TDM, drug therapy safety and pharmacovigilance

In the near future (March 20-22, 2024), the Freiburg i.Br. The 15th TDM Symposium of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) on Therapeutic Drug Monitoring (TDM), drug therapy safety and pharmacovigilance in psychiatry will take place in Berlin. First impressions….

Over 50 years ago, Asberg et al. a study on the relationship between plasma levels of the tricyclic antidepressant nortriptyline and its clinical effect in patients treated with this drug [1]. It is considered groundbreaking for the further and continuous development of TDM in psychiatry. The first indications of a genetic component in the metabolism and pharmacokinetics of this antidepressant had already emerged: steady-state concentrations of nortriptyline in the blood measured after treatment of monozygotic twins with this drug (a substrate of CYP2D6, as it later turned out) were practically identical, but they differed markedly in dizygotic twin pairs [2]. Advances in the characterization of the properties of the individual forms of cytochrome P-450 in the biotransformation of psychotropic drugs, also taking into account the different roles of genetically determined polymorphic forms, helped to better understand the mechanisms of pharmacokinetic interactions between drugs that differ in their inductive or inhibitory properties.

Taking a closer look at the therapeutic window

In view of the extensive literature with studies on plasma level-response relationships, the question of generally recognized reference ranges, also known as “therapeutic windows”, soon arose. After the first, highly regarded guidelines, there was a lack of such instruments, which covered all categories of psychotropic drugs and were regularly updated [3–5]. Within the framework of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP), a first consensus conference was held in Würzburg in 1992, which dealt with topics relating to TDM in psychiatry [6,7]. This first meeting led to the founding of the AGNP-TDM group in 1997, and in 2004 its experts published a first Consensus Guideline, which then led to renewed and considerably expanded versions in 2011 and 2018 [8–11]. Also worth mentioning is the cooperation between the AGNP-TDM Group and the American Society of Clinical Psychopharmacology in connection with the TDM of antipsychotics and the contribution of members of the AGNP-TDM group to an overview of the World Federation of Societies of Biological Psychiatry, which deals specifically with TDM, pharmacogenetics, but also with the measurement of the binding and concentration of antidepressants in the brain using imaging techniques [12,13]. The AGNP-TDM group is currently focusing its activities on a further “update” of the AGNP-TDM Consensus Guideline (Hart et al., in preparation).

The above-mentioned conference will focus in particular on topics which have already been dealt with in published papers by the AGNP-TDM group itself or with the participation of members of the group, but which will be dealt with in greater depth on this occasion. To promote closer cooperation between laboratory staff and the medical profession, information was recently provided on the achievements but also the difficulties in developing suitable laboratory methods and on the need to constantly adapt reference ranges [14]. It is striking that the number of TDM laboratories at psychiatric university hospitals has decreased in recent decades, which does not facilitate future-oriented research that is carried out jointly by the hospital and the laboratory. However, it is to be welcomed that, in view of the shortage of specialists in clinical pharmacology, clinical pharmacists are increasingly taking on the role of an information point between the laboratory and the clinic [15].

Drug safety with polymedication

Adherence monitoring is still an important indication of TDM, but many requests are related to drug safety. Polymedication, especially in patients with comorbidities in the mental and somatic area, is common, which increases the risk of drug interactions and thus of side effects. TDM allows an interaction to be objectively quantified in order to adjust the dose in a subsequent step or to replace the medication with one that has less interaction potential. On the other hand, depending on the result of the plasma level determination, a genetic peculiarity in the metabolism of the measured drugs can be postulated, which, for example, is responsible for high plasma levels in deficient metabolizers and thus also for side effects. If polymorphic enzymes of the CYP2D6 or CYP2C19 type are responsible for the metabolism of the drug in question, genotyping would be indicated. It should be noted that the costs are not automatically covered by basic insurance in Switzerland, except in cases where the treating psychiatrist presents the clinical situation to a specialist in clinical pharmacology: The latter checks the validity of the indication and, if necessary, issues a prescription for genotyping the patient. The topic of drug safety and pharmacovigilance explains why a collaboration between the AGNP-TDM Group and the SGAMSP (Swiss Society for Drug Safety in Psychiatry) has developed in recent years.

The AGNP-TDM group as such or some of its members have already published various review articles and studies as part of the focus on areas of application, in particular in the fields of child and adolescent psychiatry, addiction medicine, pregnancy and lactation, elderly patients, TDM in the treatment of patients with depot antipsychotics, interactions between drugs taking into account the pharmacogenetic status of the patient, measurement by means of imaging techniques (positron emission tomography, PET) of the occupancy of dopamine receptors in the brain by antipsychotics [16–22]. These aspects will receive a great deal of attention at the event, as new findings will be presented not only by experts from German-speaking countries, but also in an “international session”.

TDM optimizes psychopharmacotherapy

Even taking into account critical voices on the TDM of psychotropic drugs, especially when it is used repetitively and in the absence of real indications, TDM can now be considered a valuable tool for optimizing psychopharmacotherapy [23]. The interdisciplinary 15th AGNP-TDM Symposium, organized by the Department of Psychiatry, Psychotherapy and Psychosomatics at the University of Freiburg in Breisgau (Germany) and the AGNP-TDM Group (www.uniklinik-freiburg.de/kijupsych/tdm-2024.html), will therefore be of interest to many psychiatrists and other medical specialists, as well as pharmacists and clinical chemists.

Literature:

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Alexanderson B, Evans DA, Sjöqvist F: Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. British Medical Journal 1969; 4(686): 764-768.
Task Force on the use of Laboratory Tests in Psychiatry Tricyclic Antidepressants: Blood Level Measurements and Clinical Outcome: An APA Task Force report. American Journal of Psychiatry 1985; 142(2): 155-162.
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