Pharmacogenetics as a tool in the therapy of schizophrenia.
OBJECTIVE
This review summarises the present knowledge of associations between pharmacogenetics and therapeutic efficacy and side effects of antipsychotics to enable pharmacists to judge the applicability for a more tailor made therapy in patients with schizophrenia. Polymorphisms of Cytochrome P450 isoenzymes and neurotransmitter receptors involved in the efficacy and side effects of antipsychotics are highlighted in this review.


METHODS
A search was performed in Medline and EMBASE for the period 1995-August 2002. Also relevant references from the selected papers were incorporated.


RESULTS
Poor metabolism with respect to CYP2D6 seems to be related with more pronounced extrapyramidal symptoms and more specifically with a higher incidence of tardive dyskinesia. The C/C-genotype for CYP1A2 results in smokers in a reduction of enzyme activity, but an effect on the incidence of tardive dyskinesia is controversial. For dopamine D2 receptors the effect of the -141C Ins/Del polymorphism on efficacy is not clear yet, although the Taq I polymorphism is associated with greater improvement of positive, but not negative symptoms in acute psychosis. The Gly9-allele of the dopamine D3 receptor is associated with the response to clozapine, but in studies in which the choice of antipsychotics is not restricted, the role of this polymorphism is unclear. The reverse is applicable to the dopamine D(4.2/4.7) polymorphism. For the 5-HT2A receptor the His452Tyr polymorphism is associated with response to clozapine, the 102 T/C polymorphism leads to equivocal results. The polymorphism studied for 5-HT5A, 5-HT6, alpha1A- and alpha2A-receptors give no clear associations with the response to clozapine. The polymorphism studied of the dopamine D2 and D4 receptor are not related to extrapyramidal adverse effects and side effects, respectively. The 9Gly-variant of the dopamine D3 receptor, the 102C-variant, but not the His452Tyr polymorphism of the 5-HT2A-receptor and the 23Ser-variant (for females only) of the 5-HT2C receptor seem to increase the susceptibility to tardive dyskinesia. Weight gain induced by antipsychotics seems to be associated with the -759C-allele of the 5-HT2C receptor.


CONCLUSIONS
The results show the first careful steps toward application of pharmacogenetics in a more individualised, tailor-made, pharmacotherapy. A pre-condition seems to be a multifactorial approach, as can be expected for multifactorial processes.
Wilffert
Bob
B
Department of Social Pharmacy, Pharmacoepidemiology & Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands [corrected] B.Wilffert@znb.nl
Zaal
Rianne
R
Brouwers
Jacobus R B J
JR
D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*
D014150:Antipsychotic Agents; D017981:Receptors, Neurotransmitter; D003577:Cytochrome P-450 Enzyme System