Bishop Jeffrey R, Najjar Fedra, Rubin Leah H, Guter Stephen J, Owley Thomas, Mosconi Matthew W, Jacob Suma, Cook Edwin H
aDepartment of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy bDepartment of Psychiatry, University of Minnesota College of Medicine, Minneapolis, Minnesota cDepartment of Psychiatry, University of Illinois at Chicago College of Medicine, Chicago, Illinois dDepartments of Psychiatry and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Pharmacogenet Genomics. 2015 Nov;25(11):548-54. doi: 10.1097/FPC.0000000000000173.
Selective serotonin reuptake inhibitors such as escitalopram are commonly used to treat patients with autism spectrum disorder (ASD), but there are individual differences in treatment response and tolerability. CYP2C19 encodes the primary enzyme responsible for escitalopram metabolism and we investigated whether polymorphisms in CYP2C19 were related to symptoms and dosing in a pharmacogenetic study of ASD.
Participants completed the Aberrant Behavior Checklist--Community Version (ABC-CV) weekly for 6 weeks. Escitalopram was initiated at a dose of 2.5 mg per day, with weekly increases to 20 mg unless intolerable side-effects occurred. Three CYP2C19 metabolizer groups, including ultrarapid, extensive, and reduced metabolizers, were examined in relation to symptom improvement and tolerated dose.
ABC-CV scores improved over the course of treatment (P<0.0001). No differences were identified in the rate of improvement across metabolizer groups for the ABC-CV irritability subscale, which was the primary outcome for clinical symptoms. There was a trend for a metabolizer group by time interaction with respect to dose (P=0.10). This interaction was driven by the linear rate of change from week 1 to study endpoint between the reduced metabolizers and ultrarapid metabolizer groups (P=0.05). Post-hoc analyses identified significant differences in the rate of dose escalation between ultrarapid metabolizers and extensive metabolizers and for ultrarapid metabolizers compared with reduced metabolizers (P's<0.04), whereby ultrarapid metabolizers showed a slower rate of change in dose over time.
CYP2C19 ultrarapid metabolizers were associated with reduced tolerance to a fixed titration schedule of open-label escitalopram in this ASD study sample. Possible explanations may involve the altered kinetics of faster metabolizers or previously unknown activities of escitalopram metabolites.
艾司西酞普兰等选择性5-羟色胺再摄取抑制剂常用于治疗孤独症谱系障碍（ASD）患者，但治疗反应和耐受性存在个体差异。CYP2C19编码负责艾司西酞普兰代谢的主要酶，我们在一项ASD药物遗传学研究中调查了CYP2C19基因多态性是否与症状及给药剂量有关。
参与者连续6周每周完成一次异常行为检查表社区版（ABC-CV）。艾司西酞普兰起始剂量为每日2.5毫克，除非出现无法耐受的副作用，每周增加至20毫克。研究了超快代谢型、广泛代谢型和慢代谢型这三种CYP2C19代谢型组与症状改善及耐受剂量的关系。
ABC-CV评分在治疗过程中有所改善（P<0.0001）。ABC-CV易激惹分量表（临床症状的主要指标）在各代谢型组间的改善率未发现差异。在剂量方面存在代谢型组与时间的交互作用趋势（P=0.10）。这种交互作用是由慢代谢型组与超快代谢型组从第1周到研究终点的线性变化率差异驱动的（P=0.05）。事后分析发现，超快代谢型组与广泛代谢型组之间以及超快代谢型组与慢代谢型组相比，剂量递增率存在显著差异（P<0.04），超快代谢型组随时间推移剂量变化率较慢。
在该ASD研究样本中，CYP2C19超快代谢型者对开放标签的艾司西酞普兰固定滴定方案耐受性降低。可能的解释包括代谢较快者的动力学改变或艾司西酞普兰代谢产物先前未知的活性。
