“点击蓝字 关注我们赵雪毕业于上海交通大学医学院。上海市精神卫生中心主治医师、上海市精神心理疾病临床医学研究中心秘书。主要研究方向为精神药物遗传药理学。主持上海市精神卫生中心院级课题、上海交通大学“医工交叉”等科研项目多项。作为主要研究人员参与国家自然科学基金、上海市申康医院发展中心“促进市级医院临床技能与临床创新三年行动计划”等多项纵向科研课题。作为研究骨干参与多项国际多中心和国内多中心(牵头)临床试验。以第一(含共一)作者发表多篇中英文学术论文。 抗精神病药、抗抑郁药与不宁腿综合征 PPS 郭瑛睿1,钱瑞仪1,禹顺英2,沈一峰3,赵雪3*(1.上海交通大学医学院附属精神卫生中心精神科,上海 200030;2.上海交通大学医学院附属精神卫生中心遗传室,上海 200030;3.上海交通大学医学院附属精神卫生中心临床研究中心,上海 200030)[摘要] 不宁腿综合征(restless legs syndrome,RLS)是抗精神病药和抗抑郁药的常见不良反应之一,影响患者夜间睡眠、加重精神症状、降低患者生活质量,但其在临床实践尚未受到广泛重视。针对抗精神病药和抗抑郁药的 RLS 发生风险,这两类药物导致 RLS 的可能机制及相关治疗手段进行综述,以期为 RLS 的临床治疗提供参考。 不宁腿综合征(restless legs syndrome,RLS)又称不安腿综合征,是临床常见的运动感觉性神经系统疾病,主要表现为强烈、迫切想要移动肢体的冲动或欲望,常常伴随着肢体深处不舒服或难以描述的感觉,夜间睡眠或安静时出现或加重,具有昼夜节律性,按摩或活动后缓解,可导致严重睡眠障碍。在《精神障碍诊断与统计手册(第 5 版)》(the fifith edition of the diagnostic and statistical manual of mental disorders,DSM-5)中, RLS属于睡眠-觉醒障碍中异常睡眠的一类疾病。一般人群中RLS的发病率为 3%~19%,女性发病率更高[1],其中约有2.5%的患者症状严重到需要接受医疗干预[2]。根据病因不同,RLS可分为原发性和继发性2种类型。原发性RLS通常在40岁之前发病,主要与遗传因素有关。继发性RLS伴发于各类躯体疾病,如神经系统疾病、铁缺乏症、慢性肾功能衰竭、糖尿病、自身免疫性疾病、甲状腺疾病、血管疾病、精神疾病等[1, 3-4]。RLS也是精神类药物的不良反应之一。据报道,抗精神病药、抗抑郁药和抗癫痫药是引起RLS最常见的3类药物[1]。早在1999年,1例病案报告指出奥氮平可能导致RLS[5],此后越来越多的精神类药物被报道能够诱发RLS这一不良反应,不同药物发生RLS的风险有所不同。如上所述,引起RLS的精神类药物主要为抗精神病药及抗抑郁药,故本文主要针对抗精神病药和抗抑郁药引起RLS的发生风险,这两类药物导致RLS的可能机制及相关治疗手段进行综述。1抗精神病药、抗抑郁药与不宁腿综合征 Elrassas等[6]开展的横断面研究结果显示,200名接受抗抑郁药和抗精神病药治疗的患者中,服用第1代抗精神病药(除氟哌啶醇外)的患者发生RLS比 例最高(58.7%),其次是选择性5-羟色胺再摄取抑制剂(selective serotonin reuptake inhibitors,SSRIs)类药物(52.6%)和阿立哌唑(46.4%),接受曲唑酮(24.2%)和氟哌啶醇(31%)治疗的患者发生RLS可能性最小。 1.1 抗精神病药与不宁腿综合征有研究结果显示,与对照组(9.3%)相比,接受抗精神病药治疗的精神分裂症患者发生RLS的概率(21.4%)明显更高[7]。在各类抗精神病药中,奥氮平、喹硫平和氯氮平引起RLS的报道最多[1],利培酮、鲁拉西酮等药物引起RLS的报道相对较少(见表1[5,8-29])。也有部分研究结果显示,喹硫平和阿立哌唑能够改善其他抗精神病药引起的RLS症状[11,30],可能是因为相对于多巴胺D2受体,这2种药物对5-羟色胺(5-hydroxytryptamine,5-HT)受体具有更高亲和力。另有研究报道,抗精神病药与抗抑郁药联用,如喹硫平与文拉法辛[31] 或帕罗西汀[18] 联用会导致RLS,停用2种药物中的一种会改善RLS症状。1.2 抗抑郁药与不宁腿综合征在多种抗抑郁药中,SSRIs、5-HT和去甲肾上腺素再摄取抑制剂( serotonin-norepinephrine reuptake inhibitors,SNRIs)、四环类非典型抗抑郁药米氮平导致RLS的报道较多(见表2[32-46])。Cetin Erdem 等[47]报道,在198名接受4~8周SSRIs/SNRIs药物治疗的门诊患者中,RLS的发生率为25%。与女性相比,男性使用抗抑郁药后发生RLS的风险增加[48]。Kolla等[49]报道,在各种抗抑郁药中,米氮平可能与较高的RLS发生率有关,也会恶化患者原有的RLS症状[50],其次是文拉法辛,而安非他酮可能会减轻RLS症状。当联合使用2种或2种以上药物时,如氟西汀与米氮平联用[51]、帕罗西汀与度洛西汀联用[52]、艾司西酞普兰与锂盐或喹硫平联用[53],患者发生RLS的风险也会相应增加。关于新型抗抑郁药伏硫西汀是否增加RLS风险的研究结果并不一致,有研究发现其可减轻RLS症状[54-55],但也有研究报道伏硫西汀可诱发RLS[45]。2抗精神病药、抗抑郁药引起不宁腿综合征的可能机制2.1 多巴胺功能紊乱既往神经影像学研究表明,RLS患者脑内存在多巴胺能活性低下表现[56]。RLS包括运动和感觉异常两个维度的症状表现,感觉和运动回路受脊髓投射至大脑的相关区域控制,这些区域与不同神经递质有关,包括背区(5-HT)、丘脑区(去甲肾上腺素)和下丘脑后方的A11区(多巴胺)[57]。多巴胺受体激动剂是治疗RLS的一线药物,多巴胺拮抗剂(如抗精神病药)则会诱发RLS,提示多巴胺活性在RLS中的重要作用。抗精神病药与抗抑郁药增加RLS风险的具体机制目前尚不明确,多巴胺能活性降低被认为可能是抗精神病药诱发RLS的主要原因。阿立哌唑为多巴胺(D2、D3、D4)受体部分激动剂,正电子发射断层显像(positron emission tomography,PET)研究表明在治疗剂量下阿立哌唑受体占有率为95%[58],阿立哌唑通过激动多巴胺受体改善RLS症状,该效果与罗匹尼罗和普拉克索等多巴胺受体激动剂相似。然而,与其他非典型抗精神病药物(如利培酮)相比,氯氮平和喹硫平的D2受体占有率较低,如果多巴胺功能降低能够诱发RLS,这些药物诱发RLS的可能性应该较小,这与多数研究报道不符。另有研究者认为,喹硫平因其镇静催眠作用,常在夜间使用可改善患者睡眠,而夜间多巴胺受体敏感性较白天增加[59];另外,喹硫平常被用来与抗抑郁药(如SSRIs、米氮平等)合用改善情感症状,而抗抑郁药能够通过增加5-HT功能减少多巴胺释放 [60],增加RLS发生风险。此外,有研究表明泌乳素(prolactin,PRL)水平可能在抗精神病药所致 RLS中起重要作用。多巴胺受体激动剂如左旋多巴和卡麦角林能够降低泌乳素水平,这2种药物均可以治疗RLS[61]。抗精神病药(如利培酮、奥氮平)能够增加PRL水平[62],可能是引起RLS症状的间接原因。阿立哌唑可以降低抗精神病药引起的高泌乳素血症[63],可能是阿立哌唑能够缓解RLS症状的另一原因 [23]。2.2 铁缺乏有研究发现,RLS患者脑脊液中铁蛋白含量减少[64] 及转铁蛋白含量升高;脑影像学研究也发现,RLS患者大脑中铁含量减少[65];RLS患者尸检脑神经胶质细胞中铁含量较低[66]。外周铁水平正常的RLS患者补充铁剂也能改善RLS症状,可能是因为血脑屏障使大脑中铁水平独立于外周铁水平[67]。此外,脑内铁水平降低也会导致多巴胺代谢和D2受体状态改变,尤其是在黑质和壳核区域[9]。目前有研究发现,抗精神病药能够影响体内铁稳态[68]和肝脏铁代谢[69],引起低铁血症。目前仍缺乏直接证据表明使用抗精神病或抗抑郁药出现RLS的患者是否存在外周或中枢铁代谢异常,仍需更多研究证据来明确这一可能机制。 2.3 遗传因素遗传因素是RLS的重要致病因素,大部分家族性RLS呈常染色体显性遗传,少数家族则呈常染色体隐性遗传或非孟德尔遗传模式[70]。既往遗传学研究多集中于原发性 RLS,全基因组关联研究发现位于不同染色体的 RLS 风险基因,包括BTBD9基因(位于染色体6p21)、MEIS1基因(位于染色体2p14)、PTPRD 基因(位于染色体9p24.1-p23)、MAP2K5/SKOR1 基因(位于染色体15q23)和TOX3/BC034767 基因(位于染色体 16q12.1)[71]。近期有研究发现7个全新的RLS易感基因位点:RLS1(位于染色体12q12-q21)、RLS2(位于染色体 14q13-q21)、RLS3(位于染色体 9p24-p22)、RLS4( 位 于 染 色 体 2q33)、RLS5( 位 于 染 色 体20p13)、RLS6(位于染色体 19p13)及RLS7(位于染色体16p12.1)[72-73]。截至目前,抗精神病药或抗抑郁药所致RLS的遗传学研究仍较少。有研究发现,MAOA基因VNTR与MAOB基因A644g多态的单倍型频率与抗精神病药引起RLS严重程度有关[74]。另一项研究显示,MAP2K5基因多态性增加了抗精神病药物诱发RLS的风险[75]。3抗精神病药、抗抑郁药引起不宁腿综合征的治疗RLS的治疗分为非药物治疗和药物治疗。非药物治疗包括:消除或减少继发性因素的影响,如尽量避免使用能够诱发或加重RLS的药物(如多巴胺受体拮抗剂、抗抑郁药、抗组胺药等);保持良好的睡眠卫生习惯;加强体育锻炼;结合物理治疗(如重复经颅磁刺激、重复经颅电刺激)等。药物治疗包括:多巴胺激动剂(如罗匹尼罗、罗替戈汀、普拉克索),α2δ钙通道配体类药物(如普瑞巴林、加巴喷汀-恩那卡比、加巴喷汀),这些药物均为治疗RLS的一线用药 [76],也可使用苯二氮䓬类镇静药[77] 和抗癫痫药[78] 等。治疗抗精神病药或抗抑郁药引起的RLS具有一定挑战性,目前仍缺乏高水平临床研究或相关指南指导医生用药。在既往相关病例报道中,临床医生一般采取减量或停用现用药物,加用多巴胺受体激动剂或α2δ钙通道配体类药物(具体病例处理方式可参考表1和表2),上述策略均能够有效改善患者RLS症状。值得注意的是,多巴胺受体激动剂和α2δ钙通道配体类药物可能会导致患者精神症状波动或病情复发。在既往病案报道中,加用小剂量阿立哌唑也是改善 RLS症状的常用手段,阿立哌唑剂量为1~10 mg·d-1[23,30],在临床实践中医生可根据患者具体情况探索使用阿立哌唑的剂量。铁缺乏是RLS病理生理学中重要假说之一。在患者出现RLS症状后,医生可以通过相关检测指标(包括铁蛋白、转铁蛋白、血清铁、总铁结合力、转铁蛋白饱和度等)评估患者外周铁储存情况。如果患者确实存在缺铁表现,可采用铁替代疗法,如口服硫酸亚铁,若患者不能耐受或有效吸收口服铁剂,也可考虑静脉补铁,同时补充维生素C有助于促进消化道对铁的吸收[76]。在补充铁剂后,需动态观察患者RLS症状改善和评估外周铁相关指标变化。4结语 精神障碍患者常合并睡眠障碍,而RLS会进一步加重患者睡眠问题,同时伴有强烈心理不适感。此外,RLS能够增加肥胖、抑郁症、焦虑症、高血压及其他心血管疾病的发生风险,显著降低患者生活质量、延缓患者康复[79]。Cetin Erdem等[47]的研究显示,服用抗抑郁药发生RLS的患者生活质量显著下降。一项回顾性队列研究发现,自杀和自残风险与RLS呈正相关[80]。尽管在临床实践中,使用抗精神病药或抗抑郁药后出现RLS的病例并不少见,但与其他药物不良反应(如心血管不良反应、代谢综合征等)相比,RLS仍未得到有效识别和广泛重视。尤其在患者用药后出现新发睡眠问题时,不能简单地归结为疾病症状的一部分,应仔细识别是否存在RLS的可能性。目前关于精神类药物引起RLS的各方面研究仍较少,后续需要更多关注和探索,从而更好地为患者及临床服务。参考文献:[1]Patatanian E, Claborn M K. Drug-induced restless legs syndrome[J]. Ann Pharmacother, 2018, 52(7): 662-672.[2]Yeh P, Walters A S, Tsuang J W. Restless legs syndrome: a comprehensive overview on its epidemiology, risk factors, and treatment[J]. Sleep Breath, 2012, 16(4): 987-1007.[3]Dunvald A D, Henriksen D P, Hallas J, et al. Selective serotonin reuptake inhibitors and the risk of restless legs syndrome: a symmetry analysis[J]. Eur J Clin Pharmacol, 2020, 76(5): 719-722.[4]Lin S, Zhang H, Gao T, et al. The association between obesity and restless legs syndrome: a systemic review and meta-analysis of observational studies[J]. J Affect Disord, 2018, 235: 384-391.[5]Kraus T, Schuld A, Pollmächer T. Periodic leg movements in sleep and restless legs syndrome probably caused by olanzapine[J]. J Clin Psychopharmacol, 1999, 19(5): 478-479.[6] Elrassas H H, Elsayed Y A R, Abdeen M S, et al. Restless legs syndrome among patients receiving antipsychotic and antidepressant drugs[J]. Hum Psychopharmacol, 2022, 37(2): e2817.[7]Kang S G, Lee H J, Jung S W, et al. Characteristics and clinical correlates of restless legs syndrome in schizophrenia[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2007, 31(5): 1078-1083.[8] Das S, Prasad S, Anand A, et al. Olanzapine-induced restless leg syndrome (Willis-Ekbom disease): a case report[J]. SAGE Open Med Case Rep, 2022, 10: 2050313X221145583.[9]Basu A, Kundu S, Khurana H. Olanzapine-induced restless leg syndrome: a case report and review of literature[J]. Indian J Pharmacol, 2014, 46(4): 450-452.[10] Zhao M, Geng T, Qiao L, et al. Olanzapine-induced restless legs syndrome[J]. J Clin Neurosci, 2014, 21(9): 1622-1625.[11] Aggarwal S, Dodd S, Berk M. Restless leg syndrome associated with olanzapine: a case series[J]. Curr Drug Saf, 2010, 5(2): 129-131.[12] Khalid I, Rana L, Khalid T J, et al. Refractory restless legs syndrome likely caused by olanzapine[J]. J Clin Sleep Med, 2009, 5(1): 68-69.[13] Kang S G, Lee H J, Kim L. Restless legs syndrome and periodic limb movements during sleep probably associated with olanzapine[J]. J Psychopharmacol, 2009, 23(5): 597-601.[14] Soyata A Z, Celebi F, Yargc L I. Restless legs syndrome after single low dose quetiapine administration[J]. Curr Drug Saf, 2016, 11(2): 172-173.[15] Vohra A. Quetiapine induced restless legs syndrome: a series of four cases[J]. Asian J Psychiatr, 2015, 16: 73-74.[16] Rittmannsberger H, Werl R. Restless legs syndrome induced by quetiapine: report of seven cases and review of the literature[J]. Int J Neuropsychopharmacol, 2013, 16(6): 1427-1431.[17] Webb J. Co-occurring akathisia and restless legs syndrome likely induced by quetiapine[J]. J Neuropsychiatry Clin Neurosci, 2012, 24(2): E46-E47.[18] Chou K J, Chen P Y, Huang M C. Restless legs syndrome following the combined use of quetiapine and paroxetine[J].Prog Neuropsychopharmacol Biol Psychiatry, 2010, 34(6): 1139-1140.[19] Urbano M R, Ware J C. Restless legs syndrome caused by quetiapine successfully treated with ropinirole in 2 patients with bipolar disorder[J]. J Clin Psychopharmacol, 2008, 28(6): 704-705.[20] Pinninti N R, Mago R, Townsend J, et al. Periodic restless legs syndrome associated with quetiapine use: a case report[J]. J Clin Psychopharmacol, 2005, 25(6): 617-618.[21] Kumar V, Venkatasubramanian G. Gabapentin treatment in clozapineinduced restless legs syndrome: two cases and a review of the literature[J]. Ther Adv Psychopharmacol, 2017, 7(1): 42-47.[22] John A P, Adriana S, La’Brooy J A, et al. Successful treatment of clozapine-associated restless leg syndrome with pramipexole[J]. J Clin Psychopharmacol, 2014, 34(6): 764-766.[23]Raveendranathan D, Shiva L, Venkatasubramanian G, et al.Clozapine-induced restless legs syndrome treated with aripiprazole[J]. J Neuropsychiatry Clin Neurosci, 2013, 25(2): E62-E63.[24] Chathanchirayil S J. Restless legs syndrome probably due to clozapine[J]. Aust N Z J Psychiatry, 2011, 45(11): 1005-1006.[25] Duggal H S, Mendhekar D N. Clozapine-associated restless legs syndrome[J]. J Clin Psychopharmacol, 2007, 27(1): 89-90.[26] Bolaños-Vergaray J, Obaya J C, Gonzalez R, et al. Restless legs syndrome due to aripiprazole[J]. Eur J Clin Pharmacol, 2011, 67(5): 539-540.[27] Ghori A K, Sajatovic M, Tampi R R. A case of emergent restless legs syndrome with lurasidone therapy[J]. J Clin Psychopharmacol, 2016, 36(3): 293-294.[28] Wetter T C, Brunner J, Bronisch T. Restless legs syndrome probably induced by risperidone treatment[J]. Pharmacopsychiatry, 2002, 35(3): 109-111.[29] Zhu C, Bi R, Hu Y, et al. Restless legs syndrome following the use of ziprasidone: a case report[J]. Gen Psychiatr, 2020, 33(2): e100112.[30] Lee E K, Spitale N, Robillard R. Aripiprazole, a novel option in the management of restless legs syndrome (RLS) patients with augmentation and/or severe RLS symptoms: a report of 4 cases[J]. Nat Sci Sleep, 2023, 15: 779-784.[31] Michopoulos I, Ferentinos P, Oulis P, et al. Restless legs syndrome associated with the combined use of quetiapine and venlafaxine[J]. J Clin Psychopharmacol, 2014, 34(1): 159-161.[32] Makiguchi A, Nishida M, Shioda K, et al. Mirtazapine-induced restless legs syndrome treated with pramipexole[J]. J Neuropsychiatry Clin Neurosci, 2015, 27(1): e76.[33] Chopra A, Pendergrass D S, Bostwick J M. Mirtazapine-induced worsening of restless legs syndrome (RLS) and ropinirole-induced psychosis: challenges in management of depression in RLS[J]. Psychosomatics, 2011, 52(1): 92-94.[34] Park Y M, Lee H J, Kang S G, et al. Resolution of pregabalin and mirtazapine associated restless legs syndrome by bupropion in a patient with major depressive disorder[J]. Psychiatry Investig, 2009, 6(4): 313-315.[35] Pae C U, Kim T S, Kim J J, et al. Re-administration of mirtazapine could overcome previous mirtazapine- associated restless legs syndrome [J]. Psychiatry Clin Neurosci, 2004, 58(6): 669-670.[36] Ağargün M Y, Kara H, Ozbek H, et al. Restless legs syndrome induced by mirtazapine[J]. J Clin Psychiatry, 2002, 63(12): 1179.[37] Bahk W M, Pae C U, Chae J H, et al. Mirtazapine may have the propensity for developing a restless legs syndrome? A case report[J]. Psychiatry Clin Neurosci, 2002, 56(2): 209-210.[38] Hargrave R, Beckley D J. Restless leg syndrome exacerbated by sertraline[J]. Psychosomatics, 1998, 39(2): 177-178.[39] Oztürk O, Eraslan D, Kumral E. Oxcarbazepine treatment for paroxetine-induced restless leg syndrome[J]. Gen Hosp Psychiatry, 2006, 28(3): 264-265.[40] Sanz-Fuentenebro F J, Huidobro A, Tejadas-Rivas A. Restless legs syndrome and paroxetine[J]. Acta Psychiatr Scand, 1996, 94(6): 482- 484.[41] Bakshi R. Fluoxetine and restless legs syndrome[J]. J Neurol Sci,1996, 142(1/2): 151-152.[42] Nader P, Coralie L, Baleydier B, et al. Restless legs syndrome induced by citalopram: a psychiatric emergency[J]. Gen Hosp Psychiatry, 2007, 29(1): 72-74.[43] Page R L 2nd, Ruscin J M, Bainbridge J L, et al. Restless legs syndrome induced by escitalopram: case report and review of the literature[J]. Pharmacotherapy, 2008, 28(2): 271-280.[44] Yilbaş B. Restless legs syndrome due to the use of trazodone: a case report[J]. Turk Psikiyatri Derg, 2022, 33(1): 70-72.[45] Romigi A, Vitrani G, Caccamo M, et al. Restless legs syndrome related to vortioxetine: a case report[J]. J Clin Psychopharmacol, 2019, 39(5): 514-516.[46] Abdul Karim M, Al-Baz N, Ouanes S, et al. Suspected agomelatineinduced restless legs syndrome: a case report[J]. BMC Psychiatry, 2021, 21(1): 180.[47] Cetin Erdem H, Kara H, Ozcelik O, et al. Frequency, risk factors,and impacts on quality of life of the restless legs syndrome and side effects among antidepressant users in a tertiary hospital: an observational cross-sectional study[J]. Int Clin Psychopharmacol, 2023, 38(4): 209-215.[48] Odabaş F Ö, Uca A U. Is there any association between antidepressants and restless legs syndrome in a large Turkish population receiving mono or combined treatment? A cross-sectional comparative study[J]. Psychiatry Clin Psychopharmacol, 2019, 29(4): 565-569.[49] Kolla B P, Mansukhani M P, Bostwick J M. The influence of antidepressants on restless legs syndrome and periodic limb movements: a systematic review[J]. Sleep Med Rev, 2018, 38: 131- 140.[50] Teive H A G, de Quadros A, Barros F C, et al. Worsening of autosomal dominant restless legs syndrome after use of mirtazapine: case report[J]. Arq Neuropsiquiatr, 2002, 60(4): 1025-1029.[51] Prospero-Garcia K A, Torres-Ruiz A, Ramirez-Bermudez J, et al. Fluoxetine-mirtazapine interaction may induce restless legs syndrome: report of 3 cases from a clinical trial[J]. J Clin Psychiatry, 2006, 67(11): 1820.[52] Nikolaou K N, Michopoulos I, Douzenis A, et al. Restless legs syndrome associated with the combined use of duloxetine plus paroxetine[J]. J Clin Psychopharmacol, 2015, 35(3): 345-346.[53] Chen P H. Restless leg syndrome induced by escitalopram and lithium combined with quetiapine treatment in bipolar II disorder: a case report[J]. Clin Neuropharmacol, 2016, 39(2): 118-119.[54] Alıcı Y H, Kumcu M K. Potential effect of vortioxetine on restless leg syndrome[J]. Clin Psychopharmacol Neurosci, 2023, 21(3): 599-603.[55] Yılbas B. The use of vortioxetine in major depression disorder accompanying restless legs syndrome: a case report[J]. Arch Neuropsychiatry, 2022: 27827.[56] Cervenka S, Pålhagen S E, Comley R A, et al. Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding[J]. Brain, 2006, 129(Pt 8): 2017-2028[57] Kocar T D, Müller H P, Kassubek J. Differential functional connectivity in thalamic and dopaminergic pathways in restless legs syndrome: a meta-analysis[J]. Ther Adv Neurol Disord, 2020, 13: 1756286420941670.[58] Grunder G, Carlsson A, Wong D F. Mechanism of new antipsychotic medications: occupancy is not just antagonism[J]. Arch Gen Psychiatry, 2003, 60(10): 974-977.[59] Garcia-Borreguero D, Larrosa O, Granizo J J, et al. Circadian variation in neuroendocrine response to L-dopa in patients with restless legs syndrome[J]. Sleep, 2004, 27(4): 669-673.[60] Zhou F M, Liang Y, Salas R, et al. Corelease of dopamine and serotonin from striatal dopamine terminals[J]. Neuron, 2005, 46(1): 65-74.[61] Trenkwalder C, Benes H, Grote L, et al. Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: results from a multi-center, randomized, active controlled trial[J]. Mov Disord, 2007, 22(5): 696-703.[62] Koch M T, Carlson H E, Kazimi M M, et al. Antipsychotic-related prolactin levels and sexual dysfunction in mentally ill youth: a 3-month cohort study[J]. J Am Acad Child Adolesc Psychiatry, 2023, 62(9): 1021-1050.[63] Jiang Q, Li T, Zhao L, et al. Treatment of antipsychotic-induced hyperprolactinemia: an umbrella review of systematic reviews and meta-analyses[J]. Front Psychiatry, 2024, 15: 1337274.[64] Clardy S L, Earley C J, Allen R P, et al. Ferritin subunits in CSF are decreased in restless legs syndrome[J]. J Lab Clin Med, 2006, 147(2): 67-73.[65] Allen R P, Barker P B, Wehrl F W, et al. MRI measurement of brain iron in patients with restless legs syndrome[J]. Neurology, 2001, 56(2): 263-265.[66] Connor J R, Boyer P J, Menzies S L, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome[J]. Neurology, 2003, 61(3): 304-309.[67] Yu P, Chang Y Z. Brain iron metabolism and regulation[J]. Adv Exp Med Biol, 2019, 1173: 33-44.[68] Schoretsanitis G, Nikolakopoulou A, Guinart D, et al. Iron homeostasis alterations and risk for akathisia in patients treated with antipsychotics: a systematic review and meta-analysis of crosssectional studies[J].Eur Neuropsychopharmacol, 2020, 35: 1-11.[69] May M, Barlow D, Ibrahim R, et al. Mechanisms underlying antipsychotic-induced NAFLD and iron dysregulation: a multi-omic approach[J]. Biomedicines, 2022, 10(6): 1225.[70] Jiménez-Jiménez F J, Alonso-Navarro H, García-Martín E, et al.Genetics of restless legs syndrome: an update[J]. Sleep Med Rev, 2018, 39: 108-121.[71] Akçimen F, Sarayloo F, Liao C, et al. Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes[J]. Commun Biol, 2020, 3(1): 373.[72] Estiar M A, Senkevich K, Yu E, et al. Lack of causal effects or genetic correlation between restless legs syndrome and Parkinson’s disease[J]. Mov Disord, 2021, 36(8): 1967-1972.[73] Lin W S. The conundrum of the origin of restless legs syndrome[J].Sleep, 2022, 45(5): zsac018.[74] Kang S G, Park Y M, Choi J E, et al. Association study between antipsychotic-induced restless legs syndrome and polymorphisms of monoamine oxidase genes in schizophrenia[J]. Human Psychopharmacology, 2010, 25(5): 397-403.[75] Kang S G, Lee Y J, Park Y M, et al. Haplotype association of the MAP2K5 gene with antipsychotics-induced symptoms of restless legs syndrome among patients with schizophrenia[J]. Psychiatry Investig, 2018, 15(1): 84-89.[76] Liu Z, Guan R, Pan L. Exploration of restless legs syndrome under the new concept: a review[J]. Medicine (Baltimore), 2022, 101(50): e32324.[77] Walters A S, Spruyt K, Ba D M, et al. A historical overview of the role of benzodiazepines including clonazepam in the treatment of adult restless legs syndrome and periodic limb movements in sleep[J]. Tremor Other Hyperkinet Mov (N Y), 2024, 14: 21.[78] Al-Kassmy J, Alsalmi M, Kang W, et al. Anticonvulsant agents for treatment of restless legs syndrome: a case report with lamotrigine and a review of the literature[J]. Neurologist, 2024, 29(3): 173- 178.[79] Shen Y, Liu H, Dai T, et al. Association between restless legs syndrome and hypertension: a meta-analysis of nine population-based studies[J]. Neurol Sci, 2018, 39(2): 235-242.[80] Zhuang S, Na M, Winkelman J W, et al. Association of restless legs syndrome with risk of suicide and self-harm[J]. JAMA Netw Open, 2019, 2(8): e199966.美编排版:覃冰冰感谢您阅读《药学进展》微信平台原创好文,也欢迎各位读者转载、引用。本文选自《药学进展》2025年第 6 期。《药学进展》杂志由教育部主管、中国药科大学主办,中国科技核心期刊(中国科技论文统计源期刊)。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨,以综述、评述、行业发展报告为特色,以药学学科进展、技术进展、新药研发各环节技术信息为重点,是一本专注于医药科技前沿与产业动态的专业媒体。《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色;特别是医药信息内容以科学前沿与国家战略需求相合,更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据,刊物篇均下载率连续三年蝉联我国医药期刊榜首,复合影响因子1.216,具有较高的影响力。《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编,编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。联系《药学进展》↓↓↓编辑部官网:pps.cpu.edu.cn;邮箱:yxjz@163.com;电话:025-83271227。欢迎投稿、订阅!往期推荐聚焦“兴药为民·2023生物医药创新融合发展大会”“兴药为民·2023生物医药创新融合发展大会”盛大启幕!院士专家齐聚杭城,绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官!校企合作新旅程已启航我知道你在看哟