Pharmacogenetic Testing of Cytochrome P450 Metabolizing Enzymes in 28-Year-Old Man with Treatment-Resistant Schizophrenia

Abstract

Schizophrenia is a common and socially significant mental disorder that requires longterm use of antipsychotics (APs). Long-term use of APs increases the risk of developing adverse drug reactions (ADRs) and/or therapeutic resistance in some patients. This may be due to a genetically determined impairment of APs metabolism by cytochrome P450 enzymes. Pharmacogenetic testing (PGx) is a method to identify a group of patients with a high risk of developing AP-induced ADRs. Our experience of using PGx to search for low-functional and non-functional single nucleotide variants (SNVs) / polymorphisms of the CYP1A2, CYP2C9, CYP3A4, CYP3A5 and CYP2D6) genes encoding cytochrome P450 enzymes involved in APs metabolism demonstrates the importance of this new personalized approach to the choice of APs and its dosing in patients with pharmacogenetic profile poor metabolizer. The main purpose of the case report is to present the experience of using PGx in a 28-year-old patient with treatment-resistant schizophrenia and a medical history of AP-induced ADRs.

Pharmacogenetic Testing of Cytochrome P450 System Enzymes in the Therapy of Bipolar Affective Disorder

“…In different people, the set of the cytochrome P450 isoenzymes in the endoplasmic reticulum (ER) and on the inner mitochondrial membrane differs due to genetic characteristics. In this regard, the study of genetically determined changes in the expression of the functional activity of CYP family isoenzymes is of great clinical importance in psychiatry and clinical pharmacology [2][3][4][5][6][7][8][9][10].…”

“…The study of genetic predisposition to the development of PD-induced ADRs is based on associative genetic studies and genome-wide studies of single nucleotide variants (SNVs) and polymorphisms of the candidate genes involved in the metabolism, transport, cumulation, excretion of PDs and their active metabolites [6][7][8].…”

Pathophysiological Mechanisms of Antipsychotic-Induced Parkinsonism

“…Individual differences in susceptibility to haloperidol-induced parkinsonism were explained by individual pharmacokinetic variability associated with the influence of carriage of single nucleotide variants (SNVs) of the CYP3A4 and CYP3A5 genes, which affects the metabolism of haloperidol to its pyridinium ion. While taking haloperidol, pyridinium ion-related toxicity may be observed, which may be exacerbated in patients on polytherapy with antidepressants, as they interact with this system [ 6 , 86 , 113 , 114 , 115 , 116 ].…”

“…In our systematic review, the following positive associations for the risk of developing AIP were noted: rs1799732 (NG_008841.1:g.4750dup), rs1800497 (NG_012976.1:g.17316G>A), rs6275 (NG_008841.1:g.67525T>C) of the DRD2 gene; rs167771 (NG_008842.2:g.46980C>T, NG_008842.2:g.46980C>G, NG_008842.2:g.46980C>A) of the DRD3 gene; rs4680 (NG_011526.1:g.27009G>A) of the COMT gene; rs6311 (NG_013011.1:g.4692G>T, NG_013011.1:g.4692G>A) of the 5HTR2A gene; rs6318 (NG_012082.2:g.152242G>C, NG_012082.2:g.152242G>T) and rs3813929 (NG_012082.2:g.4963C>G, NG_012082.2:g.4963C>T) of the HTR2C gene; rs2179652 (NG_022822.1:g.225C>T), rs2746073 (NG_012800.1:g.6059T>A), rs4606 (NG_012800.1:g.8004C>G, NG_012800.1:g.8004C>T), rs1152746 (NC_000001.11:g.192827775C>G, NC_000001.11:g.192827775C>T), rs1819741 (NC_000001.11:g.192815708T>A, NC_000001.11:g.192815708T>A) and rs1933695 (NC_000001.11:g.192795690G>A) of the RGS2 gene; rs4795390 (NG_030330.1:g.3434G>A, NG_030330.1:g.3434G>C, NG_030330.1:g.3434G>T) of the PPP1R1B gene; rs6265 (NG_011794.1:g.68690G>A) of the BDNF gene; rs12678719 (NG_011723.2:g.189908C>G) of the ZFPM2 gene; rs938112 (NC_000003.12:g.117129003C>A, NC_000003.12:g.117129003C>T) of the LSMAP gene; rs2987902 (NG_012034.1:g.125979A>T) of the ABL1 gene. However, at present, it should be recognized that there is no definitive or single decision on the leading role of any particular SNVs/polymorphisms in AIP development [ 6 , 114 , 116 , 117 ].…”