of diagnosis.Method: Using Danish national registers, 6449 individuals with AN and 9352 individuals with OCD were examined to assess the risk of subsequent OCD and AN. Explored predictors included parental characteristics, birth characteristics, childhood adversity, autoimmune and autoinflammatory diseases, psychiatric disorders, and prescriptions. Hazard ratios (HR) were calculated using Cox regression. Parallel analyses were conducted for the risk of subsequent anxiety disorder to determine predictors unique to AN‐OCD comorbidity.Results: Among individuals with AN, high birth weight (HR = 3.06) was uniquely associated with increased risk of subsequent OCD. For individuals with OCD, a history of other eating disorders (HR = 7.47) was associated with elevated risk of developing AN, whereas anxiety disorders in first‐degree (HR = 0.32) and female first‐degree relatives (HR = 0.22) were uniquely protective against AN.Discussion: These exploratory findings suggest that distinct pathways may be involved in the order of onset for AN‐OCD comorbidity. Specifically, for individuals with AN who subsequently developed OCD, high birth weight appeared to increase risk, whereas for individuals with OCD who later developed AN, familial anxiety disorders seemed to play a protective role. Findings could inform early screening and prevention efforts for individuals with AN at high risk for OCD, and vice versa.

Background Considering the high likelihood of chronicity, it is imperative to understand the risk factors and outcomes associated with severe anorexia nervosa (AN), for which Danish registers provide a unique opportunity. We developed a measure of AN severity adapted from clinical literature for use in register-based research. Methods The study population included all Danish individuals born between 1963 and 2007 who were diagnosed with AN from 1969 to 2013. Using register data, we constructed the Anorexia Nervosa Register-based Severity Index (AN-RSI), incorporating early or late illness onset, number of inpatient admissions and outpatient treatments, cumulative treatment length, and illness duration, each weighted based on clinical importance. Associations between AN-RSI scores, evaluated five years after first AN diagnosis, and mortality were estimated using survival analysis. Results Among 9,167 individuals diagnosed with AN, 132 died during follow-up: 17 from AN; 30 from suicide; and 85 from other causes. Higher AN-RSI scores were associated with increased rates of mortality from AN, somatic anorexia diagnosis, suicide, alcohol-related causes, and any cause. AN cases who scored in the top 20% of AN-RSI had especially high mortality rates. Furthermore, severe AN cases were also more likely to be in treatment in the next five years after severity was established. Conclusions AN-RSI effectively captures mortality and long-term treatment in the absence of detailed patient records and is associated with later mortality in AN patients. AN-RSI could serve as a tool to examine epidemiological and genetic risk factors associated with AN course and outcomes.

Eating disorders—including anorexia nervosa (AN), bulimia nervosa, and binge eating disorder—are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. We conducted the first genomic meta-analysis of binge-eating behaviour (BE; 39,279 cases, 1,227,436 controls), alongside new analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six loci associated with BE, including loci associated with higher body mass index (BMI) and impulse-control behaviours. AN GWAS yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry cohorts. BE and AN exhibited similar positive genetic correlations with psychiatric disorders, but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with BMI. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

Objective Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. The authors investigated occurrences of ED transitions and presumed remission and their genetic correlates as captured by polygenic scores (PGSs) in a large Danish register-based cohort. Methods The sample compromised of 10,565 individuals with a diagnosis of anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (EDNOS) with at least two registered hospital contacts between 1995 and 2018. Based on medical records, occurrence of diagnostic transitions and periods of presumed remission were identified. Associations between 422 PGS and diagnostic transitions and presumed remission were evaluated using Cox proportional hazard models. Results A minority of ED cases (14.1%-23.1%) experienced a diagnostic transition. Presumed remission ranged between 86.9%-89.8%. Higher (one SD increase) PGS for major depressive disorder and multisite chronic pain were positively associated with transitioning from AN to either BN or EDNOS. Higher PGS on a measure of body fat percentage and financial difficulties were positively associated with presumed remission from AN. Higher PGS for mood swings was positively associated with presumed remission from EDNOS whereas higher PGS for health rating showed the opposite. Conclusions The authors found that most ED patients did not experience diagnostic transitions but were more likely to experience a period of presumed remission. Both diagnostic transitions and presumed remission have significant polygenic component.