Second-generation antipsychotics are widely used for the treatment of schizophrenia. Aripiprazole (ARI) is classified as a third-generation antipsychotic drug with a high affinity for dopamine and serotonin receptors. It is considered a dopamine-system stabilizer without severe side effects. In some patients the response to ARI treatment is inadequate and they require an effective augmentation strategy. It has been found that the response to the drug and the risk of adverse metabolic effects can be related to gene polymorphisms. A reduced dose is recommended for CYP2D6 poor metabolizers; moreover, it is postulated that other polymorphisms including CYP3A4, CYP3A5, ABCB1, DRD2, and 5-HTRs genes influence the therapeutic effect of ARI. ARI can increase the levels of prolactin, C-peptide, insulin, and/or cholesterol possibly due to specific genetic variants. It seems that a pharmacogenetic approach can help predict drug response and improve the clinical management of patients with schizophrenia.

Aripiprazole is an atypical antipsychotic drug that is mainly transformed by the hepatic enzymes CYP2D6 and CYP3A4. Dose adjustment is recommended for CYP2D6-poor metabolizers. Aripiprazole is generally well tolerated by most adult patients, but occasionally adverse effects can occur in some individuals resulting in the drug being withdrawn. Recent studies suggested that other genes involved in drug metabolism, transport, and elimination can be related to the efficacy and safety of drug therapy. This study aimed to evaluate the differences in genetic variants between patients who tolerated the therapy well and those who experienced adverse effects leading to withdrawing the drug. The genetic profiling of 20 genes was performed using MassARRAY technology. No differences between both groups in the ABCB1, COMT, CYP2D6, CYP3A4, and CYP3A5 polymorphisms were found. Unexpectedly, we observed a higher frequency of homozygous CYP1A21F/*1F (78% vs. 45%) and CYP2B6*1/*1 (80% vs. 45%) as well as the frequency of CYP1A2 ultra-rapid metabolizes in the group with adverse effects. Moreover, a combined homozygous status (CYP1A2*1F/*1F/ CYP2B6*1/*1) has been exclusively identified in patients with adverse effects. To date, there are no findings about the possible role of CYP1A2 and CYP2B6 enzymes in aripiprazole metabolism. Thus, our preliminary data suggest that the CYP1A2*F and/or CYP2B6*1 alleles may contribute to the adverse effects of aripiprazole. Therefore, further studies on larger sample sizes are needed to confirm our findings.