Pharmacogenetics as a tool in the therapy of schizophrenia

Bob Wilffert*, Rianne Zaal, Jacobus R.B.J. Brouwers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

33 Citations (Scopus)

Abstract

Aim: 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.

Method: 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 D-2 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 D-3 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, alpha(1A)- and alpha(2A)- receptors give no clear associations with the response to clozapine. The polymorphism studied of the dopamine D-2 and D-4 receptor are not related to extrapyramidal adverse effects and side effects, respectively. The 9Gly-variant of the dopamine D-3 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.

Conclusion: The results show the first careful steps toward application of pharmacogenetics in a more individualised, tailor-made, pharmacotherapy. A precondition seems to be a multifactorial approach, as can be expected for multifactorial processes.

Original languageEnglish
Pages (from-to)20-30
Number of pages11
JournalPharmacy World & Science
Volume27
Issue number1
DOIs
Publication statusPublished - Feb-2005

Keywords

  • Antipsychotics
  • Atypical antipsychotics
  • Cytochrome P450 isoenzymes
  • Literature review
  • Pharmacogenetics
  • Receptor polymorphism
  • Schizophrenia
  • alpha 1A adrenergic receptor
  • alpha 2A adrenergic receptor
  • atypical antipsychotic agent
  • bromperidol
  • chlorpromazine
  • clozapine
  • cytochrome P450 1A2
  • cytochrome P450 2D6
  • cytochrome P450 isoenzyme
  • dopamine 2 receptor
  • dopamine 3 receptor
  • dopamine 4 receptor
  • emonapride
  • fluphenazine
  • haloperidol
  • neuroleptic agent
  • neurotransmitter receptor
  • olanzapine
  • quetiapine
  • rifampicin
  • risperidone
  • serotonin 2A receptor
  • serotonin 2C receptor
  • serotonin 5A receptor
  • serotonin 6 receptor
  • spiperone
  • sulpiride
  • acute psychosis
  • allele
  • data base
  • disease predisposition
  • drug efficacy
  • drug safety
  • Embase
  • enzyme activity
  • enzyme metabolism
  • enzyme polymorphism
  • extrapyramidal symptom
  • genotype
  • human
  • Medline
  • parkinsonism
  • pharmacist
  • pharmacogenetics
  • protein polymorphism
  • review
  • schizophrenia
  • side effect
  • smoking
  • tardive dyskinesia
  • time series analysis
  • weight gain

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