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  • 1.
    Aronsson, Patrik
    et al.
    Department Pharmacology, Institution of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Booth, Shirley
    Department Pedagogical, Curricular and Professional Studies, Faculty of Education, University of Gothenburg, Gothenburg, Sweden; School of Education, University of the Witwatersrand, Johannesburg, South Africa.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Kjellgren, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Zetterqvist, Ann
    Department Pedagogical, Curricular and Professional Studies, Faculty of Education, University of Gothenburg, Gothenburg, Sweden.
    Tobin, Gunnar
    Department Pharmacology, Institution of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    The understanding of core pharmacological concepts among health care students in their final semester2015In: BMC Medical Education, ISSN 1472-6920, E-ISSN 1472-6920, Vol. 15, no 1, article id 235Article in journal (Refereed)
    Abstract [en]

    Background

    The overall aim of the study was to explore health care students´ understanding of core concepts in pharmacology.

    Method

    An interview study was conducted among twelve students in their final semester of the medical program (n = 4), the nursing program (n = 4), and the specialist nursing program in primary health care (n  = 4) from two Swedish universities. The participants were individually presented with two pharmacological clinically relevant written patient cases, which they were to analyze and propose a solution to. Participants were allowed to use the Swedish national drug formulary. Immediately thereafter the students were interviewed about their assessments. The interviews were audio-recorded and transcribed verbatim. A thematic analysis was used to identify units of meaning in each interview. The units were organized into three clusters: pharmacodynamics, pharmacokinetics, and drug interactions. Subsequent procedure consisted of scoring the quality of students´ understanding of core concepts. Non-parametric statistics were employed.

    Results

    The study participants were in general able to define pharmacological concepts, but showed less ability to discuss the meaning of the concepts in depth and to implement these in a clinical context. The participants found it easier to grasp concepts related to pharmacodynamics than pharmacokinetics and drug interactions.

    Conclusion

    These results indicate that education aiming to prepare future health care professionals for understanding of more complex pharmacological reasoning and decision-making needs to be more focused and effective.

  • 2.
    Carlsson, Björn
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Olsson, Gunilla
    Reis, Margareta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry.
    Wålinder, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Nordin, Conny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Lundmark, Jöns
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Adolescents on chronic oral dosing with racemic citalopram. Enantioselective analysis of citalopram and CYP2D6/CYP2C19 genotyping. 5 th Congress of the European Association for Clinical Pharmacology and Therapuetics, Odense, Denmark 12-15 september 20012001In: Pharmacology and Toxicology,2001, 2001, p. 132-132Conference paper (Refereed)
  • 3.
    Carlsson, Björn
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Olsson, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Reis, Margareta
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Wålinder, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Nordin, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Lundmark, Jöns
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Scordo, M. G.
    Dahl, M-L.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Enantioselective Analysis of Citalopram and Metabolites in Adolescents2001In: Therapeutic drug monitoring, ISSN 0163-4356, Vol. 23, no 6, p. 658-664Article in journal (Refereed)
    Abstract [en]

    Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent despite its increasing use in these age groups. The aim of this study was to investigate a group of adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites desmethylcitalopram and didesmethylcitalopram. Moreover, the authors studied the genotypes for the polymorphic cytochrome P450 enzymes CYP2D6 and CYP2C19 in relation to the different enantiomers. The S/R ratios of citalopram and desmethylcitalopram found in this study of 19 adolescents were similar to studies involving older patients. The concentrations of the R-(-)- and S-(+)-enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies, the R-(-)-enantiomer (distomer) being the major enantiomer. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the CYP2C19 enzyme.

  • 4.
    Dolores Cherma Yeste, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting2008In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 30, no 6, p. 682-688Article in journal (Refereed)
    Abstract [en]

    There is limited information on the pharmacokinetics of ziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linkoping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20-320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L-1 mg(-1) d(-1)) for ZIP and SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively, with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for close-normalized scruin concentrations of ZIP, SMDZ, and SMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIP concentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.

  • 5.
    Faria, Vanda
    et al.
    Uppsala University, Sweden; Harvard Medical Sch, MA USA.
    Gingnell, Malin
    Uppsala University, Sweden.
    Hoppe, Johanna M.
    Uppsala University, Sweden.
    Hjorth, Olof
    Uppsala University, Sweden.
    Alaie, Iman
    Uppsala University, Sweden.
    Frick, Andreas
    Uppsala University, Sweden; Karolinska Institute, Sweden.
    Hultberg, Sara
    Uppsala University, Sweden.
    Wahlstedt, Kurt
    Uppsala University, Sweden.
    Engman, Jonas
    Uppsala University, Sweden.
    Mansson, Kristoffer N. T.
    Uppsala University, Sweden; Karolinska Institute, Sweden; Stockholm University, Sweden.
    Carlbring, Per
    Stockholm University, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Elna-Marie
    Uppsala University, Sweden.
    Fredrikson, Mats
    Uppsala University, Sweden; Karolinska Institute, Sweden.
    Furmark, Tomas
    Uppsala University, Sweden.
    Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial2017In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 24, p. 179-188Article in journal (Refereed)
    Abstract [en]

    Background: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety, but their efficacy relative to placebo has been questioned. We aimed to test how manipulation of verbally induced expectancies, central for placebo, influences SSRI treatment outcome and brain activity in patients with social anxiety disorder (SAD). Methods: Wedid a randomized clinical trial, within an academicmedical center (Uppsala, Sweden), of individuals fulfilling the DSM-IV criteria for SAD, recruited through media advertising. Participants were 18 years or older and randomized in blocks, through a computer-generated sequence by an independent party, to nine weeks of overt or covert treatment with escitalopram(20mg daily). The overt group received correct treatment information whereas the covert group was treated deceptively with the SSRI described, by the psychiatrist, as active placebo. The treating psychiatrist was necessarily unmasked while the research staff was masked from intervention assignment. Treatment efficacy was assessed primarily with the self-rated Liebowitz Social Anxiety Scale (LSASSR), administered at week 0, 1, 3, 6 and 9, also yielding a dichotomous estimate of responder status (clinically significant improvement). Before and at the last week of treatment, brain activity during an emotional face matching task was assessed with functional magnetic resonance imaging (fMRI) and during fMRI sessions, anticipatory speech anxiety was also assessed with the Spielberger State-Trait Anxiety Inventory-State version (STAI-S). Analyses included all randomized patients with outcome data at posttreatment. This study is registered at ISRCTN, number 98890605. Findings: Between March 17th 2014 and May 22nd 2015, 47 patients were recruited. One patient in the covert group dropped out after a few days of treatment and did not provide fMRI data, leaving 46 patients with complete outcome data. After nine weeks of treatment, overt (n - 24) as compared to covert (n - 22) SSRI administration yielded significantly better outcome on the LSAS-SR (adjusted difference 21.17, 95% CI 10.69-31.65, p amp;lt; 0.0001) with more than three times higher response rate (50% vs. 14%;chi(2)(1)= 6.91, p= 0.009) and twice the effect size (d= 2.24 vs. d= 1.13) from pre-to posttreatment. There was no significant between-group difference on anticipatory speech anxiety (STAI-S), both groups improving with treatment. No serious adverse reactions were recorded. On fMRI outcomes, there was suggestive evidence for a differential neural response to treatment between groups in the posterior cingulate, superior temporal and inferior frontal gyri (all z thresholds exceeding 3.68, p amp;lt;= 0.001). Reduced social anxiety with treatment correlated significantly with enhanced posterior cingulate (z threshold 3.24, p - 0.0006) and attenuated amygdala (z threshold 2.70, p - 0.003) activity. Interpretation: The clinical and neural effects of escitalopram were markedly influenced by verbal suggestions. This points to a pronounced placebo component in SSRI-treatment of SAD and favors a biopsychosocial over a biomedical explanatory model for SSRI efficacy. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.

  • 6.
    Gingnell, Malin
    et al.
    Uppsala University, Sweden.
    Frick, Andreas
    Uppsala University, Sweden.
    Engman, Jonas
    Uppsala University, Sweden.
    Alaie, Iman
    Uppsala University, Sweden.
    Bjorkstrand, Johannes
    Uppsala University, Sweden.
    Faria, Vanda
    Uppsala University, Sweden; Harvard Medical Sch, MA USA.
    Carlbring, Per
    Stockholm University, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Karolinska Institute, Sweden.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Elna-Marie
    Uppsala University, Sweden.
    Wahlstedt, Kurt
    Uppsala University, Sweden.
    Fredrikson, Mats
    Uppsala University, Sweden; Karolinska Institute, Sweden.
    Furmark, Tomas
    Uppsala University, Sweden.
    Combining escitalopram and cognitive-behavioural therapy for social anxiety disorder: randomised controlled fMRI trial2016In: British Journal of Psychiatry, ISSN 0007-1250, E-ISSN 1472-1465, Vol. 209, no 3, p. 229-235Article in journal (Refereed)
    Abstract [en]

    Background Selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioural therapy (CBT) are often used concomitantly to treat social anxiety disorder (SAD), but few studies have examined the effect of this combination. Aims To evaluate whether adding escitalopram to internet-delivered CBT (ICBT) improves clinical outcome and alters brain reactivity and connectivity in SAD. Method Double-blind, randomised, placebo-controlled neuroimaging trial of ICBT combined either with escitalopram (n=24) or placebo (n=24), including a 15-month clinical follow-up (trial registration: ISRCTN24929928). Results Escitalopram+ICBT, relative to placebo+ICBT, resulted in significantly more clinical responders, larger reductions in anticipatory speech state anxiety at post-treatment and larger reductions in social anxiety symptom severity at 15-month follow-up and at a trend-level = 0.09) at post-treatment. Right amygdala reactivity to emotional faces also decreased more in the escitalopram+ICBT combination relative to placebo+ICBT, and in treatment responders relative to non-responders. Conclusions Adding escitalopram improves the outcome of ICBT for SAD and decreased amygdala reactivity is important for anxiolytic treatment response.

  • 7.
    Jonsson, Anna K.
    et al.
    Natl Board Forens Med, Dept Forens Chem and Genet, Linkoping, Sweden.
    Spigset, Olav
    St Olavs Univ Hosp, Norway; Norwegian Univ Sci and Technol, Norway.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Sickle Univ Hosp, Sweden.
    A Compilation of Serum Concentrations of 12 Antipsychotic Drugs in a Therapeutic Drug Monitoring Setting2019In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 41, no 3, p. 348-356Article in journal (Refereed)
    Abstract [en]

    Background: No comprehensive collection of routine therapeutic drug monitoring data for antipsychotic drugs has been published. Methods: In this compilation, data on 12 antipsychotics are presented. The drugs included are amisulpride (n = 506), aripiprazole (n = 1610), clozapine (n = 1189), flupentixol (n = 215), haloperidol (n = 390), olanzapine (n = 10,268), perphenazine (n = 1065), quetiapine (n = 5853), risperidone (n = 3255), sertindole (n = 111), ziprasidone (n = 1235), and zuclopenthixol (n = 691). Because only one sample per patient is included, the number of patients equals the number of samples. For each drug, median serum concentrations as well as that of the 10th and 90th percentiles are given for a range of daily doses. Comparisons are made between males and females, between patients younger than 65 years and 65 years and older, and between those treated with a low and a high dose of each drug. The concentration-to-dose (C/D) ratio is the primary variable used in these comparisons. Coefficients of variation (CVs) for the serum concentrations of each drug within and between subjects are presented. Results: In general, the C/D ratios were higher in females than in males, higher in those 65 years and older than in younger subjects, and lower in those treated with higher doses than in those treated with lower doses. CVs between individuals were larger than within subjects, and the CVs were highest for the drugs with short elimination half-lives. Conclusions: For each antipsychotic drug, the results presented can serve as a reference tool for pharmacokinetic interpretation of the individual patients serum drug level. The compiled serum concentrations and the C/D ratios can support the physicians decision when individualizing dosing and determining treatment strategies for a specific patient.

  • 8.
    Jönsson, Anna K
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Soderberg, Carl
    Karolinska Institute, Sweden .
    Arne Espnes, Ketil
    St Olavs University Hospital, Norway .
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Eriksson, Anders
    Umeå University, Sweden .
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Druid, Henrik
    Karolinska Institute, Sweden .
    Sedative and hypnotic drugs-Fatal and non-fatal reference blood concentrations2014In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 236, p. 138-145Article in journal (Refereed)
    Abstract [en]

    In postmortem investigations of fatal intoxications it is often challenging to determine which drug/s caused the death. To improve the interpretation of postmortem blood concentrations of sedative and hypnotic drugs and/or clonazepam, all medico-legal autopsies in Sweden - where these drugs had been detected in femoral vein blood during 1992-2006 - were identified in the databases of the National Board of Forensic Medicine. For each drug, concentrations in postmortem control cases - where the cause of death was not intoxication and where incapacitation by drugs could be excluded - were compiled as well as the levels found in living subjects; drugged driving cases and therapeutic drug monitoring cases. Subsequently, fatal intoxications were assessed with regards to the primary substances contributing to death, and blood levels were compiled for single and multiple drug intoxications. The postmortem femoral blood levels are reported for 16 sedative and hypnotic drugs, based on findings in 3560 autopsy cases. The cases were classified as single substance intoxications (N = 498), multiple substance intoxications (N = 1555) and postmortem controls (N = 1507). Each autopsy case could be represented more than once in the group of multiple intoxications and among the postmortem controls if more than one of the included substances were detected. The concentration ranges for all groups are provided. Overlap in concentrations between fatal intoxications and reference groups was seen for most substances. However, the concentrations found in single and multiple intoxications were significantly higher than concentrations found in postmortem controls for all substances except alprazolam and triazolam. Concentrations observed among drugged drivers were similar to the concentrations observed among the therapeutic drug monitoring cases. Flunitrazepam was the substance with the highest number of single intoxications, when related to sales. In summary, this study provides reference drug concentrations primarily to be used for improving interpretation of postmortem drug levels in obscure cases, but which also may assist in drug safety work and in pharmacovigilance efforts.

  • 9.
    Kallen, Bengt
    et al.
    Lund University, Sweden .
    Reis, Margareta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Neonatal Complications After Maternal Concomitant Use of SSRI and Other Central Nervous System Active Drugs During the Second or Third Trimester of Pregnancy2012In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 32, no 5, p. 608-614Article in journal (Refereed)
    Abstract [en]

    Drugs acting on the central nervous system(CNS) and given to a pregnant woman during the latter part of pregnancy may affect neonatal morbidity of the infant. Little is known on the combined effects of different categories of such drugs. The redeeming of prescriptions for CNS-active drugs during the second or third trimester of pregnancy was studied by linkage between a register of prescribed drugs and the Swedish Medical Birth Register for the deliveries during 2006-2008 (n - 15,045 live-born infants). Neonatal morbidity was defined as the presence of neonatal diagnoses of respiratory problems, hypoglycemia, convulsions, or other CNS pathologic abnormalities including intraventricular hemorrhage, or low 5-minute Apgar score. The risk of such neonatal morbidity after maternal use of selective serotonin reuptake inhibitors (SSRIs) with or without other CNS-active drugs were evaluated as odds ratios or risk ratios, comparing with unexposed infants or infants only exposed to SSRI drugs. An increased risk for neonatal morbidity was seen for most studied groups of CNS-active drugs when used alone. Benzodiazepines seemed to have a stronger effect than other sedatives/hypnotics. The combination of SSRIs with 1 or more other CNS-active drug groups increased the risk for neonatal morbidity. This was seen for all types of sedatives/hypnotics, which may suggest a confounding by indication. Polypharmacy with CNS-active drugs during the later part of the pregnancy seems to increase the occurrence of neonatal morbidity but difference in nature or strength of underlying psychiatric pathology may confound the findings.

  • 10.
    Kallen, Bengt
    et al.
    Lund University, Sweden.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Skåne University Hospital, Sweden.
    Ongoing Pharmacological Management of Chronic Pain in Pregnancy2016In: Drugs, ISSN 0012-6667, E-ISSN 1179-1950, Vol. 76, no 9, p. 915-924Article, review/survey (Refereed)
    Abstract [en]

    The article discusses possible effects of the use of analgesics during pregnancy. It summarizes the pertinent literature and reports some previously unpublished data from the Swedish Medical Birth Register. Most likely the use of analgesics does not cause spontaneous abortion. Only small malformation risk increases are seen after the use of opioids and perhaps non-steroid anti-inflammatory drug (NSAID) use. If possible, the latter should be avoided during the first trimester. If exposure has occurred there is no reason to consider an interruption of the pregnancy. Continued use of analgesics may increase the risk of preeclampsia and of preterm birth, especially valid for opioids. Use of acetylsalicylic acid (ASA) in late pregnancy should be avoided because of the risk of bleeding and (valid also for NSAIDs) premature closure of the ductus arteriosus. A small risk for neonatal abstinence syndrome may exist after the use of opioids for chronic pain, notably during the third trimester and long-lasting effects on child development can possibly occur. For a woman with chronic pain, adequate use of pain killers during pregnancy is needed. It is prudent to avoid ASA and NSAIDs towards the end of the pregnancy, while acetaminophen is an acceptable option all through pregnancy. If continued use of opioids is necessary, the associated risks are low. Triptans can be used for migraine during pregnancy. If possible sumatriptan is preferable to other triptans as data for the latter are largely lacking. Ergots are preferably avoided as not enough data are available.

  • 11.
    Kallen, Bengt
    et al.
    Lund University, Sweden.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Skåne University Hospital, Sweden.
    Use of tramadol in early pregnancy and congenital malformation risk2015In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 58, p. 246-251Article in journal (Refereed)
    Abstract [en]

    Only few studies exist regarding the risk of a teratogenic effect of tramadol when used in early pregnancy. Using the Swedish Medical Birth Register, women (deliveries in 1997-2013) who had reported the use of tramadol in early pregnancy were identified. Maternal characteristics and concomitant drug use were analyzed. Among 1,682,846 women (1,797,678 infants), 1751 (1776 infants) had used tramadol, 96 of the infants had a congenital malformation and 70 of them were relatively severe. The adjusted odds ratio for a relatively severe malformation was 1.33 (95% CI 1.05-1.70). The odds ratios for cardiovascular defects (1.56, 95% CI 1.04-2.29) and for pes equinovarus (3.63, 95% CI 1.61-6.89) were significantly increased. The study suggests a teratogenic effect of tramadol but the risk increase is moderate. (C) 2015 Elsevier Inc. All rights reserved.

  • 12.
    Källén, Bengt
    et al.
    Tornblad Institute, Lund Univeraity, Sweden.
    Borg, Natalia
    Department of Statistics, Monitoring and Analyses, National Board of Health and Welfare, Sweden.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    The Use of Central Nervous System Active Drugs During Pregnancy2013In: Pharmaceuticals, ISSN 1424-8247, E-ISSN 1424-8247, Vol. 6, no 10, p. 1221-1286Article, review/survey (Refereed)
    Abstract [en]

    CNS-active drugs are used relatively often during pregnancy. Use during early pregnancy may increase the risk of a congenital malformation; use during the later part of pregnancy may be associated with preterm birth, intrauterine growth disturbances and neonatal morbidity. There is also a possibility that drug exposure can affect brain development with long-term neuropsychological harm as a result. This paper summarizes the literature on such drugs used during pregnancy: opioids, anticonvulsants, drugs used for Parkinson’s disease, neuroleptics, sedatives and hypnotics, antidepressants, psychostimulants, and some other CNS-active drugs. In addition to an overview of the literature, data from the Swedish Medical Birth Register (1996–2011) are presented. The exposure data are either based on midwife interviews towards the end of the first trimester or on linkage with a prescribed drug register. An association between malformations and maternal use of anticonvulsants and notably valproic acid is well known from the literature and also demonstrated in the present study. Some other associations between drug exposure and outcome were found.

  • 13.
    Lind, Anna-Britta
    et al.
    Uppsala University.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Jonzier-Perey, Michele
    University of Lausanne.
    Powell, Golay K.
    University of Lausanne.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Baumann, P.
    University of Lausanne.
    Dahl, M.-L.
    Uppsala University.
    Steady-state concentrations of mirtazapine, N-desmethylmirtazapine, 8-hydroxymirtazapine and their enantiomers in relation to cytochrome P450 2D6 genotype, age and smoking behaviour2009In: Clinical Pharmacokinetics, ISSN 0312-5963, Vol. 48, no 1, p. 63-70Article in journal (Refereed)
    Abstract [en]

    Background and objective: Mirtazapine is a tetracyclic antidepressant drug available as a racemic mixture of S(+)- and R(-)-mirtazapine. These enantiomers have different pharmacological properties, and both contribute to the clinical and adverse effects of the drug. Cytochrome P450 (CYP) 2D6 has been implicated in the metabolism of S(+)-mirtazapine. However, the effect of CYP2D6 on serum concentrations of the enantiomers of mirtazapine and its metabolites has not been assessed in patients on long-term treatment. The main objective of the study was to evaluate the effect of the CYP2D6 genotype on enantiomeric steady-state trough serum concentrations of mirtazapine and its metabolites N-desmethylmirtazapine and 8-hydroxymirtazapine. The effects of sex, age and smoking behaviour were also assessed. Subjects and methods: The study included 95 patients who had depression according to the Diagnostic and Statistical Manual of Mental Disorders - 4th Edition and were treated for 4 weeks with a daily dose of mirtazapine 30 mg. The serum concentrations of the enantiomers of mirtazapine and its metabolites were analysed by liquid chromatography-mass spectrometry, and the subjects were genotyped for CYP2D6 alleles*3, *4,*5 and*6 and gene duplication. Results: Three subjects (3%) were classified as ultrarapid metabolizers (UMs), 56 (59%) as homozygous extensive metabolizers (EMs), 30 (32%) as heterozygous EMs and 6 (6%) as poor metabolizers (PMs) of CYP2D6. The median trough serum concentrations of S(+)-mirtazapine were higher in PMs (59 nmol/L, p = 0.016) and in heterozygous EMs (39 nmol/L, p = 0.013) than in homozygous EMs (28 nmol/L). PMs and heterozygous EMs also had higher mirtazapine S(+)/R(-) ratios (0.4) than homozygous EMs (0.3, p = 0.015 and 0.004, respectively). The S(+)-N-desmethylmirtazapine concentration was higher in PMs (16 nmol/L) than in homozygous EMs (7 nmol/L, p = 0.043). There was an association between the CYP2D6 genotype and the ratio between S(+)-8-hydroxymirtazapine and S(+)-mirtazapine, with a significantly higher ratio in homozygous EMs than in heterozygous EMs (0.11 vs 0.05, p = 0.007). The influence of the CYP2D6 genotype on S(+)-mirtazapine, the mirtazapine S(+)/R(-) ratio and S(+)-N- desmethylmirtazapine remained significant after correction for the influence of sex, age and smoking. Smokers had significantly lower concentrations of S(+)-mirtazapine (23 vs 39 nmol/L, p = 0.026) and R(-)-N-desmethylmirtazapine (39 vs 51 nmol/L, p = 0.036) and a significantly lower mirtazapine S(+)/R(-) ratio (0.28 vs 0.37, p = 0.014) than nonsmokers, and the effect of smoking remained significant after multivariate analysis. Conclusions: This study is the first to show the impact of the CYP2D6 genotype on steady-state serum concentrations of the enantiomers of mirtazapine and its metabolites. Our results also support the role of CYP1A2 in the metabolism of mirtazapine, with lower serum concentrations in smokers than in nonsmokers.

  • 14.
    Lundmark, Jöns
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Nordin, Conny
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Reis, Margareta
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Wålinder, Jan
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients2000In: Acta Psychiatrica Scandinavica, ISSN 0001-690X, E-ISSN 1600-0447, Vol. 101, no 5, p. 354-359Article in journal (Refereed)
    Abstract [en]

    Objective: This study was initiated in order to describe and evaluate the effects of a therapeutic drug monitoring (TDM) routine of selective serotonin reuptake inhibitors (SSRIs) on treatment strategies and drug costs in depressed elderly patients.

    Method: Blood samples were drawn from elderly depressed patients and analysed for steady-state trough serum concentrations of citalopram (n=48), paroxetine (n=48) or sertraline (n=39). A global efficacy evaluation was made at baseline and after 6–9 months. Antidepressant drug costs before and after TDM were estimated.

    Results: Eight samples were excluded due to technical problems or non-compliance. In 65 of the 127 (51.2%) remaining cases, the treatment strategy was changed according to the TDM outcome, in most a reduction of the prescribed dose. Bioanalytical TDM costs included the antidepressant drug costs after TDM were reduced by 10.2%.

    Conclusion: The results support the utility of TDM in the search for the individual minimum effective SSRI dose in the elderly.

  • 15.
    Lundmark, Jöns
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Reis, Margareta
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Serum concentrations of fluoxetine in the clinical treatment setting2001In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 23, no 2, p. 139-147Article in journal (Refereed)
    Abstract [en]

    This article discusses fluoxetine serum concentrations as displayed in a clinical setting. A racemic serum fluoxetine and norfluoxetine high-performance liquid chromatography method, including ultraviolet light detection, was used for routine therapeutic drug monitoring (TDM) purposes. In all, 508 samples were analyzed. For the scientific investigation, predefined inclusion and exclusion criteria were applied and 150 samples representative of trough values in steady-state conditions with essential clinical information provided on the assay request forms were evaluated. Fluoxetine plus norfluoxetine concentration-to-dose (C/D) ratio showed Gaussian distribution. Interindividual coefficients of variation of fluoxetine and norfluoxetine serum concentrations after different doses were found to be 40-63%. Intraindividual fluoxetine TDM variability was low. The Spearman rank correlation coefficient for fluoxetine and norfluoxetine C/D ratios in first and second samples was 0.68. Minor increases in norfluoxetine C/D and fluoxetine plus norfluoxetine C/D ratios were found in elderly patients compared with younger adult patients. A higher body-mass index was associated with minor decreases in fluoxetine and fluoxetine plus norfluoxetine C/D ratios. New fluoxetine pharmacokinetic data are added to the results from earlier phases of drug development. Moreover, the results of this study support the usefulness of a fluoxetine TDM procedure for individual dose optimization, detection of drug interactions, and assessments of patient compliance.

  • 16.
    Lundmark, Jöns
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Reis, Margareta
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Therapeutic drug monitoring of sertraline: Variability factors as displayed in a clinical setting2000In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 22, no 4, p. 446-454Article in journal (Refereed)
    Abstract [en]

    This report describes sertraline pharmacokinetics derived from routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method with ultraviolet detection was established for routine sertraline TDM, and 924 analyses were performed from April 1995 to May 1997. Extensive predefined inclusion/exclusion criteria were applied to increase the validity of scientifically evaluated data. Subsequently, 605 samples (65.5%) were excluded. The remaining 319 samples from 319 patients, representative of steady state through specimens and accompanied by essential clinical information provided on request forms, were scrutinized. A pronounced interindividual variability was observed. Smokers had significantly lower concentration-to-dose (C/D) mean ratios of serum sertraline (s-sert) and its main metabolite desmethylsertraline (s-dsert) than nonsmokers. Higher s-sert and s-dsert C/D mean ratios were found in elderly patients than in adults aged less than 65 years. In a subset of 20 patients in whom repeated TDM analyses were performed, observed intraindividual sertraline TDM outcome variability was low. The results highlight sertraline TDM as a tool for individual dose optimization and evaluation of patient drug compliance as well as drug-drug interactions.

  • 17.
    Reis, Margareta
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Pharmacokinetics of antidepressant drugs: naturalistic and clinical trials2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Depression is a major public health problem and it is predicted to be the second leading cause of disease burden by the year 2020. The pharmacological treatment period for major depressive disorder (MDD) is relatively long and sometimes prophylactic over many years. Despite the many drugs introduced on this indication in recent years, details in the drug kinetics linked to the many possible clinical scenarios arising in phase-IV have not been adequately assessed.

    The main objective of this thesis was therefore to focus on the posology of the frequently prescribed antidepressant drugs citalopram (CIT), sertraline (SERT), paroxetine (PAR) and venlafaxine (VEN) in terms of trough level serum concentrations of the parent compound and metabolite(s) under steady state conditions. Therapeutic Drug Monitoring (TDM)-based bioanalytical data were to be linked to clinical information obtained on patients in naturalistic or controlled clinical trial phase-IV settings for evaluation of the inter- as well as intraindividual PK (pharmacokinetic) variance. Specific aims were to identifY and analyze subgroups with possibly deviating PK such as adolescents, elderly patients, and the differences between the sexes. From a controlled trial setting during a six months period a possible serum concentration-effect relationship should be searched for, as well as testing the applicability of a novel type ofTDM procedure based on the metabolite/parent compound ratio to explore both total and partial pharmacological noncompliance.

    Studies I-III were applied on the naturalistic TDM-based trial design. In brief, study I contained 44 adolescents treated with CIT. Study II evaluated trough values in steady state in 749 patients treated with CIT, and study III describes the same parameters for 187 patients treated with VEN. Results revealed that interindividual PK-variations were pronounced for all compounds on all dose levels, but the intraindividual variations were low. Adolescents seemed to have CIT values similar to adults, but old age was correlated with higher dose-corrected serum concentrations of both CIT and VEN. All studied compounds displayed differences between the sexes. Polypharmacy affected the metabolism of CIT and VEN as did smoking.

    Study IV contained 353 patients treated with SERT or PAR in a prospective, randomized multi-center trial with up to eight serum samples each over six months. In study V the TDM-based "compliance method" was tested on the SERT population from the study cohort. Results revealed that no serum concentration - clinical effect relationship could be found for either PAR or SERT. It was observed that the TDM compliance method seemed to detect not only total but also significant partial non-compliance.

    In conclusion, the present thesis describes the possibility for making further PK-assessments on antidepressant drugs commonly prescribed. Thus, by building up drug specific TDM databases in naturalistic clinical phase IV-trials, combined with a structured data analysis a detailed retrospective follow up on the PK of the drugs coming into play in real life emerged. Taken together with the PK-data obtained from a prospective, randomized trial, the overall significance of this thesis may be to forward a new strategy for TDM -related postmarketing surveillance studies. This strategy may also be of interest to explore for other psychoactive drugs as well as for other new drugs commonly used on lager patient groups on chronic medications but outside psychiatric indications.

    List of papers
    1. Serum levels of citalopram and its main metabolites in adolescent patients treated in a naturalistic clinical setting
    Open this publication in new window or tab >>Serum levels of citalopram and its main metabolites in adolescent patients treated in a naturalistic clinical setting
    Show others...
    2002 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 22, no 4, p. 406-413Article in journal (Refereed) Published
    Abstract [en]

    The prescribing of selective serotonin reuptake inhibitors for adolescents is extensive despite the fact that there are few pharmacokinetic (PK), effi]cacy, safety, or tolerability studies on this group. This study reports the PK findings from two trials in adolescents treated with citalopram (CIT) in naturalistic clinical settings: one retrospective and one prospective. The aim of our study was to describe serum concentrations of CIT, desmethylcitalopram (DCIT), and didesmethylcitalopram (DDCIT) (trough values in steady state) in adolescents in relation to daily dose and clinical information obtained from therapeutic drug monitoring request forms. Altogether, 44 patients younger than 21 years were scrutinized using this combined open-label approach. The main findings were that (1) there was a pronounced interindividual variability of serum CIT, DCIT, and DDCIT concentrations in all doses prescribed, in agreement with previous studies on adults; on correcting for dose, the coefficient of variance was about 50% for CIT, DCIT, and DDCIT; (2) the transformation of CIT to DCIT and of DCIT to DDCIT was similar within the dose range 20 to 60 mg/day; (3) there was a difference between the sexes on comparing the dose-corrected concentrations of CIT and DCIT, with girls presenting significantly higher values than boys; and (4) there was a strong dose-serum concentration relationship in three identified subgroups of adolescents: (a) nonsmokers (CIT, r 2 = 0.71; DCIT, r 2 = 0.81), (b) girls not taking oral contraceptives (CIT, r 2 = 0.75; DCIT, r 2 = 0.71,), and (c) girls in the last 14 days of the menstrual cycle (CIT, r 2 = 0.68; DCIT, r 2 = 0.64). In summary, the present study tentatively supports influences of sex, oral contraceptives, and smoking habits on the disposition of CIT in younger patients. Hence, future studies on CIT should assess these parameters.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26736 (URN)10.1097/00004714-200208000-00012 (DOI)11331 (Local ID)11331 (Archive number)11331 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    2. Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992-1997
    Open this publication in new window or tab >>Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992-1997
    2003 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 25, no 2, p. 183-191Article in journal (Refereed) Published
    Abstract [en]

    Racemic citalopram (CIT) was introduced in Sweden in 1992 for management of major depression. During a 5-year period, 1992 to 1997, serum samples of CIT and desmethylcitalopram (DCIT) were collected for therapeutic drug monitoring (TDM) from patients from all over Sweden. These samples were accompanied by clinical information on a specially designed TDM request form. They represented men and women of various ages (11-94 years) usually on multiple concomitant medications and treated in a naturalistic setting. The TDM samples eligible for evaluation (n = 749), all trough values at steady state, were studied with respect to inter- and intraindividual pharmacokinetic variability. Extensive, interindividual serum concentration variability was seen on all dose levels. For dose-corrected concentrations (C/D) and for clearance (C1) we found the coefficient of variation (CV) to be approximately 55% for all variables (C/D CIT, C/D DCIT, the ratio DCIT to CIT, and for C1 CIT). The intraindividual variations over time for the same parameters were 30% to 35%. On a population level, signs of a possible saturation of CYP2D6 associated with increasing DCIT-to-CIT ratios with increasing daily doses was observed. Age and gender affected the pharmacokinetics of CIT and DCIT. Women showed significantly higher C/D CIT and C/D DCIT and lower C1 CIT values compared with men, and patients aged more than 65 years had higher C/D CIT and C/D DCIT and lower C1 CIT values compared with younger patients. Finally, concomitant medication affected the outcome of serum concentrations by a general increase in C/D CIT and C/D DCIT but without alteration in the DCIT-to-CIT ratio. Thus, this tendency of changes in the CIT disposition when multiple drugs are used (and multiple diseases are prevailing?) seems more general in character than specific for a certain drug or type of drugs.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26797 (URN)10.1097/00007691-200304000-00007 (DOI)11405 (Local ID)11405 (Archive number)11405 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    3. Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting
    Open this publication in new window or tab >>Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting
    2002 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 24, no 4, p. 545-553Article in journal (Refereed) Published
    Abstract [en]

    When Efexor® (venlafaxine) became available in Sweden, a therapeutic drug monitoring (TDM) service was developed in the authors' laboratory. This analytical service was available to all physicians in the country. From March 1996, to November 1997, 797 serum concentration analyses of venlafaxine (VEN) and its main metabolites, O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (DDV) were requested. These samples, each of which was accompanied by clinical information on a specially designed request form, represented 635 inpatients or outpatients, comprising all ages, treated in a naturalistic setting. The first sample per patient, drawn as a trough value in steady state and with documented concomitant medication, was further evaluated pharmacokinetically (n= 187). The doses prescribed were from 37.5 mg/d to 412.5 mg/d. There was a wide interindividual variability of serum concentrations on each dose level, and the mean coefficient of variation of the dose-corrected concentrations (C/D) was 166% for C/D VEN, 60% for C/D ODV, 151% for C/D NDV, and 59% for C/D DDV. The corresponding CV for the ratio ODV/VEN was 110%. However, within patients over time, the C/D VEN and ODV/VEN variation was low, indicating stability in individual metabolizing capacity. Patients over 65 years of age had significantly higher concentrations of C/D VEN and C/D ODV than the younger patients. Women had higher C/D NDV and C/D DDV, and a higher NDV/VEN ratio than men, and smokers showed lower C/D ODV and C/D DDV than nonsmokers. A number of polycombinations of drugs were assessed for interaction screening, and a trend for lowered ODV/VEN ratio was found, predominantly with concomitant medication with CNS-active drug(s) known to inhibit CYP2D6.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-27668 (URN)10.1097/00007691-200208000-00014 (DOI)12406 (Local ID)12406 (Archive number)12406 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    4. Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression
    Open this publication in new window or tab >>Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression
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    2004 (English)In: Human Psychopharmacology: Clinical and Experimental, ISSN 0885-6222, E-ISSN 1099-1077, Vol. 19, no 5, p. 283-291Article in journal (Refereed) Published
    Abstract [en]

    Sertraline and paroxetine are frequently prescribed SSRIs for long-term treatment of major depression. Nevertheless, continuous follow-ups of drug concentrations prevailing in patients during the whole treatment period are not available. Hence, in a large phase IV clinical trial, a total of 353 patients with major depression were enrolled for a 6-month comparison of sertraline (50–150 mg daily) and paroxetine (20–60 mg daily). The present study reports the pharmacokinetic results of up to eight serum samples per patient.

    1 A profound variability was found in the interindividual steady state and trough serum levels of sertraline, desmethylsertraline and paroxetine: the coefficient of variation (CV) was 59% for sertraline, 51% for desmethylsertraline, 27% for the ratio desmethylsertraline/sertraline (50 mg/day), and 71% for paroxetine (20 mg/day). The intraindividual CV for the ratio desmethylsertraline/sertraline was only 19%, indicating intraindividual metabolizing stability over time. Both sertraline and paroxetine displayed sex differences in the dose-concentration correlation.

    2 It was possible to predict sertraline, but not paroxetine, steady state levels.

    3 The terminal elimination t½ for both drugs after 6 months of treatments was similar to data previously reported from short-term withdrawal studies.

    4 No correlation between serum drug concentrations and clinical effect was detected for either sertraline or paroxetine.

    For the future, continuous efforts are warranted to perform PK investigations in the natural clinical setting in which the drugs are usually prescribed.

    Keywords
    sertraline, paroxetine, serum concentrations
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-23758 (URN)10.1002/hup.599 (DOI)3270 (Local ID)3270 (Archive number)3270 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    5. Compliance with SSRI medication during 6 months of treatment for major depression: an evaluation by determination of repeated serum drug concentrations
    Open this publication in new window or tab >>Compliance with SSRI medication during 6 months of treatment for major depression: an evaluation by determination of repeated serum drug concentrations
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    2004 (English)In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 82, no 3, p. 443-446Article in journal (Refereed) Published
    Abstract [en]

    Background: A recent estimation in a psychiatric cohort showed numbers of noncompliance between 10% and 60%. Therapeutic drug monitoring (TDM) is one method assessing compliance by analysis of drug concentration in the blood.

    Method: During a 24-week phase IV clinical trial, five repeated serum samples of sertraline (SERT) and N-desmethylsertraline (DSERT), trough values in steady state, were collected per patient. Previous results show that the intraindividual variation over time of the ratio DSERT/SERT is low. Hence, we hypothesized that significant partial noncompliance could be scrutinized further by an assessment of the DSERT/SERT ratio. The main aim was to test the applicability of a novel type of TDM procedure based on repeated metabolite/parent compound ratio measurements.

    Result: 9.4% of the per-protocol population in the trial (n=96) were in either hidden total (n=4) or hidden partial (n=5) noncompliance. Only by using the novel TDM ratio screening method could a majority of these patients be identified.

    Keywords
    SSRI, depression, sertraline
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-23759 (URN)10.1016/j.jad.2004.02.003 (DOI)3271 (Local ID)3271 (Archive number)3271 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
  • 18.
    Reis, Margareta
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Aamo, T.
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology.
    Druid, H.
    Reference concentrations of antidepressants. A compilation of postmortem and therapeutic levels2007In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 31, no 5, p. 254-264Article in journal (Refereed)
  • 19.
    Reis, Margareta
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Aamo, Trond
    St Olaf Hospital, Norway.
    Spigset, Olav
    St Olaf Hospital, Norway.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Serum Concentrations of Antidepressant Drugs in a Naturalistic Setting: Compilation Based on a Large Therapeutic Drug Monitoring Database2009In: THERAPEUTIC DRUG MONITORING, ISSN 0163-4356, Vol. 31, no 1, p. 42-56Article in journal (Refereed)
    Abstract [en]

    A compilation of therapeutic drug monitoring data for 15 antidepressant drugs in a naturalistic routine clinical setting is presented. A substantial number of serum concentrations, at different daily doses, are outlined, and the intraindividual and overall serum concentration coefficient of variation for a respective substance is presented. Also, concentration comparisons between women and men, and patients older or younger than 65 years are made. The drugs included are amitriptyline (n = 394), citalopram (n = 5457), clomipramine (n = 400), escitalopram (n = 3066), fluoxetine (n = 793), fluvoxamine (n = 165), mianserin (n = 1063), mirtazapine (n = 1427), moclobemide (n = 200), nortriptyline (n = 206), paroxetine (n = 1677), reboxetine (n = 85), sertraline (n = 2998), trimipramine (n = 158), and venlafaxine (n = 1781). Of the 9 drugs exhibiting linear (first order) kinetics, all but reboxetine gave a significant negative dose-to-dose-normalized correlation with concentrations, that is an increased clearance with higher dose. When dose was correlated to the metabolite: parent substance ratio for drugs exhibiting linear kinetics, citalopram and mianserin gave a positive slope, contrary to a negative slope shown for sertraline and venlafaxine. The intraindividual variations of the serum concentrations were lower than the overall variations, and the intraindividual variation of the metabolite: parent substance ratio was lower than the intraindividual variation of respective parent substance (except clomipramine and mianserin). Women had significantly higher serum concentrations than men (significant for citalopram, escitalopram, mianserin, mirtazapine, and venlafaxine), and patients older than 65 years had higher serum concentrations than the younger ones for all drugs except amitriptyline, moclobemide, and trimipramine. By presenting a comprehensive compilation of therapeutic drug monitoring data for each drug, a reference toot is created, in addition to improved pharmacokinetic knowledge of antidepressant drugs.

  • 20.
    Reis, Margareta
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Akerblad, A C
    Uppsala University.
    von Knorring, L
    Uppsala University.
    Ekselius, L
    Uppsala University.
    Hidden partial non-compliance with antidepressants and its effect on treatment response2009In: in EUROPEAN NEUROPSYCHOPHARMACOLOGY, vol 19, 2009, Vol. 19, p. S415-S415Conference paper (Refereed)
    Abstract [en]

    n/a

  • 21.
    Reis, Margareta
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Akerblad, Ann-Charlotte
    Uppsala University.
    Ekselius, Lisa
    Uppsala University.
    von Knorring, Lars
    Uppsala University.
    Letter: Partial Compliance as Determined From Plasma Levels of Sertraline and Its Metabolite in Depressed Patients in Primary Care2010In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 30, no 6, p. 746-748Article in journal (Other academic)
    Abstract [en]

    n/a

  • 22.
    Reis, Margareta
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Aronsson, Patrik
    Sahlgrenska akademien, Göteborgs universitet.
    Booth, Shirley
    Göteborgs universitet.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Tobin, Gunnar
    Sahlgrenska akademien, Göteborgs universitet.
    Zetterqvist, Ann
    Göteborgs universitet.
    Kjellgren, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Health Sciences.
    Lättare för studenter att återge fakta än att dra egna slutsatser2013In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, no 48, p. 2156-2157Article in journal (Other (popular science, discussion, etc.))
    Abstract [sv]

    Artikelförfattarna har genomfört en pedagogisk hypotesgenererande studie om de medicinska utbildningarna. Deras slutsats är att studenterna behöver bättre förutsättningar för att tillägna sig kunskaper, färdigheter och förhållningssätt i ämnen som anatomi, fysiologi och farmakologi.

  • 23.
    Reis, Margareta
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Cherma Yeste, Maria Dolores
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Therapeutic Drug Monitoring of Escitalopram in an outpatient setting2007In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 29, no 6, p. 758-766Article in journal (Refereed)
    Abstract [en]

    The main objectives of this study were to outline the inter- and intraindividual and overall pharmacokinetic variability of S-citalopram, S-desmethylcitalopram, and S-didesmethylcitalopram in serum by means of therapeutic drug monitoring, and to investigate potential correlations between the serum concentration and simultaneously collected clinical data. The study was conducted on outpatients in Sweden in 2002 to 2005. Included in the pharmacokinetic evaluation were 155 patients (68% women and 32% men) aged 17 to 95 years (average, 51 years). One serum sample per patient, taken as a trough value in steady state, was assessed. For the inter- and intraindividual variation calculation, 16 patients were included with two eligible samples each. The median daily dose was 20 mg/day (range, 5-40 mg). Extensive overall serum concentration variability was seen for all dose levels. The interindividual coefficient of variation for dose-normalized concentrations was 71% for S-citalopram, 36% for S-desmethylcitalopram, and 50% for S- didesmethylcitalopram. The intraindividual variations over time for the same parameters were approximately 30%, except for the ratio S-desmethylcitalopram/S- citalopram, which was 23%. The median S-desmethylcitalopram level was approximately 60% of the parent substance and the S-didesmethylcitalopram level approximately 9%. Higher age was correlated with higher serum concentrations, but no gender-related concentration differences were found. A majority (76%) of the patients took one or more drugs in addition to escitalopram, but concomitant medication did not seem to interact with escitalopram. However, women taking oral contraceptives showed a lower metabolic ratio compared with age-matched women. As a result of the wide range of the ratio in this population, these findings are not considered of clinical relevance.

  • 24.
    Reis, Margareta
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Kallen, B
    Lund University.
    Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data2010In: PSYCHOLOGICAL MEDICINE, ISSN 0033-2917, Vol. 40, no 10, p. 1723-1733Article in journal (Refereed)
    Abstract [en]

    Background. Concerns have been expressed about possible adverse effects of the use of antidepressant medication during pregnancy, including risk for neonatal pathology and the presence of congenital malformations. Method. Data from the Swedish Medical Birth Register (MBR) from 1 July 1995 up to 2007 were used to identify women who reported the use of antidepressants in early pregnancy or were prescribed antidepressants during pregnancy by antenatal care : a total of 14 821 women with 15 017 infants. Maternal characteristics, maternal delivery diagnoses, infant neonatal diagnoses and the presence of congenital malformations were compared with all other women who gave birth, using the Mantel-Haenszel technique and with adjustments for certain characteristics. Results. There was an association between antidepressant treatment and pre-existing diabetes and chronic hypertension but also with many pregnancy complications. Rates of induced delivery and caesarean section were increased. The preterm birth rate was increased but not that of intrauterine growth retardation. Neonatal complications were common, notably after tricyclic antidepressant (TCA) use. An increased risk of persistent pulmonary hypertension of the newborn (PPHN) was verified. The congenital malformation rate was increased after TCAs. An association between use of paroxetine and congenital heart defects was verified and a similar effect on hypospadias was seen. Conclusions. Women using antidepressants during pregnancy and their newborns have increased pathology. It is not clear how much of this is due to drug use or underlying pathology. Use of TCAs was found to carry a higher risk than other antidepressants and paroxetine seems to be associated with a specific teratogenic property.

  • 25.
    Reis, Margareta
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Kallen, B
    Lund University.
    IMPACT OF IN UTERO EXPOSURE TO ANTIDEPRESSANTS ON THE FETUS in JOURNAL OF PSYCHOPHARMACOLOGY, vol 25, issue 8, pp A9-A92011In: JOURNAL OF PSYCHOPHARMACOLOGY, SAGE Publications (UK and US) , 2011, Vol. 25, no 8, p. A9-A9Conference paper (Refereed)
    Abstract [en]

    n/a

  • 26.
    Reis, Margareta
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Kallen, B.
    Maternal use of antipsychotics in early pregnancy and delivery outcome.2008In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 28, no 3, p. 279-288Article in journal (Refereed)
    Abstract [en]

    The effect of various antipsychotics during pregnancy has repeatedly been studied, but for most atypical antipsychotics, only little information is available. We identified from the Swedish Medical Birth Register 2908 women who had reported the use of any antipsychotic or lithium in early pregnancy and studied malformation rates with data also from the Register of Congenital Malformations and the Hospital Discharge Register. Comparisons were made with all births (n = 958,729) after adjustment for some confounders. Risks were expressed as odds ratios (ORs).Most women had used dixyrazine or prochlorperazine mainly because of nausea and vomiting in early pregnancy. Seventy-nine women had used lithium, and these outcomes are reported separately. Hence, the main analysis was restricted to 570 women (576 infants) using other antipsychotics. There was a statistically significant increase in the risk for a congenital malformation-after exclusion of some common and minor conditions, the OR was 1.52 (95% confidence interval, 1.05-2.19). Exclusion of infants exposed to anticonvulsants reduced the OR only slightly. Most of the increased risk was caused by cardiovascular defects, mainly atrium or ventricular septum defect. No certain drug specificity was found. Except for an increased risk for congenital malformations, a nearly doubling of the risk for gestational diabetes and a 40% increased risk for cesarean delivery was noted. Because there seems to be little drug specificity, it is possible that underlying pathology or unidentified confounding explains the excess risk.

  • 27.
    Reis, Margareta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Kallen, Bengt
    Lund University, Sweden .
    Combined use of selective serotonin reuptake inhibitors and sedatives/hypnotics during pregnancy: risk of relatively severe congenital malformations or cardiac defects. A register study2013In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 3, no 2Article in journal (Refereed)
    Abstract [en]

    Objectives To investigate the proposed synergistic teratogenic effect of use of selective serotonin receptor inhibitors (SSRI) together with sedatives or hypnotics, primarily benzodiazepines, during pregnancy.

    Design Cohort study of congenital malformations after maternal use of SSRI, sedatives/hypnotics or the combination of the two drug categories.

    Setting Swedish national health registers.

    Participants A total of 10 511 infants born of women who had used SSRI drugs but no other central nervous system (CNS)-active drug, 1000 infants born of women who had used benzodiazepines and no other CNS-active drug, and 406 infants whose mothers had used both SSRI and benzodiazepines but no other CNS-active drug.

    Results None of the three groups showed a higher risk for any relatively severe congenital malformation or any cardiac defect when comparison was made with the general population risk (adjusted risk ratio (RR) for the combination of SSRI and benzodiazepines and a relatively severe malformation=1.17 (95% CI 0.70 to 1.73). Similar results were obtained for the combination of SSRI with other sedative/hypnotic drugs.

    Conclusions The previously stated increased risk associated with the combined use of these drug categories, notably for a cardiac defect, could not be replicated.

  • 28.
    Reis, Margareta
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Kugelberg, Fredrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Carlsson, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Josefsson, Martin
    Wahldeck, Bertil
    Stereokemi och läkemedelseffekter -ett försummat kunskapsområde2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, p. 1305-1311Article in journal (Other academic)
    Abstract [sv]

       

  • 29.
    Reis, Margareta
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Lundmark, Jöns
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992-19972003In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 25, no 2, p. 183-191Article in journal (Refereed)
    Abstract [en]

    Racemic citalopram (CIT) was introduced in Sweden in 1992 for management of major depression. During a 5-year period, 1992 to 1997, serum samples of CIT and desmethylcitalopram (DCIT) were collected for therapeutic drug monitoring (TDM) from patients from all over Sweden. These samples were accompanied by clinical information on a specially designed TDM request form. They represented men and women of various ages (11-94 years) usually on multiple concomitant medications and treated in a naturalistic setting. The TDM samples eligible for evaluation (n = 749), all trough values at steady state, were studied with respect to inter- and intraindividual pharmacokinetic variability. Extensive, interindividual serum concentration variability was seen on all dose levels. For dose-corrected concentrations (C/D) and for clearance (C1) we found the coefficient of variation (CV) to be approximately 55% for all variables (C/D CIT, C/D DCIT, the ratio DCIT to CIT, and for C1 CIT). The intraindividual variations over time for the same parameters were 30% to 35%. On a population level, signs of a possible saturation of CYP2D6 associated with increasing DCIT-to-CIT ratios with increasing daily doses was observed. Age and gender affected the pharmacokinetics of CIT and DCIT. Women showed significantly higher C/D CIT and C/D DCIT and lower C1 CIT values compared with men, and patients aged more than 65 years had higher C/D CIT and C/D DCIT and lower C1 CIT values compared with younger patients. Finally, concomitant medication affected the outcome of serum concentrations by a general increase in C/D CIT and C/D DCIT but without alteration in the DCIT-to-CIT ratio. Thus, this tendency of changes in the CIT disposition when multiple drugs are used (and multiple diseases are prevailing?) seems more general in character than specific for a certain drug or type of drugs.

  • 30.
    Reis, Margareta
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Lundmark, Jöns
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Björk, Henrik
    Department of Clinical Pharmacology, Lund University, Lund, Sweden.
    Bengtsson, Finn
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting2002In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 24, no 4, p. 545-553Article in journal (Refereed)
    Abstract [en]

    When Efexor® (venlafaxine) became available in Sweden, a therapeutic drug monitoring (TDM) service was developed in the authors' laboratory. This analytical service was available to all physicians in the country. From March 1996, to November 1997, 797 serum concentration analyses of venlafaxine (VEN) and its main metabolites, O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (DDV) were requested. These samples, each of which was accompanied by clinical information on a specially designed request form, represented 635 inpatients or outpatients, comprising all ages, treated in a naturalistic setting. The first sample per patient, drawn as a trough value in steady state and with documented concomitant medication, was further evaluated pharmacokinetically (n= 187). The doses prescribed were from 37.5 mg/d to 412.5 mg/d. There was a wide interindividual variability of serum concentrations on each dose level, and the mean coefficient of variation of the dose-corrected concentrations (C/D) was 166% for C/D VEN, 60% for C/D ODV, 151% for C/D NDV, and 59% for C/D DDV. The corresponding CV for the ratio ODV/VEN was 110%. However, within patients over time, the C/D VEN and ODV/VEN variation was low, indicating stability in individual metabolizing capacity. Patients over 65 years of age had significantly higher concentrations of C/D VEN and C/D ODV than the younger patients. Women had higher C/D NDV and C/D DDV, and a higher NDV/VEN ratio than men, and smokers showed lower C/D ODV and C/D DDV than nonsmokers. A number of polycombinations of drugs were assessed for interaction screening, and a trend for lowered ODV/VEN ratio was found, predominantly with concomitant medication with CNS-active drug(s) known to inhibit CYP2D6.

  • 31.
    Reis, Margareta
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Olsson, Gunilla
    Division of Child and Adolescence Psychiatry, Department of Neuroscience, Uppsala University, Uppsala.
    Carlsson, Björn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Lundmark, Jöns
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Dahl, Marja-Liisa
    Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala.
    Wålinder, Jan
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Serum levels of citalopram and its main metabolites in adolescent patients treated in a naturalistic clinical setting2002In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 22, no 4, p. 406-413Article in journal (Refereed)
    Abstract [en]

    The prescribing of selective serotonin reuptake inhibitors for adolescents is extensive despite the fact that there are few pharmacokinetic (PK), effi]cacy, safety, or tolerability studies on this group. This study reports the PK findings from two trials in adolescents treated with citalopram (CIT) in naturalistic clinical settings: one retrospective and one prospective. The aim of our study was to describe serum concentrations of CIT, desmethylcitalopram (DCIT), and didesmethylcitalopram (DDCIT) (trough values in steady state) in adolescents in relation to daily dose and clinical information obtained from therapeutic drug monitoring request forms. Altogether, 44 patients younger than 21 years were scrutinized using this combined open-label approach. The main findings were that (1) there was a pronounced interindividual variability of serum CIT, DCIT, and DDCIT concentrations in all doses prescribed, in agreement with previous studies on adults; on correcting for dose, the coefficient of variance was about 50% for CIT, DCIT, and DDCIT; (2) the transformation of CIT to DCIT and of DCIT to DDCIT was similar within the dose range 20 to 60 mg/day; (3) there was a difference between the sexes on comparing the dose-corrected concentrations of CIT and DCIT, with girls presenting significantly higher values than boys; and (4) there was a strong dose-serum concentration relationship in three identified subgroups of adolescents: (a) nonsmokers (CIT, r 2 = 0.71; DCIT, r 2 = 0.81), (b) girls not taking oral contraceptives (CIT, r 2 = 0.75; DCIT, r 2 = 0.71,), and (c) girls in the last 14 days of the menstrual cycle (CIT, r 2 = 0.68; DCIT, r 2 = 0.64). In summary, the present study tentatively supports influences of sex, oral contraceptives, and smoking habits on the disposition of CIT in younger patients. Hence, future studies on CIT should assess these parameters.

  • 32.
    Reis, Margareta
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Prochazka, Jiri
    Sitsen, Ad
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Inter- and intraindividual pharmacokinetic variations of mirtazapine and its N-demethyl metabolite in patients treated for major depressive disorder: A 6-month therapeutic drug monitoring study2005In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 27, no 4, p. 469-477Article in journal (Refereed)
    Abstract [en]

    Mirtazapine pharmacokinetic (PK) data from patients on long-term treatment for major depression have never been investigated. For this reason, in a large naturalistic outpatient study (prospective, multicenter, open-labeled, and noncomparative) conducted in Sweden in the period 2000-2002, one of the main objectives was to outline the inter- as well as intraindividual PK variance of mirtazapine and demethylmirtazapine serum concentrations in a patient cohort treated up to 6 (optionally 12) months. A total of 192 male and female outpatients aged 18 years or older were included. Serum samples of mirtazapine and demethylmirtazapine were collected, by the means of therapeutic drug monitoring, at weeks 1, 4, 8, and 24 (52). Altogether 683 serum samples were analyzed. A pronounced interindividual variability of mirtazapine and demethylmirtazapine, and the demethylmirtazapine/mirtazapine ratio was seen. The coefficient of variation was about 38%, 33%, and 36%, respectively. The intraindividual variation over time was low, about 20% on all variables. At the population level, no accumulation of mirtazapine, demethylmirtazapine, or change of the demethylmirtazapine/mirtazapine ratio was observed over time. Women had significantly higher dose-corrected concentrations of mirtazapine and demethylmirtazapine and demethylmirtazapine/mirtazapine ratio than men. Patients above 65 years of age had higher concentrations than their younger counterparts. Among patients with adverse events, lower demethylmirtazapine concentrations were observed than in patients with no adverse events. Patients on multiple drug treatment had higher dose-corrected mirtazapine and demethylmirtazapine serum concentrations than patients taking only mirtazapine. Weight and BMI had a significant negative correlation with demethylmirtazapine concentrations and with the demethylmirtazapine/mirtazapine ratio. Continued efforts are warranted to perform PK studies in a natural clinical setting to learn and understand inter- and intraindividual PK variances in real patients treated for longer periods of time. For mirtazapine as well as for most antidepressant drugs only relatively short term PK is available. To help clinicians improve their treatment of patients with major depressive disorder, the possible implications on the PK with a long-term treatment are important to study. Copyright © 2005 by Lippincott Williams & Wilkins.

  • 33.
    Reis, Margareta
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    von Knorring, Lars
    Uppsala University.
    Akerblad, Ann-Charlotte
    Uppsala University.
    Ekselius, Lisa
    Uppsala University.
    Hidden Partial Non-Compliance with Antidepressants and its Effect on Treatment Response2009In: in PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, vol 18, 2009, Vol. 18, p. S169-S170Conference paper (Refereed)
    Abstract [en]

    n/a

  • 34.
    Reis, Margareta
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Åberg-Wistedt, Anna
    Institute of Clinical Neuroscience, Department of Psychiatry, Karolinska Institute, Stockholm, Sweden.
    Ågren, Hans
    Karolinska Institute, Neurotec, Department Division of Psychiatry, Huddinge University Hospital, Huddinge, Sweden.
    Höglund, Peter
    Institute of Laboratory Medicine, Department of Clinical and Experimental Pharmacology, Lund University Hospital, Lund, Sweden.
    Åkerblad, Ann-Charlotte
    Department of Neuroscience, Psychiatry, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
    Bengtsson, Finn
    Department of Neuroscience, Psychiatry, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
    Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression2004In: Human Psychopharmacology: Clinical and Experimental, ISSN 0885-6222, E-ISSN 1099-1077, Vol. 19, no 5, p. 283-291Article in journal (Refereed)
    Abstract [en]

    Sertraline and paroxetine are frequently prescribed SSRIs for long-term treatment of major depression. Nevertheless, continuous follow-ups of drug concentrations prevailing in patients during the whole treatment period are not available. Hence, in a large phase IV clinical trial, a total of 353 patients with major depression were enrolled for a 6-month comparison of sertraline (50–150 mg daily) and paroxetine (20–60 mg daily). The present study reports the pharmacokinetic results of up to eight serum samples per patient.

    1 A profound variability was found in the interindividual steady state and trough serum levels of sertraline, desmethylsertraline and paroxetine: the coefficient of variation (CV) was 59% for sertraline, 51% for desmethylsertraline, 27% for the ratio desmethylsertraline/sertraline (50 mg/day), and 71% for paroxetine (20 mg/day). The intraindividual CV for the ratio desmethylsertraline/sertraline was only 19%, indicating intraindividual metabolizing stability over time. Both sertraline and paroxetine displayed sex differences in the dose-concentration correlation.

    2 It was possible to predict sertraline, but not paroxetine, steady state levels.

    3 The terminal elimination t½ for both drugs after 6 months of treatments was similar to data previously reported from short-term withdrawal studies.

    4 No correlation between serum drug concentrations and clinical effect was detected for either sertraline or paroxetine.

    For the future, continuous efforts are warranted to perform PK investigations in the natural clinical setting in which the drugs are usually prescribed.

  • 35.
    Reis, Margareta
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Åberg-Wistedt, Anna
    Karolinska Institute, Department of Psychiatry, Stockholm, Sweden.
    Ågren, Hans
    Karolinska Institute, Neurote Department, Division of Psychiatry, Huddinge, Sweden.
    Åkerblad, Ann-Charlotte
    Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Compliance with SSRI medication during 6 months of treatment for major depression: an evaluation by determination of repeated serum drug concentrations2004In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 82, no 3, p. 443-446Article in journal (Refereed)
    Abstract [en]

    Background: A recent estimation in a psychiatric cohort showed numbers of noncompliance between 10% and 60%. Therapeutic drug monitoring (TDM) is one method assessing compliance by analysis of drug concentration in the blood.

    Method: During a 24-week phase IV clinical trial, five repeated serum samples of sertraline (SERT) and N-desmethylsertraline (DSERT), trough values in steady state, were collected per patient. Previous results show that the intraindividual variation over time of the ratio DSERT/SERT is low. Hence, we hypothesized that significant partial noncompliance could be scrutinized further by an assessment of the DSERT/SERT ratio. The main aim was to test the applicability of a novel type of TDM procedure based on repeated metabolite/parent compound ratio measurements.

    Result: 9.4% of the per-protocol population in the trial (n=96) were in either hidden total (n=4) or hidden partial (n=5) noncompliance. Only by using the novel TDM ratio screening method could a majority of these patients be identified.

  • 36.
    Skogh, Elisabeth
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Reis, Margareta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry.
    Dahl, Marja-Liisa
    Lundmark, Jöns
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Östergötlands Läns Landsting, MC - Medicincentrum, Geriatrik-LAH.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Therapeutic drug monitoring data on olanzapine and its N-demethyl metabolite in the naturalistic clinical setting2002In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 24, no 4, p. 518-526Article in journal (Refereed)
    Abstract [en]

    Olanzapine (Zyprexa«) was approved for general prescription in Sweden in November 1996, and an HPLC-based therapeutic drug monitoring (TDM) routine for serum olanzapine (OLA) and its major metabolite, N-demethylolanzapine (DMO) was established in February 1997. During 1997 to 1999, a total of 753 TDM requests for a total of 545 Swedish patients was analyzed. Additional patient information on certain clinical variables was collected on specifically designed TDM request forms. After the exclusion process, samples from 194 patients were found to be eligible for further scrutiny. The concentration-to-dose (C/D) ratio for OLA varied 25-fold and that of DMO 22-fold. Women had a higher (P < 0.01) median C/D ratio for OLA than men (median, 7.2 nmol/L/mg vs 5.2 nmol/L/mg). Nonsmokers had a higher (P < 0.001) C/D ratio for OLA than smokers (median, 9,2 nmol/L/mg vs 4.0 nmol/L/mg). Smokers got higher prescribed (P < 0.05) doses of OLA than nonsmokers did. In the group with reported side effects, the median serum OLA concentration was 22% higher (P < 0.05) than in the group without side effects. Patients co-medicated with carbamazepine had a 71% lower median C/D ratio for OLA than patients on OLA monotherapy. The present TDM-based follow-up suggests that the influence of gender, smoking habits, and certain drug interactions may need to be considered for optimal dosage of OLA. TDM may be used for this purpose more readily in the future.

  • 37.
    Söderberg, Carl
    et al.
    Karolinska Institute, Sweden; National Board Forens Med, Department Forens Med, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Wernvik, Emma
    National Board Forens Med, Department Forens Med, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Tillmar, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Chemistry, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Spigset, Olav
    St Olavs University Hospital, Norway; Norwegian University of Science and Technology, Norway.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Chemistry, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Skåne University Hospital, Sweden.
    Jonsson, Anna K.
    National Board Forens Med, Department Forens Genet and Forens Chemistry, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Druid, Henrik
    Karolinska Institute, Sweden; National Board Forens Med, Department Forens Med, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Antipsychotics - Postmortem fatal and non-fatal reference concentrations2016In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 266, p. 91-101Article in journal (Refereed)
    Abstract [en]

    Making the diagnosis fatal intoxication is a challenging task for the forensic pathologist and toxicologist, particularly when the cases involve substances where reference information is scarce or not at all available. This study presents postmortem femoral blood concentrations for 24 antipsychotic substances, based on samples collected and analyzed from 4949 autopsy cases in Sweden during 1992-2010. In addition our study provides information about the prevalence of different antipsychotics in accidental, suicidal, homicidal and uncertain deaths. The data have been selected and evaluated according to strict inclusion and exclusion criteria as well as a manual, multi-reviewer, case-by-case evaluation. The reference information is subdivided into intoxications by one specific substance only (group A, n = 259), multi-substance intoxications (group B, n = 614) and postmortem controls, consisting of deaths not involving incapacitation by substances (group C, n = 507). Moreover, the results are compared with data based on therapeutic drug monitoring, and data collected from driving under the influence cases. Median concentrations in group A were significantly higher than in group C for all substances evaluated. For 17 of 24 substances, the median concentrations in group B were significantly higher than in group C. In general, the therapeutic drug monitoring and driving under the influence concentrations were similar to, or lower than, the concentrations in group C. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  • 38.
    Wolgast, Emelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Josefsson, Ann
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Lilliecreutz, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Drug use in pregnant women-a pilot study of the coherence between reported use of drugs and presence of drugs in plasma2018In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 4, p. 535-539Article in journal (Refereed)
    Abstract [en]

    In Sweden, information on drug use during pregnancy is obtained through an interview and recorded in a standardized medical record at every visit to the antenatal care clinic throughout the pregnancy. Antenatal, delivery, and neonatal records constitute the basis for the Swedish Medical Birth Register (MBR). The purpose of this exploratory study was to investigate the reliability of reported drug use by simultaneous screening for drug substances in the blood stream of the pregnant woman and thereby validate self-reported data in the MBR. Plasma samples from 200 women were obtained at gestational weeks 10-12 and 25 and screened for drugs by using ultra-high performance liquid chromatography with time of flight mass spectrometry (UHPLC-TOF-MS). The results from the analysis were then compared to medical records. At the first sampling occasion, the drugs found by screening had been reported by 86% of the women and on the second sampling, 85.5%. Missed reported information was clearly associated with drugs for occasional use. The most common drugs in plasma taken in early and mid-pregnancy were meclizine and paracetamol. Two types of continuously used drugs, selective serotonin reuptake inhibitors and propranolol, were used. All women using them reported it and the drug screening revealed a 100% coherence. This study shows good coherence between reported drug intake and the drugs found in plasma samples, which in turn positively validates the MBR.

  • 39.
    Zetterqvist, Ann
    et al.
    University of Gothenburg, Sweden.
    Aronsson, Patrik
    University of Gothenburg, Sweden.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Kjellgren, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Tobin, Gunnar
    University of Gothenburg, Sweden.
    Booth, Shirley
    University of Gothenburg, Sweden; University of Witwatersrand, South Africa.
    On the pedagogy of pharmacological communication: a study of final semester health science students2015In: BMC Medical Education, ISSN 1472-6920, E-ISSN 1472-6920, Vol. 15Article in journal (Refereed)
    Abstract [en]

    Background: There is a need to improve design in educational programmes for the health sciences in general and in pharmacology specifically. The objective of this study was to investigate and problematize pharmacological communication in educational programmes for the health sciences. Methods: An interview study was carried out where final semester students from programmes for the medical, nursing and specialist nursing in primary health care professions were asked to discuss the pharmacological aspects of two written case descriptions of the kind they would meet in their everyday work. The study focused on the communication they envisaged taking place on the concerns the patients were voicing, in terms of two features: how communication would take place and what would be the content of the communication. A phenomenographic research approach was used. Results: The results are presented as outcome spaces, sets of categories that describe the variation of ways in which the students voiced their understanding of communication in the two case descriptions and showed the qualitatively distinct ways in which the features of communication were experienced. Conclusions: The results offer a base of understanding the students perspectives on communication that they will take with them into their professional lives. We indicate that there is room for strengthening communication skills in the field of pharmacology, integrating them into programmes of education, by more widely implementing a problem-based, a case-oriented or role-playing pedagogy where final year students work across specialisations and there is a deliberate effort to evoke and assess advanced conceptions and skills.

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