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Clinical and Pharmacological Aspects of Selective Serotonin Reuptake Inhibitors in the Treatment of Depression in Old Age
Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Objective: The aim of the present thesis is to examine the pharmacokinetic and biochemical effects of the selective serotonin reuptake inhibitors (SSRIs) in the elderly.

Background: Symptoms of depression are found in up to 15% of the elderly and the prevalence of major depression is reported to be about 3%. At present SSRIs are the pharmacological tools most frequently used for the treatment of depression. Patients in old age account for a relatively higher proportion of SSRI expenditures, although the elderly are seriously underrepresented in pharmacological studies and are increasingly susceptible to adverse drug events.

Subjects and Methods: Serum concentrations of the SSRis fluoxetine, paroxetine, and sertraline in the elderly were compared to those in younger patients. Effects of paroxetine on cerebrospinal fiuid (CSF) monoamine concentrations were investigated. Influences of therapeutic drug monitoring (TDM) of citalopram, paroxetine, and sertraline on clinical dosing strategies and antidepressant drug costs during a 6-9-month follow-up were studied in depressed elderly patients. Various individual factors, including age, which may influence serum concentrations of fluoxetine and sertraline were evaluated using population TOM data.

Results: lnterindividual serum concentration variations were pronounced irrespective of age. Compared to the variability between subjects, the intraindividual variability of fiuoxetine and sertraline serum concentrations was found to be low. In the elderly, fiuoxetine, paroxetine, and sertraline serum concentrations were higher than in younger patients. In the case of fluoxetine, gross obesity influenced serum concentrations and sertraline serum concentrations were lower in smokers than in non-smokers. In the case of paroxetine, nonlinear pharmacokinetics were observed in some subjects and paroxetine treatment influenced both serotonergic and noradrenergic neurotransmission, as indicated by 5-HIAA and MHPG concentrations in the CSF. TDM-supported SSRI clinical dosing was found to reduce the doses used and efficacy was sustained when observed during an open follow-up.

Conclusions: The results reported in the present thesis emphasize the importance of conducting clinical and pharmacological research in the elderly in different phases of drug development. In the postmarketing phase, TOM databases provide important tools for the collection of new pharmacokinetic data from clinical populations and data important for the interpretation of population SS RI serum concentrations. TDM of the SSRis may support individual dose optimization, including assessments of drug compliance.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2000. , 94 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 650
Keyword [en]
Serum concentrations, cerebrospinal fluid, pharmacokinetics, selective serotonin reuptake inhibitors, therapeutic drug monitoring, elderly, depression, pharmaceutical economics
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-28058Local ID: 12821ISBN: 91-7219-751-X (print)OAI: oai:DiVA.org:liu-28058DiVA: diva2:248609
Public defence
2000-11-24, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-08-15Bibliographically approved
List of papers
1. Paroxetine: pharmacokinetic and antidepressant effect in the elderly
Open this publication in new window or tab >>Paroxetine: pharmacokinetic and antidepressant effect in the elderly
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1989 (English)In: Acta Psychiatrica Scandinavica, ISSN 0001-690X, E-ISSN 1600-0447, Vol. 80, no S350, 76-80 p.Article in journal (Refereed) Published
Abstract [en]

To evaluate the pharmacokinetic properties, efficacy, and tolerability of paroxetine in elderly depressed patients, a clinical study was set up - initially at Aalborg Psychiatric Hospital in Denmark, and subsequently at the University Hospital in Linköping, Sweden. A total of 21 patients with a median age of 72 years were included in the study. After a single dose of 20 or 30mg of paroxetine followed by two drug-free days, treatment continued with 20 or 30mg daily for seven weeks. The majority of patients showed a continuous reduction in their HAMD scores, starting in the second week of treatment. Paroxetine was well tolerated at the doses given, and side-effects were mostly mild and transient. Steady-state, pre-dose plasma levels of paroxetine showed considerable variability, and the median steady-state concentration was higher in elderly patients compared with data from a previous study in young volunteers. Elimination half-lives also showed variability between these elderly patients, but tended to be longer after cessation of multiple dosing than after a single dose. They also tended to be longer than in the young volunteers. The results of this study do not advocate reduced doses of paroxetine in the elderly, but further studies are warranted.

Keyword
elderly patients, depression, 5-HT uptake inhibitors, paroxetine, efficacy, tolerability, pharmacokinetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79925 (URN)10.1111/j.1600-0447.1989.tb07177.x (DOI)
Available from: 2012-08-15 Created: 2012-08-15 Last updated: 2017-12-07Bibliographically approved
2. The effect of paroxetine on cerebrospinal fluid concentrations of neurotransmitter metabolites in depressed patients
Open this publication in new window or tab >>The effect of paroxetine on cerebrospinal fluid concentrations of neurotransmitter metabolites in depressed patients
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1994 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 4, no 1, 1-6 p.Article in journal (Refereed) Published
Abstract [en]

This paper describes the effect of the selective serotonin reuptake inhibiting drug (SSRI), paroxetine, on cerebrospinal fluid concentrations of neurotransmitter metabolites in depressed patients. 5-Hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were measured at baseline and after 3 weeks of treatment with 30 mg paroxetine daily. In line with similar studies on other SSRIs, influence on both the serotonin and noradrenaline metabolite was found. The mechanism behind the action of paroxetine on both 5-HIAA and MHPG is assumed to be an expression of the linkage between the serotonergic and noradrenergic systems in the brain. A frequently reported correlation between 5-HIAA and HVA was also found. The analysis of paroxetine in CSF proves the transportation of the drug into the central nervous system.

Keyword
Cerebrospinal fluid, Serotonin, Selective serotonin reuptake inhibitors, Paroxetine, Major depression
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79926 (URN)10.1016/0924-977X(94)90308-5 (DOI)7515737 (PubMedID)
Available from: 2012-08-15 Created: 2012-08-15 Last updated: 2017-12-07Bibliographically approved
3. Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients
Open this publication in new window or tab >>Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients
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2000 (English)In: Acta Psychiatrica Scandinavica, ISSN 0001-690X, E-ISSN 1600-0447, Vol. 101, no 5, 354-359 p.Article in journal (Refereed) Published
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.

Keyword
antidepressants, serotonin uptake inhibitors, pharmacokinetics, pharmaceutical economics, depression
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27667 (URN)10.1034/j.1600-0447.2000.101005354.x (DOI)12405 (Local ID)12405 (Archive number)12405 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-10-28Bibliographically approved
4. Therapeutic drug monitoring of sertraline: Variability factors as displayed in a clinical setting
Open this publication in new window or tab >>Therapeutic drug monitoring of sertraline: Variability factors as displayed in a clinical setting
2000 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 22, no 4, 446-454 p.Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27666 (URN)10.1097/00007691-200008000-00014 (DOI)12404 (Local ID)12404 (Archive number)12404 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-10-28Bibliographically approved
5. Serum concentrations of fluoxetine in the clinical treatment setting
Open this publication in new window or tab >>Serum concentrations of fluoxetine in the clinical treatment setting
2001 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 23, no 2, 139-147 p.Article in journal (Refereed) Published
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.

Keyword
Therapeutic drug monitoring, serum concentration, selective serotonin reuptake inhibitors, fluoxetine, elderly
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27660 (URN)10.1097/00007691-200104000-00008 (DOI)12398 (Local ID)12398 (Archive number)12398 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-10-28Bibliographically approved

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