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Therapeutic Drug Monitoring in Psychiatry: Some aspects of utility in clinical practice and research
Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. (psykofarmakologi)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background and objectives: Several new psychoactive drugs for the treatment of psychiatric disorders have been introduced onto the market since the late 1980s. Basic aspects of pharmacodynamics and pharmacokinetics (PK) are investigated before approval for general prescription. Thus, a limited number of subjects are exposed to the drug before it is marketed and only sparse measurements of drug concentration are performed during phases II and III of drug development. The objective of this thesis was to provide further descriptive PK and linked patients data in naturalistic clinical settings. The PK of psychoactive drugs was also studied in the elderly and the young, major risk groups that are exposed in normal everyday clinical practice but that are underrepresented in the phases of drug development. The PK-data were to be assessed by samples sent to the Therapeutic Drug Monitoring (TDM) laboratory service. In a subset of individuals, the genotypes of the cytochrome P450 (CYP) enzymes were described.

Results: Serum concentration of the parent compound and its metabolites was provided from TDM-data on antidepressant escitalopram (Paper I) and antipsychotic ziprasidone (Paper II). A large interindividual PK variability was found. The daily dose of the drug was higher than the defined daily dose (DDD) for both escitalopram and ziprasidone (median dose 20 mg and 120 mg, respectively). The median number of drugs per patient, apart from the studied drug, was 4 and 3, respectively (range 1-18). If repeated eligible TDM-data were available, change in treatment strategies could be seen between the first and second sample for the patient, and the metabolite/parent compound (M/P) ratio had lower intraindividual than interindividual variation in the escitalopram study but opposite results were found in the ziprasidone study.

The prescription of antidepressant drugs (ADs) in the nursing homes studied was 38 % (Paper III). The concentration of the ADs was higher, or much higher, than could be expected from the dose administered in 73 %. The majority of the elderly people were treated with citalopram. No clear time schedule for how long the drug treatment should continue was found in the patients’ current medical record. The median number of drugs per patient apart from the AD was 11 (range 4-19), no monotherapy was found in these patients. The genetically impaired metabolic activity of CYP enzymes correlated to higher drug concentration as expected, in patients medicated with an AD that is substrate for the CYP enzyme genotype.

The concentrations of ADs were as expected from the dose administered in 63 % of the children/adolescents evaluated (Paper IV). The majority of TDM samples requested sertraline. PK outcome of sertraline was similar to the results in adult populations. Monotherapy was documented in 49 % (median number of drugs apart from AD was 1 per patient, range 1-7). Changes in treatment strategies were also shown, if repeated TDM-samples were available. The median variation of the M/P ratio for sertraline between the first and the last samples within the same patient was 20 % (the interindividual variation was 37 %). The poor metabolizers (PM) for CYP2D6 medicated with a CYP2D6 substrate had a lower dose than did non-PM for the same drug.

Conclusion: These studies provide reference data for the evaluation of the therapeutic response, i.e. a reference range of what is to be expected in a normal clinical setting, as well as the toxicological information concerning the psychoactive drugs studied. When available, the M/P ratio between two patients’ samples may assess patient compliance, as well as drug-drug interactions. Thus, the use of TDM can be beneficial for individual dose optimisation and drug safety, above all in the studied populations, elderly people and children/adolescents, when the selection of doses requires a consideration of PK parameters. TDM may be a tool for research, increasing knowledge of the psychoactive drug in TDM service, as well as toxicology. A more frequent clinical use of TDM and pharmacogenetic testing in clinical practice would contribute to a better quality when treating with psychoactive drugs.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , p. 84
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1152
Keywords [en]
TDM, psychoactive drug, pharmacokinetics, pharmacogenetics, naturalistic, elderly, child
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:liu:diva-52107ISBN: 978-91-7393-537-1 (print)OAI: oai:DiVA.org:liu-52107DiVA, id: diva2:279732
Public defence
2009-12-18, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-12-07 Created: 2009-12-04 Last updated: 2018-01-12Bibliographically approved
List of papers
1. Therapeutic Drug Monitoring of Escitalopram in an outpatient setting
Open this publication in new window or tab >>Therapeutic Drug Monitoring of Escitalopram in an outpatient setting
2007 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 29, no 6, p. 758-766Article in journal (Refereed) Published
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.

Keywords
Escitalopram, Serum concentration, SSRI, Therapeutic drug monitoring
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-41188 (URN)10.1097/FTD.0b013e31815b3f62 (DOI)55316 (Local ID)55316 (Archive number)55316 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
2. Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting
Open this publication in new window or tab >>Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting
Show others...
2008 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 30, no 6, p. 682-688Article in journal (Refereed) Published
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.

Keywords
Antipsychotic agents, ziprasidone, therapeutic drug monitoring, serum concentration, naturalistic setting
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16195 (URN)10.1097/FTD.0b013e31818ac8ba (DOI)
Available from: 2009-01-09 Created: 2009-01-09 Last updated: 2017-12-14Bibliographically approved
3. Assessment of the prescription of antidepressant drugs in elderly nursing home patients
Open this publication in new window or tab >>Assessment of the prescription of antidepressant drugs in elderly nursing home patients
Show others...
2008 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 28, no 4, p. 424-431Article in journal (Refereed) Published
Abstract [en]

The aim of the study was to investigate the use of antidepressant drugs among elderly people in nursing homes. Elderly residents who where found to have been prescribed at least one antidepressant drug according to the specific medication dispensing system were identified in 8 nursing homes in the county of Östergötland, Sweden. Data were collected from the medical record forms at the nursing home. Blood samples were drawn for the assessment of drug concentration, blood chemistry parameters and cytochrome P450 expression. At least one antidepressant drug was prescribed to 38% of elderly people in the nursing home studied. A total of 71 patients were evaluated, 80% women and 20% men. The median age was 84 years (range, 71-100 years). Indications for antidepressant drug treatment were found on 96% of medical record forms (depression, 60%); however, information relating to when treatment was initiated could not be found on 34% of medical record forms and a clear time schedule for how long this drug treatment was planned to continue could not be found either. A possible adverse effect of antidepressant drug treatment was retrieved in at least 77% of patients. Polypharmacotherapy was common; median number of drugs per patient was 11. Concentrations of drugs were higher than expected in 73%. Most patients were medicated with citalopram (n = 44). A clear interindividual variability of concentrations at each dose level was found for citalopram and for the metabolites desmethylcitalopram and didesmethylcitalopram. A significant correlation was found between the estimation of creatinine clearance and concentration-dose ratio of citalopram. Poor metabolizers, who had been prescribed an antidepressant drug that are substrate for the cytochrome P450 isoenzyme examined, have higher concentrations of prescribed antidepressant drug than do non-poor metabolizers in relation to dose. An increase in quality contribution to follow-up at antidepressant medications is needed. A more frequent clinical use of therapeutic drug monitoring and pharmacogenetic tests in addition to therapeutic drug monitoring may be one important tool in this process.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-20985 (URN)10.1097/JCP.0b013e31817d79eb (DOI)
Available from: 2009-09-27 Created: 2009-09-27 Last updated: 2018-01-13Bibliographically approved
4. Concentration of Antidepressant Drugs in Children and Adolescents: a naturalistic clinical study
Open this publication in new window or tab >>Concentration of Antidepressant Drugs in Children and Adolescents: a naturalistic clinical study
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: The aims of this study were to evaluate the pharmacokinetics (PKs) of antidepressant agents, in terms of steady-state and trough values, in a heterogeneous cohort of patients and to describe the utilisation of antidepressant drugs (ATDs) in Child and Adolescent Psychiatry in the south- east of Sweden.

Method: Patients from Child and Adolescent Psychiatry centres in the counties of Östergötland, Jönköping and Kalmar (Sweden) to be prescribed an antidepressant drug, were studied between 2002 and 2004. The blood concentration of ATDs and, in some cases, also CYP2D6 were determined and relevant clinical information provided.

Results: Two hundred and eleven children: 64 % girls and 36 % boys, between the ages of 8 and 20 were evaluated. The concentrations of drugs in the patient evaluated (PE) population were as expected from the dose administered in 63 % of this population, higher than expected in 26 % and lower than expected in 11 %.

Dose-concentration relationships for sertraline (rs=0.48, p<0.001) and metabolite desmethylsertraline (rs=0.5, p<0.001) were seen. No relationship was found between dose and ratio desmethylsertraline-to-sertraline. CYP2D6*4 was the most common poor metabolizer (PM) allele. The primary indication for the antidepressant treatment was depression in 69 % of subjects. Suspected adverse drug reactions were spontaneously reported in 31 %. Monotherapy was indicated in 49 % of request forms. The most common drug combinations with the antidepressant drug were oral anticontraceptives and anxiolytics/sedatives/hypnotic drugs.

Conclusion: the most prescribed antidepressant drug in children and adolescents in the present study was sertraline. The pharmacokinetic outcomes of serum concentration of sertraline, as well as daily doses administered were similar to the referenced data for adults. Antidepressant drug monotherapy was most common. No serious adverse side effects were spontaneously reported. TDM may provide support to the prescribing physicians to individual dose optimising and to assess drug compliance, above all when the antidepressant drugs are not well studied in pediatric patients before approval for general prescription. Further clinical trials, as well as naturalistic studies are necessary to ensure that children are not exposed to unnecessary risk and to determine the most appropriate dose in children of different ages.

Keywords
antidepressants, therapeutic drug monitoring, dosage, serum concentration, pediatrics
National Category
Pharmacology and Toxicology Psychiatry
Identifiers
urn:nbn:se:liu:diva-52106 (URN)
Available from: 2009-12-04 Created: 2009-12-04 Last updated: 2018-01-12Bibliographically approved

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