Dopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia

Kaiser, Rolf; Könneker, M.; Henneken, Maren; Dettling, Michael; Müller‐Oerlinghausen, B.; Roots, Ivar; Brockmöller, Jürgen

doi:10.1038/sj.mp.4000729

Cited by 76 publications

(33 citation statements)

References 27 publications

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“…Three independent studies failed to confirm these associations. [108][109][110] Studies of genetic variants in the dopamine transporter gene (DAT1) reported several associations between a VNTR polymorphism and response to methylphenidate, a treatment for attention deficit and hyperactivity disorder (ADHD), 163,164 but no association has been reported with antipsychotic response. 102,103,111 The final reading of these association findings is that they confirm the contribution of dopamine receptors to antipsychotic efficacy.…”

Section: Pharmacodynamic Factorsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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Section: Pharmacodynamic Factorsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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“…[214][215][216][217][218] For typical (ie predominantly dopamine D-2 antagonistic) antipsychotics, only few studies were found on dopamine receptor genes (DRD2, DRD3, and DRD4). 210,[289][290][291][292][293] Most results were negative findings for response prediction. One study observed a slight over-representation of the DRD3 Ser9Gly amino-acid exchange (allele *2) in patients with poor response to antipsychotics, particularly in the non-Ashkenazi, Israeli schizophrenics.…”

Section: Dopaminergic Systemmentioning

confidence: 99%

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

et al. 2004

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Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

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“…These have reported associations between polymorphisms in DRD4 and catatonia 18 and delusions, 19 DRD2 and disorganization and delusions 20 CCK and positive symptoms, 21 5-HT promoter and auditory hallucinations 22 and affective symptoms, 23 HkCa3 and negative symptoms 24 and BDNF and DAT1 and negative symptoms. 23 Moreover, these polymorphisms were not associated with illness in these samples.…”

Section: Susceptibility Vs Modifier Genesmentioning

confidence: 99%

Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework

2004

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Dopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia

Cited by 76 publications

References 27 publications

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework

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