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|Genetische Faktoren in der pharmakologischen Behandlung der Schizophrenie|
Müller, Daniel J.
|Main title||Genetische Faktoren in der pharmakologischen Behandlung der Schizophrenie|
|Title variations||Genetic factors in the pharmacological treatment of schizophrenia|
|Author(s)||Müller, Daniel J.
Place of birth: Bonn
|1. Referee||Prof. Dr. med. J. Deckert|
|Further Referee(s)||Prof. Dr. med. H. J. Möller|
|Keywords||Genetics, Pharmacogenetics, Schizophrenia, reponse, side effects, tardive dyskinesia, weight gain|
|Classification (DDC)||610 Medical sciences; Medicine|
|Summary||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.
|FU Department||Department of Medicine - Charité - University Medicine Berlin|
|Year of publication||2008|
|Document type||Habilitation treatise|
|Date of defense||2008-05-19|
|Created at||2008-11-20 : 08:23:24|
|Last changed||2012-06-20 : 09:33:44|