Therapeutic Drug Monitoring in Psychiatry

Therapeutic drug monitoring (TDM) is a tool for optimisation of pharmacotherapy. The absence of comprehensive guidelines regarding this technique in psychopharmacotherapy prompted a group of authors, the AGNP-TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) to publish consensus guidelines for TDM in psychiatry in 2004 [1]. In the meantime, these guidelines experienced a successful disclosure (with almost 200 citations in the scientific literature) and acceptance. Many laboratories adopted the proposed reference ranges. However, new scientific realizations and increasing clinical knowledge lead to the categorical imperative to revise and update these guidelines.

The new guidelines represent the core of this special issue of Pharmacopsychiatry. For TDM-guided pharmacotherapy, the whole clinical context, including patient specific variables and pharmacological properties of the drugs, must be taken into account to be of maximal benefit for treatment optimization. Literature based “therapeutic reference ranges” and “dose related reference ranges” were elaborated for 128 neuropsychiatric drugs after an extensive literature search and a broad and profound internal review process. A “laboratory alert level” for potentially toxic plasma levels was newly introduced guaranteeing the physician to be informed immediately in case of suspected intoxication. Supportive information such as cytochrome P450 substrate and inhibitor properties of drugs, “normal” ranges of ratios of concentrations drug metabolite to parent drug and recommendations for the interpretative services are given. This document aims at responding to the needs of psychiatrists and other physicians, clinical pharmacologists and TDM laboratories working in this field.

During the IX^th international congress of the interdisciplinary AGNP-TDM task force at Bolzano, Italy, in September 2010, the publication of the updated TDM consensus guidelines was definitely scheduled. It was also decided that other TDM relevant topics should be integrated into this special issue.

Gründer and co-workers show that positron emission tomography (PET) of molecular drug targets in the brain (neurotransmitter receptors and transporters) allows to establish relationships between drug plasma levels and target concentrations in the brain, thereby providing guidance for TDM services of the most commonly used antidepressant and antipsychotic drugs. They give strong evidence for the assumption of rational pharmacotherapy that plasma concentrations are directly related to target occupancy by the respective drug in the brain.

The contribution of Egberts and her colleagues deals with the conflicting issue of pharmacotherapy in children and adolescents. They describe how TDM studies in these age groups are necessary to identify age and specific therapeutic reference ranges of serum concentrations. They also outline the value of systematic collection of data on drug exposure, drug serum concentrations and on clinical characteristics such as outcome. This information helps to generate practice-based evidence for psychopharmacotherapy in a patient group that has many legal and ethical limitations to be studied prospectively in a broad way.

The potential of TDM in pharmacovigilance and drug safety programs is described by Haen. In the so called AGATE ( A rbeits g emeinschaft A rzneimittel t herapie bei psychiatrischen E rkrankungen) net, more than 50 hospitals specialized in the treatment of psychiatric disorders in adults, adolescents and children (most of them in Germany) cooperate to promote rational drug therapy. The AGATE has become a net of pharmacocompetence in which pharmacovigilance is linked to pharmacoinformation to optimize therapeutic outcomes and prevent adverse drug effects (ADE).

Despite existing evidence for the advantages of TDM and its positive impact on clinical reality, Conca and co-workers found a strong restriction of TDM to only few drugs and a weak knowledge base in their nationwide survey on TDM in Italian psychiatry. On the other hand, mental health workers in this country expressed a high interest for TDM. As a consequence, teaching about TDM should be developed systematically and laboratories should be encouraged to establish TDM services for psychotropic drugs.

Finally, Stassen and colleagues deal with the prediction of response to psychopharmacological treatment in an excellent summary about their research beyond the rigorous pharmacokinetic and pharmacodynamic concepts. They explain the impact of the severity of illness, early onset of improvement, unwanted side-effects, and medical comorbidity as predictors of response. They corroborate the fact that the mechanisms by which antidepressants and antipsychotics ultimately exert their therapeutic effects are only marginally understood. Therefore, this contribution gives evidence that psychopharmacotherapy should not only consider TDM in accordance with the reported new guidelines, but also symptom rating to quantify the patient’s psychopathology.

One of the highlights of the Bolzano meeting was the oral presentation by Hans Stassen. It was the special lecture in honour to the meritorious Prof. Dr. Bruno Müller-Oerlinghausen, who retired from the TDM group at this occasion, but who remains an honorary member of the task force. As former editor of Pharmacopsychiatry and head of the Drug Commission of the German Medical Association, he contributed to a large extent for the implementation of TDM as an officially accepted tool to guide psychopharmacotherapy. We wish to thank Prof. Dr. Bruno Müller-Oerlinghausen by dedication of this special issue.

Last but not least, this issue is dedicated also to Prof. Dr. Marie Luise Rao and Dr. Hans-Joachim Kuss, who also retired from our TDM group after they had contributed substantially to the evolution of TDM in psychiatry during the last 3 decades. MLR’s input is documented by numerous publications on TDM for antipsychotic, antidepressant and mood stabilizing drugs, whereas HJK’s clinical studies, e. g., his report published 1984 in Lancet and entitled “Amitriptyline: looking through the therapeutic window” [2], and his achievements in analytical methodology considerably helped to implant TDM in psychiatry.·

Andreas Conca, Pierre Baumann and Christoph Hiemke

Bolzano, Italy, Lausanne, Switzerland, and Mainz, Germany

• References

• 1 Baumann P, Hiemke C, Ulrich S et al. Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 2004; 37: 243-265
• 2 Kuss HJ, Jungkunz G, Holsboer F. Amitriptyline: looking through the therapeutic window. Lancet 1984; 25: 464-465