Analysis of the Deleterious Single-Nucleotide Polymorphisms Associated With Antidepressant Efficacy in Major Depressive Disorder

Abstract

Major depressive disorder (MDD) is a serious mental disease with negative effects on both mental and physical health of the patient. Currently, antidepressants are among the major ways to ease or treat MDD. However, the existing antidepressants have limited efficacy in treating MDD, with a large fraction of patients either responding inadequately or differently to antidepressants during the treatment. Pharmacogenetics studies have found that the genetic features of some genes are associated with the antidepressant efficacy. In order to obtain a better understanding on the relationship between the genetic factors and antidepressant treatment response, we compiled a list of 233 single-nucleotide polymorphisms (SNPs) significantly associated with the antidepressant efficacy in treating MDD. Of the 13 non-synonymous SNPs in the list, three (rs1065852, rs3810651, and rs117986340) may influence the structures and function of the corresponding proteins. Besides, the influence of rs1065852 on the structure of CYP2D6 was further investigated via molecular dynamics simulations. Our results showed that compared to the native CYP2D6 the flexibility of the F-G loop was reduced in the mutant. As a portion of the substrate access channel, the lower flexibility of F-G loop may reduce the ability of the substrates to enter the channel, which may be the reason for the lower enzyme activity of mutant. This study may help us to understand the impact of genetic variation on antidepressant efficacy and provide clues for developing new antidepressants.

Effects of Pharmacokinetic Gene Variation on Therapeutic Drug Levels and Antidepressant Treatment Response

“…This is supported by the fact that rs1065852 is located in a conserved region of CYP2D6 and therefore, possibly important for protein function [32]. Modeling studies showed that the flexibility in the F-G loop, which may affect the entrance of a substrate into the protein, is lower in the mutant than the wild type, which may account for lower enzyme activity [32]. Consistent with this observation, in a previous genome-wide association study, rs1065852 was found to be associated with the metabolism of escitalopram [33].…”

“…Carriers of the A-allele showed higher serum concentrations of amitriptyline then the wild type (G). This is supported by the fact that rs1065852 is located in a conserved region of CYP2D6 and therefore, possibly important for protein function [32]. Modeling studies showed that the flexibility in the F-G loop, which may affect the entrance of a substrate into the protein, is lower in the mutant than the wild type, which may account for lower enzyme activity [32].…”

NRG1, PIP4K2A, and HTR2C as Potential Candidate Biomarker Genes for Several Clinical Subphenotypes of Depression and Bipolar Disorder

“…Age of onset of MDD Saus et al, 2010 Interaction of rs6782799, rs6265 (BDNF), and negative life events MDD Yang et al, 2010BDNF rs6265 MDD Tsai et al, 2003Schroter et al, 2020 Interaction of rs6265 and stressful life events MDD Hosang et al, 2014 rs6265 Recurrent MDD Xiao et al, 2011;Lee Y. et al, 2013 rs6265 Severity of depression Losenkov et al, 2020 rs6265 Response to antidepressant therapy and remission in MDD Choi et al, 2006;Alexopoulos et al, 2010;Chi et al, 2010;Zou et al, 2010;Taylor et al, 2011;Murphy et al, 2013;Wang et al, 2014;Colle et al, 2015;Xin et al, He et al, 2007 Various intronic deletions and insertions 29 bp from the exon 9-intron 9 junction BD Stopkova et al, 2003 FIGURE 1 | Shown are molecular interactions involving protein products of PIP4K2A and NRG1 associated with time to recurrence of an episode in bipolar disorder and antidepressant treatment response. Phospholipids phosphatidylinositol-5-phosphate (PI5P) and phosphatidylinositol-5,4-bisphosphate (PIP2) are located on the intracellular leaflet of the plasma membrane, while the channel KCNQ and the receptor ERBB4 are transmembrane.…”

The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy

“…In addition to various environmental, physiological, and psychological factors, these individual differences might be largely due to genetic factors [3,4]. Therefore, various pharmacogenetic studies have been conducted to identify genetic variants that can predict patients who may optimally benefit from specific, individually tailored treatments [5][6][7][8][9] (Figure 1).…”