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Background: Selective serotonin reuptake inhibitors (SSRIs) have a wide and increasing use for the treatment of depression and anxiety. Previous studies have indicated an increased risk of hyponatremia during the first months of treatment. We aimed to investigate the detailed time-course of SSRI-associated hyponatremia with a high temporal resolution, using registry data encompassing the total Swedish population. Methods: This was a population-based case control study using several national registers. Patients hospitalized with a principal diagnosis of hyponatremia ( n = 11,213) were compared with matched controls ( n = 44,801). Multivariable regression was applied to explore time-dependent associations between SSRIs and hospitalization due to hyponatremia. Results: Individuals initiating treatment with SSRIs were exposed to an immediately increased risk for hospitalization at week 1, reaching an adjusted odds ratio (aOR) (95% confidence interval) of 29 (19–46). The associations then gradually declined, reaching an aOR of 2.1 (1.0–4.2) by week 13. The aOR for individuals treated for longer than 13 weeks was 0.78 (0.71–0.85). Conclusions: This study revealed a dramatically increased risk of hyponatremia exclusively related to newly initiated treatment. Consequently, even subtle symptoms consistent with hyponatremia during the first weeks of SSRI treatment should prompt analysis of sodium levels. In patients treated with SSRIs for several months or years, other causes should primarily be sought in the event of hyponatremia.

Purpose Thiazide diuretics are the most common origin of drug-induced hyponatremia. However, population-based studies on clinical outcomes are lacking. We therefore explored the time course and absolute risk of thiazide-associated hospitalization due to hyponatremia in Sweden. Methods Population-based case-control study including patients hospitalized with a principal diagnosis of hyponatremia (n = 11,213) compared with controls (n = 44,801). Linkage of registers was used to acquire data. Multivariable regression was applied to explore time-dependent associations between thiazide diuretics and hospitalization due to hyponatremia. Attributable risks were calculated assessing the disease burden attributable to thiazides. Results Individuals initiating thiazide treatment were exposed to an immediate increase in risk for hospitalization with adjusted odds ratio (aOR) (95% CI) of 48 (28–89). The associations gradually declined reaching an aOR of 2.9 (2.7–3.1) for individuals treated for longer than 13 weeks. The attributable risk of hyponatremia-associated hospitalization due to thiazides of any treatment length was 27% (3095/11,213). Among 806 patients initiating treatment < 90 days before hospitalization, hyponatremia could be attributed to thiazides in 754. Based on nationwide data, 616,678 individuals were initiated on thiazides during the 8-year study period suggesting an absolute risk of 0.12% (754/661,678) for subsequent hospitalization with a main diagnosis of hyponatremia. Conclusions Thiazide diuretics attributed to more than one in four individuals hospitalized due to hyponatremia. The risk increase was very pronounced during the first month of treatment and then gradually declined, without returning to normal. However, the absolute risk for the development of hyponatremia demanding hospitalization may for most individuals be modest.

Purpose To study the association between interacting drugs and bleeding or thromboembolism in atrial fibrillation outpatients treated with non-vitamin K antagonist oral anticoagulants (NOACs). Methods Population-based cohort study of outpatients treated with NOACs in Sweden from 2008 to 2017. Patients with atrial fibrillation and newly initiated NOAC treatment were identified in the Prescribed Drug Register. Comorbidities and outcome data were retrieved from the Patient Register and the Cause of Death Register. Cox-regression analyses were performed to evaluate the primary endpoints any severe bleed and ischemic stroke/transient ischemic attack/stroke unspecified during the first six months of treatment. Secondary endpoints were gastrointestinal bleeding, intracranial bleeding, ischemic stroke, and venous thromboembolism. Results Increased risk of any severe bleed was found when NOAC treatment, and drugs with pharmacodynamic effect on bleeding were combined, compared to NOAC only. An increased risk with these combinations was evident for apixaban (hazard ratio (HR) 1.47; 95% CI 1.33–1.63), rivaroxaban (HR 1.7; 95% CI 1.49–1.92), and dabigatran (HR 1.26; 95% CI 1.05–1.52). For apixaban, there was an increased risk of any severe bleed when combined with CYP3A4 and/or P-glycoprotein (P-gp) inhibitors (HR 1.23; 95% CI 1.01–1.5). The use of inducers of CYP3A4 and/or P-gp was low in this cohort, and effects on ischemic stroke/TIA/stroke unspecified could not be established. Conclusion Increased risk of bleeding was seen for pharmacodynamic and pharmacokinetic interactions with NOACs. Prescribers need to be vigilant of the effect of interacting drugs on the risk profile of patients treated with NOACs.

Context A seasonal variation in hyponatremia, with higher incidence rates during hot summer days, has been demonstrated. Whether this applies to cool temperate regions is currently unknown. Objective The aim of this study was to investigate the influence of ambient temperature on hyponatremia in the Swedish population under current and future climate scenarios. Methods This nationwide cohort study identified all patients hospitalized with a first-ever principal diagnosis of hyponatremia between October 2005 and December 2014. Incidence rates for hyponatremia were calculated as number of hospitalizations divided by person-days at risk in the adult Swedish population at a given temperature, in increments of 1 °C. Results The incidence of hyponatremia was stable at 0.3 per million person-days from −10 to 10 °C, but increased rapidly at 24-hour mean temperatures above 15 °C, with 2.26 hospitalizations per million days at the highest recorded temperature of 25 °C. Women and elderly carried the greatest risk, with an incidence of 35 hospitalizations per million days in individuals ≥ 80 years of age on the hottest days, corresponding to a 15-fold increase in incidence compared with cool days. A future 1 or 2 °C increase in mean temperature is expected to increase the incidence of hyponatremia by 6.3% and 13.9%, respectively. Conclusion The risk of hospitalization due to hyponatremia increases rapidly at temperatures above 15 °C, indicating a threshold effect. Over the next decades, rising global temperatures are expected to increase the inpatient burden of hyponatremia by approximately 10%. Strategies for protecting vulnerable groups are necessary to reduce this risk.

Some data indicate that simvastatin may increase the anticoagulative effect in patients treated with warfarin, but the evidence is scarce. The aim of the present study was to investigate how the anticoagulative effect of warfarin is affected by the initiation of simvastatin in a very large patient sample. In a retrospective cohort study, we included 5637 individuals on warfarin treatment initiating simvastatin. INR values and warfarin doses were calculated week-by-week during co-treatment. Data were obtained from two large Swedish warfarin registers and from the Swedish Prescribed Drug Register. INR increased from 2.43 at baseline to 2.58, 4 weeks after simvastatin initiation, and did not stabilize until the last quarter of the year studied. Consequently, the proportion of patients with an INR above 3 increased from around 8 to 15%. In conclusion, initiation of simvastatin resulted in moderately increased INR values and subsequent dose decreases in patients already on warfarin. In order to avoid the increased risk of bleeding, the initiation of simvastatin may be accompanied by closer INR monitoring.

Background Antipsychotics have been claimed to cause hyponatremia. The risk associated with individual antipsychotics, or groups (first-generation [FGAs] or second-generation [SGAs] antipsychotics), is not well-documented. The objective of this study was to investigate the association between antipsychotics and hospitalization due to hyponatremia. Methods The general Swedish population was the base of this register–based case–control study. Comparisons were made between patients hospitalized with a principal diagnosis of hyponatremia (n = 14,359) and matched controls (n = 57,383). Multivariable logistic regression adjusting for concomitant drugs, medical conditions, previous hospitalizations and socioeconomic factors was performed to investigate the association between hyponatremia and antipsychotic use. In addition newly initiated (≤90 days) or ongoing use was analysed separately. Results Compared to controls, the adjusted OR (95%CI) for hospitalization due to hyponatremia was for any antipsychotic 1.67(1.5–1.86). Individuals on FGA were more likely to experience severe hyponatremia (2.12[1.83–2.46]) than those on any SGA (1.32[1.15–1.51]). No increased risks, neither as newly initiated nor ongoing therapy, were found for risperidone (0.86[0.56–1.31] and 0.83[0.67–1.02]) and aripiprazole (1.16[0.30–4.46] and 0.62[0.27–1.34]), respectively. Conclusions There was an association between antipsychotic therapy and hospitalization due to hyponatremia. The association was stronger for FGAs than SGAs. Risperidone was not associated with an increased risk.

Background:Many drugs used in psychiatry have been reported to cause hyponatraemia. However, lithium may be an exception due to its potential for causing nephrogenic diabetes insipidus, but clinical data are largely absent. The objective of this investigation was to study the association between lithium therapy and hospitalization due to hyponatraemia.Methods:This study was a register-based case–control investigation of the general Swedish population. Patients hospitalized with a principal diagnosis of hyponatraemia ( n=11,213) were compared with matched controls ( n=44,801). Analyses using multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations and socioeconomic factors were deployed to calculate the association between severe hyponatraemia and the use of lithium. Additionally, newly initiated (⩽90 days) and ongoing lithium therapy was studied separately.Results:Compared with controls, the unadjusted odds ratio (OR) (95% confidence interval (CI)) for hospitalization due to hyponatraemia was 1.07 (0.70–1.59) for lithium. However, after adjustment for confounding factors the risk was reduced (adjusted OR: 0.53 (0.31–0.87)). Newly initiated lithium therapy was not significantly associated with hyponatraemia (adjusted OR 0.73 (0.35–5.38)). In contrast, for ongoing therapy the corresponding adjusted OR was significantly reduced (adjusted OR: 0.52 (0.30–0.87)).Conclusions:A marked inverse association was found between ongoing lithium therapy and hospitalization due to hyponatraemia.

Purpose Drug-induced hyponatremia is common, with medications from many drug-classes implicated. Lipid-lowering agents are among the most prescribed drugs. Limited evidence suggests an inverse association between statins and hyponatremia, while data on other lipid-lowering agents is absent. The objective of this investigation was to study the association between lipid-lowering drugs and hospitalization due to hyponatremia. Methods This was a register-based case–control study of the general Swedish population. Those hospitalized with a main diagnosis of hyponatremia (n = 11,213) were compared with matched controls (n = 44,801). Multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations, and socioeconomic factors was used to explore the association between severe hyponatremia and the use of lipid-lowering drugs. Results Unadjusted ORs (95% CI) for hospitalization due to hyponatremia were 1.28 (1.22–1.35) for statins, 1.09 (0.79–1.47) for ezetimibe, 1.38 (0.88–2.12) for fibrates, and 2.12 (1.31–3.35) for resins. After adjustment for confounding factors the adjusted odds ratios (95% CI) compared with controls were 0.69 (0.64–0.74) for statins, 0.60 (0.41–0.86) for ezetimibe, 0.87 (0.51–1.42) for fibrates, and 1.21 (0.69–2.06) for resins. Conclusions Use of statins and ezetimibe was inversely correlated with severe hyponatremia. Consequently, these drugs are unlikely culprits in patients with hyponatremia, and they appear safe to initiate in hyponatremic patients. A potential protective effect warrants further studies on how statins and other lipid-lowering drugs are linked to dysnatremias.

Background Data indicate that codispensing flucloxacillin to patients already on warfarin may result in decreased warfarin efficacy. Objectives This article investigates the effect of flucloxacillin on warfarin anticoagulation. Patients and Methods In a retrospective cohort study of warfarin users, using three nationwide registers we included 5,848 patients receiving 10 days flucloxacillin treatment and 201 with ≥30 days treatment. To assess the potential for confounding by indication, we also identified 21,430 individuals initiating phenoxymethylpenicillin. International normalized ratio (INR) values and warfarin doses were calculated day-by-day and proportion of patients with a subtherapeutic INR week-by-week during cotreatment. Results Following initiation of flucloxacillin with a planned treatment duration of 10 days and ≥30 days, the mean INR decreased from 2.36 (95% confidence interval [CI] 2.34; 2.37) to 2.20 (95% CI 2.19; 2.21) and from 2.24 (95% CI 2.16; 2.32) to 1.96 (95% CI 1.89; 2.02), respectively. Consequently, for individuals with 10 days treatment the proportion of patients with a subtherapeutic INR of Conclusion One in three patients with 10 days flucloxacillin and almost two in three patients initiating long-term treatment, was exposed to a subsequent subtherapeutic anticoagulant effect. To avoid unnecessary thromboembolic complications, the initiation of flucloxacillin should be accompanied by closer INR monitoring which may be especially important among individuals with lengthy treatments.

Background Although tramadol and codeine occasionally have been reported to cause hyponatremia the evidence is scarce. The objective of this investigation was to study the association between weak opioids (tramadol and codeine) and hospitalization due to hyponatremia. Methods This was a register-based case-control study of the general Swedish population. Those hospitalized with a principal diagnosis of hyponatremia (n = 14,359) were compared with matched controls (n = 57,383). Multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations and socioeconomic factors was used to explore the association between severe hyponatremia and the use of tramadol or codeine. Furthermore, newly initiated (≤90 days) and ongoing use was investigated separately. Results Compared to controls, the unadjusted OR (95%CI) for hospitalization due to hyponatremia was 2.45 (2.26–2.66) for tramadol and 3.19 (2.92–3.47) for codeine. However, after adjustment for confounding factors the risk decreased (adjusted OR: 1.17 [1.08–1.26] and 1.14 [1.03–1.26], respectively). Newly initiated treatment with tramadol or codeine showed a significant association (adjusted OR 2.34 [95%CI 2.01–2.72] and 2.20 [95%CI 1.87–2.60], respectively). In contrast, for ongoing therapy the corresponding adjusted ORs were not elevated (adjusted OR: 0.70 [95%CI 0.61–0.80] and 1.14 [95%CI 0.99–1.30, respectively). Conclusions Associations were found between tramadol or codeine usage and hospitalization due to hyponatremia which were markedly increased in those newly initiated. The risk associated with long-term use was not increased. The association may be causally related to the drugs, although an effect due to pain, nausea or the underlying disease cannot be excluded.

PURPOSE In a patient with clinically significant hyponatremia without other clear causes, thiazide treatment should be replaced with another drug. Data describing to which extent this is being done are scarce. The aim of this study was to investigate sociodemographic and socioeconomic factors that may be of importance for the withdrawal of thiazide diuretics in patients hospitalized due to hyponatremia. METHODS The study population was sampled from a case-control study investigating individuals hospitalized with a main diagnosis of hyponatremia. For every case, four matched controls were included. In the present study, cases (n = 5204) and controls (n = 7425) that had been dispensed a thiazide diuretic prior to index date were identified and followed onward regarding further dispensations. To investigate the influence of socioeconomic and sociodemographic factors, multiple logistic regression was used. RESULTS The crude prevalence of thiazide withdrawal for cases and controls was 71.9% and 10.8%, respectively. Thiazide diuretics were more often withdrawn in medium-sized towns (adjusted OR, 1.52; 95% CI, 1.21-1.90) and rural areas (aOR, 1.81; 95% CI, 1.40-2.34) compared with metropolitan areas and less so among divorced (aOR, 0.72; 95% CI, 0.53-0.97). However, education, employment status, income, age, country of birth, and gender did not influence withdrawal of thiazides among patients with hyponatremia. CONCLUSIONS Thiazide diuretics were discontinued in almost three out of four patients hospitalized due to hyponatremia. Educational, income, gender, and most other sociodemographic and socioeconomic factors were not associated with withdrawal of thiazides.

Background Small observational studies and case reports have indicated that proton pump inhibitors (PPIs) may cause hyponatremia. Whether there is a difference between the individual PPIs is yet unknown. Since PPIs are one of the most commonly prescribed groups of drugs, even a rare adverse reaction may have large implications. The objective was to study the association between PPIs and hospitalization due to hyponatremia. Methods This register–based case–control study was based on the general Swedish population. Patients hospitalized with a principal diagnosis of hyponatremia ( n = 14,359) were compared to matched controls ( n = 57,383). The association between newly initiated (≤90 days) and ongoing PPI use was explored using multivariable logistic regression adjusting for concomitant drugs, medical conditions, previous hospitalizations and socioeconomic factors. Results Adjusted ORs (95%CI) for hospitalization due to hyponatremia, compared to controls, were for newly initiated: omeprazole 2.67 (2.37–3.01); pantoprazole 2.06 (1.32–3.19); lansoprazole 1.19 (0.72–1.94); esomeprazole 2.89 (2.21–3.79) and any PPI 2.78 (2.48–3.11). Only one individual had been newly initiated on rabeprazole and had been hospitalized due to hyponatremia. Adjusted ORs (95%CI) for individuals with ongoing treatment were for: omeprazole 1.04 (0.97–1.11); pantoprazole 0.81 (0.62–1.05); lansoprazole 0.90 (0.70–1.15); rabeprazole 3.34 (0.84–11.43); esomeprazole 1.12 (0.94–1.33) and any PPI 1.04 (0.98–1.11). Conclusions With the exception of lansoprazole, this study suggests an association between any newly initiated PPI-treatment and hospitalization due to hyponatremia. Ongoing PPI use was not associated with an increased risk.

Purpose Hyponatremia induced by antiepileptic drugs is common, but detailed evidence is lacking. This can be problematic for the treating neurologist confronted with a patient with severe hyponatremia in need of an alternative drug. The objective of this study was to examine the association between individual antiepileptic drugs and hospitalization due to hyponatremia. Methods This was a register-based case–control study of patients in the general Swedish population. We included 14,359 individuals with a principal diagnosis of hyponatremia and 57,383 matched controls. The association between newly initiated (≤90 days) and ongoing antiepileptic treatment was investigated using multivariable logistic regression adjusting for concomitant drugs, medical conditions, previous hospitalizations and sociaoeconomic factors. Results For newly initiated antiepileptic drugs, adjusted ORs (95% CI) for hospitalization due to hyponatremia, compared to controls, were: carbamazepine 9.63 (6.18–15.33); phenytoin 4.83 (1.14–25.76); valproate 4.96 (2.44–10.66); lamotrigine 1.67 (0.70–4.08); levetiracetam 9.76 (4.02–27.59) and gabapentin 1.61 (1.08–2.38). Newly initiated oxcarbazepine treatment was only found in the hyponatremia group and not in controls. Adjusted ORs (CI) for individuals with ongoing treatment ranged from 7.97 (3.70–18.50) for oxcarbazepine to 0.83 (0.64–1.06) for gabapentin. Conclusion There was a strong association between newly initiated treatment with carbamazepine, oxcarbazepine and levetiracetam, and hospitalization due to hyponatremia. The corresponding association for phenytoin and valproate was moderate. The risk for hyponatremia was lower during ongoing treatment. Lamotrigine and gabapentin had the lowest risk both during initiation and ongoing treatment and may be advantageous in patients at risk of developing hyponatremia.

Background Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are important as a cause of hyponatremia. However, most studies have focused on the effect on sodium levels regardless of clinical symptoms, or have been too small to be able to discriminate between the effects of specific antidepressant drugs. The objective of the present study was to investigate the association between different groups of antidepressants and the risk of hospitalization due to hyponatremia. Methods In this register-based case-control study of patients in the general Swedish population, we identified 14,359 individuals with a main diagnosis of hyponatremia. For every case, 4 matched controls were included (n = 57,382). To investigate the temporal aspects of drug-induced hyponatremia, antidepressant exposure was divided into patients with newly initiated and ongoing treatment. Univariable and multivariable logistic regression was used to analyze the association of antidepressant use and hospitalization. Results For newly initiated antidepressants, adjusted odds ratios (95% confidence interval) for a main diagnosis of hyponatremia compared with controls were: citalopram 5.50 (4.71-6.44); sertraline 4.96 (3.81-6.48); venlafaxine 5.28 (3.20-8.83); tricyclic antidepressants 1.59 (1.13-2.24); and mirtazapine 2.54 (2.04-3.16). Adjusted odds ratio (confidence interval) for individuals with ongoing treatment ranged from 0.57 (0.52-0.63) for citalopram to 1.08 (0.85-1.36) for other SSRIs. Conclusions There was a strong association between newly initiated treatment with SSRIs or venlafaxine and hospitalization due to hyponatremia. The association for tricyclic antidepressants and mirtazapine was small to moderate. In contrast, there was no evidence that ongoing treatment with antidepressants increases the risk for hospitalization due to hyponatremia.

The purpose of the present study was to investigate the predictive value of the risperidone metabolic ratio for the individual CYP2D6 genotype.The determination of risperidone, 9-hydroxyrisperidone, and CYP2D6 genotype was performed in 89 schizophrenic patients. The receiver operator characteristic (ROC) method and the area under the ROC curve (AUC) were used to illustrate the predictive value of risperidone metabolic ratio for the individual CYP2D6 genotype. The area under the ROC curve (AUC) was used as a global measure of this predictive value. To evaluate the proposed cutoff levels of1 and0.1 to identify individuals with a poor or ultrarapid CYP2D6 genotype the sensitivity, specificity, positive predictive value and negative predictive were calculated.The area under the ROC curve (AUC) for poor and ultrarapid metabolisers was 0.85 and 0.86, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of a risperidone/9-OH-risperidone ratio1 to CYP2D6 poor metaboliser genotype were 75 %, 95 %, 60 % and 97 %, respectively. The corresponding measures for a metabolic ratio0.1 to predict ultrarapid metabolisers were 80 %, 77 %, 18 % and 98 %.A metabolic ratio1 or0.1 may be a useful therapeutic biomarker to recommend CYP2D6 genetic testing to guide the present or future treatment of patients in need of psychotropic drugs.

AimsTramadol, a widely used analgesic drug, inhibits the reuptake of noradrenaline and serotonin impairing the aggregation function of thrombocytes. However, the risk for severe bleeding has previously not been studied. The aim of the present study is to investigate the association between tramadol and bleeding peptic ulcer in the Swedish population.MethodsIn this register based case-control study based on the Swedish national patient registry and prescription drug registry, we included 18 306 patients hospitalized with a first-time diagnosis of bleeding peptic ulcer. For every case, 4 matched controls were included. To investigate the temporal aspects of tramadol induced bleeding ulcer, exposure was divided into patients with newly initiated and ongoing treatment. To explore a possible confounding by indication, the effect of codeine, a drug also prescribed for the treatment of moderate pain, but not known to affect thrombocyte function, was investigated. Univariable and multivariable logistic regression was used to analyse the association between tramadol use and bleeding ulcer.ResultsTramadol was associated with an increased risk of bleeding ulcer (adjusted odds ratio (aOR) 2.1, 95% confidence interval: (2.0-2.3). The association was stronger for newly initiated treatment with tramadol 2.8 (2.5-3.2) and weaker for ongoing treatment 1.7 (1.6-1.9). Codeine was also associated with an increased risk of bleeding ulcer 1.9 (1.7-2.1) and this association was also stronger for newly initiated treatment with codeine 2.3 (2.0-2.6) and weaker for ongoing treatment 1.7 (1.5-1.9).ConclusionTreatment with tramadol was associated with an increased risk of bleeding peptic ulcer. Most of this association may be mediated by factors related to the pain condition rather than the pharmacologic effect per se.

The study aimed to investigate the clinical adherence to drug label recommendations on important drug-drug interactions (DDIs). Dispensing data on drug combinations involving selective serotonin reuptake inhibitor (SSRI) antidepressants could help to identify areas for intensified medical education.This was a retrospective, cross-sectional analysis of individual dispensing data regarding all individualsor =15 years old in Sweden. The study analysed the prescribing and dispensing of CYP2D6 drugs (metoprolol, donepezil, galantamine, codeine, tamoxifen) together with CYP2D6-blocking SSRIs (paroxetine/fluoxetine) or SSRIs without significant CYP2D6 inhibition (citalopram/escitalopram/sertraline), and the related prescribing of CYP2D6-independent comparator drugs (atenolol, rivastigmine, propoxyphene, anastrozole). Odds were calculated between each CYP2D6 drug and the corresponding comparator drug in patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline, respectively. The odds ratio (OR) was calculated by dividing the obtained odds in patients on fluoxetine/paroxetine by the corresponding odds in patients on citalopram/escitalopram/sertraline.Compared with patients that were dispensed citalopram/escitalopram/sertraline, patients dispensed fluoxetine/paroxetine had lower prescribing rates of metoprolol (adjusted OR 0.80; 95% confidence interval 0.76, 0.85), donepezil (0.65; 0.49, 0.86) and galantamine (0.58; 0.41, 0.81). In contrast, the use of prodrugs codeine (compared woth propoxyphene) or tamoxifen (compared with anastrozole) was similar among patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline (adjusted OR 1.03; 0.94, 1.12 and 1.29; 0.96, 1.73, respectively).Clinically important DDIs that are associated with impaired bioactivation of prodrugs might be more easily neglected in clinical practice compared with DDIs that cause drug accumulation and symptomatic adverse drug reactions.

The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia. A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine. In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact. At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established.

To evaluate the clinical relevance of the Janus Web Application (JWA) in screening for potential drug-drug interactions (DDIs). One hundred and fifty patients taking two drugs or more were studied. Potential DDIs were identified by the JWA. Interviewing the patient and looking into his/her medical records provided complementing information. A clinical pharmacologist judged which potential DDIs were clinically relevant. Potentially relevant DDIs identified by the JWA were then correlated with clinically relevant DDIs. A total of 150 significant potential DDIs were found. Sixteen percent (24/150) were judged to be clinically relevant. A very small proportion of DDIs was considered clinically relevant in the specific clinical context. To optimise the software’s user-friendliness, the following points need to be considered: the possibility of eliminating trivial potential DDIs, individualising drug alerts, and providing written information, accessible via a hyperlink.

To study the validity and reliability of the new disease-specific extension of the CHP, Cardiac Health Profile congestive heart failure (CHPchf), used to assess QoL specifically for patients with heart failure.Eighty-three consecutive patients with chronic heart failure were enrolled. Criteria and construct validity were studied by correlating the Global Mean Score (GMS) for the CHPchf with the total sum score of the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and other measures predicted to correlate with QoL. Reliability was evaluated on the basis of internal consistency.Significant correlations for CHPchf were found with MLHFQ (r=0.76, p=0.0001), the Boston Heart Failure Score (BHFS) (p0.001), the generic second section of the CHP, maximal workload at exercise test (p0.05) and the New York Heart Association (NYHA) classification (p0.01). Cronbach's alpha was calculated to 0.82.CHPchf was shown to be valid and reliable. CHPchf has favourable psychometric properties. Further studies are needed to explore its discriminative abilities.

Essentials Data on the effect of introducing amiodarone in patients already using warfarin regime are scarce. Information on 754 patients was extracted from three nationwide registers in Sweden. With amiodaron, 37% of patients had an international normalized ratio (INR) over 3.0 To avoid bleeding, the initiation of amiodarone should be accompanied by closer INR monitoring. SummaryBackground Data indicate that the interaction between warfarin and amiodarone results in an increased warfarin effect. There are several large, well-performed studies using genetic and clinical factors such as co-medication to predict an adequate starting dose of warfarin. However, longitudinal data on the effect of introducing amiodarone in patients on an ongoing warfarin regime are more scarce. Objectives An investigation of how initiation of amiodarone affects the anticoagulant effect and dosing of warfarin, using data from three nationwide registries. Patients/Methods In a retrospective cohort study including 754 patients, warfarin doses were compared between two 4-week periods, before and 18–21 weeks after initiating co-treatment with amiodarone. In addition, warfarin doses and international normalized ratio (INR) values were calculated week-by-week after the initiation of amiodarone. Results The initiation of amiodarone increased the mean INR from 2.6 to 3.1. The proportion of patients with a supratherapeutic INR over 3.0 and 4.0 increased from 12% to 37% and 0.9% to 5.5%, respectively. The subsequent mean decrease in warfarin dose was 24.6% (95% confidence interval [CI], 23.5, 25.6). The frequency of INR monitoring within 1 and 2 weeks after initiation of amiodarone was 67% and 90%. Conclusions Although warfarin doses in most patients were within the therapeutic range, more than one in three patients initiating co-treatment with amiodarone were exposed to a supratherapeutic anticoagulative effect within 3 weeks. In order to further avoid severe unnecessary bleeding, the initiation of amiodarone should be accompanied by closer INR monitoring, anticipating an average dose reduction of 25%.

To investigate the predictive value of the risperidone and venlafaxine metabolic ratios and CYP2D6 genotype.The determination of risperidone, 9-hydroxyrisperidone, and venlafaxine, O-desmethylvenlafaxine, N-desmethylvenlafaxine and CYP2D6 genotype was performed in 425 and 491 patients, respectively. The receiver operator characteristic method and the area under the receiver operator characteristic curve were used to illustrate the predictive value of risperidone metabolic ratio for the individual CYP2D6 genotype. To evaluate the proposed cutoff levels of1 to identify individuals with a poor CYP2D6 genotype, the sensitivity, specificity, positive predictive values, and negative predictive values were calculated.Area under the receiver operator characteristic curve to predict poor metabolizers for risperidone/9-hydroxyrisperidone and N-desmethylvenlafaxine/O-desmethylvenlafaxine ratios was 93% and 99%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value (confidence interval) of a risperidone/9-hydroxyrisperidone ratio1 to predict a CYP2D6 poor metabolizer genotype were 91% (76%-97%), 86% (83%-89%), 35% (26%-46%), and 99% (97%-100%), respectively. The corresponding measures for N-desmethylvenlafaxine/O-desmethylvenlafaxine were 93% (76%-97%), 87% (83%-89%), 40% (32%-51%), and 99% (98%-100%).Risperidone/9-hydroxyrisperidone and N-desmethylvenlafaxine/O-desmethylvenlafaxine metabolic ratios1 strongly predict individuals with poor metabolizer genotype, which could guide psychotropic drug treatment to avoid adverse drug reactions and to increase their therapeutic efficacy in patients prescribed these drugs.

OBJECTIVE There has been conflicting evidence regarding the potential role of vitamin D in glucose homeostasis. This study was designed to investigate the effect of high-dose vitamin D3 treatment on β-cell function, insulin sensitivity, and glucose tolerance in subjects with prediabetes or diet-treated type 2 diabetes. RESEARCH DESIGN AND METHODS Subjects (n = 44) were randomized to 30,000 IU vitamin D3 once weekly or placebo for 8 weeks. Hyperglycemic clamp assessed first-phase (0–12 min) and second-phase (12–120 min) insulin response, insulin sensitivity, and disposition index (DI). An oral glucose tolerance test assessed glucose tolerance and glycosylated hemoglobin assessed glycemic control. RESULTS A total of 21 (vitamin D) and 22 (placebo) subjects completed the study, respectively. Season-adjusted 25-OH-vitamin D [25(OH)D] levels were doubled in the active treated group (43–82 nmol/L). No effect of vitamin D treatment, compared with placebo, was seen on first-phase or second-phase insulin secretion. There were no group differences in insulin sensitivity, DI, or any measures of glycemic control. No hypercalcemia or other adverse effects of vitamin D treatment were seen compared with placebo. Subgroup analyses of those with the lowest basal and greatest increase in 25(OH)D levels did not change these results. CONCLUSIONS This study gives no support for any substantial effect of high-dose vitamin D treatment for 8 weeks in prediabetes or diet-treated type 2 diabetes on β-cell function, insulin sensitivity, or glycemic control.

Purpose To investigate the effect of vitamin D3 on hepatic Cytochrome P450 enzyme (CYP) 3A4 in patients with abnormal glucose regulation using the endogenous marker 4β-hydroxycholesterol (4β-OHC):cholesterol ratio. Methods The present study took advantage of a trial primarily aiming to investigate the effect of vitamin D3 on beta cell function and insulin sensitivity in patients with abnormal glucose regulation. 44 subjects were randomized to receive vitamin D3, 30000 IU given orally once weekly or placebo for 8 weeks. The two sample t-test was used to test the means of the intra-individual differences of 4β-OHC:cholesterol ratio between the two groups. Results Mean (SD) 4β-OHC in the whole group of patients before and after the intervention was 26 (11) ng/ml and 26 (12). Mean (SD) 4β-OHC:cholesterol ratio in the whole group of patients before and after the intervention was 0.12 (0.046) and 0.13 (0.047). In the Vitamin D group mean (SD) serum 25-OH-vitamin D3 increased from 46 (16) to 85nM (13) during the corresponding time period. To investigate the impact of vitamin D3 on hepatic CYP3A4 we calculated the mean intra-individual differences in 4β-OHC:cholesterol ratio (delta 4β-OHC:cholesterol ratio) before versus after the intervention in the two treatment groups. The difference (95% CI) between delta 4β-OHC:cholesterol ratio in the control group and intervention group was -0.0010 (-0.0093, 0.0072), a difference being not statistically significant (p = 0.80). Conclusions We provide further evidence that vitamin D3 may not substantially affect hepatic CYP3A4. This does not exclude the possibility of an impact of intestinal first-pass metabolism of orally administered drugs which should be investigated. Trial Registration ClinicalTrials.gov NCT01497132

PURPOSE: To investigate the extent to which clinicians avoid well-established drug-drug interactions associated with warfarin. We hypothesised that clinicians would avoid combining non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and sulfamethoxazole with warfarin. METHODS: A cross-sectional analysis of nationwide dispensing data was performed in Swedish individuals 18 years or older (n = 7,563,649). Odds ratios of interacting NSAIDs, tramadol and sulfamethoxazole versus respective prevalence of comparator drugs codeine, and ciprofloxacin in patients co-dispensed interacting warfarin versus patients unexposed was calculated. RESULTS: The odds of receiving an interacting NSAID versus the comparator codeine was markedly lower in patients with warfarin than in the remaining population (adjusted OR 0.21; 95% CI 0.20 - 0.22). Also, the interacting drugs tramadol and sulfamethoxazole were less common among patients dispensed warfarin as compared to the remaining population, although the decrease was much more modest (adjusted OR 0.83; CI 0.80-0.87 and 0.81; CI 0.73 - 0.90). CONCLUSIONS: In conclusion, Swedish doctors in the vast majority of cases refrain from prescribing NSAIDs to patients already on warfarin. Tramadol and sulfamethoxazole are however rarely avoided.

PurposeTo investigate the extent to which clinicians avoid well-established drug-drug interactions that cause statin-induced myopathy. We hypothesised that clinicians would avoid combining erythromycin or verapamil/diltiazem respectively with atorvastatin or simvastatin. In patients with statin-fibrate combination therapy, we hypothesised that gemfibrozil was avoided to the preference of bezafibrate or fenofibrate. When combined with verapamil/diltiazem or fibrates, we hypothesized that the dispensed doses of atorvastatin/simvastatin would be decreased.MethodsCross-sectional analysis of nationwide dispensing data. Odds ratios of interacting erythromycin, verapamil/diltiazem versus respective prevalence of comparator drugs doxycycline, amlodipine/felodipine in patients co-dispensed interacting statins simvastatin/atorvastatin versus patients unexposed (pravastatin/fluvastatin/rosuvastatin) was calculated. For fibrates, OR of gemfibrozil versus fenofibrate/bezafibrate in patients co-dispensed any statin was assessed.ResultsOR of interacting erythromycin versus comparator doxycycline did not differ between patients on interacting and comparator statins either in patients dispensed high or low statin doses (adjusted OR 0.87; 95% CI 0.60-1.25 and 0.92; 95% CI 0.69-1.23). Interacting statins were less common among patients dispensed verapamil/diltiazem as compared to patients on amlodipine/felodipine (OR high dose 0.62; CI 0.56-0.68 and low dose 0.63; CI 0.58-0.68). Patients on any statin were to a lesser extent dispensed gemfibrozil compared to patients not dispensed a statin (OR high dose 0.65; CI 0.55-0.76 and low dose 0.70; CI 0.63-0.78). Mean DDD (SD) for any statin was substantially higher in patients co-dispensed gemfibrozil 178 (149) compared to patients on statin monotherapy 127 (93), (pConclusionsPrescribers may to some extent avoid co-prescription of statins with calcium blockers and fibrates with an increased risk of myopathy. We found no evidence for avoiding co-prescriptions of statins and antibiotics with an increased risk of statin-induced adverse drug reactions. Co-prescription of statins and gemfibrozil is paradoxically associated with a marked increased statin dose, further aggravating the risk for severe myopathy.

To describe the scenario and frequency of drug-related problems (DRPs) in in-patients and to determine whether a pharmacotherapeutic advisory intervention aiming at reducing DRPs could affect rates of re-hospitalisation and/or death within 6 months. This prospective, randomised, controlled advisory intervention study was carried out at the Clinic of Internal Medicine at Stockholm Soder Hospital. Three hundred patients from four wards took part in the study. Patients taking two drugs or more were included. In the intervention arm, potential drug interactions were found using a computer system. Medical symptoms were estimated by a nurse together with the patient. Creatinine clearance was calculated. Thereafter a clinical pharmacologist scrutinised the patient´s medical record for DRPs together with the nurse. DRPs judged to be clinically relevant resulted in written advice to the physician in charge of the patient. The control group received usual care. In the intervention group, a total of 299 DRPs were found among 71% of the patients (106/150). The number of written letters of advice to the physicians in charge was 106. Of these, 63% were accepted. After 6 months, the proportion of re-hospitalisations or death in the intervention group was 49% (73/150) compared to 46% (69/150) in the control group. The difference was not significant. DRPs were common. Potential drug interactions and adverse drug reactions dominated. Hospital-based medication review by a clinical pharmacologist was not associated with reduced rates of re-hospitalisation and/or death. The clinical relevancy of DRPs might be overestimated as a risk for re-hospitalisation or death. It is of great importance to clarify if and how drug-related problems can be prevented. In designing such studies, one should consider choosing inclusion criteria that accumulate risk.

Background The prevailing view that advocates long-term hormonal follow-up of adrenal incidentalomas is currently under debate. The purpose of the present study was to examine all adrenal incidentalomas presented during five years to a single centre. We hypothesized that 24-month biochemical follow-up in patients with an initial normal screening would fail to increase the sensitivity in finding hormone producing tumours. Methods The present study is a retrospective register based cohort study of 194 patients referred to the Department of Endocrinology at Södersjukhuset between the years 2006–2010. Computerized medical records were used to find and extract information on patients with newly discovered adrenal incidentalomas. The sensitivity, specificity, positive predictive value and negative predictive value were calculated to evaluate the validity of an initial normal screening when used to identify individuals with hormone producing tumours. Results Of the incidentalomas 94% consisted of benign, non-functioning tumours. Three patients were diagnosed with cortisol hypersecretion and one with pheochromocytoma. The sensitivity, specificity, positive predictive value and negative predictive value of an initial complete negative screening to predict a hormone producing tumour were 100%, 63%, 12% and 100%, respectively. Conclusion Patients with an initially normal hormonal screening may not need further biochemical follow-up.