Zur Response untersuchten wir den Einfluss der Polymorphismen des SNAP-25, des TNF-alpha- und des GNB3-Gens und fokussierten uns dabei auf symptombezogene Analysen. Hierbei fand sich unter anderem ein signifikanter Befund des 825C/T Polymorphismus des GNB3-Gens, der insbesondere mit Besserung positiver Symptome assoziiert gewesen ist. Die hier vorgelegten Arbeiten sind als Stimulus für Replikationsstudien geeignet, die bei komplex vererbten Phänotypen von essentieller Bedeutung sind. Des Weiteren dienen die Studien dazu, wichtige methodologische Prinzipien der Pharmakogenetik aufzuzeigen um die gewonnenen Erkenntnisse in zukünftige Studien einfließen lassen zu können. Durch die zurzeit auch in unserer Klinik laufenden Erstellung größerer und prospektiv erfasster Kollektive sind weiterführende und wichtige Ergebnisse zu erwarten. Durch Berücksichtigung genetischer Faktoren ist der Weg zu einer wirkungsvolleren und nebenwirkungsärmeren Therapie inzwischen gebahnt worden. Die Fiktion einer individualisierten Therapie kann in naher Zukunft zur Realität werden und Pharmakogenetik ein fester Bestandteil der klinischen Praxis sein.
Studies and research summarized in this thesis have led to new insights that aim to a achieve an individualized pharmacological therapy of schizophrenia that is based on pharmacogenetics. In particular, these studies have been focussing on side effects (tardive dyskinesia and weight change) and response to antipsychotics. The first study has included family members of schizophrenic individuals and has demonstrated a genetic component in the incidence of tardive dyskinesia. In molecular genetic based studies, however, no particular associations between tardive dyskinesia and CYP2D6 gene variants were found, although various clinical and demographic factors were included to correct for potential confounders. In contrast, in a later study, a significant association between the functional relevant 759 C/T polymorphism of the DRD2 gene with tardive dyskinesia could be detected. In a further pilot study, focussing on the Pro179Leu polymorphism of the GPX1-gene and tardive dyskinesia, no significant association has been detected. Regarding antipsychotic induced weight gain, the influence of the 957C/T promoter polymorphism of the 5-HT2C gene has been investigated for the first time by doing a meta-analysis. Despite a significant heterogeneity across studies, a significant association could be detected. The SNAP-25 gene has been analysed for the first time where two polymorphisms (MnlI, TaiI) were found to be associated with weight gain and response, although a significant relationship with other co-factors has also been detected. Finally, we investigated the G-308A polymorphism of the TNF-alpha gene and found a non-significant trend with weight gain induced by antipsychotics. Analyses on the SNAP-25, TNF-alpha and GNB3 genes then also focussed on specific schizophrenia related symptoms. Here, a significant association between the 825C/T polymorphism of the GNB3-gene and improvement in positive symptoms has been observed. The studies presented here may serve as stimulus for replication studies, which are of utmost importance in complex inherited phenotypes such as outcome to antipsychotic drugs. Furthermore, these studies may also serve to illustrate important methodological principles in pharmacogenetics. Individualized therapy does not have to remain a fiction but is likely to become a reality soon. Pharmacogenetics is on its way to become a common and indispensable tool in clinical practice.
