Vol 6 n° 1 - Predictors of Response to Treatment in Neuropsychiatry
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7 1 P h a r m a c o l o g i c a l   a s p e c t s Differing response to antipsychotic therapy in schizophrenia: pharmacogenomic aspects Manfred Ackenheil, MD; Klaus Weber, MPharm Keywords: antipsychotic; pharmacogenomics; pharmacokinetics; nonresponse; schizophrenia Author affiliations: Psychiatric Hospital of the University of Munich, Munich, Germany Address  for  correspondence:  Psychiatric  Hospital  of  the  University  of Munich, Nussbaumstrasse 7, D-80336 Munich, Germany   (e-mail: Manfred.Ackenheil@med.uni-muenchen.de) Copyright © 2004 LLS SAS.  All rights reserved www.dialogues-cns.org onresponse is a frequent phenomenon in both somatic and psychiatric pharmacotherapy. A consider- able number of drugs have become available for the treatment of various psychiatric diseases since the dis- covery of chlorpromazine 50 years ago.1 Despite all the progress in this field, there are still many patients who do not respond to treatment, so-called nonresponders. Around 20% to 30% of the patients with schizophrenia are thought to be nonresponders to one or more psy- chotropic drugs. Several reasons for nonresponse to treatment have been considered.The main issue is the heterogeneity of schiz- ophrenic disorders, which can result in different clinical pictures. The existing theories discussed for schizophre- nia (Figure 1) may be only a small part of the existing mechanisms causing schizophrenia. Consequently, the research strategy is to focus on the effects of alterations N Treatment-resistance in schizophrenia remains a public health problem: about 20% to 30% of patients do not respond to antipsychotic therapy. Clozapine has been shown to be effective in about one-third of patients, but the medical risks and weekly blood tests limit its broad application. While the heterogeneity of the disease and the duration of untreated psychosis are important, pharmacogenomic aspects must also be considered. Pharmacogenomic investiga- tions offer the opportunity to individualize antipsychotic therapy according to the growing knowledge of the func- tion and effect of the genetic polymorphisms that affect the pharmacokinetics and pharmacodynamics of antipsy- chotics. On the pharmacokinetic level, polymorphic phase I and II drug-metabolizing enzymes and transport proteins affect drug concentration at the target structure. The cytochrome P450 enzymes, N-acetyltransferase, and multidrug resistance protein (MDR1) particularly influence this parameter. Genetic alterations affecting drug pharmacodynamic properties have an impact on therapeutic outcome that is generally independent of the applied dosage regimen. A combined analysis of genetic polymorphisms in the dopaminergic and serotonergic receptors, neurotransmitter trans- porters, and other target structures involved in psychiatric disorders is already a powerful predictor of therapeutic out- come. An understanding of other factors influencing gene expression and protein production will facilitate individ- ualized therapy in the future.   © 2004, LLS SAS Dialogues Clin Neurosci. 2004;6:71-77.