Clinical Information

The neurotransmitter dopamine acts via dopamine receptors in the central nervous system. Dopamine receptor subtypes D1 through 5 (DRD1-5) are of interest in schizophrenia research because many of the antipsychotic drugs interact with and block 1 or several of these receptors. There has been a strong association between DRD2 receptor blockade and antipsychotic drug dose for typical antipsychotics (eg, haloperidol, chlorpromazine). However, this association has not been maintained for the atypical antipsychotics (eg, clozapine, risperidone). The atypical antipsychotic medications have high binding affinity for the polymorphic DRD3 receptor.

For DRD3, a single nucleotide change (DRD3 25A->G) results in an amino acid coding polymorphism, Ser9Gly, which is associated with variable response to treatment with atypical antipsychotic medications and predisposition to tardive dyskinesia, a side effect of certain antipsychotic drugs. Worldwide, the frequency of the A (DRD3 25A) and G (DRD3 25G) alleles is nearly equal. However, the allele frequencies are markedly different in different populations (see below) and this may impact the risk of tardive dyskinesia within a given population or cohort following treatment with antipsychotic drugs.

Population Frequencies for DRD3 25A and DRD3 25G alleles:

-Allele frequency

 - European: G=35%, A=65%

 - African American: G=70%, A=30%

 - Han Chinese Beijing: G=37%, A=63%

 - Japanese: G=24%, A=76%

Other polymorphisms in the 5' promoter region of DRD3 have also been studied, but results are too preliminary to be used in the management or diagnoses of psychiatric illnesses.

Tardive dyskinesia:

The DRD3 25G polymorphism is associated with the presence and severity of typical neuroleptic-induced tardive dyskinesia in schizophrenic patients. Higher mean movement scores were found in patients homozygous for the DRD3 25G allele as compared to both heterozygous and DRD3 25A homozygous patients.(1,2) The risk for tardive dyskinesia increases with the number of DRD3 25G alleles. Individuals homozygous for the DRD3 25G allele have an odds ratio of 2.8 for developing tardive dyskinesia compared to individuals homozygous for the DRD3 25A allele.(2)

Treatment responses:

The DRD3 25G allele has been associated with treatment response to clozapine(3) and olanzapine. Among a group of Chinese patients with schizophrenia treated with risperidone, patients homozygous for the DRD3 25A allele had a better response, as measured by improved scores on the Positive and Negative Symptom Scale (PANSS), a questionnaire used to evaluate symptoms associated with schizophrenia, compared to patients homozygous for the DRD3 25G allele.(4) These improved responses included decreased social and emotional withdrawal, improved abstract thinking, and increased spontaneity and flow of conversation. A better response was observed in the heterozygous state (DRD3 25AG) compared to the homozygous groups (DRD3 25GG, P=0.05; DRD3 25AA P=0.06) in another study of patients receiving a variety of typical and atypical antipsychotics.(5)