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Leon Alexander Mclaren Berge, 1, 2 Bettina Kulle Andreassen, 1 Jo S Stenehjem, 1–3 Trond Heir, 4, 5 Kari Furu, 6 Asta Juzeniene, 7 Ingrid Roscher, 8 Inger Kristin Larsen, 9 Adele C Green, 10, 11 Marit B Veierød, 2 Trude E Robsahm 1 1Department of Research, Cancer Registry of Norway, Oslo, Norway; 2Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; 3Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway; 4Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; 5Oslo Ischemia Study, Oslo University Hospital, Oslo, Norway; 6Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway; 7Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; 8Department of Rheumatology, Dermatology and Infectious Diseases, Oslo University Hospital, Oslo, Norway; 9Department of Registration, Cancer Registry of Norway, Oslo, Norway; 10QIMR Berghofer Medical Research Institute, Brisbane, Australia; 11CRUK Manchester Institute, University of Manchester, Manchester, UKCorrespondence: Leon Alexander Mclaren BergeCancer Registry of Norway, P.O. Box 5313 Majorstuen, Oslo N-0304, NorwayTel +47 99605034Email Leon.Berge@kreftregisteret.noPurpose: Melanoma is the cancer with the most rapidly rising incidence rate in Norway. Although exposure to ultraviolet radiation (UVR) is the major environmental risk factor, other factors may also contribute. Antidepressants have cancer inhibiting and promoting side effects, and their prescription rates have increased in parallel with melanoma incidence. Thus, we aimed to prospectively examine the association between use of antidepressants and melanoma by using nation-wide data from the Cancer Registry of Norway, the National Registry, the Norwegian Prescription Database and the Medical Birth Registry of Norway.Patient and Methods: All cases aged 18– 85 with a primary cutaneous invasive melanoma diagnosed during 2007– 2015 (n=12,099) were matched to population controls 1:10 (n=118,467) by sex and year of birth using risk-set sampling. We obtained information on prescribed antidepressants and other potentially confounding drug use (2004– 2015). Conditional logistic regression was used to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) for the association between overall and class-specific use of antidepressants and incident melanoma.Results: Compared with ≤ 1 prescription, ≥ 8 prescriptions of antidepressants overall were negatively associated with melanoma (RR 0.81 CI 0.75– 0.87). Class-specific analyses showed decreased RRs for selective serotonin reuptake inhibitors (RR 0.82 CI 0.73– 0.93) and mixed antidepressants (RR 0.77 CI 0.69– 0.86). The negative association was found for both sexes, age ≥ 50 years, residential regions with medium and highest ambient UVR exposure, all histological subtypes, trunk, upper and lower limb sites and local disease.Conclusion: Use of antidepressants was associated with decreased risk of melanoma. There are at least two possible explanations for our results; cancer-inhibiting actions induced by the drug and less UVR exposure among the most frequent users of antidepressants.Keywords: antidepressants, melanoma, prescription drugs, pharmacoepidemiology, registry-based

Objective: To compare antidepressant utilization in individuals aged 5–19 years from the Scandinavian countries. Methods: A population‐based drug utilization study using publicly available data of antidepressant use from Denmark, Norway, and Sweden. Results: In the study period from 2007 to 2017, the proportion of antidepressant users increased markedly in Sweden (9.3–18.0/1000) compared to Norway (5.1–7.6/1000) and Denmark (9.3–7.5/1000). In 2017, the cumulated defined daily doses (DDD) of selective serotonin reuptake inhibitors were 5611/1000 inhabitants in Sweden, 2709/1000 in Denmark, and 1848/1000 in Norway. The use of 'other antidepressants' (ATC code N06AX) also increased in Sweden with a higher DDD in 2017 (497/1000) compared to Denmark (225/1000) and Norway (170/1000). The use of tricyclic antidepressants was generally low in 2017 with DDDs ranging between 30–42 per 1000. The proportion of antidepressant users was highest among 15‐ to 19‐year‐old individuals. Girls were more likely to receive treatment than boys, and the treated female/male ratios per 1000 were similar in Sweden (2.39), Denmark (2.44), and Norway (2.63). Conclusion: Even in highly comparable healthcare systems like the Scandinavian countries', variation in antidepressant use is considerable. Swedish children and adolescents have a markedly higher and still increasing use of antidepressants compared to Danish and Norwegian peers. [ABSTRACT FROM AUTHOR]

Objective There is some evidence that clozapine is significantly underutilised. Also, clozapine use is thought to vary by country, but so far no international study has assessed trends in clozapine prescribing. Therefore, this study aimed to assess clozapine use trends on an international scale, using standardised criteria for data analysis. Method A repeated cross-sectional design was applied to data extracts (2005-2014) from 17 countries worldwide. Results In 2014, overall clozapine use prevalence was greatest in Finland (189.2/100 000 persons) and in New Zealand (116.3/100 000), and lowest in the Japanese cohort (0.6/100 000), and in the privately insured US cohort (14.0/100 000). From 2005 to 2014, clozapine use increased in almost all studied countries (relative increase: 7.8-197.2%). In most countries, clozapine use was highest in 40-59-year-olds (range: 0.6/100 000 (Japan) to 344.8/100 000 (Finland)). In youths (10-19 years), clozapine use was highest in Finland (24.7/100 000) and in the publicly insured US cohort (15.5/100 000). Conclusion While clozapine use has increased in most studied countries over recent years, clozapine is still underutilised in many countries, with clozapine utilisation patterns differing significantly between countries. Future research should address the implementation of interventions designed to facilitate increased clozapine utilisation. [ABSTRACT FROM AUTHOR]

Objective To study trends in use of antidepressants (ADs) by adolescents, and psychiatric morbidity and use of other psychotropic drugs as a measure of psychiatric comorbidity. Methods One-year prevalence of AD drug use was analyzed for 13- to 17-year-old Norwegians during 2004-2013. Use of other psychotropic drugs and specialist healthcare services was analyzed for incident AD users in 2012, using linked data from the Norwegian Prescription Database and the Norwegian Patient Register. Results The 1-year prevalence of AD drug use increased from 6.4/1000 to 9.1/1000 during 2004-2013, with the steepest increase from 2010, particularly among girls. The highest prevalence was found in 17-year-old girls (17.8/1000 in 2010, 27.5/1000 in 2013). Of incident AD drug users in 2012, 84.4% had been in contact with specialist health care. As the first drug, 78.4% were prescribed a selective serotonin reuptake inhibitor. The most common types of other psychotropic drugs were melatonin (24.6%), antipsychotic drugs (13.2%), stimulants (8.8%), and anxiolytics (6.0%). Conclusions Use of ADs among adolescents has increased over the last 3-4 years, particularly among 16- to 17-year-old girls. A total of 85% of incident users had been in contact with specialist health care, which may indicate that drug-therapy is used by adolescents with more severe symptoms. [ABSTRACT FROM AUTHOR]

Objectives: To estimate the association between prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and motor development in children considering the effect of maternal symptoms of anxiety and depression before, during and after pregnancy.Design: Population-based prospective pregnancy cohort study.Setting: The Norwegian Mother and Child Cohort study (MoBa) (1999-2008).Population: A total of 51 404 singleton pregnancies.Methods: Self-reported use of SSRIs was collected for the 6 months before pregnancy and prospectively during pregnancy. We used ordinal logistic regression as the statistical analysis.Main Outcome Measures: Motor development was assessed by maternal reports of fine and gross motor development at child age 3 years by items from the Ages and Stages Questionnaire (ASQ). The maternal ASQ scores were compared with data from a MoBa sub-study where clinicians assessed motor development with the Gross and Fine Motor Mullen scales of early learning.Results: In all 381 women (0.7%) reported use of SSRIs during pregnancy, of these 159 reported on at least two questionnaires (prolonged use). Prolonged SSRI exposure was associated with a delay in fine motor development, odds ratio 1.42 (95% CI 1.07-1.87) compared with no SSRI exposure, after adjusting for symptoms of anxiety and depression before and during pregnancy. Severity of maternal depression seemed to explain the association only partially. Stratifying on depression after pregnancy had no impact on the estimated effect of SSRIs.Conclusions: Prolonged prenatal exposure to SSRIs was weakly associated with a delayed motor development at age 3 years, but not to the extent that the delay was of clinical importance.Tweetable Abstract: Long-term prenatal SSRI exposure is weakly associated with delayed motor development independent of depression. [ABSTRACT FROM AUTHOR]

Objective: To assess whether the use of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, mirtazapine, venlafaxine or other antidepressants is associated with late elective termination of pregnancy.Design: Case-control study using data from national registers.Setting: Denmark, Finland, and Norway during the period 1996-2007.Population: A total of 14,902 women were included as cases and 148,929 women were included as controls.Methods: Cases were women with elective termination of pregnancy at 12-23 weeks of gestation. Controls continued their pregnancy and were matched with cases on key factors.Main Outcome Measures: Association between antidepressant use during pregnancy and elective termination of pregnancy at 12-23 weeks of gestation for fetal anomalies, or for maternal ill health or socio-economic disadvantage.Results: At least one prescription of antidepressants was filled by 3.7% of the cases and 2.2% of the controls. Use of any type of antidepressant was associated with elective termination of pregnancy for maternal ill health or socio-economic disadvantage (odds ratio, OR 2.3; 95% confidence interval, 95% CI 2.0-2.5). Elective termination of pregnancy for fetal anomalies was associated with the use of mirtazapine (OR 2.2, 95% CI 1.1-4.5). There was no association between the use of any of the other antidepressants and elective termination of pregnancy for fetal anomalies.Conclusion: The use of any type of antidepressants was associated with elective termination of pregnancy at 12-23 weeks for maternal ill health or socio-economic disadvantage, but not with terminations for fetal anomalies. Further studies need to confirm the findings concerning mirtazapine and termination of pregnancy for fetal anomalies. [ABSTRACT FROM AUTHOR]

Background: Small non-coding RNAs play essential roles in gene regulation, however, the interplay between RNA groups, their expression levels and deregulations in tumorigenesis requires additional exploration. In particular, a comprehensive analysis of microRNA (miRNA), PIWI-interacting RNAs (piRNAs), and tRNA-derived small RNAs in human testis and testicular germ cell tumor (TGCT) is lacking. Results: We performed small RNA sequencing on 22 human TGCT samples from 5 histological subtypes, 3 carcinoma in situ, and 12 normal testis samples. miRNA was the most common group among the sequences 18–24 nt in length and showed histology-specific expression. In normal samples, most sequences 25–31 nucleotides in length displayed piRNA characteristics, whereas a large proportion of the sequences 32–36 nt length was derived from tRNAs. Expression analyses of the piRNA population demonstrated global loss in all TGCT subtypes compared to normal testis. In addition, three 5' small tRNA fragments and 23 miRNAs showed significant (p < 10−6) differential expression in cancer vs normal samples. Conclusions: We have documented significant changes in the small RNA populations in normal adult testicular tissue and TGCT samples. Although components of the same pathways might be involved in miRNA, piRNA and tRNA-derived small RNA biogenesis, our results showed that the response to the carcinogenic process differs between these pathways, suggesting independent regulation of their biogenesis. Overall, the small RNA deregulation in TGCT provides new insight into the small RNA interplay. [ABSTRACT FROM AUTHOR]

Aims: To study the relationship between mental distress and later use of anxiolytic drugs, taking into account potential confounders such as lifestyle and socioeconomic factors. Methods: In a prospective cohort study, data from population-based health surveys from three Norwegian counties (2000-01) were linked to data from the Norwegian Prescription Database (NorPD) (2004-07). In the surveys, 9,386 men (43.1% of those invited) and 1, 44 women (52.4%) participated. The two age cohorts were 40 and 45 years old (cohort 1) and 60 years old (cohort 2). Participants in each age group were divided into quartiles (Q1-Q4) separately for men and women according to the degree of mental distress, measured by increasing Hopkins Symptom Checklist-10 score (HSCL-10 score) at baseline. Multivariate logistic regression was performed to assess predictors of anxiolytic drug use. Results: At baseline: Increasing HSCL-10 score was associated with: increasing use of specified prescribed drugs, poor health, ever having sought help because of mental distress, musculoskeletal pain, being married or in partnership, low educational level, receiving disability pension and current smoking (except for women 60 years old). Predictors found: There was a graded positive relationship between HSCL-10 score at baseline (2000-01) and the chance of a prescription of anxiolytics during follow-up (2004-07) in the 40 and 45 year olds. Predictors, regardless of age, were: female gender, reported use of hypnotics, having previously sought help because of mental distress and current smoking. Conclusions: HSCL-10 score was related to later use of anxiolytic drugs in a dose response manner. [ABSTRACT FROM AUTHOR]

PURPOSE: To assess 1-year prevalence, incidence rates and minimum refill of anti-osteoporosis drug use in Norway by age, gender and place of residence during 2004-2007. METHODS: Data from patients aged > or = 40 years receiving anti-osteoporosis drugs (AOD) were retrieved from the Norwegian Prescription Database (NorPD). AOD were defined as bisphosphonates (alendronate with or without cholecalciferol, risedronate, ibandronate and etidronate with or without calcium), raloxifene, teriparatide and nasal calcitonin. The NorPD covers the total Norwegian population in ambulatory care. Key measurements were 1-year prevalence, incidence rate and minimum refill. RESULTS: Among Norwegian women and men > or = 40 years, 4.3 and 0.45% respectively used AOD in 2004. In 2007, the prevalence of AOD use had slightly increased to 4.6% in women and to 0.52% in men. In 2007, 90% of users were women. The use of alendronate, representing 88% of all AOD use in 2007, increased from 2004 to 2007 while the use of other bisphosphonates decreased. The counties with highest overall bisphosphonate use were the counties with the historically lowest incidence of osteoporotic fractures. The incidence rate of overall bisphosphonate use decreased from 2005 to 2007. Among those patients who were dispensed a bisphosphonate in 2005, 72% refilled at least one prescription both in 2006 and 2007. CONCLUSION: There was an increasing prevalence and a decreasing incidence of AOD use over this limited time period. There was substantial geographical variation in the prevalence of anti-osteoporosis drugs. We also observed a high minimum refill rate. [ABSTRACT FROM AUTHOR]

The aim was to study the introduction of the new low dose transdermal buprenorphine (LD-TD-BUP) in Norway, particularly with regard to former use and co-medication with other potentially addictive drugs. The nationwide Norwegian Prescription Database contains information on all prescription drugs dispensed to individual non-institutionalised patients, and we may follow all individuals who received LD-TD-BUP (Norspan) after marketing on the Norwegian market on 15/11/05. We studied all prescriptions of opioids and other potentially addictive drugs to patients receiving at least two LD-TD-BUP prescriptions during 2004-2006. Poisson regressions were run with concomitant use of addictive drugs (yes, no) as the endpoint. Overall, 1884, non cancer individuals received at least two prescription of LD-TD-BUP. Of these 91.7% received prescriptions of other opioids and 58.6% of them had also been prescribed benzodiazepines/carisoprodol before the prescription of LD-TD-BUP. Of the LD-TD-BUP users who received more than one prescription, 60% co-medicated with at least one other potentially addictive drug, and 24% with at least two. In the multivariate analysis, the variables associated with a higher likelihood of using co-medicated drugs were: previous use of benzodiazepines/carisoprodol relative risk RR=16.7 (95% CI 10.4-26.9), previous use of opioids RR=4.0 (1.9-8.7) and younger age 20-40 years RR=1.9 (1.6-2.3). So far, it is questionable whether the introduction of LD-TD-BUP actually has stabilised opioids consumption or whether it has complicated and increased the consumption of potentially addictive drugs. [ABSTRACT FROM AUTHOR]

Objective. To assess Norwegian general practitioners' (GPs') level of potentially harmful drug prescribing for elderly patients. Design. Prescription data for 12 months were retrospectively retrieved from the Norwegian Prescription Database (NorPD). Data were assessed in relation to 13 prescription quality indicators. Setting. General practice. Subjects. A total of 454 GPs attending continuous medical education (CME) groups in Southern Norway, 85 836 patients >=70 years who received any prescription from the GPs during the study period. Main outcome measures. Number of prescriptions assessed in relation to pharmacological inappropriateness based on a list of 13 explicit prescription quality indicators. Results. Some 18.4% of the patients (66% females with mean age 79.8 years, 34% males with mean age 78.7 years) received one or more inappropriate prescriptions from their GP. An NSAID in a potentially harmful combination with another drug (7%) and a long-acting benzodiazepine (4.6%) were the most frequent inappropriate prescriptions made. Doctor characteristics associated with more inappropriate prescribing practice were old age and working single-handed with many elderly patients. Conclusion. The study reveals areas where GPs' prescribing practice for elderly patients can be improved and which can be targeted in educational interventions. [ABSTRACT FROM AUTHOR]