Bernini de Brito Rodrigo, Ghedini Paulo César
Department of Pharmacology, Laboratory of Biochemistry and Molecular Pharmacology, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil.
Brain Institute, Bueno Medical Center, Goiânia, GO, Brazil.
Heliyon. 2020 May 30;6(5):e04015. doi: 10.1016/j.heliyon.2020.e04015. eCollection 2020 May.
Escitalopram (ESC), a selective serotonin reuptake inhibitor indicated for the treatment of depression and anxiety disorders, is primarily metabolized by cytochrome P450 (CYP) 2C19, which is a highly polymorphic enzyme known to cause inter-individual differences in pharmacokinetics. We hypothesized that CYP2C19 polymorphisms are associated with major depressive disorder (MDD) remission in patients treated with ESC in the long term. Thirty-one patients with MDD receiving chronic treatment with ESC monotherapy or combination therapy with other antidepressants (mirtazapine and bupropion), in naturalistic conditions, were included in the study. For comparison of genotype and phenotype frequencies, a group of 126 healthy subjects was also included. The CYP2C19∗2, CYP2C19∗3, and CYP2C19∗17 polymorphisms were analyzed by RFLP-PCR genotyping. The CYP2C19 genotypes and phenotypes were similar in patient and healthy subject groups. Four phenotypes were found in the healthy subject group: ultra-rapid (UM; 28%), extensive (EM; 52%), intermediate (IM; 17%), and poor metabolizers (PM; 3%). The patient group showed the UM (22.5%), EM (55%), and IM (22.5%) phenotypes. The UM patients had significantly higher ESC doses than both EM and IM patients (20.7 ± 4.5, 15.7 ± 3.8, and 14.0 ± 3.3 mg/day, respectively; p = 0.0041). Furthermore, all patients using ESC in combination with mirtazapine or bupropion antidepressants (ESC plus mirtazapine or bupropion) were UM metabolizers, suggesting that the ∗17 ultra-rapid allele seems to be the factor responsible for lower response to ESC, even at higher doses. The CYP2C19 UM phenotype is associated with higher ESC doses and antidepressant combinations for symptom remission in MDD patients.
艾司西酞普兰（ESC）是一种用于治疗抑郁症和焦虑症的选择性5-羟色胺再摄取抑制剂，主要通过细胞色素P450（CYP）2C19代谢，这是一种高度多态性的酶，已知会导致个体间药代动力学差异。我们假设，CYP2C19基因多态性与长期接受ESC治疗的抑郁症患者的缓解有关。本研究纳入了31例在自然条件下接受ESC单药治疗或与其他抗抑郁药（米氮平和安非他酮）联合治疗的抑郁症患者。为了比较基因型和表型频率，还纳入了一组126名健康受试者。通过限制性片段长度多态性聚合酶链反应（RFLP-PCR）基因分型分析CYP2C19∗2、CYP2C19∗3和CYP2C19∗17基因多态性。患者组和健康受试者组的CYP2C19基因型和表型相似。在健康受试者组中发现了四种表型：超快代谢型（UM；28%）、广泛代谢型（EM；52%）、中间代谢型（IM；17%）和慢代谢型（PM；3%）。患者组表现出UM（22.5%）、EM（55%）和IM（22.5%）表型。UM患者的ESC剂量显著高于EM和IM患者（分别为20.7±4.5、15.7±3.8和14.0±3.3mg/天；p = 0.0041）。此外，所有将ESC与米氮平或安非他酮抗抑郁药联合使用的患者（ESC加米氮平或安非他酮）都是UM代谢者，这表明∗17超快等位基因似乎是导致即使在高剂量下对ESC反应较低的因素。CYP2C19 UM表型与MDD患者症状缓解所需的较高ESC剂量和抗抑郁药联合使用有关。
