Trends in antidepressant use among children and adolescents: a Scandinavian drug utilization study.

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.

International trends in clozapine use: a study in 17 countries.

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.

Antidepressant drug use among adolescents during 2004-2013: a population-based register linkage study.

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.

Motor development in children prenatally exposed to selective serotonin reuptake inhibitors: a large population-based pregnancy cohort study.

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.

Profiling of the small RNA populations in human testicular germ cell tumors shows global loss of piRNAs.

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.

Use of antidepressants and association with elective termination of pregnancy: population based case-control study.

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.

The Nordic prescription databases as a resource for pharmacoepidemiological research--a literature review.

PURPOSE: All five Nordic countries have nationwide prescription databases covering all dispensed drugs, with potential for linkage to outcomes. The aim of this review is to present an overview of therapeutic areas studied and methods applied in pharmacoepidemiologic studies using data from these databases. METHODS: The study consists of a Medline-based structured literature review of scientific papers published during 2005-2010 using data from the prescription databases in Denmark, Finland, Iceland, Norway, and Sweden, covering 25 million inhabitants. Relevant studies were analyzed in terms of pharmacological group, study population, outcomes examined, type of study (drug utilization vs. effect of drug therapy), country of origin, and extent of cross-national collaboration. RESULTS: A total of 515 studies were identified. Of these, 262 were conducted in Denmark, 97 in Finland, 4 in Iceland, 87 in Norway, and 61 in Sweden. Four studies used data from more than one Nordic country. The most commonly studied drugs were those acting on the nervous system, followed by cardiovascular drugs and gastrointestinal/endocrine drugs. A total of 228 studies examined drug utilization and 263 focused on the effects and safety of drug therapy. Pregnant women were the most commonly studied population in safety studies, whereas prescribers' adherence to guidelines was the most frequent topic of drug utilization studies. CONCLUSIONS: The Nordic prescription databases, with their possibility of record-linkage, represent an outstanding resource for assessing the beneficial and adverse effects of drug use in large populations, under routine care conditions, and with the potential for long-term follow-up.

Hip fracture and other predictors of anti-osteoporosis drug use in Norway.

UNLABELLED: This study aims to find predictors of anti-osteoporosis drug (AOD) use. Known risk factors of osteoporosis, i.e., age, hip fracture, and corticosteroid use were found to be predictors of AOD use, in addition to a number of other drugs used. Higher socioeconomic position did not favor the use of AOD. INTRODUCTION: This study deals with studying predictors of anti-osteoporosis drug treatment in Norwegian women and men. METHODS: All Norwegian women and men≥50 years were included (n=1,407,392). Data were taken from different data sources, (1) the Norwegian Prescription Database (drug use in 2004-2005); (2) the Nationwide Census 2001 (marital status, education and resident county); (3) the National Hip Fracture Database (hip fractures 2003-2005); and (4) the National Population Register (date of death/emigration). We estimated the hazard ratios (HR) for incident treatment by Cox proportional hazard regression. RESULTS: In 2005, 10,332 women (1.5%) and 1,387 men (0.2%) were new users of anti-osteoporosis drugs (incident treatment). Age was a statistically significant predictor of incident treatment in both women and men, with HR ranging from 1.7 to 3.2 (per 10 years). A middle educational level in men strongly predicted incident treatment [HR 2.0 (CI 1.1-3.8)], but not in women after full adjustment. A previous hip fracture, increasing number of drugs used and use of corticosteroids were all predictors of incident treatment in both genders after adjustments. Corticosteroid use [HRwomen=4.0 (CI 3.8-4.2)] had a higher HR for incident treatment than hip fracture [HRwomen=2.0 (CI 1.8-2.3)]. Marital status and area of residency were not predictors of incident treatment in either gender, after adjustments. The predictors of prevalent treatment were only slightly different from incident treatment in 2005. CONCLUSIONS: Age, previous hip fracture, number of drugs used, and use of corticosteroids were positively related to treatment in both genders. In men, a middle educational level predicted treatment.

Outcomes after anti-rheumatic drug use before and during pregnancy: a cohort study among 150,000 pregnant women and expectant fathers.

OBJECTIVES: To study (i) the drug utilization pattern of anti-rheumatic drugs in pregnant women and expectant fathers and (ii) the association between the use of anti-rheumatic drugs during pregnancy and the risk of congenital malformations. METHOD: Pregnancies registered in the Medical Birth Registry of Norway (MBRN) were linked to the Norwegian Prescription Database (NorPD) in the period 2004-2007. Prescriptions for anti-rheumatic drugs issued to women 3 months prior to and during pregnancy and to men 3 months prior to conception were identified. Congenital malformations were recorded according to the European Surveillance of Congenital Anomalies (EUROCAT) guidelines. RESULTS: In 154,976 singleton pregnancies, 1461 of the women (0.9%) and 1198 (0.8%) of the known fathers (150,530) were dispensed anti-rheumatic drugs at least once during the study period: 723 had non-steroidal anti-inflammatory drugs (NSAIDs), 633 prednisolone (CS), 119 sulfasalazine (SASP), 101 azathioprine (AZA), 58 hydroxychloroquine (HQC), 37 etanercept (ETAN), eight methotrexate (MTX), two leflunomide (LEF), and three adalumimab (ADA). Odds ratios (ORs) for malformations in children born of women (w) or men (m) who had received the drugs were OR(w) = 1.06 [95% confidence interval (CI) 0.85-1.32] and OR(m) = 1.19 (95% CI 0.93-1.51), respectively, and for major malformation OR(w) = 1.05 (95% CI 0.79-1.40) and OR(m) = 1.26 (95% CI 0.93-1.71), respectively. None of the children whose mother had received MTX, LEF, ETAN, or ADA were reported to be born with major malformations. CONCLUSIONS: This study revealed no major malformations of the alert drugs MTX, LEF, ETAN, or ADA. Although the numbers are limited, this provides important population-based information to both expectant parents and prescribers.

Effect of the market withdrawal of carisoprodol on use of other prescribed drugs with abuse potential.

Carisoprodol, a centrally acting muscle relaxant indicated for acute lower back pain, has been available in Europe and the United States since 1959. Studies indicating increased risk of abuse or addiction led to withdrawal of the drug from the market in Norway and other EU countries in 2008. In this nationwide longitudinal prescription study of 53,116 individuals in Norway, previous users of carisoprodol switched, to a limited extent, to other prescribed drugs with abuse potential after the withdrawal.

Use of ADHD drugs in the Nordic countries: a population-based comparison study.

OBJECTIVE: To compare national use of attention-deficit/hyperactivity disorder (ADHD) drugs between five Nordic countries. METHOD: A population-based drug utilisation study based on nationwide prescription databases, covering in total 24 919 145 individuals in 2007. ADHD drugs defined according to the World Health Organization Anatomic Therapeutic Chemical classification system as centrally acting sympathomimetics (N06BA). RESULTS: The 2007 prevalence of ADHD drug use among the total Nordic population was 2.76 per 1000 inhabitants, varying from 1.23 per 1000 in Finland to 12.46 per 1000 in Iceland. Adjusting for age, Icelanders were nearly five times more likely than Swedes to have used ADHD drugs (Prev.Ratio = 4.53, 95% CI: 4.38-4.69). Prevalence among boys (age 7-15) was fourfold the prevalence among girls (Prev.Ratio = 4.28, 95% CI: 3.70-4.96). The gender ratio was diminished among adults (age 21 +) (Prev.Ratio = 1.24, CI: 1.21-1.27). CONCLUSION: A considerable national variation in use of ADHD drugs exists between the Nordic countries.

Body mass index as predictor for asthma: a cohort study of 118,723 males and females.

The objective of the present study was to quantify the relationship between body mass index (BMI; in kilogrammes per metre squared) and asthma in middle-aged males and females, and to evaluate change in BMI as a risk factor for asthma. Asthma incidence was estimated from data on redeemed prescriptions of anti-asthmatic drugs during the period 2004-2007, retrieved from the nationwide Norwegian Prescription Database. BMI was measured during health surveys in 1994-1999 in >100,000 individuals born during 1952-1959. Change in BMI was based on self-report. Relative risks were estimated using Poisson regression. The relative risk associated with a 3-unit increase in BMI ranged from 1.14 (95% confidence interval 1.10-1.18) in current smokers to 1.27 (1.22-1.32) in never-smokers after adjusting for confounders. The relative risk associated with a 3-unit increase in BMI was 1.21 (1.16-1.26) after adjusting for confounders, including sex, smoking and BMI. Asthma incidence, as measured by anti-asthmatic drug use, was positively related to both BMI and change in BMI. For BMI, the association was stronger for never-smokers than for ex-smokers and current smokers.

Undertreatment and overtreatment with statins: the Oslo Health Study 2000-2001.

OBJECTIVE: We examined the prevalence and factors associated with use of cholesterol-lowering statins in the population. METHODS: Demographic, medical, anthropometric and lifestyle data was obtained from 6233 men and 7521 women born in 1924/25, 1940/41, 1955 and 1960 that participated in the Oslo Health Study 2000-2001. A nonfasting blood sample was collected. RESULTS: Of subjects with a heart attack, angina, stroke or diabetes 45% of men and 35% of women were taking a statin (P < 0.001). Of subjects with cardiovascular disease (CVD) or diabetes taking statins 61% of men and 40% of women achieved total serum cholesterol levels < or =5 mmol L(-1). The odds ratio for taking a statin was increased amongst subjects who also took antihypertensive drug(s) or acetylsalicylic acid, subjects with a family history of coronary heart disease (CHD) and women who had visited the general practitioner within the last year. Amongst presumed healthy subjects use of statins increased from about 1% in women aged 40-45 years, to 7% at age 60 and to 12% at age 75 whilst the corresponding figures for men were 3%, 8% and 9%, respectively. About 22% of men but <2% of women aged 60 who were not taking statins had a 10-year Framingham CHD risk score >20%. Determinants of statin use were similar to those amongst subjects with CVD or diabetes. CONCLUSION: People with CVD or diabetes remain undertreated with statins, women more so than men. Use of other preventive drugs, the family history and recent contact with the general practitioner were the most important determinants of statin use in primary and secondary prevention. Amongst healthy subjects aged 60 or 75 years women received statins disproportionately to their low CHD risk compared with men.

Validity of questions in the use of specific drug-groups in health surveys.

OBJECTIVE: The aim of this study was to investigate whether morbidity in the general population could be assessed by questions on drug use in the Norwegian Health Survey 1995. MATERIAL AND METHOD: A sample of 6,702 persons, aged 20-79 years was interviewed in their homes using computer-assisted personal interviewing (CAPI). MEAN OUTCOME MEASURE: The validity of questions on use of analgesics and drugs against dyspepsia/peptic ulcer has been assessed according to categories of self-evaluated health. RESULTS: There was a difference between sporadic and daily users of the drugs to what extent they rated their health as poor. The validity of the drug questions assessed by sensitivity and specificity, showed that only using a dichotomous outcome variable, is too low to give a sufficiently valid measure of the morbidity in the population. CONCLUSIONS: Using "yes" or "no" as the only outcome of drug questions has the unfortunate effect of putting together chronic users of drugs with infrequent users for all of the subsequent analyses, which results in a considerable measurement error. This implies a need for improved methods to determine the optimal recall period for different drugs and it is crucial to include more details in questions on drug use to increase the validity of this information.

Use of antacids in a general population: the impact of health-related variables, lifestyle and sociodemographic characteristics.

Self-medication with antacids is very common in patients with less severe forms of dyspepsia, but we know very little about the users of antacids and their incentive to take them. The aim of this study was to analyze the relationship between self-reported use of antacids and health-related variables, lifestyle, and sociodemographic characteristics in order to characterize the use of antacids in a general population. The use of antacids was assessed by a questionnaire answered by men and women aged 20-62 years (n = 15,986; response rate 75.9%). Logistic regression analysis was used to quantify the relationships between the use of antacids and health-related variables, lifestyle, and sociodemographic characteristics. Approximately 10% of the population had used antacids during the preceding 14 days. There was no overall gender difference. Among those who had no dyspeptic symptoms, 1.5% reported use of antacids, whereas among those who had all three dyspeptic symptoms (heartburn, epigastric pain, peptic ulcer), 46.5% had used antacids. Heartburn was the most important predictor for antacid use in both men (odds ratio [OR] = 8.57 [6.65-11.04]) and women (OR = 9.35 [7.16-12.221) followed by self-reported epigastric pain and peptic ulcer (both: OR = approximately 2). The importance of these self-reported health conditions remained unchanged after adjusting for lifestyle and sociodemographic variables. There were fewer antacid users among unmarried women than married women, and coffee-drinking was inversely associated with antacid use. These findings were consistent in both bivariate and multivariate analysis. The present study provides population-based information showing that self-medication with antacids in Norway appeared to be appropriate. Because dyspeptic symptoms play a major role in the consumption of antacids, this study shows the importance of including information about specific clinical variables in the analysis and interpretation of patterns of drug use.

Legal drug use in a general population: association with gender, morbidity, health care utilization, and lifestyle characteristics.

Legal drug use was assessed by a questionnaire to 15,986 men and women participating in the Finnmark Health Survey 1987-1988. Logistic regression analysis was used to quantify the relationships between legal drug use and gender, morbidity, utilization of health services, and lifestyle and sociodemographic characteristics. Drug use was higher in women than men, but the gender difference decreased with age. Women used more drug groups than men, and the gender difference increased with number of drugs used. Participating in outdoor activities was associated with lower use of drugs in both men and women. The data support the notion that alcohol use plays a more important role in the prediction of drug use in men compared with women. A significant gender difference in the consumption of legal drugs do persist after adjusting for co-morbidity and utilization of health services. Overall, this analysis shows that drug use depends on need (morbidity), followed by use of health services and lifestyle. Sociodemographic variables were shown to have minor influence.

[Clinical trials reported to the Norwegian Drug Control Authority during the period 1982-1986]. / Kliniske legemiddelutprøvninger meldt til Statens legemiddelkontroll 1982-86.

During the five-year period 1982-86, 1,087 clinical drug trials were notified to the Norwegian Medicines Control Authority. There was in this period a slight decline in the annual number of notifications, whereas the number of patients/volunteer subjects in clinical trials rose. During the five-year period, every fifth professionally active physician in Norway notified at least one clinical trial to the Authority. Less than 10% of the trials notified did not involve participation by manufacturers. The trials covered a large number of substances. Most trials concerned drugs in the cardiovascular (c) and central nervous system (N) therapeutic groups. The frequency of reports on completed trials is low, and there are signs that some obligatory notifications of clinical trials are not sent to the Authority.

[Clinical trials of antineoplastic agents reported to the Norwegian Drug Control Authority during the period 1982-1986]. / Kliniske utprøvninger med legemidler mot kreft meldt til Statens legemiddelkontroll 1982-86.

We surveyed clinical trials of anti-tumour drugs notified to the Norwegian Medicines Control Authority during the period 1982 to 1986. 91 trials of anti-tumour drugs were notified during the period. A relatively large number of the trials were carried out without a control group, and a statistical rationale for the number of patients was lacking in almost 60% of the protocols. In 40% of the notified trials the manufacturers were not involved. Records of written information to patients have improved, as has insurance of the patients. On the other hand, reports on ongoing and completed clinical trials are still too often neglected.

The mechanism of [3H]dexamethasone uptake into prolactin producing rat pituitary cells (GH3 cells) in culture.

Glucocorticosteroids stimulate growth hormone (GH) synthesis and inhibit prolactin (PRL) synthesis and cell growth in cultured GH3 cells, a clonal cell strain derived from a rat pituitary tumour. This model system was used to study the mechanism by which glucocorticosteroids enter target cells. The cellular uptake of [3H]dexamethasone was temperature dependent and was further inhibited by addition of an excess amount of cold dexamethasone. Half maximal uptake was obtained after about 5 min at 37 degrees C. The initial rates of [3H]dexamethasone uptake were a linear function of the extracellular hormone concentration. The uptake of [3H]dexamethasone in intact cells studied at different temperatures resulted in linear Arrhenius plots, with a calculated energy of activation of 91.0 kJ x mole-1 x degree-1. Scatchard analysis of specifically cell bound [3H]dexamethasone at equilibrium (0 degrees C) showed a straight line with a calculated dissociation constant (Kd) of 1.6 x 10(-9) M and a maximal uptake of 180 x 10(-15) mole/mg cell protein. Specific binding of [3H]dexamethasone to cytosol proteins could only be demonstrated at 0 degrees C. These results indicate that [3H]dexamethasone diffuses passively into the cell, and binds to specific receptors in an energy dependent way.