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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Erik Eliasson, Karolinska Institutet, Sweden
- Second opponent: Associate Professor Enrico Callegari, Østfold University of Applied Sciences, Norway
- Third member and chair of the evaluation committee: Associate Professor Marit Haram, University of Oslo
Chair of the Defence
Associate Professor Olav Bjerkehagen Smeland, University of Oslo
Principal Supervisor
Marit Tveito, Head of Department, Diakonhjemmet Hospital
Summary
In this PhD thesis we investigated sources of variability in antipsychotic drug exposure, with particular emphasis on age, sex and pharmacogenetics.
The main research questions were whether age influences the dose-adjusted serum concentrations of antipsychotics, whether these effects differ between males and females, and, for quetiapine, the impact of pharmacogenetic variation. In patients receiving antipsychotic polytherapy, total antipsychotic dose and serum concentration were compared with patients receiving monotherapy across age groups.
The work was based on naturalistic, real-world data from a therapeutic drug monitoring (TDM) database at the Center for Psychopharmacology, Diakonhjemmet Hospital. Serum concentrations, prescribed doses and patient characteristics were analysed using linear mixed models. Across the three studies, more than 30,000 patients treated with various antipsychotics were included.
Exposure, measured as the dose-adjusted serum concentration (C:D ratio), increased with age for all investigated antipsychotics: quetiapine, amisulpride, aripiprazole, olanzapine, clozapine, risperidone and zuclopenthixol. For most drugs, the age effect was more pronounced in females than in males, and its magnitude varied between agents. The largest effect was observed for risperidone: among patients aged over 75 years, C:D ratios were 81% higher in males and 92% higher in females than in those aged 18–50 years.
For quetiapine, CYP2D6 poor metabolisers had higher exposure of the metbolite N-desalkylquetiapine. Antipsychotic load was approximately doubled in patients receiving polytherapy compared with monotherapy, and with increasing age, prescribed doses decreased, while serum concentrations remained similar.
Overall, older patients, particularly older females, exhibit higher exposure to antipsychotic medications than younger adults. If doses are not adequately reduced, this may result in an increased risk of adverse effects.
Additional information
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