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Concentration of Antidepressant Drugs in Children and Adolescents: a naturalistic clinical study
Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. (psykofarmakologi)
Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Child and Adolescent Psychiatry . Linköping University, Faculty of Health Sciences.
(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.

Keyword [en]
antidepressants, therapeutic drug monitoring, dosage, serum concentration, pediatrics
National Category
Pharmacology and Toxicology Psychiatry
URN: urn:nbn:se:liu:diva-52106OAI: diva2:279703
Available from: 2009-12-04 Created: 2009-12-04 Last updated: 2009-12-07Bibliographically approved
In thesis
1. Therapeutic Drug Monitoring in Psychiatry: Some aspects of utility in clinical practice and research
Open this publication in new window or tab >>Therapeutic Drug Monitoring in Psychiatry: Some aspects of utility in clinical practice and research
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. 84 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1152
TDM, psychoactive drug, pharmacokinetics, pharmacogenetics, naturalistic, elderly, child
National Category
Pharmacology and Toxicology
urn:nbn:se:liu:diva-52107 (URN)978-91-7393-537-1 (ISBN)
Public defence
2009-12-18, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Available from: 2009-12-07 Created: 2009-12-04 Last updated: 2009-12-07Bibliographically approved

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Chermá Yeste, Maria Dolores
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Clinical Pharmacology Faculty of Health SciencesDepartment of Medicine and Health SciencesChild and Adolescent Psychiatry
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