Johan Reutfors

Importance: Clozapine is the only evidence-based treatment for treatment-resistant schizophrenia (TRS), yet substantial international variation in its use has been reported. Objective: To provide a comprehensive and updated assessment of international clozapine utilisation by estimating prevalence across countries using a standardised methodology and examining factors associated with variation in use. Design, Setting, and Participants: Repeated cross-sectional study using population-based data from 2015 to 2024. Individual-level data were obtained from 36 countries and 1 special administrative region, supplemented by national clozapine consumption data from 5 additional countries. Analyses were conducted separately for adults (20-64 years; primary analysis), adolescents (10-19 years), and older adults (≥65 years). Main Outcomes and Measures: Annual outpatient clozapine utilisation prevalence per 100,000 population by age group, sex, country and calendar year. Associations between clozapine utilisation prevalence and country-level health system, demographic, and socioeconomic indicators were also examined. Results: We analysed data from more than 1.1 billion people across all inhabited continents. In 2024, crude adult clozapine use prevalence was highest in Croatia (415.3 per 100,000 population) and Finland (302.0 per 100,000), and lowest in Oman (0.5 per 100,000) and Ethiopia (0.3 per 100,000), representing a 1,384-fold difference. Across most countries, utilisation peaked among individuals aged 50 to 59 years. The male-to-female prevalence ratio ranged from 0.4 in the United Arab Emirates to 2.8 in Colombia. Among adolescents, prevalence was highest in Colombia (42.7 per 100,000) and Croatia (24.4 per 100,000), while among older adults it was highest in Croatia (406.9 per 100,000) and Iceland (339.7 per 100,000). Across all countries, adult clozapine utilisation increased by 17% (95% CI, 16%-18%), from 44.7 per 100,000 population (95% CI, 44.5-44.9) to 52.2 per 100,000 population (95% CI, 51.1-52.4). Country-specific trends ranged from a 71% decrease to a 342% increase. None of the examined indicators explained variation in clozapine utilisation across countries. Conclusion and relevance: Clozapine use increased modestly over the past decade but remained highly variable between countries. This variation was not explained by national socioeconomic, healthcare-system, or monitoring-related factors, suggesting an important role for clinical and service-level barriers. The concentration of clozapine use in later adulthood is consistent with delayed initiation and highlights opportunities to improve timely access to evidence-based treatment for TRS. Funding: Hsien-Yuan Lane: National Science and Technology Council, Taiwan (NSTC 114-2629-B-039-001-); The China Medical University Hospital Research Project (DMR-113-009 and DMR-114-046). Philippe Mortier: Miguel Servet grant CP21/00078 co–financed by the Instituto de Salud Carlos III (ISCIII) and co–funded by the European Union; grant PI22/00107 funded by ISCIII and co–funded by the European Union; and grant 202220–30–31 from the Fundació la Marató de TV3. Heidi Taipale: Sigrid Jusélius Foundation grant.

Background: Guidelines across countries demonstrate a lack of consensus regarding continued treatment with antidepressants during pregnancy, but little is known about how prescribing patterns vary in clinical practice.Methods: This cohort study used individual-level healthcare databases from Australia (2014-2019); Denmark (2010-2023); Hong Kong (2010-2022); Norway (2009-2020); South Korea (2016-2023); Sweden (2010-2022); Taiwan (2010-2021); and the UK (2010-2021). Individuals with ≥1 prescriptions or dispensings of antidepressants in each half of the 1-year pre-pregnancy period were included. We assessed antidepressant use in the year before pregnancy, during pregnancy, and in the year after delivery, including continuation rate, temporal trends, and switching patterns.Findings: We identified a total of 194,495 pregnancies from all collaborating sites. European countries, Australia, and Hong Kong exhibited substantially higher continuation rates (≥30%), which increased steadily over time (annual absolute change [%p/year]: Australia: +1.3; Denmark: +1.9; Hong Kong +1.3; Norway: +0.8; Sweden: +3.7; UK: +1.5). Conversely, less than one in ten pregnancies in South Korea and Taiwan continued treatment and the rate remained consistently low throughout the study period (South Korea: 0.0; Taiwan: +0.6). They also had relatively higher proportions of postpartum treatment reinitiators. Lastly, sertraline, a commonly recommended antidepressant for pregnant women, was the most frequently switched-to agent across countries.Interpretation: We observed substantial variation in the continuation rates and annual trends, potentially attributed to differences in national guidelines as well as underlying cultural contexts and healthcare systems. These findings emphasize the need for internationally harmonized clinical guidelines, grounded in robust evidence on the safety of antidepressant use during pregnancy, to promote optimal management of pregnant women with psychiatric conditions while supporting both maternal and fetal health.Funding: MFDS, South Korea (RS-2024-00393167); NRF, South Korea (RS-2026-25474077); SKKU fellowship program, South Korea; Hong Kong Research Grants Council General Research Fund (17114921); NSTC, Taiwan (NSTC 114-2628-B-006-005-).

Background: Data on antipsychotic use for the Swedish paediatric population is limited. Objective: We assessed the incidence, likely indication and extent of off-label antipsychotic use among children and adolescents in Sweden. Methods: In this nationwide register-based study, individuals younger than 18 years with at least one antipsychotic dispensing between 1 January 2008 and 31 December 2021 were identified. Yearly age-standardised and sex-standardised incidence per 1000 persons was estimated and temporal trends were assessed using Poisson log-linear regression. We also assessed the likely indication and the proportion of on-label and off-label use. Findings: Among 4 108 171 individuals who were children or adolescents at some point during the study period, 24 742 initiated antipsychotic treatment at least once, contributing 25 576 incident dispensings during the study period. Incidence increased from 0.48 to 1.28 per 1000 persons (risk ratio, RR per year 1.08, 95% CI 1.05 to 1.11; cumulative increase 180%), with a more pronounced rise in females (0.43 to 1.51 per 1000; RR 1.11, 95% CI 1.10 to 1.12; 284%) than males (0.53 to 1.06 per 1000; RR 1.06, 95% CI 1.05 to 1.07; 113%), driven by adolescents aged 12–17 years. The largest drug-specific increases were observed for quetiapine (0.04 to 0.33 per 1000; RR per year 1.18, 95% CI 1.17 to 1.19; cumulative increase 804%) and aripiprazole (0.03 to 0.36 per 1000; RR per year 1.16, 95% CI 1.14 to 1.18; cumulative increase 608%). A likely indication was identified in 64.3% (n=16 455) of incident dispensings, most commonly autism spectrum disorder (15.4%), attention-deficit hyperactivity disorder (10.9%) and anxiety disorders (9.6%). Among those with an identifiable indication, 81% were dispensed off label, mainly due to non-approved indications (64.8%) and most frequently among adolescent females. Conclusions: In the paediatric population in Sweden, incidence of antipsychotic use increased between 2008 and 2021, especially among adolescent females and most incident dispensing with an identifiable indication were off label, underscoring the need to evaluate the long-term effectiveness and safety of antipsychotics in children and adolescents. Clinical implications: These patterns highlight the need to evaluate the long-term effectiveness and safety of antipsychotics in children and adolescents.

Objectives: Lithium is a first-line treatment option for preventing relapse in bipolar disorder but may be discontinued periconceptionally due to safety concerns. We aimed to examine the prevalence of lithium discontinuation among pregnant women with bipolar disorder in Sweden, using a novel method to identify daily dose, and to describe the characteristics of the discontinuers and continuers. Design: Cohort study. Setting: Swedish population-based registers (2006–2019). Participants: Women with bipolar disorder and an ongoing lithium treatment episode 6 months prior to pregnancy were identified. Natural language processing (NLP) of the prescription free-text information was used to define the daily dose, and to construct treatment episodes. Interventions: Not applicable. Main outcome measures: Lithium discontinuation was defined as the end of a continuous treatment episode between 6 months before the start of pregnancy and delivery. The performance of the NLP method was compared with manual review of the prescription texts. The characteristics of the discontinuers and the continuers were described, including psychiatric comorbidities and other medications used. Findings: In 662 pregnancies, 438 women (70%) discontinued lithium treatment, the majority in prepregnancy or first trimester. The NLP method showed high internal validity compared with manual review of prescription texts; however, the estimated date of discontinuation could not be validated against measures of actual drug use. Discontinuers, compared with continuers, had a higher prevalence of comorbid substance use disorder (7.8% vs 2.7%), personality disorder (11.4% vs 6.0%) and attention-deficit/hyperactivity disorder (13.5% vs 7.6%). After discontinuation, there was no increased use of other mood stabilisers, and 46% had a new dispensation of lithium within 6–12 months. Conclusions: The majority of lithium-treated women with bipolar disorder discontinued treatment around the start of pregnancy; however, lithium discontinuation is also common outside pregnancy, and the reason for discontinuation in our cohort remains unknown. Discontinuers had a higher rate of psychiatric comorbidity, and switches to other mood stabilising treatments did not appear to be common. Given that both the peripartum period and withdrawal of mood stabilising treatment may contribute to increased risk of relapse, the consequences of lithium discontinuation for maternal psychiatric health should be studied further.

During the first year following electroconvulsive therapy (ECT) for major depressive disorder (MDD) there is a large risk of relapse. Previous studies have shown favourable results for lithium after ECT for MDD. However, lithium is infrequently prescribed after ECT. While some evidence exists for other pharmacological strategies such as TCAs and TCA-lithium combinations, comparative data remain limited. The aim of this study was to explore pharmacological treatments after ECT for MDD and analyse their association with relapse following response to ECT for MDD. We hypothesized that lithium would be associated with a lower risk of relapse. We conducted a nationwide cohort study using data from Swedish registers. Patients 18 years or older with MDD who received ECT 2013-2019 and responded distinctly to ECT were followed for a year. Specified drugs dispensed up to four weeks after the ECT series were considered the exposure. Relapse was defined as psychiatric hospitalisation, renewed ECT, intentional self-harm, or death by suicide. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated using Cox models controlled for several potential confounders. The study population included 2 858 patients with distinct response to ECT. The most common psychiatric drugs dispensed after ECT were antipsychotics (39.7%), mirtazapine (38.0%), and selective serotonin reuptake inhibitors (SSRI) (35.9%). There was a statistically non-significant lower risk of relapse associated with lithium (aHR 0.86, 95% CI 0.69-1.07, p = 0.17). Antipsychotics were associated with a greater risk of relapse (aHR 1.17, 95% CI 1.05-1.31, p = 0.006). For other pharmacological treatments there were no associations with risk of relapse.

Background: Pain is common during pregnancy, yet there are few contemporary studies of opioid use in pregnancy. This study aimed to describe prescription analgesic opioid use during pregnancy across four regions: Oceania (New South Wales, Australia, and New Zealand), North America (Ontario, Canada, and United States), Northern Europe (Denmark, Finland, Iceland, Norway, Sweden, and United Kingdom), and East Asia (Hong Kong, South Korea, and Taiwan). Methods: A common protocol was applied to population-based data to measure analgesic opioid dispensing or prescriptions during pregnancy before birth in 2000 to 2020. The populations captured included those with public and private insurance in the United States, a sample of primary care practices in the United Kingdom, and whole-of-population cohorts in the remainder of the locations. This study examined prevalence of use, defined as at least one dispensing or prescribing and estimated trends over time. Use by sociodemographic and pregnancy characteristics is described. Results: Among a total of 20,306,228 pregnancies, 1,115,853 (55 per 1,000) had at least one analgesic opioid dispensing or prescription, ranging from 4 per 1,000 in the United Kingdom to 191 per 1,000 in the U.S. publicly insured population. The greatest relative decrease in prevalence was observed in Hong Kong (prevalence ratio, 0.2; 95% CI, 0.1 to 0.2 between 2005 and 2020), and the greatest increase was in Iceland (prevalence ratio, 4.4; 95% CI, 3.7 to 5.2 between 2004 and 2017). Codeine and tramadol were among the three most prevalent opioids in most populations. In a sensitivity analysis defining opioid use as two or more opioid -dispensing or -prescribing events, the prevalence of opioid use across populations was 17 per 1,000. Conclusions: In this large multinational study, wide global variation in the prevalence of analgesic opioid use in pregnancy was observed, yet patterns of use by sociodemographic and pregnancy characteristics were relatively consistent. Analgesic opioid use remained stable or downward trending over time in most, but not all, countries.

The aim of this study was to examine variations in use of antidepressants among children and adolescents in the three Scandinavian countries (Sweden, Norway, and Denmark). We identified new users of antidepressants (5–17 years) during 2007–2018 and described the annual incidence rate, treatment duration, concomitant psychotropic drug use, and the clinical setting of the prescribing physician (in Sweden and Denmark). Incident use of antidepressants increased by a factor 1.9 in Sweden, 1.3 in Norway and decreased by a factor 0.6 in Denmark during the study period. In Sweden, 58% of antidepressant users were covered by a prescription 12 months after initiation compared to 40% in Norway and 49% in Denmark. Also, 34% of Swedish antidepressant users were in continuous treatment after 12 months compared to 26% in Norway and 31% in Denmark. Concomitant use of other psychotropics was more common in Sweden (57%) than in Norway (37%) and Denmark (27%). During 2007–2018, clinicians from psychiatry settings initiated 75% of antidepressant treatments in Sweden, while this was the case for 50% of prescriptions in Denmark, although the proportion increased over time. The number of new antidepressant users is high and still rising in Sweden compared to Norway and Denmark. Swedish antidepressant users are more likely to use other psychotropics and to be covered by an antidepressant prescription after one year. Most antidepressants in Sweden are prescribed by physicians within psychiatric settings suggesting that they are based on specialized psychiatric evaluation.