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Application of single nucleotide polymorphisms of risk genes in schizophrenia in choosing the appropriate antipsychotic drug

Felix-Martin Werner and Rafael Coveñas

Schizophrenia has a genetic etiology in about 80% of patients concerned. In recent years, some risk genes have been described. Table 1 summarizes some important risk genes, the functions of these risk genes in the neurotransmission in the brain areas involved in schizophrenia, the SNPs of the risk genes and an improved therapeutic effect or a lack of efficacy regarding a specific antipsychotic drug. The rs 165599 SNP of the COMT gene is connected with a higher therapeutic efficacy of risperidone, whereas the SNP of this risk gene is linked with a pharmacotherapy resistance. The SNP (rs 1799836) of the MAO B gene is correlated with schizophrenia and hyperprolactinemia. Both risk genes encode a reduced activity of enzymes catalyzing the dopamine degradation. Consequently, an increased dopamine release occurs via D2 receptors in the mesolimbic system and hippocampus. The GAD 67 gene is associated with a disturbed GABAergic neurotransmission, and in the hippocampus, GABAergic neurons which coexist with CCK weakly inhibt D2 dopaminergic neurons. The neuregulin-1 gene is linked with a glutamatergic dysfunction via NMDA receptors and an increased activation of the D2 receptor. In the hippocampus, glutamatergic neurons weakly activate GABAergic neurons which enable dopamine hyperactivity through a reduced presynaptic inhibition. The DAOA gene encodes as well a glutamatergic dysfunction via NMDA receptors. The SNPs of the D2 receptor (rs 1801028) and D3 receptor (rs 6280) genes are correlated with a better therapeutic efficacy of risperidone, whereas the SNPs (rs 4680 and rs 1800497) of the D2 receptor gene are more frequently found in patients with a pharmacotherapy resistance. In this review, the neural networks in the mesolimbic system, hippocampus and prefrontal cortex are updated according to the reviewed literature. In the future, it is of importance to examine the SNPs of schizophrenic patients in order to differentiate patients with a better response to a specific antipsychotic drug and patients with a pharmacotherapy resistance. The latter patients could be treated with the antipsychotic drug clozapine and an additional therapy with cariprazine, a partial D2 and D3 receptor agonist.