Efficacy and Side-Effects of Clozapine: Testing for Association with Allelic Variation in the Dopamine D4 Receptor Gene

Abstract

Genetic factors are supposed to play a major role not only in the etiology of psychiatric disorders but also in individual response to medications. To test the hypothesis that inter-individual differences in response to clozapine and the occurrence of side-effects might be influenced by variations in the dopamine D4 receptor gene, we examined frequencies of four known polymorphic sites affecting protein structure in the dopamine D4 receptor gene in 149 patients with schizophrenia or schizoaffective disorder treated with clozapine. The D4 polymorphisms included a 13-base pair deletion, which through a frameshift leads to a truncated nonfunctional receptor protein. There were, however, no significant differences in genotype counts between responders and nonresponders. Furthermore, no side-effect was found to be associated with genetic variants of the dopamine D4 receptor.

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

“…We therefore studied the population frequencies of the 48-bp repeat region in a large Caucasian population composed of schizophrenic patients, healthy subjects, and non-psychiatric patients. In accordance with the observations of Asghari et al, 8,9 van Tol et al, 7 and Cohen et al, 11 we grouped all individuals carrying DRD4 48-bp VNTR genotypes with Յ 4-repeat alleles (genotypes: 14,22,23,24,33,34,44) and Ն 5-repeat alleles (all other genotypes as shown in Table 1), and all individuals carrying only Յ 4-repeat alleles with Ն 5-repeat alleles. We were primarily interested in the relation between therapeutic response and the 48-bp VNTR in patients treated with clozapine, as well as in patients treated with typical antipsychotics.…”

“…9 A number of clinical studies 10,11 have confirmed, and others have denied, the association between different alleles of the 48-bp repeat and the response to antipsy-chotic drug treatment. [12][13][14] The DRD4 receptor has also been investigated for possible linkage to schizophrenia, since DRD4 density was found in post-mortem brain tissues of schizophrenic patients 15 which was six times greater than that among non-psychiatric controls. Most studies investigating schizophrenia have not been able to find significant association of the DRD4 48-bp VNTR.…”

Potential clozapine target sites on peripheral hematopoietic cells and stromal cells of the bone marrow

“…38 Of note also is the widespread distribution of d4 mRNA, a high affinity site for clozapine, 39 although no association between the polymorphic forms of d4 or variable clozapine response has been found. 40,41 The mapping of serotonin receptors in peripheral blood cells indicated variable levels of expression, with 5ht7 mRNA most widely distributed and 5ht2c and 5ht6 mRNA undetected. Serotonin-mediated regulation of hematopoiesis via programmed cell death has been reported.…”

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

“…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.…”