| Research Abstract |
Relationship between neurotransmitter receptor polymorphisms and antipsychotic drug response together with clinical implication of these polymorphisms as pharmacodynamic markers for neuroleptic response have been investigated, mainly focusing on genetic polymorphisms of dopamine receptor, which is closely related to pharmacological action of antipsychotics. Research results are summarized as follows;
1) TaqI A dopamine D_2 receptor polymorphism
The A1 carriers for TaqI A dopamine D_2 receptor polymorphism, which is associated with lowered dopamine receptor density, showed a greater improvement in positive and overall symptoms in schizophrenic patients treated with dopamine D_2 antagonists (Suzuki et al., Pharmacogenetics, 2000). Regarding adverse effects of antipsychotic drugs, A1 carriers showed higher risks for neuroleptic malignant syndrome (Suzuki et al., 2001, Am J Psychiatry) and hyperprolactinemia in females (Mihara et al., Psychopharmacology, 2000; Mihara et al., Am J Med Genet,
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2001). It is thus suggested that TaqI A dopamine D_2 receptor polymorphism is useful as a predictor of both therapeutic and adverse effects of antipsychotic drugs since A1 carriers appear to be sensitive to antidopaminergic effects.
2) -141C Ins/Del dopamine D_2 polymorphism
The effects of -141C Ins/Del dopamine D_2 polymorphism, which is directly related to dopamine D_2 receptor expression, on neuroleptic response have been investigated in schizophrenic patients. The Del noncarriers, which is associated with lowered dopamine receptor density, showed a greater improvement in anxiety-depression symptoms (Suzuki et al., Pharmacogenetics, 2001), suggesting that this polymorphism modifies anxiolytic and antidepressive effects of antipsychotic drug treatment.
3) Combination of TaqI A and -141C Ins/Del dopamine D2 polymorphisms
Clinical implication of combined determination of TaqI A and -141C Ins/Del dopamine D2 polymorphisms for prediction of response to selective dopamine receptor antagonists has been investigated. The A1 noncarriers of TaqI A polymorphism with Del allele(s) of -141C Ins/Del polymorphism showed markedly poor improvement in positive and anxiety-depression symptoms, and were found to be resistant to treatment with antidopaminergic agents (The 12th Japanese Society of Clinical Neuropsychopharmacology, Niigata, 2002: Paul Janssen Award). Less
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