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Pharmacogenetic studies in schizophrenia aim to use genetic information as a guide to establish individualized treatment options and to optimize the effectiveness of treatment. The heterogeneity of response to antipsychotics results in polypharmacy along and combination therapy into clinical practice, which lead to an increase in drug-related side effects and non-adherence to treatment.
Dopamine and serotonin systems may provide some of the genetic polymorphisms and have been proposed to predict the efficacity of antipsychotic drugs. Affecting the intensity of the D2 receptors in the striatum, the DRD2- 141C Ins/Del polymorphism has been associated with unresponsiveness to clozapine in treatment-resistant patients and a longer response time to olanzapine and risperidone in first-episode patients. The D3 receptor DRD3 Ser9Gly polymorphism has been associated with unresponsiveness to clozapine and good response to first generation antipsychotics.
The 5-HT2A receptor gene HTR2A-A-1438G and T102C polymorphisms may cause lower promoter activities and decreased 2A receptor density in some brain regions. A-1438G G/G carriers have been found to be less likely to respond to clozapine, olanzapine, and aripiprazole. The T102C SNP C/C genotype has been associated with no response to clozapine and good response to risperidone and aripiprazole.
The long allele of the serotonin transporter gene has been reported to be associated with better response to antidepressants, but there are only a few studieson schizophrenic patients. The effectiveness of pharmacogenetics-based combination therapies in patients unresponsive to treatment has not been studied yet; the DRD2 and DRD3 genes may be candidates for study.
Antipsychotic metabolism: The Met/Met genotype of the COMT gene causes a 3- to 4-fold lower enzyme activity. The met allele carriers were more likely to respond to clozapine, especially showing improvement in cognitive functions. This polymorphism, seems to deserve assessment of the effectiveness of combination therapies in dealing with cognitive symptoms.
The CYP2D6 enzyme plays an important role in the metabolism of antipsychotic drugs. Individuals carrying duplicate or multiple copies of the CYP2D6 gene are known as ultrarapid metabolizers. In ultrarapid metabolizers, due to the decrease in therapeutic efficacy of antipsychotic drugs, a combination of drugs that are metabolized by the same cytochrome enzyme would not provide further improvement in drug response.
Antipsychotic-induced side effects: The DRD2 A2 allele of SNP Taq1A, the DRD3 Ser9 Gly Gly allele genetic polymorphisms related to D2 and D3 receptors, the COMT Val allele and the CYP2D6 gene variants have been reported to be associated with an increased risk of tardive dyskinesia.
CYP2D6 poor and intermediate metabolizers may be more sensitive to the extrapyramidal side effects of antipsychotics. The 5HT2C gene (759T SNP) and the leptin gene are the most studied polymorphisms for antipsychotic-induced weight gain. All of the aforementioned polymorphisms may have implications for choice of rational antipsychotic combinations.
Pharmaco-genetics-based rational antipsychotic combinations may yield promising results for cytochrome enzyme and COMT genes and the genes associated with side effects in schizophrenia. However, this issue should be supported and confirmed by clinical pharmacogenetics studies.