Veterans Affairs (VA) Boston Healthcare System, Boston.
Harvard South Shore Psychiatry Residency Training Program, Brockton.
Curr Opin Psychiatry. 2018 Sep;31(5):403-408. doi: 10.1097/YCO.0000000000000440.
To examine recent literature regarding the pharmacogenomics of clozapine (CLZ) efficacy, pharmacokinetics, and agranulocytosis.
Several genetic loci (FKBP5, NR3C1, BDNF, NTRK2) along the hypothalamic pituitary adrenal axis have been investigated as targets for CLZ response. Homozygous FKBP5-rs1360780, homozygous NTRK2-rs1778929, and homozygous NTRK2-rs10465180 conferred significant risks for CLZ nonresponse - 2.11x risk [95% confidence interval (CI) 1.22-3.64], 1.7x risk (95% CI 1.13-2.59), and 2.15x risk (95% CI 1.3-3.55), respectively. BDNF and NR3C1 had no significant associations with CLZ response. Candidate genes within neurotransmitter pathways continue to be explored including dopaminergic (DRD1-4, COMT) and glutamatergic pathways (GRIN2B, SLC1A2, SLC6A9, GRIA1, GAD1). Despite promising trending data, no significant associations between CLZ response and glutamatergic system variants have been found. Synergistic effect of catecholamine O-methyltransferase (COMT) Met and dopamine receptor-4 (DRD4) single 120 bp duplicate associated with improved CLZ response odds ratio (OR) 0.15 (95% CI 0.03-0.62) while COMT Val/Val confer a risk of CLZ nonresponse OR 4.34 (95% CI 0.98-23.9). Diagnostic performance testing continues through human leukocyte antigen (HLA) and other genetic loci but have yet to find statistically or clinically meaningful results.
Current landscape of pharmacogenomic research in CLZ continues to be limited by small sample sizes and low power. However, many promising candidate genes have been discovered and should be further investigated with larger cohorts.
研究氯氮平（CLZ）疗效、药代动力学和粒细胞缺乏症的遗传药理学。
沿着下丘脑-垂体-肾上腺轴的几个遗传位点（FKBP5、NR3C1、BDNF、NTRK2）已被研究为 CLZ 反应的靶点。FKBP5-rs1360780 纯合子、NTRK2-rs1778929 纯合子和 NTRK2-rs10465180 纯合子与 CLZ 无反应显著相关-2.11 倍风险（95%CI1.22-3.64）、1.7 倍风险（95%CI1.13-2.59）和 2.15 倍风险（95%CI1.3-3.55）。BDNF 和 NR3C1 与 CLZ 反应无显著相关性。神经递质通路中的候选基因仍在探索中，包括多巴胺能（DRD1-4、COMT）和谷氨酸能通路（GRIN2B、SLC1A2、SLC6A9、GRIA1、GAD1）。尽管有有希望的趋势数据，但尚未发现 CLZ 反应与谷氨酸能系统变异之间存在显著关联。儿茶酚-O-甲基转移酶（COMT）Met 和多巴胺受体-4（DRD4）单 120bp 重复的协同作用与改善 CLZ 反应优势比（OR）0.15（95%CI0.03-0.62）相关，而 COMT Val/Val 则具有 CLZ 无反应的风险 OR4.34（95%CI0.98-23.9）。诊断性能测试仍在通过人类白细胞抗原（HLA）和其他遗传位点进行，但尚未发现具有统计学或临床意义的结果。
CLZ 遗传药理学研究的当前格局仍然受到样本量小和效能低的限制。然而，已经发现了许多有前途的候选基因，应该用更大的队列进一步研究。
