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.

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. Cohort study. Swedish population-based registers (2006–2019). 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. Not applicable. 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. 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. 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.

Hypnotics are frequently used in depressed patients, but factors determining long-term use remain uncertain. Using national health registers, we included patients aged ≥18 years in Sweden 2007-2018 who filled a prescription for any drug indicated for sleep within three months after a diagnosis of depression in psychiatric specialist care. We excluded patients with dementia, bipolar or psychotic disorders, and those who had been Swedish residents for <12 months. Patients were followed for one year. Long-term use was defined as >180 defined daily doses of hypnotics across ≥3 prescription fills, including ≥1 fill in the second half of the year. Logistic regression was used to calculate unadjusted and adjusted odds ratios (ORs, aORs) with 95% confidence intervals (CI) to identify factors associated with long-term hypnotic use. We included 78,383 patients (mean age 39.4 years, 58.4% women). The most commonly initiated drug was a benzodiazepine-like hypnotic (Z-drug; n = 40,008; 51.0%), followed by the phenothiazine propiomazine (n = 30,940; 39.5%), melatonin (n = 6415; 8.2%), and benzodiazepine hypnotics (n = 1020; 1.3%). Overall, 23,476 of 78,383 patients (30.0%) met the criteria for long-term hypnotic use. In the adjusted model, older age was strongly associated with long-term hypnotic use (≥70 vs. 18-29 years: aOR 2.27, 95%CI 2.08-2.47), as was higher number of antidepressants in the past year (≥3 vs. 0: aOR 3.23, 95%CI 2.97-3.53). In this large cohort of patients with unipolar depression initiating hypnotic treatment, long-term use was more likely in older patients and those with multiple prior antidepressant trials, highlighting the need for careful clinical attention in these groups.

BACKGROUND:Sexual dysfunction (SD) is a consequence of major depressive disorder (MDD) and a common adverse effect of antidepressants. However, population-level evidence on SD in MDD remains limited. OBJECTIVE:To examine the incidence, prevalence, and predictors of SD among individuals with MDD. METHODS:We conducted a nationwide Swedish cohort study (2006-2014) of 169,430 adults (18-65 years) with incident MDD. SD was identified via diagnoses and prescriptions for erectile dysfunction medications (predominantly PDE5 inhibitors). We estimated 3-year incidence and prevalence pre- and post-diagnosis. A nested case-control analysis among men assessed associations between SD, antidepressants, and clinical factors using conditional logistic regression. RESULTS:Among 67,783 men and 101,647 women, SD incidence peaked within one year post-MDD diagnosis. Three-year prevalence increased from 6.1% pre-diagnosis to 8.5% post-diagnosis in men, and from 0.11% to 0.18% in women. In case-control analyses, SSRIs (aOR 1.36, 95% CI 1.15-1.61), SNRIs (aOR 1.75, 95% CI 1.40-2.18), and multiple antidepressants (aOR 1.68, 95% CI 1.39-2.02) were associated with increased SD risk within one year post-diagnosis. Mirtazapine showed no significant association. Bupropion was associated with increased odds for SD (aOR 2.01, 95% CI 1.16-3.48). CONCLUSION:SD is infrequently recorded in psychiatric care, particularly among women, which likely reflects differential ascertainment. Associations with SSRIs and SNRIs suggest pharmacological contributions, whereas the association for bupropion likely reflects confounding by indication, given its preferential prescribing for pre-existing anhedonia or SD.

BACKGROUND:Adverse birth outcomes are important public health measures and account for a substantial public health burden. There is considerable diversity of these health endpoints, as well as in the many factors suspected or recognized to increase their risk. This diversity renders it challenging to synthesize the totality of the evidence by carrying out a systematic review. METHODS:We undertook an expert elicitation to characterize the state of the literature on this topic, the interconnections amongst risk factors, and identify those that are a priority for future research. A panel of 30 scientists and physicians with expertise in birth outcome epidemiology were solicited to identify a series of health outcomes, and associated risk factors. RESULTS:This resulted in a listing of 15 birth outcomes, and 247 possible risk factors in total, with varying numbers of risk factors for each health outcome. Each panel member was asked to score the weight of evidence (WOE) of each risk factor and birth outcome combination (n = 1127) on a scale of 1 (no evidence) to 5 (strong evidence) for which the expert had a working knowledge of the literature. Not all experts scored each/every outcome/risk factor combination, reflecting the different types of expertise on the panel. The compilation of these WOE scores was used to create a publicly available database for birth outcomes risk factors (https://scipinion-rfbo.onrender.com) that is intended to be updated over time so as to serve as an up to date resource for the research and medical community. CONCLUSIONS:This expert approach serves as a unique and valuable approach to data reduction that can help to inform research priorities, while providing an open access resource to identify risk factors that may act as confounders and/or modifiers in future epidemiology studies and clinical trials.

BACKGROUND:An increasing number of women of childbearing age are treated for attention-deficit hyperactivity disorder (ADHD). Limited evidence exists on risk of pregnancy loss associated with ADHD medication use in early pregnancy. AIMS:To assess whether ADHD medication use during pregnancy is associated with increased risk of miscarriage. METHOD:We conducted a nationwide, register-based, case-control study, using linked Norwegian data from Medical Birth Registry of Norway, Norwegian Patient Registry, Norwegian Control and Payment of Health Reimbursements Database and Norwegian Prescription Database. Among pregnant women with ADHD, those with miscarriage (n = 2993 cases) were matched with up to four live births (n = 10 305 controls) by maternal age and year of conception. ADHD medication exposure during pregnancy was defined as any use (one or more filled prescriptions) and categorised into tertiles of total defined daily doses (DDDs) as a proxy for dose. The main outcome was miscarriage (pregnancy loss before 20 weeks). Conditional logistic regression was used to estimate adjusted odds ratios (aORs) with 95% confidence intervals, adjusting for psychiatric comorbidities, psychotropic and teratogenic medications, and maternal age at conception. RESULTS:Of 13 298 pregnancies, 1389 (10.5%) were exposed to ADHD medications. Any ADHD medication use was associated with increased miscarriage risk (aOR 1.60, 95% CI 1.41-1.83). Methylphenidate (aOR 1.55, 95% CI 1.35-1.79), lisdexamfetamine (aOR 1.81, 95% CI 1.06-3.10) and atomoxetine (aOR 2.34, 95% CI 1.41-3.89) were associated with increased risks. Higher levels of medication exposure, categorised by DDD tertiles, were associated with increased odds of miscarriage, increasing from 1.14 (95% CI 0.91-1.42) for the lowest tertile to 2.11 (95% CI 1.71-2.60) for the highest. CONCLUSIONS:ADHD medication use during pregnancy is associated with increased miscarriage risk. However, filled prescriptions may not reflect actual use. Further research is needed to clarify these associations and refine risk estimates.

BACKGROUND:Suicide attempts (SA) are common in depression, yet little is known about healthcare utilization (HCU) and psychiatric drug utilization (PDU) following a SA. This study assesses and compares HCU and PDU patterns in patients with depression with and without a SA. METHODS:We retrieved data from population-based registers on 359,276 patients with incident depression. Patients with a first-time SA (n = 16,748), were matched with comparators (n = 330,764). Patients with a history of SA (n = 11,764) were analyzed separately. Inpatient days, outpatient visits, and the amount of psychiatric medications were measured until five years after the SA. RESULTS:Patients with a first-time SA had four times higher psychiatric inpatient HCU (ratio 3.8 [95 % CI 3.6-4.0]) and twice higher outpatient HCU (ratio 1.7 [95 % CI 1.7-1.8]) than comparators in the year following the SA. PDU was higher for most drug classes in the SA patients, with the largest difference observed for anxiolytics and sedatives (ratio 1.9 [95 % CI 1.8-1.9]). Higher HCU and PDU in SA patients persisted throughout the five-year follow-up period. LIMITATIONS:Our data did not include depressed patients from primary care, indicating that the findings may be more generalizable to patients with moderate or severe depression. CONCLUSIONS:Patients with depression who attempted suicide had higher HCU and PDU than comparators during the five-year follow-up period. The association between SA and increased HCU and PDU underscores the ongoing suffering of these individuals as well as the substantial burden placed on the healthcare system.

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.

Glioma patients often suffer from psychiatric and neurological conditions. However, little is known about the patterns of use of psychotropic drugs pre- and post-glioma diagnosis. Therefore, we assessed temporal patterns of psychotropic prescriptions among glioma patients, compared to an age and sex matched comparison cohort in four European countries. Incident gliomas were identified in Wales from the Secured Anonymized Information Linkage Databank (2005–2016) and population-based registries in Denmark (2001–2016), Norway (2006–2019), and Sweden (2008–2018). From each data source, a cancer-free comparison cohort was matched to the glioma cases by age and sex. We calculated rates of new psychotropic prescriptions and any psychotropic prescriptions during the 2 years prior to and post glioma diagnosis. Analyses were stratified by histological subtypes and subclasses of psychotropic medications. We identified 16,007 glioma patients. The rate of new psychotropic drug use increased from 7 months before diagnosis, peaking around the month of glioma diagnosis (with peak rates ranging from 227 to 753 new psychotropic drugs per 1000 person-months). New use remained substantially higher among glioma patients than comparators throughout the 2-year follow-up period after glioma diagnosis, though rates of new use continued to decline throughout. New use was largely driven by antiepileptics, anxiolytics, hypnotics, and sedatives. Patterns were similar when analyses were stratified by histological subtype. Psychotropic drug use among glioma patients was high, and elevations observed around the time of cancer diagnosis, largely driven by antiepileptics, anxiolytics, hypnotics, and sedatives, are likely associated with the consequences of the disease.

BACKGROUND:Medication use during pregnancy for attention-deficit/hyperactivity disorder (ADHD) is increasing, but evidence on its safety in pregnancy for foetal health is limited, with little attention to time-related biases in observational research. OBJECTIVE:To determine the association between ADHD medication use in early and late pregnancy and the risk of preterm birth. METHODS:This population-based cohort study utilised data from national registers, including records on births, prescription medications, specialist healthcare visits, hospitalisations and educational attainment, to account for relevant potential confounders. We included singleton births delivered between 22 and 44 gestational weeks among pregnant individuals with ADHD medication use in the year before conception from Norway (2009-2020) and Sweden (2007-2019). ADHD medications (amphetamine, dexamphetamine, methylphenidate, atomoxetine, lisdexamfetamine and guanfacine) were assessed during early (conception to 21 gestational weeks) and late pregnancy (22-36 gestational weeks). The main outcome was preterm birth, defined as a live birth before 37 completed weeks of pregnancy. Risk ratios (RR) and hazard ratios (HR) with 95% confidence intervals (CI) were estimated using log-binomial regression and flexible parametric survival modelling to determine the risk of preterm birth in early and late pregnancy, respectively. RESULTS:Among 11,075 pregnancies, early pregnancy ADHD medication use was associated with higher preterm birth risk with ≥ 2 filled prescriptions (aRR 1.29, 95% CI 1.08, 1.53), but not as ≥ 1 prescription (aRR 1.08, 95% CI 0.93, 1.25). Any medication use in late pregnancy increased preterm birth risk (aHR 1.15, 95% CI 0.95, 1.39). For every 30 days of cumulative exposure to ADHD medication, the risk of preterm birth increased in late pregnancy (aHR 1.07, 95% CI 1.02, 1.12), but not in early pregnancy (aHR 1.01, 95% CI 0.97, 1.05). CONCLUSIONS:ADHD medication may modestly increase the risk of preterm birth, especially with atomoxetine early and methylphenidate late in pregnancy, and with longer durations of use.

PURPOSE:To investigate the risk for adverse outcomes among offspring of parents with depression and with treatment-resistant depression (TRD), compared with matched offspring in the general population. METHODS:Parents diagnosed with depression in specialized psychiatric care in 2006-2018 were identified in nation-wide Swedish registers. Those starting a third sequential antidepressant trial were defined as treatment-resistant. Parents and their 2,359 first-born offspring, aged 6-15 years when parents were defined with TRD, were closely matched 1:1 with parent-offspring pairs with other parental depression as well as with parent-offspring pairs from the general population. Offspring cohorts were followed prospectively for psychiatric outcomes and school- and work-related disability. RESULTS:Offspring of parents with both TRD and other depression had substantially elevated risks for all outcomes compared to general population offspring. Adjusted hazard ratios for offspring of parents with TRD were: depression 4.6 (95%CI 3.2-6.5); contact with psychiatry 3.3 (2.8-4.0); psychiatric medication 3.6 (3.0-4.2); suicide attempt 3.2 (1.9-5.5); sick leave for mental health reasons 2.3 (1.1-4.6); and disability pension 4.2 (2.2-8.1). The adjusted odds ratio for non-completion of secondary school when expected was 2.1 (1.5-2.9). In direct comparisons between offspring of parents with TRD vs. other depression, relative risks for all outcomes were similar, with no statistically significant differences. CONCLUSION:Offspring of parents with TRD and other depression are at similarly elevated risks of adverse clinical, educational, and work-related outcomes. Parental TRD, as defined in administrative health care data, may not serve as a risk indicator for long-term offspring burden in parental depression.

Importance:Nicotine replacement therapy (NRT), varenicline, and bupropion are effective smoking cessation pharmacotherapies, but evidence on fetal safety is limited. Objective:To assess whether prenatal use of smoking cessation pharmacotherapies was associated with increased risks of major congenital malformations (MCMs). Design, Setting, and Participants:This retrospective cohort study was conducted across 4 countries, and results were pooled via meta-analyses. Records of all births (2001-2020) in New South Wales (NSW; Australia), New Zealand (NZ), Norway, and Sweden were linked to prescribed medicine dispensings, hospital admission, outpatient, and death data. Follow-up ended December 31, 2021, and the data were analyzed between August and October 2023. The base cohort comprised 391 474 infants among 267 522 women who smoked during the first trimester or were dispensed a smoking cessation pharmacotherapy 90 days before conception or during the first trimester. Exposures:Supply of NRT, varenicline, and bupropion overlapping the first trimester. Unexposed infants were born to women who smoked but were not dispensed a pharmacotherapy 90 days preconception and the first trimester. Propensity score matching (1:10) was used. Main Outcomes and Measures:MCM overall and subgroups. Results:The mean (SD) maternal age at childbirth was 27.2 (6.0) years. Analyses included 9325 infants exposed to NRT (NSW, NZ), 3031 to varenicline (NSW, NZ, Norway, and Sweden), and 1042 to bupropion (NSW, NZ). Compared with unexposed infants, there were no differences in prevalence of MCMs overall following NRT exposure (37.6 vs 34.4 per 1000 live births; adjusted relative risk [aRR], 1.10; 95% CI, 0.98-1.22), varenicline (32.7 vs 36.6; aRR, 0.90; 95% CI, 0.73-1.10), or bupropion (35.5 vs 38.8; aRR, 0.93; 95% CI, 0.67-1.29). NRT analyses showed no difference in the risk of MCMs of the heart, limbs, genital organs, kidney/urinary tract, respiratory system, and orofacial clefts but a higher risk of digestive organ MCMs (3.8 vs 2.5 per 1000 live births; aRR, 1.53; 95% CI, 1.05-2.23; P = .41 after multiple comparison adjustment). Varenicline analyses revealed no difference in the risk of heart, limb, and genital MCMs but a higher risk of kidney/urinary tract MCMs (11.5 vs 4.2 per 1000 live births; aRR, 2.75; 95% CI, 1.42-5.34; P = .09 after multiple comparison adjustment), with findings for other MCMs being too imprecise. For bupropion, data were too sparse to estimate the risk of MCM subgroups. Conclusions and Relevance:The results of this cohort study suggest that there is no clear increased risk of MCMs associated with prenatal use of NRT and varenicline compared with smoking during the first trimester.

AIMS:As clinical trial evidence on the effectiveness of smoking cessation pharmacotherapies during pregnancy is inconclusive, we conducted a large cohort study examining their effectiveness and comparative effectiveness during pregnancy. DESIGN:Population-based cohort study. We used propensity score matching and conditional Poisson regression to compare pharmacotherapy-exposed with unexposed pregnancies, and to compare varenicline-exposed with nicotine replacement therapy (NRT) -exposed pregnancies. SETTING:Birth records (2005-2020) from New South Wales (NSW) Australia, New Zealand (NZ) and Norway/Sweden linked to pharmacotherapy dispensing records. PARTICIPANTS/CASES:Women with a birth record indicating smoking in early pregnancy [during first 20 weeks' gestation (NSW), at lead maternity registration (NZ) or during the first trimester (Norway/Sweden)]. Participants were dispensed prescription NRT, varenicline or bupropion in the first 18 weeks of gestation (NSW, Norway/Sweden) or between the first antenatal visit and childbirth (NZ). MEASUREMENTS:We defined smoking cessation as not smoking after gestational week 20 (NSW), at gestational week 32-36 (Norway/Sweden) and at two weeks postpartum (NZ), identified via self-report and documented in the birth record. FINDINGS:Our NRT analyses included 623, 7074 and 70 exposed and 6026, 68 161 and 700 propensity-score-matched unexposed pregnancies from NSW, NZ and Norway/Sweden, respectively. The associations between NRT and smoking cessation were mixed but tended toward reduced cessation compared with no pharmacotherapy. In NSW, NRT was associated with a reduction in cessation [relative risk (RR) = 0.68, 95% confidence interval (CI) = 0.48-0.97], while in NZ, the effect was smaller (RR = 0.93, 95% CI = 0.89-0.98) but inconclusive in Norway/Sweden (RR = 0.91, 95% CI = 0.61-1.35). Smoking cessation was also equally or less common among varenicline-exposed pregnancies (NSW: 308 exposed vs 3077 matched unexposed, RR = 0.89, 95% CI = 0.72-1.09, Norway/Sweden: 196 exposed vs 1960 matched unexposed, RR = 0.49, 95% CI = 0.34-0.70). Our comparison of varenicline-exposed with NRT-exposed pregnancies indicated increased smoking cessation among varenicline-exposed pregnancies (NSW: 108 vs 154 exposed, RR = 1.91, 95% CI = 1.10-3.22). There were too few bupropion-exposed pregnancies to support interpretation. CONCLUSIONS:Varenicline appears to be more effective at smoking cessation than nicotine replacement therapy during pregnancy. The uncertainty about the real-world effectiveness of nicotine replacement therapy and bupropion remains as this study's analyses were impacted by non-adherence and biased by unmeasured confounding.

OBJECTIVE:To characterize multinational trends and patterns of opioid analgesic prescribing by sex and age. DESIGN, SETTING, AND PARTICIPANTS:We studied opioid analgesic prescribing from 2001 to 2019 with common protocol using population-based databases from eighteen countries and one special administrative region. MAIN OUTCOME MEASURES:We measured opioid prescribing by geographical region, sex and age, estimating annual prevalent, incident, and nonincident opioid prescribing per 100 population with a 95% confidence interval (CI) and meta-analyzed the multinational and regional opioid prescribing with a random-effects model. Time trends were reported through average annual absolute changes, estimated using linear mixed models. We further explored the effect of sex and age on prevalent opioid prescribing in the multivariable analysis. RESULTS:Over 248 million individuals were included. Pooled multinational opioid prescribing prevalence was 9.0% amongst included countries/regions. Opioid prescribing prevalence in 2015 ranged from 2.7% in Japan to 19.7% in Iceland. Average annual absolute changes in opioid prescribing prevalence per year ranged from - 1.53% (95% CI - 2.06, - 1.00; United States Medicaid) to + 1.24% (95% CI 1.02, 1.46; South Korea). Pooled multinational incident opioid prescribing (4.9%; 95% CI 4.1, 5.9) was higher than pooled multinational nonincident opioid prescribing (3.7%; 95% CI 2.9, 4.8). The female sex and older age were associated with higher opioid prescribing. Main limitations of this study include the absence of data from study duration or individuals not covered by the data sources and the lack of information on medication adherence and indication. CONCLUSIONS:Opioid prescribing remains unbalanced across geographical regions; however, results suggest a tendency to convergence across countries/regions. Differences in opioid prescribing by sex and age were identified.

ABSTRACT Objective To describe the use of central stimulants and amantadine for fatigue in MS and evaluate a potential association with reduced work loss in people with MS. Methods We conducted a nationwide, matched, register‐based cohort study in Sweden (2006 to 2023) using national registers with prospective data collection. We included individuals with MS, identified via the Swedish MS register or ≥ 3 MS diagnoses in the National Patient Register, who initiated treatment with modafinil, amantadine, or central stimulants for ADHD (ADHD‐Drugs), along with untreated individuals matched on modafinil start date, age, sex, time since MS diagnosis, and prior‐year work loss. The main outcome was monthly work loss, defined as the sum of net days on sick leave, disability pension, and activity compensation. Results We identified 2162 new modafinil users, 462 amantadine, 424 ADHD drugs, and 9762 untreated. All cohorts showed increasing work loss before index, followed by no change in work loss over the subsequent 24 months. Modafinil users had a significantly greater attenuation, but with low effect size, of the increasing trajectory of average monthly work loss than untreated (−0.17 days; 95% CI: −0.22, −0.12), with no significant differences between modafinil and other treated groups. Modafinil was the most prescribed treatment, with 1‐year prevalence of 8.5% in 2006 and 7% in 2023. Interpretation A potential minor treatment benefit is suggested by the statistically significant, small attenuation of worsening work loss following fatigue treatment initiation compared with untreated people with MS. No differences in treatment benefit were observed across fatigue treatments.

[This corrects the article DOI: 10.1016/j.eclinm.2024.102531.].

BACKGROUND:Depression is associated with higher risk of major adverse cardiovascular events (MACE). Whether patients with treatment-resistant depression (TRD) or severe depression have an even higher risk is uncertain. METHODS:Patients 18-75 years old with a depressive episode in specialized psychiatric care were identified using national Swedish registers. Patients with depression were matched with population comparators, patients with TRD with non-TRD comparators, and severe depression with non-severe depression comparators. The primary outcome was MACE, including acute myocardial infarction, stroke, heart failure, and cardiovascular death. Hazard ratios were calculated, adjusting for sociodemographic and clinical covariates. RESULTS:We identified 143,731 patients with depression, including 23,335 with TRD and 45,217 with severe depression. Patients with depression had a higher hazard of MACE vs comparators (aHR 1.50, 95%CI 1.40-1.62). Hazards of MACE were overall similar in patients with TRD vs comparators (aHR 1.06, 95%CI 0.93-1.22) and severe depression vs comparators (aHR 1.04, 95%CI 0.96-1.13). Analyzing separate outcomes, patients with TRD had a higher hazard of cardiovascular death (aHR 1.32, 95 %CI 1.03-1.69). Stratified by age, there was an elevated hazard of MACE among patients 18-29 years old with severe depression (aHR 2.82, 95%CI 1.24-6.41). LIMITATIONS:Register data lacks information on some potential confounders. CONCLUSIONS:Patients with TRD or severe depression are not at additional overall risk of MACE compared to other depressed patients. However, an additional risk may exist in younger patients with severe depression and specifically of cardiovascular death in patients with TRD.

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.