In connection with the widespread use of anticonvulsants (antiepileptic drugs – AEDs) in psychiatric and neurological practice and the need for their long-term use to treat a wide range of mental disorders and neurological diseases, the question of their safety profile, including the assessment of the risk of developing life-threatening conditions and adverse reactions (ADRs), becomes relevant. In this regard, from the position of personalized medicine, it is critical to develop an interdisciplinary approach with the participation of doctors of various specialties and a new strategy of a personalized approach to predicting AED-induced prolongation of the QT interval as one of the most prognostically unfavorable cardiological ADRs (including sudden death syndrome – SDS). We searched for full-text publications for the period from 2011 to 2021 databases using the following keywords and its combination. We have found and systematized monogenic and multifactorial forms of long QT syndrome (LQTS) and candidate genes that slow down AEDs metabolism in the liver. Identification of risk alleles of single nucleotide variants (SNVs) of the candidate genes predisposing to the development of AED-induced LQTS and SDS will make it possible to adjust the choice and dosage of these drugs and prevent the development of ADRs, which will improve the quality of life of patients and prevent SDS in the patients with psychiatric and neurological disorders.
Antipsychotics (APs) are a class of psychotrophic medication primarily used to managepsychosis (including delusions, hallucinations, paranoia or disordered thought), principally inschizophrenia but also in a range of other psychotic disorders. Biotransformation is a major mechanism for APs elimination. Most APs undergo biotransformation, or metabolism, after they enter the body. There are three phases of APs metabolism. Cytochrome P450 (CYP) monooxygenase (mixed function oxidase) plays a central role in the most APs biotransformation. CYP’s functional activity depends on gene-drug and drug-drug interaction and influences on occurrence of adverse drug reactions (ADRs). So, it is extremely important for a practicing psychiatrist to know the oxidation pathway of APs, since most of them are metabolized in the liver and this is important both to prevent ADRs and to avoid unwanted drug-drug interactions, which will undoubtedly increase theeffectiveness and safety of AP therapy.
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.
(1) Introduction: Quetiapine (QTP) is a dibenzothiazepine derivative, a second generation antipsychotic (AP), which is structurally similar to clozapine. The main indications for use are schizophrenia and depressive disorder. Under manic episodes in bipolar disorder can be used alone or in combination with lithium. The frequency of prescribing QTP is on average 11,987 per 100,000 population, with a positive trend in dynamics: a growth rate of more than 800% within the period 2002 to 2017.(2) Purpose: The review of studies of pharmacogenetic pharmacokinetic and pharmacogenetic pharmacodynamic markers of QTP efficacy and safety.(3) Materials and Methods: A search was carried out for publications of the Science Index, PubMed, Web of Science, Springer databases by keywords and their combinations over the last 10 years. In addition, the review includes earlier publications of historical interest. Despite extensive searches of these commonly used databases and search terms, it cannot be ruled out that some publications may have been missed.(4) Results: The review considers the following pharmacokinetic markers of QTP efficacy and safety: genes are coding isoforms of cytochrome P450 (CYP2D6, CYP2C19, CYP3A4, CYP3A5), P-glycoprotein (ABCB1); pharmacogenetic pharmacodynamic markers of the efficacy and safety of QTP : genes of dopamine receptor isoform (DRD3), dopamine transporter (SCL1A1) and catecholO-methyltransferase (COMT), serotonin receptor isoforms (HTR2C), melanocortin receptor (MC4R), NOTCH protein (NOTCH4), phosphodiesterase 4D (PDE4D), SPoPL protein (SPoPL), multiple EGFlike domain (MEGF10), protocadherin-7 (PCDH7), contactin-associated protein 5 (CNTNAP5) , TRAF2 and NCK-interacting protein kinase (TNIK), spermatogenesis-associated protein 6 (SPATA6L), neurobihin (NBEA), synaptic vesicle protein-2C (SVC2) .(5) Conclusion: Disclosure of pharmacogenetic markers of pharmacokinetics and pharmacodynamics of QTP efficacy and safety in the treatment of patients with schizophrenia and other psychiatric disorders, may provide a key to developing a strategy for its personalized prevention of adverse grug reactions (ADRs) and therapy strategy in real clinical practice.
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