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Kasper Bruun Kristensen,1 Lars Christian Lund,1 Peter Bjødstrup Jensen,1 Anne Broe,1 Emelie Rotbain,2 Per Damkier,1,3,4 Anton Pottegård,1 Jacob Harbo Andersen,1 Mikkel Højlund,1,5 Morten Olesen,1 Lotte Rasmussen,1 Morten Rix Hansen,1,3,4 Martin Thomsen Ernst,1 Rikke Wesselhoeft,1,6 Daniel Pilsgaard Henriksen,3 Mette Reilev,1 Mette Bliddal,1,7 Jesper Hallas1 1Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Department of Hematology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark; 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark; 6Child and Adolescent Psychiatry Odense, Mental Health Services in the Region of Southern Denmark, Odense, Denmark; 7Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Jesper Hallas, Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19, 2, Odense, 5000, Denmark, Tel +4565503010, Email jhallas@health.sdu.dkPurpose: To develop the Nordic Multimorbidity Index (NMI), a multimorbidity measure specifically suited to the Nordic health and administrative registry data based on current diagnosis, treatment, and coding practices.Methods: The NMI was developed to predict 5-year mortality in a population-based cohort of randomly sampled Danish residents aged ≥ 40 years (n = 425,087) followed from 2013 to 2018. Included predictors were selected from hospital diagnoses and filled drug prescriptions based on a combination of subject matter knowledge and a data-driven approach using backwards elimination. The performance of the NMI was assessed in a temporal validation cohort of Danish residents followed from 2007 to 2012 and in six cohorts of new users of selected drugs. The discriminative performance of the NMI, Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) was assessed using the c-statistic from logistic regression models with 5-year mortality as dependent variable and the multimorbidity index score, age, and sex as independent variables.Results: The NMI included 50 predictors. In the temporal validation cohort, the c-statistic of the NMI (0.887, 95% CI 0.883– 0.890) exceeded that of the CCI (0.871, 95% CI 0.868– 0.874) and ECI (0.866, 95% CI 0.863– 0.870). In all new user cohorts, the NMI outperformed the other indices with c-statistics ranging from 0.781 (95% CI 0.779– 0.784) to 0.838 (95% CI 0.834– 0.842).Conclusion: The NMI predicted 5-year mortality in a general Danish population and six cohorts of new users of selected drugs and was superior to the CCI and ECI. The NMI could be preferred over these indices to quantify the level of multimorbidity for, eg, descriptive purposes or confounding control. The NMI should be validated in other patient populations and other Nordic countries.Keywords: multimorbidity, comorbidity, pharmacoepidemiology, prognosis, risk score

Introduction: Use of antipsychotic drugs is common in nonpsychotic disorders such as depression, anxiety, autism spectrum disorders, and insomnia. But exposure to antipsychotic drugs has been associated with a range of serious adverse events from arrythmias to diabetes. There is a need for detailed information on current practice and trends in the utilization of this drug class to guide future initiatives on the rational use of antipsychotic drugs. Objectives: To investigate trends in dosing and prevalence of antipsychotic prescriptions in Scandinavia. Methods:Weretrieved data on antipsychotic use between 2006 and 2016 from Danish, Norwegian and Swedish national prescription registers. For each antipsychotic, we calculated prevalence of use and mean doses, overall and for specific age groups. Results: Antipsychotic use in Scandinavia increased from 16.5 to 17.2 users/1,000 inhabitants between 2006 and 2016 (+2.4%, p=0.02). In 2006, chlorprothixene and levomepromazine were the most commonly used antipsychotics. By 2016, quetiapine was the most used antipsychotic in all three countries and across all age groups, with an overall one-year prevalence of 4.05 to 9.97 users/1,000 inhabitants. Mean doses of quetiapine decreased markedly during the 11-year study period (0.46 to 0.28 DDD/user/day), while mean doses for clozapine and olanzapine remained high (0.90-1.07 resp. 0.66-0.88DDD/user/day). Conclusions: We found an increasing prevalence of antipsychotic prescriptions that coincides with low and/or decreasing mean doses of the majority of commonly used antipsychotics in Scandinavia. Of all antipsychotics, this development was most pronounced for quetiapine. Reasons for and consequences of increased antipsychotic use that lasts shorter periods of time requires further study. [ABSTRACT FROM AUTHOR]

Introduction: Prolongation of theQT-interval is a risk factor for fatal cardiac arrhythmias, and several commonly used antidepressants and -psychotics are associated with QT-interval prolongation. Electrocardiographically monitoring is recommended during antidepressant and -psychotic treatment, and significantly prolonged QT-interval is a contraindication for further treatment. For patients with prevalence of left or right bundle branch block (LBBB/RBBB) conventional methods will lead to overestimation of the QT-interval, because the QT-prolongation is caused by a delay in cardiac depolarization and a delay in repolarization as in drug-induced QT-prolongation. Introduction: Prolongation of theQT-interval is a risk factor for fatal cardiac arrhythmias, and several commonly used antidepressants and -psychotics are associated with QT-interval prolongation. Electrocardiographically monitoring is recommended during antidepressant and -psychotic treatment, and significantly prolonged QT-interval is a contraindication for further treatment. For patients with prevalence of left or right bundle branch block (LBBB/RBBB) conventional methods will lead to overestimation of the QT-interval, because the QT-prolongation is caused by a delay in cardiac depolarization and a delay in repolarization as in drug-induced QT-prolongation. Methods: Systematic literature search in PubMed and Embase, and subsequent review of the literature to discuss alternative approaches to QT-interval estimation in patients with LBBB or RBBB. Results: For LBBB, different solutions have been proposed: Wang et al. (1) suggest a correction formula based on QT- and QRS durations: QTm=QT-(0.86*QRS-71) milliseconds. Bogossian et al. (2) propose a similar solution, also based on QT- and QRS-durations: QTm=QT-0.485*QRSmilliseconds. Also, the JT-interval can be used for this purpose in both LBBB and RBBB, as discussed by Rautaharju et al. (3) and Zhou et al. (4). Conclusions: QT-interval prolongation in patients with LBBB or RBBB does not necessarily represent a contraindication for psychopharmacological treatment with QT-prolonging drugs. Linear correction formulas for QT-interval can be used to determine the modified QT-intervals in patients with LBBB/RBBB. [ABSTRACT FROM AUTHOR]

Background: Antipsychotics increase the risk of developing diabetes, but clinical trials are not generalizable with short follow-up, while observational studies often lack important information, particularly hemoglobin A1c (HbA1c)., Methods: We followed two Danish cohorts with schizophrenia. First, using Danish nationwide registers, we identified all individuals diagnosed with first-episode schizophrenia (FES) between 1999 and 2019 (n = 31,856). Exposure was a redeemed prescription for an antipsychotic, and the outcome was diabetes, defined via hospital-based diagnosis and redeemed prescriptions for glucose-lowering drugs. Adjusted Cox regression calculated hazard rate ratios (HRR). Second, using data from the Central Denmark Region, we identified all individuals diagnosed with FES from October 2016 to September 2022 (n = 2671). Using a within-subject design, we analyzed the change in HbA1c during the 2 years after initiation of specific antipsychotics compared to the 2 years before., Results: In the nationwide cohort, 2543 (8.0%) individuals developed diabetes (incidence rate = 9.39 [95% CI = 9.03-9.76] per 1000 person-years). Antipsychotics, compared to periods without, were associated with an increased risk of developing diabetes (HRR = 2.04, 95% CI = 1.75-2.38). We found a dose-response association, particularly for second-generation antipsychotics, and different risk rates for specific antipsychotics. In the Central Denmark Region cohort, a total of 9.2% developed diabetes but mean HbA1c levels remained stable at 37 mmol/mol during the 2 years after initiation of antipsychotic medication., Conclusion: This comprehensive real-world two-cohort study emphasizes that diabetes affects almost 10% of patients with FES. Antipsychotics increase this risk, while HbA1c deterioration requires longer treatment. These findings are important for clinicians and young patients with FES., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Introduction: People with severe mental illness have poor cardiometabolic health. Commonly used antidepressants and antipsychotics frequently lead to weight gain, which may further contribute to adverse cardiovascular outcomes., Areas Covered: We searched MEDLINE up to April 2023 for umbrella reviews, (network-)meta-analyses, trials and cohort studies on risk factors, prevention and treatment strategies of weight gain associated with antidepressants/antipsychotics. We developed 10 clinical recommendations., Expert Opinion: To prevent, manage, and treat antidepressant/antipsychotic-related weight gain, we recommend i) assessing risk factors for obesity before treatment, ii) monitoring metabolic health at baseline and regularly during follow-up, iii) offering lifestyle interventions including regular exercise and healthy diet based on patient preference to optimize motivation, iv) considering first-line psychotherapy for mild-moderate depression and anxiety disorders, v)choosing medications based on medications' and patient's weight gain risk, vi) choosing medications based on acute vs long-term treatment, vii) using effective, tolerated medications, viii) switching to less weight-inducing antipsychotics/antidepressants where possible, ix) using early weight gain as a predictor of further weight gain to inform the timing of intervention/switch options, and x) considering adding metformin or glucagon-like peptide-1 receptor agonists, or topiramate(second-line due to potential adverse cognitive effects) to antipsychotics, or aripiprazole to clozapine or olanzapine.

Background: Antipsychotic polypharmacy remains a clinical reality, despite an increased risk of adverse events and little evidence of additional efficacy compared with antipsychotic monotherapy. In this systematic review and meta-analysis, we aimed to provide a comprehensive assessment of antipsychotic polypharmacy prevalence, trends, and correlates across mental disorders., Methods: We searched MEDLINE and Embase from Jan 1, 2009 to April 30, 2024, for any original study (observational and interventional) reporting antipsychotic polypharmacy prevalence in populations with mental disorders or use of antipsychotics, regardless of age or diagnosis. Relevant studies before May 1, 2009, were identified from two previous systematic reviews of antipsychotic polypharmacy prevalence. Pooled antipsychotic polypharmacy prevalence was estimated using random-effects meta-analysis. Using subgroup and mixed-effects meta-regression analyses, we sought to identify relevant correlates of antipsychotic polypharmacy. People with lived experience were not involved in the project. This review is registered with PROSPERO (CRD42022329953)., Findings: We analysed 517 studies with 599 individual timepoints reporting on 4 459 149 individuals (mean age 39·5 years [range 6·4-86·3]; data on sex and ethnicity were infrequently reported). Most studies included patients with schizophrenia spectrum disorders (SSDs; k=270, 52%). Overall, 24·8% (95% CI 22·9-26·7) of the populations received antipsychotic polypharmacy, ranging from 33·2% (30·6-36·0) in people with SSDs to 5·2% (4·0-6·8) in people with dementia. Antipsychotic polypharmacy prevalence varied by region from 15·4% (95% CI 12·9-18·2) in North America to 38·6% (27·7-50·6) in Africa. Overall antipsychotic polypharmacy prevalence increased significantly from 1970 to 2023 (β=0·019, 95% CI 0·009-0·029; p=0·0002) and was higher in adults than in children and adolescents (27·4%, 95% CI 25·2-29·8 vs 7·0%, 4·7-10·3; p<0·0001) and among inpatients than among outpatients (31·4%, 27·9-35·2 vs 19·9%, 16·8-23·3; p<0·0001). Compared with antipsychotic monotherapy, antipsychotic polypharmacy was associated with an increased risk of relapse (relative risk [RR] 1·42, 95% CI 1·04-1·93; p=0·028), psychiatric hospitalisation (1·24, 1·12-1·38; p<0·0001), worse global functioning (standardised mean difference [SMD] -0·31, 95% CI -0·44 to -0·19; p<0·0001), and more adverse events, including extrapyramidal symptoms (RR 1·63, 95% CI 1·13-2·36; p=0·0098), dystonia (5·91, 1·20-29·17; p=0·029), anticholinergic use (1·91, 1·55-2·35; p<0·0001), higher side-effect scores (SMD 0·33, 95% CI 0·24-0·42; p<0·0001), longer corrected QT interval (0·24, 0·23-0·26; p<0·0001), and greater all-cause mortality risk (RR 1·19, 95% CI 1·00-1·41; p=0·047)., Interpretation: The prevalence of antipsychotic polypharmacy has increased globally over the past 50 years and is particularly high in patients with SSDs. Prescription of antipsychotic polypharmacy is associated with greater illness severity and poorer outcomes than is antipsychotic monopharmacy but does not resolve these issues. Furthermore, antipsychotic polypharmacy is associated with higher side-effect burden, including all-cause mortality., Funding: None., Competing Interests: Declaration of interests MH has received honoraria for lectures from and been a consultant for Lundbeck and Otsuka. OK-F has received honoraria for lectures for Lundbeck Pharma and is a consultant for WCG. CUC has been a consultant or advisor to or has received honoraria from AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Johnson & Johnson Innovative Medicine, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris; has provided expert testimony for Janssen and Otsuka; has served on a data safety monitoring board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; has received grant support from Janssen and Takeda and royalties from UpToDate; and is a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Antipsychotic polypharmacy (APP) is frequent but evidence-based guidelines on reducing APP to antipsychotic monotherapy (APM) are sparse. We aimed to systematically review clinical interventions randomizing patients to reducing APP to APM versus continuing APP., Methods: Systematic literature review searching Medline and Embase (latest search January 10, 2024) for randomized clinical trials (RCTs) studying interventions comparing individuals randomized to reduction of APP to APM with individuals continuing on APP. Two independent reviewers performed the literature screening, data extraction, and risk of bias assessment (RoB2). We performed random effects meta-analyses on the main outcome all-cause discontinuation/"acceptability" of the treatment strategy and secondary outcomes change in psychopathology, functional level, and side effects., Results: The search identified 4672 hits, whereof 8 trials (N = 1204, 6 patient-level RCTs and 2 cluster-RCTs) were included, primarily in patients with schizophrenia. All trials were associated with high risk of bias. Compared to APP continuation, reduction to APM was associated with no significant change in all-cause discontinuation (studies = 6, n = 455, RR = 1.48, 95%CI = 0.74-2.95, I 2  = 78 %) or inefficacy-related discontinuation (studies = 5, n = 351, RR = 1.60, 95%CI = 0.46-5.55, I 2  = 70 %). Patients randomized to APM showed a trend towards greater reduction in psychopathology (studies = 5, n = 244, SMD = -0.24, 95%CI = -0.49, 0.02, I 2  = 0 %) but no difference in functional level nor side effects. The cluster-RCTs found that interventions at the departmental level can result in lower rates of APP., Conclusion: Although switching patients from APP to APM can be a viable approach, too few RCTs exist on this important topic. Clinicians need to evaluate potential benefits and risks of APP and APM on an individual basis., Prospero Registration: CRD42022329955., Competing Interests: Declaration of competing interest OKF reports honoraria for lectures for Lundbeck Pharma A/S and consultant work for WCG Clinical. MH reports honoraria for lectures for Lundbeck Pharma A/S and Otsuka, and consultant work for Lundbeck Pharma A/S. C.R. received the 2020 Lundbeck Foundation Talent Prize. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Car dio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: This survey assessed psychiatry residents'/early-career psychiatrists' attitudes towards the utility of therapeutic drug monitoring (TDM) of antipsychotics., Methods: A previously developed questionnaire on attitudes on TDM utility during antipsychotic treatment was cross-sectionally disseminated by national coordinators between 01/01/2022-31/12/2023. The frequency of using TDM for antipsychotics other than clozapine was the main outcome in a linear regression analysis, including sex, clinical setting, caseload, and factors generated by an exploratory factor analysis. Comparisons between residents and early-career psychiatrists, respondents working in in- and outpatient settings, and low-/middle- and high-income countries were performed., Results: Altogether, 1,237 respondents completed the survey, with 37.9% having never used TDM for antipsychotics. Seven factors explained 41% of response variance; six of them were associated with frequency of TDM use ( p  < 0.05). Items with highest loadings for factors included clinical benefits of TDM (factors A and E: 0.7), negative expectations for beliefs of patients towards TDM (factor B: 0.6-0.7), weak TDM scientific evidence (factor C: 0.8), and TDM availability (factor D: -0.8). Respondents from low-/middle-income countries were less likely to frequently/almost always use TDM compared to high-income countries (9.4% vs. 21.5%, p  < 0.001)., Discussion: TDM use for antipsychotics was poor and associated with limited knowledge and insufficient availability.

Eating disorders (EDs) are known to be associated with high mortality and often chronic and severe course, but a recent comprehensive systematic review of their outcomes is currently missing. In the present systematic review and meta-analysis, we examined cohort studies and clinical trials published between 1980 and 2021 that reported, for DSM/ICD-defined EDs, overall ED outcomes (i.e., recovery, improvement and relapse, all-cause and ED-related hospitalization, and chronicity); the same outcomes related to purging, binge eating and body weight status; as well as mortality. We included 415 studies (N=88,372, mean age: 25.7±6.9 years, females: 72.4%, mean follow-up: 38.3±76.5 months), conducted in persons with anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), other specified feeding and eating disorders (OSFED), and/or mixed EDs, from all continents except Africa. In all EDs pooled together, overall recovery occurred in 46% of patients (95% CI: 44-49, n=283, mean follow-up: 44.9±62.8 months, no significant ED-group difference). The recovery rate was 42% at <2 years, 43% at 2 to <4 years, 54% at 4 to <6 years, 59% at 6 to <8 years, 64% at 8 to <10 years, and 67% at ≥10 years. Overall chronicity occurred in 25% of patients (95% CI: 23-29, n=170, mean follow-up: 59.3±71.2 months, no significant ED-group difference). The chronicity rate was 33% at <2 years, 40% at 2 to <4 years, 23% at 4 to <6 years, 25% at 6 to <8 years, 12% at 8 to <10 years, and 18% at ≥10 years. Mortality occurred in 0.4% of patients (95% CI: 0.2-0.7, n=214, mean follow-up: 72.2±117.7 months, no significant ED-group difference). Considering observational studies, the mortality rate was 5.2 deaths/1,000 person-years (95% CI: 4.4-6.1, n=167, mean follow-up: 88.7±120.5 months; significant difference among EDs: p<0.01, range: from 8.2 for mixed ED to 3.4 for BN). Hospitalization occurred in 26% of patients (95% CI: 18-36, n=18, mean follow-up: 43.2±41.6 months; significant difference among EDs: p<0.001, range: from 32% for AN to 4% for BN). Regarding diagnostic migration, 8% of patients with AN migrated to BN and 16% to OSFED; 2% of patients with BN migrated to AN, 5% to BED, and 19% to OSFED; 9% of patients with BED migrated to BN and 19% to OSFED; 7% of patients with OSFED migrated to AN and 10% to BN. Children/adolescents had more favorable outcomes across and within EDs than adults. Self-injurious behaviors were associated with lower recovery rates in pooled EDs. A higher socio-demographic index moderated lower recovery and higher chronicity in AN across countries. Specific treatments associated with higher recovery rates were family-based therapy, cognitive-behavioral therapy (CBT), psychodynamic therapy, and nutritional interventions for AN; self-help, CBT, dialectical behavioral therapy (DBT), psychodynamic therapy, nutritional and pharmacological treatments for BN; CBT, nutritional and pharmacological interventions, and DBT for BED; and CBT and psychodynamic therapy for OSFED. In AN, pharmacological treatment was associated with lower recovery, and waiting list with higher mortality. These results should inform future research, clinical practice and health service organization for persons with EDs., (© 2024 World Psychiatric Association.)

Background: Patients with psychotic disorders (PD) often have comorbid alcohol use disorder (AUD), which is typically treated pharmacologically. Up till now, no systematic review has examined the effectiveness and safety of AUD treatment in PD patients., Objectives: This study aimed to systematically review the literature on (1) the effects of pharmacological treatments for AUD on drinking outcomes, (2) the side effects of the drugs, and (3) the effects of polypharmacy in patients with comorbid AUD and PD., Methods: Bibliographic searches were conducted in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and PsycINFO. At least two reviewers extracted the data, assessed the risk of bias, and performed the qualitative synthesis of the collected evidence., Results: Twelve eligible studies were identified, half being randomized controlled trials (RCTs). Three studies examined disulfiram, nine naltrexone, two acamprosate, and one nalmefene by comparing the effects of treatment to placebo, baseline, or pharmacological agents. Disulfiram and naltrexone were shown to reduce alcohol intake. Regarding acamprosate, the findings were mixed. Nalmefene decreased alcohol intake. All pharmacological agents appeared safe to use as AUD monotherapy, but cardiac events were reported when combining naltrexone and disulfiram. Nine studies had a high risk of bias, and three had some other concerns., Conclusion: The studies provide tentative support for the use of naltrexone and disulfiram in this population, although combinations of pharmacological AUD treatments and other polypharmacy remain unexplored. The studies had high adherence rates that are hardly replicable in real-world settings. Thus, the findings should be confirmed in larger high quality efficacy and effectiveness RCTs with longer follow-ups., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Long-acting injectable antipsychotics (LAIs) are an effective, but potentially underutilized treatment option in schizophrenia and other severe mental illnesses. Prescribing information typically focuses on how to initiate treatment from the corresponding oral formulations. However, in clinical practice other scenarios, such as switching from other oral antipsychotics or other LAIs, occur frequently, requiring guidance., Areas Covered: Pharmacodynamic properties of antipsychotics and their relation to rebound symptoms. Pharmacokinetic properties of LAIs and their implications for switching approaches. Specific approaches to switching to LAIs., Expert Opinion: The LAI landscape has evolved significantly in the last decade with more formulations available, longer dosing intervals, and extended indications. However, currently available LAIs have various shortcomings, e.g. short dosing intervals, need for oral supplementation, loading regimens, deep intramuscular injection and/or restricted indications. Recent improvements include a one-day initiation option for aripiprazole lauroxil, aripiprazole monohydrate once-monthly, risperidone in situ microparticles and subcutaneous risperidone. Future LAI developments should focus on longer dosing intervals, subcutaneous administration, expansion of LAIs beyond currently available antipsychotic agents and indications beyond schizophrenia and bipolar disorder. In the future, LAIs might become a first-line treatment after initial oral stabilization for chronic mental disorders with need for maintenance treatment and presence of significant non-adherence.

Background: Patients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population., Methods: PubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5., Results: Of 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42-8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies >13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05-12.65) vs 5.51 (4.73-6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and >13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration., Conclusions: In RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting >13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered., (© The Author(s) 2023. Published by Oxford University Press on behalf of CINP.)

Objectives: The aim of this study was to compare neonatal and maternal outcomes in twin pregnancies with elective cesarean section (ECS) and induction of labor (IOL) to better inform women during the counselling process., Materials and Methods: We conducted a cohort study including all twin pregnancies referred to the Department of Obstetrics at Kolding University Hospital, Denmark between January 2007 to April 2019 (n = 819). The primary analysis compared maternal and neonatal outcomes in pregnancies planned for IOL with those planned for ECS after week 34. A secondary analysis compared maternal and neonatal outcomes in pregnancies who underwent IOL followed by successful vaginal delivery with outcomes in those who underwent ECS., Results: Among 587 eligible twin pregnancies, the rates of unplanned CS did not differ between those planned for ECS compared to those planned for IOL (38% vs. 33%; p = 0.27). IOL resulted in successful vaginal delivery in 67% (155/231) of those planned for IOL. Maternal outcomes did not differ between women who were planned for, or received, delivery with either IOL or ECS. Regarding neonatal outcomes, significantly more neonates required treatment with C-PAP in ECS group, than in the IOL group, and a higher median number of maturity days among mothers planned for ECS. However, no other significant difference in neonatal outcomes was observed when comparing successful IOL with successful ECS., Conclusion: Induction of labor was not associated with worse outcomes compared to elective caesarean section in this large cohort of routinely handled twin pregnancies. In women with twin pregnancies indicated for delivery, who does not go into spontaneous labor, induction of labor is a safe option for both the mothers and their neonates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

One of the primary challenges prohibiting demonstrations of practical quantum advantages for near-term devices amounts to excessive measurement overheads for estimating relevant physical quantities such as ground state energies. However, with major differences between the electronic and vibrational structures of molecules, the question of how the resource requirements of computing anharmonic, vibrational states can be reduced remains relatively unexplored compared to its electronic counterpart. Importantly, bosonic commutation relations, distinguishable Hilbert spaces and vibrational coordinates allow manipulations of the vibrational system that can be exploited to minimize resource requirements. In this work, we investigate the impact of different coordinate systems and measurement schemes on the number of measurements needed to estimate anharmonic, vibrational states for a variety of three-mode (six-mode) molecules. We demonstrate an average of 3-fold (1.5-fold), with up to 7-fold (2.5-fold), reduction in the number of measurements required by employing appropriate coordinate transformations, based on an automized construction of qubit Hamiltonians from a conventional vibrational structure program., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010-08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes., Competing Interests: Conflict of interest S Cortese declares honoraria and reimbursement for travel and accommodation expenses for lectures from the following non-profit associations: Association for Child and Adolescent Central Health (ACAMH), Canadian ADHD Alliance Resource (CADDRA), British Association of Pharmacology (BAP), and from Healthcare Convention for educational activity on ADHD. M Højlund has been a consultant to or has received honoraria from the Lundbeck Foundation, H. Lundbeck, and Otsuka. C Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. I Baeza has received honoraria and travel support from Angelini, Otsuka-Lundbeck and Janssen. T Banaschewski served in an advisory or consultancy role for eye level, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche, and Takeda. He received conference support or speaker’s fee by Janssen, Medice and Takeda. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. JK Buitelaar has been a consultant to / member of advisory board of / and/or speaker for Takeda, Medice, Angelini, Janssen, Boehringer-Ingelheim and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. D Coghill served in an advisory or consultancy role for Medice, Novartis, Servier, and Shire/Takeda. He received conference support or speaker’s fee from Medice, Servier, and Shire/Takeda. He received royalties from Cambridge University Press and Oxford University Press; He is not an employee of any of these companies, and not a stock shareholder of any of these companies and the present work is unrelated to these relationships. D Cohen has been a consultant or has received honoraria from Janssen/J&J and Otsuka; he served on a Data Safety Monitoring Board for Lundbeck. CU Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. E Grunblatt received grant support from MEDICE Arzneimittel Pütter GmbH & Co KG. C Moreno has received honoraria as a consultant and/or advisor and/or for lectures from Angelini, Esteve, Exeltis, Janssen, Lundbeck, Neuraxpharm, Nuvelution, Otsuka, Pfizer, Servier and Sunovion outside the submitted work. M Parellada has been a consultant to or has received honoraria or grants from Angelini, Janssen Cilag, Exeltis, Lundbeck, Otsuka, Pfizer, Roche, Sage, Servier. A.M. Persico has been a consultant to and/or speaker for and has received honoraria from Servier, Sanofi, and Healx Limited. In the last 3 years, D. Purper-Ouakil reports honoraria/non-financial support from Medice and Shire/Takeda, non-financial support from HAC Pharma, and has worked as an unpaid scientific coordinator for Mensia, all outside the submitted work. In the last 2 years, B Vitiello was a paid consultant for Medice, Menarini, Angelini, and Alkermes Pharmaceuticals. ICKW reports research funding outside the submitted work from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Takeda, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, the Hong Kong Innovation and Technology Commission, the NIHR, the European Commission, and the Australian National Health and Medical Research Council, and has also received expert testimony payment from the Hong Kong Court of Final Appeal in the previous 3 years and consultancy fee from IQVIA and World Health Organization. In the last 3 years, V Roessner received no honoraria from pharmaceutical companies. He received royalties from Hogrefe, Oxford University Press; the present work is unrelated to these relationships. The other authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite considerable progress in pharmacotherapy over the past seven decades, many mental disorders remain insufficiently treated. This situation is in part due to the limited knowledge of the pathophysiology of these disorders and the lack of biological markers to stratify and individualize patient selection, but also to a still restricted number of mechanisms of action being targeted in monotherapy or combination/augmentation treatment, as well as to a variety of challenges threatening the successful development and testing of new drugs. In this paper, we first provide an overview of the most promising drugs with innovative mechanisms of action that are undergoing phase 2 or 3 testing for schizophrenia, bipolar disorder, major depressive disorder, anxiety and trauma-related disorders, substance use disorders, and dementia. Promising repurposing of established medications for new psychiatric indications, as well as variations in the modulation of dopamine, noradrenaline and serotonin receptor functioning, are also considered. We then critically discuss the clinical trial parameters that need to be considered in depth when developing and testing new pharmacological agents for the treatment of mental disorders. Hurdles and perils threatening success of new drug development and testing include inadequacy and imprecision of inclusion/exclusion criteria and ratings, sub-optimally suited clinical trial participants, multiple factors contributing to a large/increasing placebo effect, and problems with statistical analyses. This information should be considered in order to de-risk trial programmes of novel agents or known agents for novel psychiatric indications, increasing their chances of success., (© 2023 World Psychiatric Association.)

Neurodevelopmental disorders - including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders - manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence - from two or more studies from independent research groups, with results going into the same direction - of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice., (© 2023 World Psychiatric Association.)

Introduction: People with mental disorders have higher mortality from lifestyle diseases than the general population. Forensic mental health patients (FMHPs) are often hospitalised for longer periods of time than non-FMHPs. Thus, hospitalisation may have a greater effect on the risk of lifestyle diseases in FMHPs., Objective: Investigate associations between proportional hospitalisation time (PHT) and change in body weight or other cardiometabolic risk factors among FMHPs., Methods: Retrospective cohort study including all FMHPs with schizophrenia or bipolar disorder, prescribed antipsychotics, and treated between 01 January 2016 and 06 April 2020 in the Region of Southern Denmark either in forensic units or as outpatients. Associations between PHT and, respectively, primary and secondary outcomes were analysed using linear regression. PHT was determined between each measurement of the outcomes as the number of days hospitalised divided by the total number of days within the time-period. The primary outcome was weight change and secondary outcomes were change in waist circumference (WC), blood pressure, estimated average glucose (eAG), HDL, LDL, total cholesterol, and triglycerides. Analyses were adjusted for gender, age, smoking, and antipsychotics., Results: The cohort included 490 FMHPs, of which 440 were diagnosed with schizophrenia. PHT had a significant positive dose-response association with weight change, with an estimated difference of +4.0 kg/year for FMHPs who were hospitalised 100% of the time, compared to FMHPs who were exclusively treated as outpatients. The association interacted with baseline BMI. From the secondary outcomes, the association with PHT was only statistically significant for WC., Conclusions: PHT was positively associated with weight gain.

Objective: Quetiapine use at standard doses has been associated with hyperglycemia and dyslipidemia. However, whether even frequently prescribed low-dose quetiapine results in significant metabolic disturbances remains unclear. Thus, this study aimed to investigate the association between off-label, low-dose quetiapine and changes in glycosylated hemoglobin (HbA1c) levels/lipid parameters., Methods: We identified new users of low-dose quetiapine (≤50 mg tablets) in Denmark 2008-2018 with measurements of HbA1c, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), or fasting triglycerides (fTG) within 365 days before and after quetiapine initiation. Mixed-effects linear regression models were used to estimate coefficients (β) with 95% confidence intervals (95%CIs) for change in cardiometabolic parameters after quetiapine initiation. Inverse probability weighting was used to mitigate selection bias. Higher doses of quetiapine (>50 mg) were included in sensitivity analyses., Results: Among 106,711 eligible new low-dose quetiapine users (median age = 45 years, females = 55%), low-dose quetiapine initiation was associated with increased fTG (β = 1.049[95%CI:1.027-1.072]) and decreased HDL-C (β = 0.982[0.978-0.986]). Although HbA1c did not change significantly and TC and LDL-C even decreased considering all subjects, all three metabolic parameters increased significantly among individuals with normal pre-quetiapine initiation levels. The adverse metabolic effect of quetiapine on HbA1c, TC, LDL-C, and HDL-C was dose-dependent, which was not the case for fTG., Conclusions: Low-dose quetiapine was associated with a significant increase in fTG and decreases in HDL-C in all subjects, as well as with significant increases in HbA1c, TC, and LDL-C among those with normal baseline values. The risk of metabolic worsening with quetiapine was dose-dependent, except for fTG., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Use of benzodiazepines (BZ) and related drugs is subject to considerable debate due to problems with dependency and adverse events. We aimed to describe and compare their use across the Nordic countries. Data on the use of clonazepam, BZ-sedatives, BZ-hypnotics, and benzodiazepine-related drugs (BZRD) in adults (≥20 years) were obtained from nationwide registers in Denmark, Finland, Iceland, Norway, and Sweden, 2000-2020. Main measures were therapeutic intensity (TI:DDD/1000 inhabitants [inhab.]/day) and annual prevalence (users/1000 inhab./year). Overall, TI of BZ and related drugs decreased in all Nordic countries from 2004 to 2020. However, there were considerable differences between countries in TI. In 2020, the TI of BZ and related drugs ranged from 17 DDD/1000 inhab./day in Denmark to 93 DDD/1000 inhab./day in Iceland. BZRD accounted for 55-78% of BZ use in 2020, followed by BZ sedatives at 20-44%, BZ-hypnotics at <1-5%, and clonazepam at <1-2%. Annual prevalence of BZ use increased with age in all countries, and the highest annual prevalence was observed among people ≥80 years. Overall, the use of BZ and related drugs has decreased in all Nordic countries from 2004 to 2020, however, with considerable differences in their use between countries. The highest prevalence was observed among the oldest age groups-despite warnings against their use in this population., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Introduction: Current antipsychotics are postsynaptic dopamine-2(D 2 ) receptor blockers, which often, but not always, effectively improve acute psychotic symptoms and prevent relapse in schizophrenia and other severe mental disorders, but are associated with various side effects, including parkinsonism, akathisia, sedation/somnolence, and cardiometabolic alterations. Furthermore, the efficacy of current antipsychotics for negative and cognitive symptoms in schizophrenia is limited. Ulotaront is a novel trace-amine-associated receptor-1(TAAR1) agonist with serotonin-1A receptor agonist activity, and without postsynaptic D2-receptor antagonism. Phase 2 clinical data for ulotaront in patients with acutely exacerbated schizophrenia are promising regarding the potential improvement in positive, negative, and depressive symptoms., Areas Covered: An overview of the pharmacokinetic and pharmacodynamic properties of ulotaront is given. Summary of clinical efficacy and safety/tolerability from Phase 1/2-trials, and of ongoing Phase 3-trials, is also given., Expert Opinion: Ulotaront is a promising agent for the treatment of schizophrenia with an apparent benign safety profile, which might provide a much-needed new and different treatment option for various domains of schizophrenia. Data from larger Phase 3-trials, including for relapse prevention, schizophrenia subdomains, and in adolescents, are awaited. If ongoing Phase 3-trials in adults are successful, further research on combination regimens with existing antipsychotics, and in treatment-resistant schizophrenia as well as in mood disorders would be desirable.

At standard doses used for schizophrenia or bipolar disorder, quetiapine has been associated with weight gain and increased levels of triglycerides, to-tal cholesterol and low-density lipoprotein (LDL) cholesterol, which are risk factors for cardiovascular morbidity and mortality. However, this drug is also commonly used off-label at low doses for anxiolytic or hypnotic purposes, and its cardiovascular safety at these doses is unknown. We aimed to assess the risk of major adverse cardiovascular events with use of low-dose quetiapine compared to use of Z-drug hypnotics in a nationwide, active comparator-controlled cohort study. The cohort included new users of either drugs in Denmark from 2003 to 2017, aged 18-85 years, without history of ischemic stroke, myocardial infarction, cancer, and severe mental illness. The main outcome was the occurrence of major adverse cardiovascular events, defined as non-fatal myocardial infarction or ischemic stroke, or death from cardiovascular causes. Selective serotonin reuptake inhibitors (SSRIs) were used as an alternative comparator in sensitivity analyses. Altogether, we compared 60,566 low-dose quetiapine users with 454,567 Z-drug users, followed for 890,198 person-years in intent-to-treat analysis, and 330,334 person-years in as-treated analysis. In intention-to-treat analysis, low-dose quetiapine was associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR=1.13, 95% CI: 1.02-1.24, p=0.014) and cardiovascular death (aHR=1.26, 95% CI: 1.11-1.43, p<0.001). In as-treated analysis, continuous low-dose quetiapine use was associated with increased risk of major adverse cardiovascular events (aHR=1.52, 95% CI: 1.35-1.70, p<0.001), non-fatal ischemic stroke (aHR=1.37, 95% CI: 1.13-1.68, p=0.002) and cardiovascular death (aHR=1.90, 95% CI: 1.64-2.19, p<0.001). The risk of major adverse cardiovascular events was greater in women (aHR=1.28, p=0.02) and those aged ≥65 years at initiation (aHR=1.24, p<0.001). Compared to SSRIs, low-dose quetiapine use was associated with an increased risk of major adverse cardiovascular events (aHR=1.42, p<0.001), non-fatal ischemic stroke (aHR=1.27, p=0.0028) and cardiovascular death (aHR=1.72, p<0.001). So, we conclude that the use of low-dose quetiapine is associated with an increased risk of major adverse cardiovascular events, especially in women and the elderly. On the basis of these findings, we suggest that use of off-label low-dose quetiapine for sedative or hypnotic purposes should be discouraged., (© 2022 World Psychiatric Association.)

Objective: Free-of-charge dispensing of antipsychotics for schizophrenia was introduced in Denmark around 2008. However, free-of-charge dispensing is not recorded in the Danish National Prescription Register (DNPR), potentially introducing bias and misclassification., Methods: We identified all 30 275 individuals with a first-episode schizophrenia diagnosis in Denmark between 1 January 1999 and 1 March 2017 including all redeemed prescriptions registered in the DNPR during the 2 years after the schizophrenia diagnosis. For each calendar year, we calculated the proportion of individuals who had filled ≥1 prescription for psychotropic and/or somatic medications within the first 2 years after the schizophrenia diagnosis., Results: From 2007 to 2017, the proportion of individuals with prescription-records for any psychotropic medication during the 2 years after the schizophrenia diagnosis decreased from 88% to 74%, particularly antipsychotics (from 83% to 61%) and antidepressants (from 49% to 35%). This was particularly observed among those aged 18-30 years at the schizophrenia diagnosis. A similar decrease was not observed for prescription-records of somatic medications., Conclusion: The introduction of free-of-charge antipsychotics has affected the redemption of specific psychotropic drugs in the DNPR in first-episode schizophrenia. This limitation needs to be considered in register-based studies and emphasizes the need to identify solutions., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

The second-generation antipsychotic quetiapine is commonly used off-label for its anxiolytic and hypnotic properties. However, quetiapine is associated with problematic side-effects. We used Danish Medicinal Product Statistics and a 20% random sample of the Danish population's prescription fills (2001-2020) to describe the utilization of quetiapine and proportion of various prescriber types (general practitioner [GP], specialist in private practice, hospital physician and other prescribers) both in connection to first-time and subsequent prescriptions. In 2020, 92% of all quetiapine was dispensed outside hospitals and the average daily dispensed quantity of quetiapine per user corresponded to 100 mg/user/d. A GP issued 53% of first-time prescriptions and 75% of subsequent prescriptions for quetiapine in 2020. The proportion of quetiapine prescriptions issued by GPs varied by age group-from 14% among 0-17-year-olds to 93% among the ≥80-year-olds. Future initiatives on the rational use of quetiapine and related drugs, especially among adults, should target GPs., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Many patients with schizophrenia experience psychiatric symptoms long before being diagnosed. We investigated patterns of pre-diagnostic psychopharmacological treatment in individuals diagnosed with first-episode schizophrenia during the last two decades., Design: Using Danish nationwide healthcare registers, we identified all individuals aged ≥10 years registered with their first ICD-10 schizophrenia diagnosis between January 1999 and March 2019. For each calendar year from 1999 to 2019, we calculated the proportion of patients - among those having received their first schizophrenia diagnosis in the respective calendar year - who redeemed prescriptions for various psychotropics in the two years preceding the schizophrenia diagnosis. We calculated proportions of all pre-diagnostic prescriptions since 1995 for a sub-population diagnosed 2011-2019 and for an age- and sex-matched reference group without schizophrenia., Results: Among 33,361 individuals with schizophrenia (58 % males), the schizophrenia incidence rate was stable during the study period but the mean age at diagnosis decreased by >10 years. In the two pre-diagnostic years, 69 % received psychopharmacological treatment (52 % antipsychotics, 40 % antidepressants). This was stable between 1999 and 2019. Among 14,425 individuals diagnosed 2011-2019, psychotropic drug use was observed among 14-20 % between 24 and 10 years before the diagnosis, being four times higher than the reference group. Particularly antipsychotic and antidepressant drug use increased steadily during the ten pre-diagnostic years., Conclusions: Pre-diagnostic psychotropic drug use in schizophrenia was frequent but stable between 1999 and 2019 despite an earlier identification of schizophrenia patients. Our findings emphasize the continued importance of thorough diagnostic interviews, particularly among patients in need of antipsychotic treatment., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The association between lithium use and chronic kidney disease (CKD) needs further evaluation. We aimed to investigate this association using Danish nationwide healthcare registers and routinely collected plasma creatinine measurements from the Funen Laboratory Cohort. We conducted a case-control study nested within the population of Funen, 2001-2015. Incident cases of CKD (estimated glomerular filtration rate <60 ml/min/1.73m 2 ; n = 21 432) were matched with four CKD-free controls on age, sex and calendar time (n = 85 532). We estimated odds ratios (OR) for the association between lithium exposure and CKD using conditional logistic regression models, adjusted for known risk factors for CKD. Ever-use of lithium was associated with an increased risk of CKD (adjusted OR [aOR]: 1.57; 95% confidence interval [CI]: 1.33-1.85). A stronger association was seen with current use of lithium (aOR: 1.92; 95%CI: 1.58-2.33) and long-term use of lithium (>10 years: aOR: 3.02; 95%CI: 2.00-4.56). Furthermore, we found evidence of a dose-response relationship between cumulative dose of lithium and the risk of CKD. In conclusion, the use of lithium, especially long-term, is associated with an increased risk of CKD, although the extent to which detection bias and confounding by indication contribute to the association is unclear. Monitoring of kidney function in lithium users remains mandatory to identify individuals in which switching to alternative medications should be considered., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objective: To determine the diagnostic accuracy of point-of-care ultrasound in suspected pulmonary embolism., Design: Systematic review and meta-analysis., Data Sources: MEDLINE, Embase, CINAHL and Cochrane library were searched on 2 July 2020 with no restrictions on the date of publication. Subject headings or subheadings combined with text words for the concepts of pulmonary embolism, ultrasound and diagnosis were used., Eligibility Criteria and Data Analysis: Eligible studies reported sensitivity and specificity of deep venous, lung, cardiac or multiorgan ultrasound in patients with suspected pulmonary embolism, using an adequate reference-test. Prospective, cross-sectional and retrospective studies were considered for eligibility. No restrictions were made on language. Studies were excluded if a control group consisted of healthy volunteers or if transesophageal or endobronchial ultrasound was used. Risk of bias was assessed using quality assessment of diagnostic accuracy studies-2. Meta-analysis of sensitivity and specificity was performed by construction of hierarchical summary receiver operator curves. I 2 was used to assess the study heterogeneity., Main Outcome Measures: The primary outcome was overall sensitivity and specificity of reported ultrasound signs, stratified by organ approach (deep venous, lung, cardiac and multiorgan). Secondary outcomes were stratum-specific sensitivity and specificity within subgroups defined by pretest probability of pulmonary embolism., Results: 6378 references were identified, and 70 studies included. The study population comprised 9664 patients with a prevalence of pulmonary embolism of 39.9% (3852/9664). Risk of bias in at least one domain was found in 98.6% (69/70) of included studies. Most frequently, 72.8% (51/70) of studies reported >24 hours between ultrasound examination and reference test or did not disclose time interval at all. Level of heterogeneity ranged from 0% to 100%. Most notable ultrasound signs were bilateral compression of femoral and popliteal veins (22 studies; 4708 patients; sensitivity 43.7% (36.3% to 51.4%); specificity 96.7% (95.4% to 97.6%)), presence of at least one hypoechoic pleural-based lesion (19 studies; 2134 patients; sensitivity 81.4% (73.2% to 87.5%); specificity 87.4% (80.9% to 91.9%)), D-sign (13 studies; 1579 patients; sensitivity 29.7% (24.6% to 35.4%); specificity 96.2% (93.1% to 98.0%)), visible right ventricular thrombus (5 studies; 995 patients; sensitivity 4.7% (2.7% to 8.1%); specificity 100% (99.0% to 100%)) and McConnell's sign (11 studies; 1480 patients; sensitivity 29.1% (20.0% to 40.1%); specificity 98.6% (96.7% to 99.4%))., Conclusion: Several ultrasound signs exhibit a high specificity for pulmonary embolism, suggesting that implementation of ultrasound in the initial assessment of patients with suspected pulmonary embolism may improve the selection of patients for radiation imaging., Prospero Registration Number: CRD42020184313., Competing Interests: Competing interests: JEM has received grants and personal fees from Abiomed, personal fees from Novartis, personal fees from Orion Pharma and personal fees from Boeinger Ingleheim outside the submitted work., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Chlorprothixene is commonly used off-label in low doses for sedative-hypnotic purposes although it might carry a risk of cardiometabolic adverse events due to its pharmacodynamic profile. We investigated the risk of diabetes and major adverse cardiovascular events (MACE) with use of low-dose chlorprothixene, compared with use of low-dose quetiapine in a nationwide cohort study, including all new users of low-dose chlorprothixene (n = 81 328) and low-dose quetiapine (n = 91 163) in Denmark 2000-2017. Main outcomes were diabetes and MACE (myocardial infarction, stroke and death from cardiovascular causes). The association between cumulative dose of chlorprothixene and the outcomes was tested in a case-control analysis. Low-dose chlorprothixene use was associated with increased risk of diabetes (intention-to-treat [ITT]-hazard ratio [HR]: 1.16; 95% CI: 1.08-1.25), compared with low-dose quetiapine use. This association strengthened when follow-up was restricted to time on treatment (as-treated [AT]-HR: 1.34; 95% CI: 1.14-1.56). Low-dose chlorprothixene use was also associated with increased risk of MACE (ITT-HR: 1.12; 95% CI: 1.04-1.21) and stroke (ITT-HR: 1.21; 95% CI: 1.06-1.37) but not with myocardial infarction (ITT-HR: 1.11; 95% CI: 0.95-1.30) nor death from cardiovascular causes (ITT-HR: 1.07; 95% CI: 0.96-1.20). Cumulative dose of chlorprothixene ≥6000 mg was associated with increased risk of diabetes (OR: 1.15-1.63; test for trend: p < 0.001), whereas cumulative dose of chlorprothixene ≥1500 mg was associated with increased risk of MACE (OR: 1.10-1.85; test for trend: p < 0.001). In conclusion, low-dose chlorprothixene use is associated with increased risk of cardiometabolic adverse events compared with low-dose quetiapine use., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Purpose: Sodium-glucose cotransporter-2 inhibitors (SGLT2-I) are frequently used in type 2 diabetes and have recently been associated with lower rates of gout compared to glucagon-like peptide-1 receptor agonists (GLP1-RA). Our objective was to assess the association between SGLT2-I initiation and gout using a cohort study design and a symmetry analysis., Methods: Using the Danish nationwide health registries, we conducted an active comparator, new user cohort study comparing the 3-year risk of gout among SGLT2-I users with propensity score matched GLP1-RA users. Individuals were followed according to the intention-to-treat, and incidence rate differences (IRD) and hazard ratios (HR) were obtained. To address unmeasured confounding that is stable over time, a corresponding symmetry analysis was performed., Results: 11 047 pairs of SGLT2-I and GLP1-RA users were identified, contributing 42 201 person-years of follow-up. The incidence rate of gout was 4.1 and 7.0 events per 1000 person years among SGLT2-I and GLP1-RA users, yielding an IRD of -3.0 (95% confidence interval: -4.4 to -1.5) and HR of 0.58 (0.44 to 0.75). In the symmetry analysis, 80 individuals initiated SGLT2-Is prior to gout; 118 patients initiated treatment after gout. The trend adjusted SR was 0.63 (0.47 to 0.84) and the active comparator adjusted estimate was 0.67 (0.44 to 0.86)., Conclusions: Initiation of SGLT2-Is was associated with a markedly decreased risk of gout compared to initiation of GLP1-RAs. The findings are comparable to prior studies addressing this association., (© 2021 John Wiley & Sons Ltd.)

Background: Dose reduction of antipsychotic maintenance treatment in individuals with schizophrenia could be desirable to minimise adverse effects, but evidence for this strategy is unclear. We aimed to compare risks and benefits of reduced versus standard doses of antipsychotics., Methods: We searched Embase, Medline, PsycINFO, and the Cochrane Library from database inception until June 17, 2020, for randomised trials in adults with schizophrenia or schizoaffective disorder lasting at least 24 weeks, including individuals clinically stable at baseline, and comparing at least two doses of the same antipsychotic, excluding trials in first-episode psychosis or treatment-resistant schizophrenia. We compared low-dose (within 50-99% of the lower limit of the standard dose) and very-low dose (less than 50% of the lower limit) with standard dose, defined as doses higher than the lower limit of the treatment dose recommended by the International Consensus Study. Data from published reports on number of participants, treatment, sex, age, number of events, and changes in psychopathology scores were extracted independently by at least two authors. Investigators or sponsors were contacted by email to obtain missing information regarding outcomes. Co-primary outcomes were relapse and all-cause discontinuation. Study-level data were meta-analysed using random-effects models, calculating risk ratios (RRs) for dichotomous data, and Hedges' g for continuous data. The protocol was registered with OSF registries., Findings: 7853 references were identified in the database search and one additional reference from a manual review of relevant studies. 5744 abstracts were assessed for eligibility, and 101 references were assessed for full-text review. Of these, 79 were excluded for a variety of reasons, resulting in 22 studies being included in the meta-analysis, reporting on 24 trials and 3282 individuals. Study participants had a median age of 38 years (IQR 36-40) with 2166 (65·9%) males and 1116 (34·0%) females. Compared with standard dose, low dose increased the risk of relapse by 44% (16 trials, 1920 participants; RR 1·44, 95% CI 1·10-1·87; p=0·0076; I 2 =46%) and the risk of all-cause discontinuation by 12% (16 trials, 1932 participants; RR 1·12, 1·03-1·22; p=0·0085; I 2 =0%). Very low dose increased the risk of relapse by 72% (13 trials, 2058 participants; RR 1·72, 95% CI 1·29-2·29; p=0·0002; I 2 =70%) and all-cause discontinuation by 31% (11 trials, 1866 participants; RR 1·31, 1·11-1·54; p=0·0011; I 2 =63%). Compared with low dose, very low dose did not significantly increase the risk of relapse (five trials, 686 participants; RR 1·31, 95% CI 0·96-1·79; p=0·092; I 2 =51%) or all-cause discontinuation (five trials 686 participants; RR 1·11, 95% CI 0·95-1·30; p=0·18; I 2 =43%). Subgroup analyses comparing double-blind versus open-label studies, first-generation versus second-generation antipsychotics, and oral versus long-acting injectable antipsychotics were consistent with the overall results. Most studies were classified as having some concerns in the risk of bias assessment, which was mainly caused by absence of publicly available study registrations., Interpretation: During maintenance treatment in multi-episode schizophrenia, antipsychotic doses should probably not be reduced below the standard dose range recommended for acute stabilisation, because reducing the dose further is associated with an increased risk of both relapse and all-cause discontinuation., Funding: None., Competing Interests: Declaration of interests Since 2018, PMH has received honoraria for lecturing and consultancy from Janssen, Lundbeck, NewBridge Pharmaceuticals, Otsuka and Sunovion. Since 2018, JCN has received honoraria for consultancy from Janssen and Lundbeck. Since 2018, CUC reports personal fees from Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter-Recordati, Gerson Lehrman Group, IntraCellular Therapies, Janssen and Johnson & Johnson, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva; personal fees from Bristol-Myers Squibb, Janssen, and Otsuka; royalties from UpToDate; and stock options from LB Pharma, outside of the submitted work. MH and AFK declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: Quetiapine has been associated with increased risk of type 2 diabetes when used in medium or high doses for the treatment of severe mental disorders. It is not known whether low doses, commonly used off-label for sedative-hypnotic purposes, are also associated with increased risk of type 2 diabetes., Objective: To investigate whether there is an association between prescription of low-dose quetiapine and the risk of type 2 diabetes., Design, Setting, and Participants: This cohort study examined nationwide Danish health registers for data regarding new users of quetiapine (n = 185 938) or selective serotonin reuptake inhibitors (SSRIs) (n = 1 031 920) who were aged 18 years or older between January 1, 1998, and December 31, 2018. Individuals with schizophrenia or bipolar disorder were excluded. Quetiapine-initiators were matched 1:1 with initiators of SSRIs, using a high-dimensional propensity score (hdPS). Maximum follow-up was 5 years. Association with cumulative dose was investigated, using a case-control approach nested among quetiapine users. Data analysis was performed from May to September 2020., Exposures: Dispensing of quetiapine or SSRIs. Quetiapine prescriptions were limited to tablet strengths of 25 mg and 50 mg to focus on low-dose use., Main Outcomes and Measures: Incident type 2 diabetes was defined as first filling of an antidiabetic medication, first register diagnosis of type 2 diabetes or first hemoglobin A1C measurement greater than or equal to 6.4% (≥48 mmol/mol). Incidence rates (IRs), incidence rate ratios (IRRs), and number-needed-to-harm (NNH) were calculated for full and matched cohorts using as-treated and intention-to-treat approaches. Odds ratios (ORs) were calculated for the association with cumulative quetiapine dose., Results: Altogether, 896 285 patients were included in the full cohort; 538 164 (60%) were female and the median (interquartile range) age was 47 (33-67) years. There were 57 701 low-dose quetiapine initiators and 838 584 SSRI initiators. The matched cohort consisted of 54 616 pairs. In as-treated analyses, the incidence of type 2 diabetes during treatment with low-dose quetiapine (425 cases) was 9.59 cases/1000 person-years (PY) (95% CI, 8.72-10.5/1000 PY), which was slightly higher than for SSRI users (8462 cases; IR, 8.13/1000 PY; 95% CI, 7.96-8.30/1000 PY), resulting in a significant IRR of 1.18 (95% CI, 1.07-1.30) and NNH of 684 (95% CI, 418-1873). However, the between-group difference was nonsignificant in the hdPS-matched cohort (IR, 9.49 vs IR, 9.58; IRR, 0.99; 95% CI, 0.87-1.13). The case-control analysis found no dose-response association of low-dose quetiapine with diabetes (OR for doubling of the cumulative dose: 1.02; 95% CI, 0.95-1.09; P = .54), but in sensitivity analyses higher daily doses were associated with diabetes (all tablet strengths: OR, 1.08; 95% CI, 1.03-1.13)., Conclusions and Relevance: In this cohort study, use of low-dose quetiapine was not associated with excess risk of type 2 diabetes in comparison with SSRIs.

Purpose/background: Prolonged QT interval related to psychopharmacological treatment is a risk factor for potentially life-threatening arrhythmias. Electrocardiographic measurements are recommended in patients with cardiovascular risk factors before initiating treatment with potentially QT-prolonging medications, such as certain antidepressants or antipsychotics. In patients with left bundle branch block (LBBB) or right bundle branch block (RBBB), conventional QT-estimation methods will lead to overestimation of the QT interval, as the conduction defect, reflected by the QRS duration, will increase the QT interval without representing longer repolarization as in drug-induced QT prolongation., Methods/procedures: We conducted a systematic review of methods to estimate QT interval in the presence of LBBB or RBBB. We searched electronic databases Embase and Medline (last search, August 12, 2020)., Findings/results: We found 8 different methods, including linear correction formulae with and without correction for heart rate, or simpler formula correcting QRS duration with empirically derived modifiers. Only 3 of 8 methods were applicable in the presence of RBBB, whereas all 8 methods could be applied in the presence of LBBB., Implications/conclusions: The QT interval is overestimated in patients with LBBB or RBBB, when using conventional measurements. Several alternative correction formulae exist, which can be applied using standard measurements from ordinary electrocardiographic readings. However, it is currently unknown whether or not the QT prolongation observed in the presence of bundle branch block significantly increases the risk of arrhythmias, as these formulae have not been tested against patient-specific clinical outcomes., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) are two distinct phenotypes of chronic lung allograft dysfunction (CLAD) in lung transplant (LTx) recipients. Contrary to BOS, RAS can radiologically present with a pleuroparenchymal fibroelastosis (PPFE) pattern. This study investigates lung ultrasound (LUS) to identify potential surrogate markers of PPFE in order to distinguish CLAD phenotype RAS from BOS., Methods: A prospective cohort study performed at a National Lung Transplantation Center during June 2016 to December 2017. Patients were examined with LUS and high-resolution computed tomography of the thorax (HRCT)., Results: Twenty-five CLAD patients (72% males, median age of 54 years) were included, corresponding to 19/6 BOS/RAS patients. LUS-identified pleural thickening was more pronounced in RAS vs. BOS patients (5.6 vs. 2.9 mm) compatible with PPFE on HRCT. LUS-identified pleural thickening as an indicator of PPFE in RAS patients' upper lobes showed a sensitivity of 100% (95% CI; 54-100%), specificity of 100% (95% CI; 82-100%), PPV of 100% (95% CI; 54-100%), and NPV of 100% (95% CI; 82-100%)., Conclusion: Apical pleural thickening detected by LUS and compatible with PPFE on HRCT separates RAS from BOS in patients with CLAD. We propose LUS as a supplementary tool for initial CLAD phenotyping.

Background: Lifestyle interventions aimed at reducing cardiovascular risk factors in patients with first-episode schizophrenia (FES) have shown modest efficacy, probably owing to a short observation period and the presumption of linear trajectories of cardiovascular risk factors., Study Question: How prevalent are abnormal cardiovascular values in patients with FES and how do cardiovascular risk factors develop during a 30-month program?, Study Design: A 30-month naturalistic longitudinal study of 136 consecutively referred patients with FES from 2 outpatient clinics. The health-promoting program consisted of individual guidance, group sessions, and normal treatment and care., Measures and Outcomes: The prevalence of abnormal cardiovascular risk factors (body mass index, waist circumference (WC), body fat percentage, systolic and diastolic blood pressure, pulse, total cholesterol, high- and low-density lipoproteins, triglycerides, mean glucose, and visceral adiposity index) was estimated at index. The cardiovascular risk factor trajectories were analyzed with longitudinal mixed-effect models., Results: The patient with FES showed elevated cardiovascular risk factors at index. Thus, 56.8% of the patients were overweight in different grades and 50.4% had increased WC. A total of 81.8% had high level of body fat and hypertension prevalence with only 20% with normal blood pressure. Important changes during the intervention period were that the risk factors weight and WC were increasing the first 581 and 646 days, after which they decreased. Almost all cardiovascular risk factors worsened initially, improving after 1-2 years., Conclusions: Patients with FES show increases in cardiovascular risk factors at index. Short observation periods and the presumption of linear trajectories may indicate that the effect of health-promoting programs is ineffective, as the effects are curvilinear and improvements appear only after 1 year. The implication clinically is the importance of a long intervention period regarding lifestyle modifications to ascertain improvement among patients with FES.

Objectives: To examine the association between use of second-generation antipsychotics (SGA) and the risk of chronic kidney disease (CKD)., Design: Population-based case-control study., Setting: Routinely collected laboratory, prescription and diagnostic information on all inhabitants with creatinine measurements residing on the island of Funen, Denmark (2001 to 2015)., Participants: 21 434 cases with incident CKD matched with 85 576 CKD-free population controls by risk-set sampling using age, sex and calendar year., Primary and Secondary Outcome Measures: CKD was defined as an estimated glomerular filtration rate below 60 mL/min/1.73 m 2 in a period longer than 3 months. Information on drug exposure and comorbidities were obtained from the Danish National Prescription Register and the Danish National Patient Register. We calculated OR for the association between SGA use and CKD using conditional logistic regression., Results: Use of SGAs was associated with increased risk of CKD among ever users (OR 1.24, 95% CI: 1.12 to 1.37) and current users (OR 1.26, 95% CI: 1.12 to 1.42). We found no clear evidence of dose-response relationship. Both short duration (one to two antipsychotic prescriptions; OR 1.22, 95% CI: 1.01 to 1.48) as well as long-term use (>30 prescriptions; OR 1.45, 95% CI 1.19 to 1.76) were associated with an increased risk of CKD. Both use of SGAs with mild and high risk of metabolic disturbances was associated with increased risk of CKD (OR 1.21, 95% CI: 1.06 to 1.39 and OR 1.36, 95% CI: 1.11 to 1.68, respectively). Recent use of non-steroidal anti-inflammatory drugs, prior use of lithium, hypertension or prior acute kidney injury were not clearly associated with development of CKD connected to SGA exposure. The highest risk of CKD was found for clozapine (OR 1.81, 95% CI: 1.22 to 2.69)., Conclusion: Use of SGA is associated with a small-to-moderately increased risk of incident CKD. All investigated SGAs, except for aripiprazole, were associated with an increased risk of CKD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The aim of this study was to investigate time trends in dosing and prevalence of antipsychotic prescriptions in Scandinavia., Methods: We retrieved data on antipsychotic use between 2006 and 2016 from Danish, Norwegian and Swedish national prescription registers. For each antipsychotic, we calculated prevalence of use and mean doses, overall and for specific age groups (young, adults and elderly)., Results: Antipsychotic use in Scandinavia increased from 16.5 to 17.2 users/1000 inhabitants between 2006 and 2016 (+2.4%, annual change: 0.07 users/1000 inhabitants/year, 95% CI: 0.02-0.20, P = 0.02). In 2006, chlorprothixene and levomepromazine were the most commonly used antipsychotics. By 2016, quetiapine was the most used antipsychotic in all three countries and across all age groups, with an overall 1-year prevalence of 4.05-9.97 users/1000 inhabitants (annual change: 0.57 users/1000 inhabitants/year, 95% CI: 0.54-0.60, P < 0.001). Quetiapine showed a marked decrease in mean doses during the 11-year study period (0.46-0.28 defined daily doses (DDD)/user/day: 39.1%, -0.02 DDD/user/day/year, 95% CI: -0.020 to -0.015, P < 0.001). In 2016, the highest mean doses were seen for clozapine (0.90-1.07 DDD/user/day) and olanzapine (0.66-0.88 DDD/user/day)., Conclusions: There is an increased prevalence of antipsychotic prescriptions that coincides with low and/or decreasing mean doses of the majority of commonly used antipsychotics in Scandinavia. Of all antipsychotics, this development was most pronounced for quetiapine. Reasons for and consequences of increased antipsychotic use that lasts shorter periods of time requires further study., (© 2019 The British Pharmacological Society.)