Merete Osler

The prevalence of ADHD is increasing rapidly, and lisdexamfetamine is increasingly popular, but few studies investigate its safety. We performed a sequence symmetry analysis (SSA) using Danish register data to identify potential ADRs associated with lisdexamfetamine in 2013–2023. Outcomes were incident prescriptions or incident discharge diagnoses. We calculated trend‐adjusted sequence ratios (SR) with 95% confidence intervals (CI). We additionally performed two comparator SSAs for the same outcomes following incident use of stimulants (methylphenidate and dexamfetamine) or non‐stimulants (guanfacine and atomoxetine). This study is reported according to RECORD‐PE guidelines. We included 48 740 incident lisdexamfetamine users with a median age of 24 years (IQR 16–35). SRs were calculated for 1426 exposure–diagnosis and 1337 exposure–prescription pairs. The 50 highest SRs from each category were evaluated. Among these, 28 exposure–outcome combinations had a 95% CI lower bound above 1. Of the 100 outcomes, 33 were considered known ADRs, while 60 were previously unknown. Two outcomes indicating increased urinary symptoms were identified (‘hematuria’, SR: 1.88 [95% CI: 1.25; 2.85] and ‘other urinary symptoms’, SR: 1.63 [1.20; 2.23]). We also identified serious gastrointestinal outcomes as a potential safety alert. Further investigation into these symptoms as potential ADRs is warranted.

Aims: We examined whether the association between depression and return to work (RTW) varied by municipality characteristics. Methods: In this nationwide register-based cohort study (2012–2018), adults aged 25–55 years with a first-time in- or outpatient contact for depression were matched 1:3 by birth year and sex to the general population. For comparison, parallel cohorts were established for first-time antidepressant users and individuals with cancer. Labour market affiliation was tracked from 1 year before to 3 years after diagnosis. Municipalities were characterized by urbanicity, unemployment level, and tax revenue. Among individuals outside the workforce, Cox proportional hazard regression estimated hazard ratios (HR) for RTW (early and late), comparing depression and reference groups, with interaction by municipality characteristics. Difference-in-difference analyses assessed absolute changes in the proportion in work, with parallel analyses for antidepressant use and cancer. Results: In the main analyses, HRs of RTW varied by urbanicity. The smallest difference (depression vs. reference group) was observed in capital municipalities (early HR 0.54, 95% confidence interval (CI) (0.51, 0.57)), late HR 0.72 (0.68, 0.75)) while larger differences were seen in upland (early HR 0.38 (0.35, 0.42)) or rural municipalities (late HR 0.59, 95% CI (0.55, 0.63)). Absolute workforce loss ranged from −9.6% (95% CI ( −10.7%, −8.4%)) in capital to −13.6% (−15.3%, −11.9%) in big city municipalities. A similar variation by urbanicity, though of smaller magnitude, was observed for antidepressant use but not for cancer. Conclusions: The association between depression and RTW varied by municipality urbanicity, whereas no clear differences were observed for cancer.

Purpose: We aimed to study how the timing of incident maternal emotional disorders is associated with male offspring’s cognitive ability in early adulthood using cognitive test data from military conscription in a population-based cohort. Methods: We linked all males (conscripts) born in Denmark 1996–2001 to parental hospital records to identify anxiety or depression (emotional disorders). Linear regression assessed the association between the timing of the first maternal diagnosis (before, during, or after birth (0–1, 1–5, 6–17 years)) and cognitive ability measured at the Danish Conscription Board Examination 2014–2019. Paternal emotional disorders served as negative controls to differentiate maternal pregnancy exposures from genetic and postnatal influences. Results: The study included 119,387 males, with 9,959 (8.3%) having mothers diagnosed with emotional disorders. Exposed offspring had lower cognitive test scores (ranging from − 0.22 to -0.10 standard deviations (SD) lower than unexposed) at mean age 18, particularly if the mother was diagnosed during pregnancy (-0.22 SD, 95% CI: -0.36; -0.08). There was no difference when comparing incident diagnosis before/after vs. during pregnancy. Paternal emotional disorders were also linked to a lower cognitive test score, with more consistent associations across all time points (-0.18 to -0.14 SD lower than unexposed). Conclusion: Maternal emotional disorders were overall associated with male offspring’s long-term cognitive ability. Paternal disorders showed similar associations. While the findings require cautious interpretation, the findings suggest a weak signal of a window of sensitivity for maternal disorders during gestation, with no equivalent signal for paternal disorders. We encourage similar studies with female offspring. Trial Registration: The project was registered in OSF in July 2024 ( https://doi.org/10.17605/OSF.IO/SV7W4 ).

Background: Antipsychotic medications are recommended for schizophrenia spectrum disorders, yet their long-term effects on functional recovery remain unclear, with conflicting evidence often derived from between-subject comparisons vulnerable to confounding by indication. Methods: We conducted a nationwide register-based cohort study of 65,630 individuals with incident schizophrenia spectrum disorders in Denmark (1998–2023). We modeled antipsychotic exposure against ‘productive engagement’ (employment or education). We used two analytical approaches: (1) within-subject stratified Cox models with time-varying covariates to eliminate time-invariant confounding; and (2) Fine–Gray competing risks models with baseline exposure, accounting for mortality and emigration. Results: Over 26.9 million person-weeks, the overall productive engagement rate was 48.2%. Integration of hospital pharmacy data revealed 6.1% exposure misclassification in studies relying solely on community records. The primary within-subject analysis revealed significant temporal heterogeneity: medication use was associated with reduced engagement rates in the acute (0–2 years; HR = 0.908) and consolidation phases (2–5 years; HR = 0.946), but reversed to a small positive association in the maintenance phase (5+ years; HR = 1.019). The between-subject Fine–Gray model, which estimates cumulative engagement probabilities, yielded an SHR of 1.002 (95% CI = 0.988–1.015), a population-level average that obscured these phase-specific dynamics. Conclusions: Antipsychotic pharmacotherapy exerts a time-dependent, biphasic impact on vocational recovery. We identified a window of vulnerability during the post-acute ‘consolidation’ phase (years 2–5) where treatment is associated with a transient reduction in productive engagement, before becoming protective after 5 years. These findings challenge the assumption that symptomatic stability automatically facilitates functional reintegration.

The purpose of the study is to examine the association between parental mental disorders diagnosed before age six and cognitive ability at age 18, using data from a population-based cohort of male adolescents attending military conscription. Further, we tested whether other childhood adversities modified this association. All males born in Denmark 1996–2001 were linked to national registers. Parental mental disorders were identified from psychiatric hospital diagnoses. We assessed other childhood adversities before age six, including family health-related, socioeconomic, and family instability, as well as the number of adversities experienced. Cognitive scores from the mandatory military conscription were standardized (mean 100, SD = 15). Associations were estimated using multiple linear regression, and effect modification was evaluated using Wald tests. We included 125,791 males (mean age 18 years, SD = 0.66), of whom 6708 had a parent with a mental disorder. Parental mental disorders were associated with a 0.91-point reduced cognitive ability score (95% confidence interval − 1.3, − 0.53). This association was not observed in adolescents who lived with only one parent (− 0.35 (− 0.85, 0.15)), those placed in out-of-home care (3.2 (0.59, 5.8)), and those with ≥ 3 additional adversities before age six. Effect modification tests were statistically significant for these groups ( p < 0.01). Conclusion : Parental mental disorders before age six were associated with a modest reduction in cognitive ability in males at age 18, compared with those without parental mental disorders. Our findings show the association varies across family contexts, although unmeasured genetic and environmental confounding should be considered in interpreting these results. What is Known: • Parental mental disorders are common and linked to lower cognitive ability in offspring .• Childhood adversities often cluster within families and are associated with poorer cognitive outcomes . What is New: • In this nationwide Danish cohort, parental mental disorders before age six were associated with slightly lower cognitive ability at age 18 .• This association was not observed among adolescents with > 2 additional adversities, those who lived with only one parent, or those placed in out-of-home care before age six, suggesting the association varies across family context .

Background: Schizophrenia is associated with widespread cognitive impairments. Several early risk factors for schizophrenia have been identified, and some studies suggest associations between these early risk factors and cognition, yet the literature is sparse in psychosis. Methods: Clinical cohorts of child/adolescent and adult patients with first-episode psychosis (FEP) and healthy controls (HC) were linked with register-based information (N=276). Gestational age, Apgar scores, birth weight and length, parental age, and season of birth were extracted from the Danish medical birth registry. Cognition was assessed at time of diagnosis using BACS, CANTAB, and WAIS-III/WISC-IV. Missing data was imputed using MICE. Canonical correlation analysis (CCA) was used to examine patterns of associations. Post hoc analyses explored group differences according to diagnosis, age, and sex. Results: CCA resulted in two significant patterns of associations. CCA1 was stable across imputations (r=0.44, p =.036, p _min = .017, p _max = .055), and constituted by a risk profile of lower maternal age, lower birth length, being small for gestational age, and lower birth weight and a cognitive profile of lower estimated IQ and poorer working memory, mental flexibility, processing speed, verbal fluency, and motor latency. The pattern was more expressed in FEP compared to HC and in adults compared to children. CCA2 was more unstable across imputations (r=0.38, p =.033, p _min =.003, p _max =.168) and constituted by a broad pattern of minor loadings. Conclusion: Cognitive functioning later in life is associated with multiple early risk factors, underscoring the complexity of developmental processes and the importance of the early developmental context in shaping cognitive trajectories.

The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have raised concerns about a potential link between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicide or suicide attempts. We conducted two new-user, active comparator cohort studies. The GLP1-RAs vs sodium-glucose cotransporter-2 (SGLT-2) inhibitors cohort included new users of GLP-1 RAs ( n = 83,464 ) or SGLT-2 inhibitors ( n = 78,366 ), and the GLP1-RAs vs dipeptidyl peptidase-4 (DPP-4) inhibitors cohort included new users of GLP-1 RAs ( n = 108,322 ) or DPP-4 inhibitors ( n = 55,411 ). We also employed a self-controlled case series design to compare suicide, or suicide attempts before and after GLP-1 RA treatment initiation across three time periods. In the cohort analyses patients who initiated GLP-1 RAs did not differ in the hazard ratio (HR) for suicide or suicide attempts from SGLT-2 inhibitor users (HR: 0.93; 95% CI: 0.57–1.52), and GLP-1 RA users had a lower risk of suicide or suicide attempts compared with DPP-4 inhibitor users (HR: 0.58; 95% CI: 0.37–0.91). In the self-controlled case series design, use of GLP-1 RAs was associated with a lower incidence rate ratio (IRR) of suicide or suicide attempts one year after treatment initiation (IRR: 0.45; 95% CI: 0.10–0.50) and 13–24 months after treatment initiation compared with pretreatment. This study showed that use of GLP-1 RAs was not associated with increased incidence of suicide or suicide attempts in either the active comparator new-user design or in the self-controlled case series design.

Background: In individuals with depression, lower socioeconomic position is associated with poorer prognostic outcomes, which may be attributed to inequitable care. We investigated educational differences in treatment of individuals diagnosed with depression at a psychiatric hospital. Methods: This nationwide register‐based cohort study included 156,922 Danish citizens with a first‐time psychiatric hospital diagnosis of depression (ICD‐10: F32–F33) between 2000 and 2022. Highest attained educational level was categorized as short, medium, or long. Treatment data included antidepressant prescriptions, electroconvulsive therapy (ECT), and contacts with private practicing psychiatrists or psychologists. Logistic regression and Cox proportional hazard regression models with adjustments for covariates were used to estimate associations between educational level and treatment before and after diagnosis. Results: Within 2 years before diagnosis, 72.0% of individuals had redeemed at least one antidepressant prescription, and 83.8% had initiated or continued pharmacological treatment within 2 years after diagnosis. Education was not associated with redeemed prescriptions of antidepressants regardless of type before diagnosis, whereas long education was associated with higher rates of treatment with any type of antidepressants after diagnosis. For specific antidepressants, individuals with long education were less likely to redeem prescriptions for noradrenergic and specific serotonergic antidepressants (NaSSAs) and more likely to redeem monoamine oxidase inhibitors (MAOIs) and newer antidepressants such as vortioxetine. Longer educated also more often consulted private practicing mental health specialists both before and after diagnosis, respectively. After diagnosis, individuals with long education were also more likely to receive ECT. Conclusion: Educational differences in pharmacological treatment and private specialist visits among individuals with depression are present both before and after their first hospital contact. Individuals with long education seem more likely to receive specialized and high‐value care (ECT, MAOIs, newer antidepressants, and consultations with private psychiatrists and psychologists) compared to individuals with short or medium education.

Background: Antipsychotic medications are recommended for schizophrenia spectrum disorders, yet their long-term effects on functional recovery remain unclear, with conflicting evidence often derived from between-subject comparisons vulnerable to confounding by indication. Methods: We conducted a nationwide register-based cohort study of 65,630 individuals with incident schizophrenia spectrum disorders in Denmark (1998–2023). We modeled antipsychotic exposure against ‘productive engagement’ (employment or education). We used two analytical approaches: (1) within-subject stratified Cox models with time-varying covariates to eliminate time-invariant confounding; and (2) Fine–Gray competing risks models with baseline exposure, accounting for mortality and emigration. Results: Over 26.9 million person-weeks, the overall productive engagement rate was 48.2%. Integration of hospital pharmacy data revealed 6.1% exposure misclassification in studies relying solely on community records. The primary within-subject analysis revealed significant temporal heterogeneity: medication use was associated with reduced engagement rates in the acute (0–2 years; HR = 0.908) and consolidation phases (2–5 years; HR = 0.946), but reversed to a small positive association in the maintenance phase (5+ years; HR = 1.019). The between-subject Fine–Gray model, which estimates cumulative engagement probabilities, yielded an SHR of (95% CI = 0.988–1.015), a population-level average that obscured these phase-specific dynamics. Conclusions: Antipsychotic pharmacotherapy exerts a time-dependent, biphasic impact on vocational recovery. We identified a window of vulnerability during the post-acute ‘consolidation’ phase (years 2–5) where treatment is associated with a transient reduction in productive engagement, before becoming protective after 5 years. These findings challenge the assumption that symptomatic stability automatically facilitates functional reintegration. Danish Lay Summary: I denne undersøgelse har vi set på, hvordan personer kommer tilbage i arbejde eller uddannelse, efter de er startet i medicinsk behandling for skizofreni. Formålet er at forstå, om antipsykotisk medicin øger eller mindsker deres mulighed for at vende tilbage til arbejde eller uddannelse. Resultaterne peger på et udviklingsforløb, som kan forklares i tre faser: De første 2 år har en person i medicinsk behandling 9 % lavere sandsynlighed for at være i arbejde eller uddannelse, sammenlignet med perioder hvor personen er uden behandling. Efter 2–5 år bliver forskellen mindre (omkring 5 %). Medicinen forsinker stadig tilbagevenden til arbejdsmarkedet eller uddannelse, men i mindre grad end før. Efter 5–10 år vender billedet. Her ses en tendens til, at flere som får medicinsk behandling er i arbejde eller uddannelse. Effekten er lille, men den går i en positiv retning. På kort sigt kan antipsykotisk medicin begrænse muligheden for arbejde eller uddannelse. På længere sigt kan medicinen give den stabilitet, der gør det lettere at fastholde eller vende tilbage til arbejde eller uddannelse.