Hedenmalm Karin, Güzey Cüneyt, Dahl Marja-Liisa, Yue Qun-Ying, Spigset Olav
Clinical Trial Unit, Medical Products Agency, Uppsala, Sweden.
J Clin Psychopharmacol. 2006 Apr;26(2):192-7. doi: 10.1097/01.jcp.0000203200.96205.34.
Extrapyramidal symptoms (EPS) are rare adverse drug reactions to selective serotonin reuptake inhibitors (SSRIs). This study aimed to investigate the potential risk factors for EPS associated with SSRIs including polymorphisms of cytochrome P-450 isoenzymes, and serotonin and dopamine transporters and receptors.
All spontaneous adverse drug reaction reports received by the Swedish Medical Products Agency until December 1999 that were coded with EPS and judged to be at least possibly related to SSRI treatment were included in the study. Reporting physicians received a form for collection of relevant information including current and previous use of SSRIs and antipsychotics, alcohol or substance abuse, central nervous system damage, a history of epilepsy or EPS, and a family history of Parkinson disease. A blood sample was also requested for genotyping of selected cytochrome P-450, and serotonin and dopamine transporter and receptor mutations.
A total of 64 cases of EPS were reported. Twenty-eight forms (46%) were returned, and 20 blood samples were obtained. Identified potential risk factors included age of 65 years or older and the presence of the A1 allele of the D2 dopamine receptor gene (DRD2) Taq1A polymorphism (relative risk, 2.4; 95% confidence interval, 1.2-4.5 vs literature controls). No relationship was apparent for sex, drug dose, or other genetic polymorphisms. At least 1 additional potential risk factor for EPS, such as a history of central nervous system damage, alcohol or substance abuse, epilepsy, Parkinson disease, previous or current exposure to antipsychotic drugs, concomitant treatment with other antidopaminergic or serotonergic agents, or a history of EPS, was found in 93% of the cases.
The risk of EPS with SSRIs seems to increase with advanced age and with the presence of the A1 allele of DRD2 Taq1A polymorphism. Because of the small sample size of our study and the use of historical controls rather than patients who did not experience EPS during SSRIs treatment, the DRD2 finding is preliminary and needs to be replicated in other studies before firm conclusions can be drawn. At least 1 additional potential risk factor was found in almost all cases.
锥体外系症状（EPS）是选择性5-羟色胺再摄取抑制剂（SSRI）罕见的药物不良反应。本研究旨在调查与SSRI相关的EPS潜在风险因素，包括细胞色素P-450同工酶、5-羟色胺和多巴胺转运体及受体的多态性。
瑞典药品管理局截至1999年12月收到的所有自发药物不良反应报告，只要编码为EPS且判断至少可能与SSRI治疗有关，均纳入本研究。报告医生收到一份收集相关信息的表格，包括当前和既往使用SSRI和抗精神病药物情况、酗酒或药物滥用、中枢神经系统损伤、癫痫或EPS病史以及帕金森病家族史。还要求采集血样以对选定的细胞色素P-450、5-羟色胺和多巴胺转运体及受体突变进行基因分型。
共报告64例EPS。28份表格（46%）被退回，获得20份血样。确定的潜在风险因素包括65岁及以上年龄以及D2多巴胺受体基因（DRD2）Taq1A多态性的A1等位基因的存在（相对风险，2.4；95%置信区间，1.2 - 4.5，与文献对照相比）。性别、药物剂量或其他基因多态性方面未发现明显关系。在93%的病例中发现至少1个EPS的其他潜在风险因素，如中枢神经系统损伤史、酗酒或药物滥用、癫痫、帕金森病、既往或当前接触抗精神病药物、与其他抗多巴胺能或5-羟色胺能药物联合治疗或EPS病史。
使用SSRI时EPS的风险似乎随着年龄增长和DRD2 Taq1A多态性A1等位基因的存在而增加。由于本研究样本量小且使用历史对照而非在SSRI治疗期间未发生EPS的患者，DRD2的研究结果是初步的，在得出确切结论之前需要在其他研究中重复验证。几乎在所有病例中都发现至少1个其他潜在风险因素。
