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Background According to previous studies, older patients frequently have serum concentrations of antidepressant medication above the recommended reference range. Objective The aim of this study was to investigate whether prescribed doses of antidepressants and the proportion of individuals with serum concentrations above the recommended reference range in older individuals (≥ 65 years) have changed over a 10-year period in Norway. Methods Serum concentration measurements and prescribed daily doses of antidepressants in 2007 and 2017 were extracted from a therapeutic drug monitoring (TDM) database at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. The database contains routine follow-up serum concentration measurements of psychotropic drugs for patients from all parts of the country. For citalopram, escitalopram, sertraline, mirtazapine and venlafaxine, the differences between 2007 and 2017 in mean prescribed doses and the proportion of patients with at least one serum concentration above the reference range, according to the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) guidelines, were compared. For the proportion of patients with serum concentrations above the recommended reference range, differences between individuals aged 65–79 and ≥ 80 years were also examined. Results The analyses of prescribed doses included 806 patients from 2007 and 1932 patients from 2017, with 972 and 2441 TDM samples, respectively. Between 2007 and 2017, modest reductions in prescribed daily doses were observed for citalopram (20 vs. 17 mg/day) and escitalopram (11 vs. 10 mg/day), but the proportion of patients with serum concentrations above the recommended reference range was unchanged for both drugs, i.e. 11.5% vs. 12.4% for citalopram and 3.6% vs. 2.9% for escitalopram. For mirtazapine and venlafaxine, prescribed doses were reduced from 28 to 25 mg/day and 150 to 125 mg/day, respectively. A significant reduction in the proportion of individuals with serum concentrations above the recommended reference range was observed for mirtazapine (27.1% vs. 11.5%) and for individuals aged ≥ 80 years using venlafaxine (60.0% vs. 30.0%). For sertraline, no differences in prescribed doses or serum concentrations above the recommended reference range were observed. Conclusions Over a 10-year period, prescribed doses of antidepressants have been slightly reduced in older Norwegian patients, but a considerable proportion is still exposed to high serum concentrations of antidepressants. Electronic supplementary material The online version of this article (10.1007/s40266-020-00784-9) contains supplementary material, which is available to authorized users.

BackgroundHypoglycemic incidents in older people can cause severe health problems, enhance general age-related disabilities, and cause frailty. Little is known about incidences of hypoglycemia in older home-dwelling people with diabetes. Thus, the aim of this study was to examine the feasibility of capturing hypoglycemia and issues associated with increased risk of hypoglycemia by use of continuous glucose monitoring (CGM) and standardized questionnaires among older home-dwelling individuals with diabetes type 2 receiving home care.MethodsCGM with the Ipro2-blinded monitoring system were performed for 5 days in six home-dwelling individuals ≥ 75 years diagnosed with diabetes and receiving home care. Demographic (age, gender, living arrangements) and clinical data (diabetes diagnoses and duration, diabetes medication, documented treatment goal, available glycosylated hemoglobin (HbA1c)) were collected from electronic patient records in home care services. Feasibility (ease of use, quality of data, time spent) of standardized questionnaires to identify the risk of hypoglycemia (the McKellar Risk Assessment Tool), risk of malnutrition (the Mini Nutritional Assessment (MNA)), functional status (the Individual-based Statistics for Nursing and Care Services (IPLOS)), and cognitive status (the Mini Mental Status Exam (MMSE)) was also assessed. Questionnaire data was collected by a study nurse in the individuals’ home.ResultsThe practical use of CGM was satisfactory, with no major remarks about discomfort or technical errors, except for one participant with skin reaction (redness). Collecting data with the McKellar Risk Assessment Tool, MNA and IPLOS worked well according to quality of data, time spent, and ease of use. The MMSE survey required extensive training of personnel to be conducted.ConclusionThe feasibility study informs an upcoming study on the incidence and risk factors of hypoglycemia in home-dwelling older individuals. We will ascertain that personnel who will use the MMSE questionnaire to collect cognitive status and skills are familiar with the tool and adequately educated and trained before study start. The use of blinded CGM in this population was well tolerated and can be used “as is” for future studies.

Aim: The purpose of this study was to investigate how old persons perceived their life to be, how they viewed the ageing process and their need of health care and societal support. Background: The purpose of WHO’s Healthy Ageing strategy and development of age-friendly environments is to support physiological and psychosocial changes in old persons by facilitating basic needs. Interventions to operationalize these needs in older people living at home are often developed from a professional perspective and to a small extent involves the perceptions, experience and expectations of the older persons. Method: This qualitative study has an explorative design using focus group discussions to collect data. In all, 34 persons between 69 and 93 years of age participated in seven group discussions. The interviews were analyzed using inductive manifest content analysis. Findings: The main results suggest that most old persons enjoyed life and wished it to continue for as long as possible. Important was to sustain networks and to feel useful. Unexpected changes were described as threats and the need to use health care services was associated with illness and being dependent. The result is presented in three categories with sub-categories: ‘Embracing life’, ‘Dealing with challenges’ and ‘Considering the future’.

Background: Risks associated with polypharmacy and drug–drug interactions represent a challenge in drug treatment, especially in older adults. The aim of the present study was to assess the use of prescription and non-prescription drugs and the frequency of potential drug–drug interactions in home-dwelling older individuals. Methods: A cross-sectional study design was applied. Data were collected during preventive home visits among individuals aged ≥ 75 in three separate communities of Western Norway. A questionnaire, which was filled out by the individual, their next-of-kin, and the nurse performing the home visit was used for the collection of demographic and clinical data (age, sex, medication use, diagnoses, need of assistance with drug administration). Potential drug–drug interactions were identified electronically by IBM Micromedex Drug Interaction Checking. Point prevalence of potential drug–drug interactions and polypharmacy (≥ 5 drugs) were calculated. Binary logistic regression analyses were performed to assess factors potentially associated with polypharmacy or potential drug–drug interactions. Results: Among the 233 individuals (mean age 78± 3 years, 46% male) included in the study, 43% used ≥ 5 drugs, 3.4% ≥ 10 drugs, while 4.3% used no drugs. In 54% of the 197 individuals using two or more drugs, at least one potential drug–drug interaction was detected. Low-dose aspirin and simvastatin were most frequently involved in potential drug–drug interactions. In total, 25% of the individuals reported current use of drugs sold over the counter of which more than 95% were analgesic drugs. Potential drug–drug interactions involving ibuprofen were identified in nine of 11 (82%) individuals using over-the-counter ibuprofen. Conclusion: The study revealed a high prevalence of polypharmacy and potential drug–drug interactions with both prescription and non-prescription drugs in older home-dwelling individuals. Close monitoring of the patients at risk of drug–drug interactions, and increased awareness of the potential of over-the-counter drugs to cause drug–drug interactions, is needed.

BackgroundHypoglycaemia is associated with cognitive and functional decline in older people with diabetes. Identification of individuals at risk and prevention of hypoglycaemia is therefore an important task in the management of diabetes in older home-dwelling individuals. The purpose of this scoping review was to map the literature on hypoglycaemia in home-dwelling older people with diabetes.MethodsThis scoping review included original research articles on hypoglycaemia in older (≥ 65 years) individuals with diabetes from developed countries. A broad search of the databases Cinahl, Embase and Medline was performed in July 2018. The report of the scoping review was conducted in accordance with the PRISMA Extension for Scoping Reviews.ResultsOur database search identified 577 articles of which 23 were eligible for inclusion. The identified literature was within four areas: 1) incidence of hypoglycaemia in older home-dwelling people with diabetes (11/23 articles), 2) risk factors of hypoglycaemia (9/23), 3) diabetes knowledge and self-management (6/23) and 4) consequences of hypoglycaemia for health care use (6/23). The majority of the literature focused on severe hypoglycaemia and the emergency situation. The literature on diabetes knowledge and management related to preventing adverse events relevant to older home-dwellers, was limited. We found no literature on long-term consequences of hypoglycaemia for the use of home health care services and the older persons’ ability to remain home-dwelling.ConclusionsWe identified a lack of studies on prevention and management of hypoglycaemia in the older individuals’ homes. Such knowledge is of utmost importance in the current situation where most western countries’ governmental policies aim to treat and manage complex health conditions in the patient’s home. Future studies addressing hypoglycaemia in older individuals with diabetes are needed in order to tailor interventions aiming to enable them to remain home-dwelling as long as possible.

BackgroundHome care services plays an important role in diabetes management, and to enable older adults remain home-dwellers. Adequate follow-up and systematic nursing documentation are necessary elements in high quality diabetes care. Therefore, the purpose of this study was to examine the diabetes treatment and management for older persons with diabetes receiving home care services.MethodsA cross-sectional study was used to assess the diabetes treatment and management in a Norwegian municipality. Demographic (age, sex, living situation) and clinical data (diabetes diagnose, type of glucose lowering treatment, diabetes-related comorbidities, functional status) were collected from electronic home care records. Also, information on diabetes management; i.e. follow-up routines on glycated haemoglobin (HbA1c), self-monitoring of blood glucose, insulin administration and risk factors (blood pressure, body mass index and nutritional status) were registered. HbA1cwas measured upon inclusion. Descriptive and inferential statistics were applied in the data analysis.ResultsA total of 92 home care records from older home-dwelling persons with diabetes, aged 66–99 years were assessed. Only 52 (57 %) of the individuals had the diabetes diagnosis documented in the home care record. A routine for self-monitoring of blood glucose was documented for 27 (29 %) of the individuals. Only 2 (2 %) had individual target for HbA1cdocumented and only 3 (3 %) had a documented routine for measuring HbA1cas recommended in international guidelines. Among 30 insulin treated older individuals, a description of the insulin regimen lacked in 4 (13 %) of the home care records. Also, documentation on who performed self-monitoring of blood glucose was unclear or lacking for 5 (17 %) individuals.ConclusionsThe study demonstrates lack of documentation in home care records with respect to diagnosis, treatment goals and routines for monitoring of blood glucose, as well as insufficient documentation on responsibilities of diabetes management among older home-dwelling adults living with diabetes. This indicates that home care services may be suboptimal and a potential threat to patient safety.

Background Hypoglycemic incidents in older people can cause severe health problems, enhance general age-related disabilities and cause frailty. Little is known about incidence of hypoglycemia in older home-dwelling people with diabetes. Thus, the aim of this study was to investigate the feasibility of using continuous glucose monitoring (CGM) and standardized questionnaires on issues associated with increased risk of hypoglycemia among older home dwelling individuals with diabetes type 2 receiving home care. Methods CGM with the Ipro2 blinded monitoring system were performed for five days in six home-dwelling individuals ≥ 75 years diagnosed with diabetes and receiving home care. Demographic (age, gender, living arrangements) and clinical data (diabetes diagnoses and duration, diabetes medication, documented treatment goal, available glycosylated hemoglobin (HbA1c),) were collected from electronic patient records in home care services. Feasibility (ease of use, quality of data, time spent) of standardized questionnaires to identify the risk of hypoglycemia (the McKellar Risk Assessment Tool), risk of malnutrition (the Mini Nutritional Assessment (MNA)), functional status (the Individual-based Statistics for Nursing and Care Services (IPLOS)) and cognitive status (the Mini Mental Status Exam (MMSE)) was also assessed. Questionnaire data were collected by a study nurse in the individuals’ home.Results The practical use of CGM was satisfactory, with no major remarks about discomfort or technical errors, except for one participant with skin reaction (redness). Collecting data with the McKellar Risk Assessment Tool, MNA and IPLOS worked well according to quality of data, time spent and ease of use. The MMSE survey required extensive training of personnel to be conducted. Conclusion The feasibility study inform an upcoming study on the incidence and risk factors of hypoglycemia in home dwelling older individuals, were we will reconsider the use of the MMSE questionnaire. The use of blinded CGM in this population was well tolerated and can be used ‘as is’ for future studies.

Background Assessing self-rated health by preventive home visits of older people can provide information about the person’s well-being, quality of life and risk of developing illness. The aim of this study was to examine associations between self-rated health and factors related to demographics, lifestyle, health conditions and medical diagnoses by older people participating in a preventive home visit program. Methods A cross-sectional study including 233 participants (age 75–79) from three municipalities of Western Norway was conducted. Data were collected through preventive home visits performed by six nurses, using a questionnaire including self-rated health assessment and questions and tests related to demographics (e.g. education and housing), lifestyle (e.g. social activities, alcohol and smoking), health conditions (e.g. sensory impairment, pain and limited by disease) and medical diagnoses. Descriptive and inferential statistics including linear block-wise regression model were applied. Results The block-wise regression model showed that the variables Limited by disease and Pain were negatively associated with self-rated health and Use internet was positively associated. The model had a R2 0.432. The variable that contributed to largest change in the model was Limited by disease (R2 Change; 0.297, p-value Conclusions In the present study, being limited by disease and pain were strongly associated with poor self-rated health, indicating that these are important factors to assess during a preventive home visit. Also, digital competence (Use internet) was associated with a better self-rated health, suggesting that it could be useful to ask, inform and motivate for the use of digital tools that may compensate for or improve social support, social contact and access to health -related information.

Tacrolimus is currently the cornerstone of immunosuppressive protocols for renal transplant recipients. Despite therapeutic whole blood monitoring, tacrolimus is associated with nephrotoxicity and it has been hypothesized that intrarenal accumulation of tacrolimus and/or its metabolites are involved. As tacrolimus is a substrate of P-glycoprotein (P-gp), the expression and activity of this efflux transporter could influence the levels of tacrolimus in renal tissue. The primary aim of this study was to develop and validate a method for quantification of tacrolimus in tissue homogenates from single human renal core biopsies. The secondary aim was to provide measures of P-gp expression and of the demethylated metabolites of tacrolimus in the same renal biopsy. Human renal tissue, with and without clinical tacrolimus exposure, was used for method development and validation. Homogenates were prepared with bead-beating, and concentrations of tacrolimus and its demethylated metabolites were analyzed with liquid chromatography tandem mass spectrometry after protein precipitation. A Western blot method was used for semi-quantification of P-gp expression in the homogenates. The final methods were applied to renal core biopsies from two transplant patients. The tacrolimus assay showed within- and between-run mean accuracy between 99.7 % and 107 % and coefficients of variation ≤6.7 %. Matrix effects were non-significant and samples were stable for three months pre-analytically when stored at -80 °C. Tacrolimus concentrations in the renal core biopsies were 62.6 and 43.7 pg/mg tissue. The methods for measurement of desmethyl-tacrolimus and P-gp expression were suitable for semi-quantification in homogenates from renal core biopsies. These methods may be valuable for the elucidation of the pharmacokinetic mechanisms behind tacrolimus-induced nephrotoxicity in renal transplant recipients.

Aims To determine use of psychotropic drugs and weak opioids in hip fracture patients by analysing plasma samples at admission, and compare detected drug frequencies with prescription registry data and drug records. Methods Plasma from 250 hip fracture patients aged ≥65 years sampled at hospital admission were analysed by ultra-performance liquid chromatography–tandem mass spectrometry methods for detection of psychotropic drugs and weak opioid analgesics (alcohol also determined). Odds ratios for drugs detected in plasma of hip fracture patients vs. prescription frequencies of the same drugs in an age-, time- and region-matched reference population were calculated. Moreover, recorded and measured drugs were compared. Results Psychotropic drugs and/or weak opioid analgesics were detected in 158 (63%) of the patients (median age 84 years; 76% females), while alcohol was found in 19 patients (7.6%). The occurrence of diazepam (odds ratio 1.6; 95% confidence interval 1.1–2.4), nitrazepam (2.3; 1.3–4.1), selective serotonin reuptake inhibitors (1.9; 1.3–2.9) and mirtazapine (2.3; 1.2–4.3) was significantly higher in plasma samples of hip fracture patients than in prescription data from the reference population. Poor consistency between recorded and measured drugs was disclosed for z-hypnotics and benzodiazepines; e.g. diazepam was detected in 29 (11.6%), but only recorded in six (2.4%) of the patients. Conclusions Plasma analysis shows that use of antidepressants and benzodiazepines in hip fracture patients is significantly more frequent than respective prescription frequencies in the general elderly population. Moreover, consistency between recorded and actual use of psychotropic fall-risk drugs is poor at hospital admission of hip fracture patients.

PURPOSE Individuals with intellectual disabilities (IDs) have more health problems, a poorer general health, and a shorter life expectancy than individuals in general. High rates of drug use in IDs have been reported. Despite the increasing interest in health problems in individuals with IDs, little is known about their drug use. METHOD Drug use in a community sample of adults with IDs (N = 593) was compared with dispensed drugs in a time-, age-, and region-matched comparison group of adults in Western Norway (N = 289 325). A logistic regression model was employed by using the main group effect to describe and analyze the differences between the ID sample and the comparison sample and by using the interaction term (group × age) to describe the rate change differences from the reference age (18-30 years) between the two groups. RESULTS Total drug use in the ID sample was 62% compared with 50% in the reference sample (P = 0.0001). The high prevalence of drugs for the nervous system (ATC N) in the ID sample (50%) explained the difference. From age 51 and over, the increase in the drug use rate for the cardiovascular disease was significantly lower in the ID sample than in the reference sample (P value range: 0.002-0.019). CONCLUSIONS Adults with IDs use more drugs than adults in general. However, the findings showed lower rates of drug use in the ID sample than in the general population for drugs targeting diseases that are the leading causes of death in individuals with IDs.

Elderly patients are at increased risk for elevated serum concentrations from treatment with selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to examine the use of therapeutic drug monitoring (TDM) of SSRIs in elderly compared with younger patients.All serum concentration measurements of SSRIs (escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) performed at our laboratory in 2011 were included. The use of TDM (relative frequency) in older versus younger patients was examined by comparing the use of TDM in patients aged 60 years or older with that in patients younger than 60 years and by evaluating the use of TDM relative to age (age groups in decennials). The number of patients with an SSRI dispensed by prescription in the same region and period (the Norwegian Prescription Database) was used as reference. Additionally, the number of samples above the upper limit of the recommended reference range in patients aged 60 years or older and patients younger than 60 years was evaluated.TDM of an SSRI had been performed in 6333 patients. For all SSRIs, the use of TDM was significantly lower (8.2% versus 10.6% for citalopram, 10.0% versus 13.8% for escitalopram, 8.6% versus 17.0% for fluoxetine, 5.6% versus 10.3% for paroxetine, and 8.1% versus 15.0% for sertraline) in patients aged 60 years or older compared with those younger than 60 years (P0.001). There was a gradual decline in the use of TDM with increasing age, with a 3-fold difference between the youngest (10-19) and oldest (90+) patients (P0.0001). The percentage of samples above the upper limit of the recommended reference range was 2-fold higher in patients aged 60 years or older (6.7%) compared with patients younger than 60 (3.4%) years (P0.0001).Clinical follow-up of patients with TDM of SSRIs is less frequent in older patients compared with younger patients. This is in contrast to the general guidelines for TDM where patients of advanced age are considered of particular importance to monitor closely.

To investigate the impact of genetic variability in CYP2D6, CYP3A5, and ABCB1 on steady-state serum concentrations of quetiapine and the active metabolite, N-desalkylquetiapine, in psychiatric patients.Measured serum concentrations of quetiapine and N-desalkylquetiapine from patients with biobanked DNA samples were included retrospectively from a routine therapeutic drug monitoring database. The impact of CYP2D6, CYP3A5, and ABCB1 (345CT) genotypes on dose-adjusted serum concentrations (C/D ratios) of quetiapine and N-desalkylquetiapine was investigated by multivariate mixed model analysis.In total, 289 patients with 633 serum measurements were included. In the multivariate analysis, mean C/D ratio of N-desalkylquetiapine was estimated to be 33% and 22% higher in inherent CYP2D6 poor metabolizers (P = 0.03) and heterozygous extensive metabolizers (P0.001), respectively, compared with inherent extensive metabolizers. The ABCB1 3435CT polymorphism and CYP3A5 genotype had no significant influence on either of the substances in the present material.Genetic variability in CYP2D6 contributes to the interindividual variability in steady-state serum concentrations of N-desalkylquetiapine. Although the metabolite exhibits relevant pharmacological activity, the quantitative effect of CYP2D6 genotype on serum concentration of N-desalkylquetiapine is probably of limited clinical relevance for quetiapine treatment.

Background: Patients with high tacrolimus clearance eliminate more drug within a dose interval compared to those with low clearance. Delays in dosing time will result in transient periods of lower concentrations in high- versus low clearance patients. Transient subtherapeutic tacrolimus concentrations may induce acute rejection episodes. Methods: A retrospective study in all renal transplant patients treated with tacrolimus at our centre from 2009 to 2013 was conducted. The association between individually estimated tacrolimus clearance (daily tacrolimus dose [mg] / trough concentration [µg/L]) and biopsy-proven acute rejection (BPAR) the first 90 days posttransplantation was investigated. Results: In total, 638 patients treated with oral tacrolimus were included in the analysis. Eighty-five (13.3%) patients experienced BPAR. Patients were stratified into four groups according to their estimated clearance. The patients in the high clearance group had significantly higher incidence of BPAR (20.6%) with a HR of 2.39 (95% CI; 1.30-4.40) compared to the low clearance group. Clearance estimate (as a continuous parameter) showed a hazard ratio of 2.25 (95% CI; 1.70-2.99) after adjusting for other risk factors. There were no significant differences in neither trough concentrations the first week after transplantation nor time to target trough concentration between patients later experiencing BPAR or not. Conclusion: High estimated clearance is significantly associated with increased risk of BPAR the first 90 days post-transplantation, and may predict an increased risk of rejection in the early phase following renal transplantation. This research has been accepted and published in Transplantation. © 2017 Lippincott, Williams & Wilkins

The aim of the present study was to investigate the effect of age on venlafaxine and escitalopram serum concentrations in various cytochrome P450 (CYP) 2D6 and CYP2C19 genotype subgroups.Serum concentration measurements from CYP-genotyped patients treated with venlafaxine (n = 255) or escitalopram (n = 541) were collected retrospectively from a therapeutic drug monitoring database. Patients were divided into three CYP2D6 (venlafaxine) or CYP2C19 (escitalopram) phenotype subgroups according to inherited genotype, i.e., poor metabolizers (PMs), heterozygous extensive metabolizers (HEMs), and extensive metabolizers (EMs), and subsequently distributed into three age groups, i.e.,40 (control), 40-65, and65 years. The effect of age on dose-adjusted serum concentrations (i.e., nmol/L/mg/day) of venlafaxine and escitalopram in each of the phenotype subgroups was evaluated by separate multivariate mixed model analyses.In CYP2D6 PMs, the mean dose-adjusted serum concentration of venlafaxine was 8-fold higher in patients65 years compared with those40 years (p 0.001). In comparison, the respective age-related differences in mean dose-adjusted serum concentrations of venlafaxine were much less pronounced in CYP2D6 HEMs and EMs (2-fold differences between age groups). A similar genotype-related effect of age was not observed for escitalopram (1.5-fold age differences in all CYP2C19 subgroups).This study suggests that the effect of age on serum concentration of venlafaxine is dependent on CYP genotype, in contrast to escitalopram. Thus, to prevent potential side effects, it might be particularly relevant to consider CYP2D6 genotyping prior to initiation of venlafaxine treatment in older patients.

Background: Myopathic complaints are common in the general population and are more frequent with increasing age. When myopathic symptoms arise in a patient treated with a HMG-CoA reductase inhibitor (statin), it is always a question of whether the symptoms are due to statin-induced myopathy (SIM) or not (non-SIM). Diagnosis of SIM is not as straightforward as previously thought, because the most commonly used biomarker, serum creatine kinase, shows low specificity and selectivity, except in serious cases of rhabdomyolysis. There is a definite need for a novel biomarker for SIM. Objective: Based on a previous study reporting an altered metabolic profile with increased systemic exposure to the suspected muscle-toxic metabolite atorvastatin lactone in patients with SIM compared with healthy controls, this study aimed to explore the use of atorvastatin metabolite measurements to diagnose muscular complaints during statin treatment as being either SIM or non-SIM. Patients, Setting, and Study Design: Fifty-three patients with self-reported myopathic symptoms during atorvastatin treatment were recruited from our outpatient clinic. The symptoms were clinically evaluated as being SIM or non-SIM, on the basis of atorvastatin re-challenge testing. Atorvastatin and its metabolites were measured at steady state in all patients and compared with the clinical evaluation to see if this could predict the outcome and hence be suitable as a diagnostic tool for SIM. Main Outcome Measure: This was an exploratory study to investigate the proportion of patients correctly diagnosed by different metabolite cut-off ratios. Results: With a cut-off ratio set at 1.1 for the atorvastatin lactone to atorvastatin acid ratio, 15 of 28 SIM patients (sensitivity of 54%) and 20 of 24 non-SIM patients (specificity of 83%) were correctly diagnosed. This corresponds to a positive predictive value of 79% and a negative predictive value of 61% (p = 0.006). Conclusion: The present study confirms an altered metabolic pattern of atorvastatin in patients with SIM and substantiates a central role of the lactone forms of statins in future investigations of statin myotoxicity. The atorvastatin lactone to acid ratio seems to be a valuable supportive diagnostic tool with high specificity and moderate sensitivity, adding to ordinary clinical evaluations when diagnosing SIM. Trial registration number (clinicaltrials.gov): NCT00414531

Previous studies have categorized duloxetine as a moderate inhibitor of CYP2D6. The aim of the present study was to investigate the potential interactions between duloxetine and the two CYP2D6 substrates risperidone and aripiprazole in psychiatric patients. Serum concentration data from patients treated with risperidone (n = 8) or aripiprazole (n = 7) in combination with duloxetine were retrieved from therapeutic drug monitoring files at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. The degree of interaction was assessed by comparing the data with a control group of CYP2D6-genotyped patients (homozygous "extensive metabolizers") using oral risperidone or aripiprazole without duloxetine. Coadministration of duloxetine did not significantly increase the concentration of the parent drug or the parent drug/metabolite ratio of either risperidone or aripiprazole. The present study therefore indicates that duloxetine may safely be used concomitantly with risperidone or aripiprazole.

An increased risk of adverse effects and discontinuation of risperidone therapy is observed in patients with impaired cytochrome P450 2D6 (CYP2D6) function on oral risperidone therapy. The present study is the first to investigate the impact of CYP2D6 genotype on serum concentrations of risperidone and 9-hydroxyrisperidone in patients using injectable long-acting risperidone. Two hundred three patients were divided into groups according to administered risperidone formulation (long-acting injection; n = 90) and CYP2D6 genotype. Dose-adjusted serum concentrations were compared using the CYP2D6*1/*1 subgroup as reference. The total serum concentration of risperidone plus 9-hydroxyrisperidone was 80% (P < 0.03) and 32% (P < 0.03) higher, whereas the risperidone-9-hydroxyrisperidone ratios were 6.3-fold (P < 0.01) and 12.5-fold (P < 0.01) higher in the CYP2D6def/def (def means defective allele, ie, CYP2D6*3, *4, *5, or *6) subgroup for long-acting and oral risperidone, respectively. In conclusion, CYP2D6 genotype significantly affects the pharmacokinetics of both oral and long-acting risperidone formulations.

Aripiprazole, a relatively new antipsychotic drug, is metabolized by cytochrome P450 3A4 (CYP3A4) and CYP2D6 to an active metabolite, dehydroaripiprazole. As studies on pharmacokinetic drug interactions with aripiprazole are so far limited, the aim of the present study was to investigate the impact of comedication on serum concentrations of aripiprazole and dehydroaripiprazole in psychiatric patients in a clinical setting. A therapeutic drug monitoring database was screened for patients receiving aripiprazole tablets as part of their treatment. Of the 361 samples included, 78% were from patients receiving comedication. The remaining 79 samples constituted the control group. Steady-state dose-adjusted serum concentrations (concentration to dose ratios, C:D ratios) of aripiprazole, dehydroaripiprazole and the sum of aripiprazole and dehydroaripiprazole, and the metabolic ratio (dehydroaripiprazole/aripiprazole) in the different comedication groups were compared with controls. Coadministration of a CYP3A4 inducer resulted in approximately 60% lower mean C:D ratios of aripiprazole, dehydroaripiprazole, and the sum of aripiprazole and dehydroaripiprazole (P < 0.05, P < 0.01, and P < 0.01, respectively). Combination with a CYP2D6 inhibitor resulted in a 45% higher mean C:D ratio of aripiprazole (P < 0.05), with no effect on the C:D ratio of dehydroaripiprazole. When aripiprazole was coadministered with alimemazine or lithium, a 56% (P < 0.01) and 43% (P = 0.05) higher mean C:D ratio of aripiprazole, respectively, was observed. Olanzapine, risperidone injections, escitalopram, or lamotrigine also had statistically significant effects on aripiprazole disposition but to a lesser extent. In conclusion, concurrent treatment with CYP3A4 inducers, CYP2D6 inhibitors, alimemazine, or lithium resulted in changes in the systemic exposure of aripiprazole between 40% and 60%. This is of such a magnitude that dose adjustments of aripiprazole may be required.

To investigate the impact of CYP2C19 genotype on serum concentrations of sertraline and N-desmethyl sertraline in psychiatric patients.Patients treated with sertraline (n = 121) were divided into six subgroups according to CYP2C19 genotype: CYP2C19*17/*17, CYP2C19*1/*17, CYP2C19*1/*1, CYP2C19*17/def, CYP2C19*1/def and CYP2C19def/def (def = allele encoding defective CYP2C19 metabolism, i.e. *2 and *3). Dose-adjusted serum concentrations were compared by linear mixed model analyses using the CYP2C19*1/*1 subgroup as reference.Subgroups carrying one or two alleles encoding defective CYP2C19 metabolism achieved significantly higher mean dose-adjusted serum concentrations of sertraline and N-desmethyl sertraline compared to the CYP2C19*1/*1 subgroup (P0.05). The effect of CYP2C19 genotype was expressed as 3.2-fold (sertraline) and 4.5-fold (N-desmethyl sertraline) higher dose-adjusted serum concentrations in the CYP2C19def/def subgroup compared to the CYP2C19*1/*1 subgroup (P0.01). The CYP2C19*17 allele had no influence on the dose-adjusted serum concentrations of sertraline and N-desmethyl sertraline.The significantly higher serum concentrations associated with alleles encoding defective CYP2C19 metabolism might be of relevance for the clinical outcome of sertraline treatment.

BACKGROUND Cytochrome P450 2D6 intermediate metabolizer phenotype (CYP2D6 IM) comprises various genotype subgroups. The aim of this study was to evaluate serum concentrations of the CYP2D6 substrates risperidone and aripiprazole in psychiatric patients with various CYP2D6 genotypes encoding IM phenotype. METHODS The study was based on therapeutic drug monitoring data from CYP2D6-genotyped patients (mainly of white origin) treated with orally administered risperidone (n = 190) or aripiprazole (n = 266). Patients were divided into 3 genotype subgroups encoding IM phenotype: (1) heterozygous carriers of fully functional and nonfunctional variant alleles (*1/def), (2) homozygous carriers of reduced-function variant alleles (red/red), and (3) heterozygous carriers of reduced-function and nonfunctional variant alleles (def/red). Dose-adjusted serum concentrations of risperidone and aripiprazole were compared between the genotype subgroups using *1/def, the most frequent CYP2D6 genotype among these subgroups, as the reference group. RESULTS Median serum concentrations were 4.5- and 1.6-fold higher in the def/red genotype than the *1/def genotype for risperidone and aripiprazole, respectively (P < 0.01 for both). Correspondingly, the serum concentrations were 3.4- and 1.8-fold higher in the red/red subgroup compared with the reference group (P < 0.05 for both). CONCLUSIONS In conclusion, this study revealed substantial variability in serum concentrations of risperidone and aripiprazole between CYP2D6 genotypes associated with IM phenotype. A considerable phenotypical difference was observed between patients carrying 1 and 2 variant alleles.

Atorvastatin is commonly used to reduce cholesterol. Atorvastatin acid is converted to its corresponding lactone form spontaneously or via glucuronidation mediated by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A3. Atorvastatin lactone is pharmacologically inactive, but is suspected to be muscle toxic and cause statin-induced myopathy (SIM). A several fold increase in systemic exposure of atorvastatin lactone has previously been observed in patients with SIM compared with healthy control subjects. In this study we aimed to investigate the association between polymorphisms in the UGT1A gene locus and plasma atorvastatin lactone levels. DNA was extracted from whole blood obtained from a previous pharmacokinetic study of patients carefully diagnosed as having true SIM (n = 13) and healthy control subjects (n = 15). The UGT1A1*28(TA) 7 , UGT1A3*2, UGT1A3*3, and UGT1A3*6 polymorphisms were detected by pyrosequencing. Carriers of the low-expression allele UGT1A1*28(TA) 7 tended to have lower levels of atorvastatin lactone (p

Through the last decades it has become increasingly evident that disease-states involving cytokines affect the pharmacokinetics of drugs through regulation of expression and activity of drug metabolizing enzymes, and more recently also drug transporters. The clinical implication is however difficult to predict, since these effects are dependent on the degree of inflammation and may be changed when the diseases are treated. This article will give an overview of the present understanding of the effects of cytokines on cytochrome P450 enzymes and drug transporters, and highlight the importance of considering these issues in regard to increasing use of the relatively new class of drugs, namely therapeutic proteins.

The elderly is the most rapidly growing subpopulation in many countries, and the use of antidepressant drugs among elderly patients may be increasing as depression is one of the most common comorbid conditions in age-related diseases. The aim of the present study was to compare serum concentrations of antidepressants in older versus younger individuals in a naturalistic setting.Serum concentrations from patients treated with antidepressant drugs were withdrawn from a routine therapeutic drug monitoring database and stratified into the age groups younger than 40 years, 40-65 years, and older than 65 years. Dose-adjusted serum concentrations (concentration to dose ratios; nanomoles per liter per milligram per day) and absolute serum concentrations were compared between the subgroups using patients younger than 40 years as control.Altogether, 32,126 serum concentration samples from 17,930 patients treated with selective serotonin reuptake inhibitors, tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, or tetracyclic antidepressant drugs were included. Only minor differences in mean concentration to dose ratios and absolute serum concentrations were observed between patients aged 40-65 years and controls. In contrast, for 12 of the 14 drugs included, approximately 1.5- to 2-fold higher mean concentration to dose ratios were observed in patients older than 65 years versus controls (P0.01). Significantly higher absolute serum concentrations were also observed in the former compared with the latter subgroup for 8 of these 12 agents (P0.01).Patients older than 65 years had a 1.5- to 2-fold higher exposure of most antidepressant drugs compared with those younger than 40 years when given equal doses. This may indicate an increased risk of concentration-dependent side effects in the elderly.

Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback. Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4+PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors.