S-15-01

Genetic polymorphisms of enzymes: Clinical relevance psychotropic drug metabolizing

P. Baumann, E. Jaquenoud, C. Eap. Unite de biochimie et psychopharmacologie clinique, Prilly-Lausanne, Switzerland

In a very recently published consensus paper on therapeutic drug monitoring (TDM) of psychotropic drugs, some recommendations concerning its combination with pharmacogenetic tests (phenotyping, genotyping) were included (Baumann et al., 2004). As a matter of fact, both environmental and genetic factors contribute to the large interindividual variablility of plasma drug concentrations observed in patients, and the study of the clinical relevance (response, occurrence of adverse effects) of these observations is an important research field. CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 are the main isoforms of cytochrome P-450 implicated in the metabolism of psychotropic drugs, and for some of them, genetic polymorphisms have been described, while for others, the interindividual variability in activity remains unexplained. For methodological reasons, relatively few prospective studies were carried out in groups of phenotyped and/or genotyped patients on the relationship between pharmacogenetic, pbarmacokinetic and clinical parameters. On the other hand, rous case reports illustrate the usefulness of pharmacogenetic tests in patients treated with antidepressants or antipsychotics, as they constitute a potent diagnostic tool with regard to the individual drug metabolising capacity. In conclusion, pharmacogenetic tests are increasingly recommended in phase IIIV studies, but also in pharmacovigilance programs, and in patients, who poorly respond or tolerate psychotropic medication. P. Baumann, C. Hiemke, S. Ulrich. I. Gaertner, M.-L. Ran, G. Eckermann, M. Gerlach, H.-J. Kuss, G. Laux, B. Miiller- Oerlinghausen, P. Riederer, G. Zernig. The AGNP-TDM expert group consensus guidelines: Therapeutic Drug Monitoring in Psychiatry. Pharmacopsychiatry 37 (2004) 243 - 265

S-15-02

The pharmacogenetics of antipsychotics

J. Scharfetter. Uni-Klinik f. Psychiatrie Abt. f Allg. Psychiatrie, Wien, Austria

Since a considerable number of psychotic patients treated with antipsychotic medication do not or not fully respond to treatment and some, but not all, suffer from serious side effects, scientific interest has centered on genetic factors determining individual susceptibility to antipsychotic treatment. Genetic polymorphisms of metabolizing enzymes (especially cytochrome P450) have been shown to influence kinetics of antipsychotics and consequently treatment outcome and side effects. Furthermore there are a number of studies investigating the association between genetic polymorphisms of neurotransmitter receptors targeted by antipsychotics and effectivity of treatment, as well as agranulocytosis, weight gain and extrapyramidal symptoms, being the most prominent side effects. The association studies conducted so far are mainly addressing dopamine and serotonin receptor polymorphisms, yielding promising results. These results will be presented and prospects for an individualized treatment will be discussed.

S-15-03

The influence of ABCB1 transport proteins (MDRI, Pglycoprotein) on the blood-brain barrier function: Therapeutic implications

M. Uhr. Max Planck Institute for Psychiatry, München, Germany

Objective: The clinical efficacy of drugs targeting the central nervous system critically depends on the compounds' ability to pass the blood-brain barrier, which is regulated by active transporter molecules, such as ABCB I (MDR1, P-glycoprotein (Pgp). One of the reasons for an only partial response or refractoriness is an insufficient intracerebral concentration. We hypothesized that genetic variability in ABCB 1 influence the response to drugs with central nervous system (CNS) actions, including the clinical response to antidepressants. We used transgenic mice lacking the two homologues of the human ABCB1 drug transporter gene (abcbla and abcblb) to assess whether antidepressants were substrates of P-gp following subchronic administration. We than genotyped 56 single nucleotide polymorphisms (SNPs) in ABCB 1 in 286 depressed in patients treated with antidepressants and tested for associations with treatment response. The animal experiments showed that the intracerebral concentrations of some but not all antidepressants were regulated by P-glycoprotein. In the human genetics studies, there was an association of ABCB I SNPs with remission status after 6 weeks of antidepressant treatment. This association was present in patients treated with antidepressants that are substrates of P-gp, but not in patients treated with antidepressants that are not substrates of P-gp. Our findings indicate that polymorphisms in ABCB1 influence intracerebral concentrations of antidepressants and by that response to treatment. Genotyping ABCB1 polymorphisms may thus help to optimize antidepressant treatment. These implications are likely to extend to other classes of CNS drugs.

S-15-04

Adverse drug reactions: Role of pharmacogenomics

P. Zill. Psychiatric CLinic, Munich, Germany

Objective: The inter individual variability of drug response is a major problem in clinical practice and drug development, which can lead to therapeutic failure or adverse effects in patients. There is growing evidence that not only the involvement of pharmacokinefic factors (drug metabolism) might predispose to adverse effects, but also genetic variations in drug targets (pharmacodynamic factors) play an important role. Moreover the existence of comorbid disorders, as for example the metabolic syndrome, characterized by elevated abdominal obesity, uiglycerides, blood pressure, fasting glucose, which has been suggested to be associated with depression and schizophrenia is supposed to have an impact on the incidence of side effects after psychopharmacological treatment, rous previous studies could demonstrate an involvement of polymorphisms in drug metabolizing enzymes (e.g. Cyp450 system), as well as in drug target genes and the incidence of adverse effects, but these results remain partially inconclusive.

Results: In own studies with 160 schizophrenic patients and 272 patients with major depression we found that a -579C/T polymorphism in the 5-HT2C gene seems to be involved in weight gain during neuroleptic and antidepressant treatment. The 5HT2C −597 C/T and a B2-adrenergic receptor polymorphisms (Arg 16Gly) might also be involved in glucose metabolism.

Conclusion: These results suggest that symptoms of the metabolic syndrome are among the common side effects, but these findings have to be replicated in further prospective studies. Knowledge from these studies will ultimately lead to the individualization of psychiatric drug treatment, as well as to future treatment strategies. This project is supported by the German Federal Research Ministry within the promotional emphasis “Competence Nets in Medicine”