精神科治疗药物监测的现状及发展方向

中国精神科治疗药物监测的

现状及发展方向2前言自氯丙嗪的抗精神病作用被发现60年来，已经上市的精神药物已经达到130余种。这些药物在精神疾病或症候群的治疗或缓解方面正在发挥愈来愈重要的作用。如何选好、用好精神药物，保证精神疾病药物治疗的有效性和安全性是精神科面临的一个重要问题。治疗药物监测是实现精神疾病的个体化精准药物治疗的重要手段。3对精神药物实施TDM的必要性精神疾病多属慢性病，需要长期用药，而且精神药物的不良反应较多；精神药物在药动学上的个体差异明显，相同剂量的血浓度可相差几倍到几十倍；起效时间长，通常给药2~4周后起效；疗效指标不够简明，且受医生主观因素影响；精神病患者的服药依从性差；中毒反应可隐匿性出现，且不易与疾病本身症状的加重相区别；血药浓度与疗效和毒副作用相关，过高或过低疗效均不好。BenefitsofTDMinPsychiatrydosagetitrationadversereactionandintoxication(overdose)identificationpharmacogeneticparticularityevaluationdruginteractionevaluationrelapsepreventionpatient’scomplianceassessment45需要进行TDM的药物种类抗抑郁药物三环类抗抑郁药新型抗抑郁药抗精神病药传统抗精神病药非典型抗精神病药情感稳定剂碳酸锂、丙戊酸、卡马西平、拉莫三嗪戒毒药及其它6精神药物TDM必要性的等级划分最应该监测的药物（15种）锂盐、阿米替林（去甲替林）、丙咪嗪（去甲丙咪嗪）、氯丙咪嗪（去甲氯丙咪嗪）、去甲替林、氟哌啶醇、奋乃静、氟奋乃静、甲硫哒嗪、甲哌丙嗪、氨磺必利、氯氮平（去甲氯氮平）、奥氮平、苯巴比妥、苯妥英钠应该监测的药物（52种）多虑平（去甲多虑平）、麦普替林、西酞普兰、氟西汀（去甲氟西汀）、舍曲林、文拉法辛（o-去甲文拉法辛）、曲唑酮、度洛西汀、米氮平、依他普仑、米那普仑、氯丙嗪、舒必利、利培酮（9-羟利培酮）、喹硫平、舍吲哚、溴哌利多、阿立哌唑、齐拉西酮、氟哌噻吨、卡马西平、拉莫三嗪、丙戊酸、美沙酮等监测有用的药物（44种）潜在有用的药物（19种）HistoryofTDMinChinavd.HELMHJ,ANDRIESSED.ClinChimActa.1961;6:747-748.王见义;吴贞喜;葛志荣.

神经精神疾病杂志1980(05):

276-278陈刚;卓海通.中国医院药学,1983(2):12-14吴莱文.中国临床药理学杂志,19862(3):151-157196119801983中国大陆精神科TDM现状调查调查范围：中国大陆地区三级精神病专科医院、省（市）级精神卫生中心调查时间：2010年6月-12月数据采集时间：2009年调查者：北京安定医院临床精神药理实验室论文发表：中国新药杂志，2013年，22(11):1347-1352TherDrugMonit,December2013,35(6):816-8228910主要调查内容basicinformationofthefacilityTDMrequestformsresultinterpretationtypesofpsychotropicdrugsmonitoredandannualworkloadsanalyticalmethodsinternalqualitycontrolandexternalqualityassessment11问卷发放及回收情况12有效问卷的地理分布图13监测项目及年样本检测量14ThestatusofanalyticalmethodsLithium32ionselectiveelectrode(ISE)25theatomicabsorptionspectrometry(AAS)2atomicemissionspectrometry(AES)2flamephotometryassay(FPA)2ValproicAcid7fluorescencepolarizationimmunoassay2enzymeimmunoassay2chemiluminescence2reversedphaseliquidchromatographymethod115ThestatusofanalyticalmethodsOtherPsychotropicDrugsHighperformanceliquidchromatography(HPLC)withdifferentdetectorssingle-wavelengthUVdetector20diodearraydetector4fluorescencedetector2Amperometricelectrochemicaldetector2Coulometricelectrochemicaldetector3Evaporativelight-scatteringdetector1HPLC-MS/MS31617我国精神科开展TDM的质控情况2009-2015年北京安定医院

TDM项目样本检测量18年度2009201020112012201320142015氯氮平3018376033472661260233113198去甲氯氮平3018376033472661260233113198利培酮34784151458639924180491052009-羟利培酮3509423147554337466562336729氯丙嗪269249329246202224188阿米替林8212000去甲替林8213000多虑平1422000去甲多虑平1421000卡马西平216962757511569丙戊酸3935548769626970713989639829血锂全项3696386770575467575373847921合计（例次）20962255863045126417272183445136332精神科TDM的发展方向精神药物血药浓度测定技术的研究精神药物血药浓度测定的质量控制浓-效关系研究遗传药理学检测与TDM相结合群体药代动力学研究实验室建设与管理精神科TDM服务体系建设19精神药物血药浓度测定技术的研究血清锂浓度测定生化试剂盒的开发丙戊酸的HPLC-UV检测技术蛋白沉淀-在线富集-柱切换-HPLC技术的研发液-质联用技术在精神科TDM中的应用游离药物浓度测定技术的开发研究2021血锂浓度的酶动力学检测法磷酸酶法的原理磷酸酶的活性依赖锂离子的浓度，锂离子的浓度越高，磷酸酶的活性越低。通过选用特定的磷酸酶底物（腺苷双磷酸，PAP），并经过一系列的酶促反应偶联，产生过氧化氢（H2O2）过氧化氢与显色的Trinder反应偶联，可以产生有颜色的醌式化合物，在556nm波长下检测醌式化合物的生成速率，即可反映磷酸酶的活性高低和锂离子的浓度大小在一定范围内，醌式化合物的生成速率与锂离子的浓度成反比。22锂测定试剂盒（磷酸酶法）国内首家采用生化-磷酸酶法检测血锂浓度试剂盒；液体双试剂，全自动生化分析仪上机即用，操作方法简便；检测结果准确，与原子吸收光谱法和离子选择电极法相关性良好，适合临床实验室常规使用；丙戊酸的HPLC-UV检测技术免疫学测定方法灵敏度高，方法成熟，自动化程度高，检测通量高；试剂价格贵，成本高；特异性差HPLC-UV检测法方法尚不成熟，需要前处理，检测通量较低；自配试剂，成本低特异性高23蛋白沉淀-在线富集-柱切换

-HPLC技术的研发简化样本前处理，减少手工操作提高方法的准确度、精密度、灵敏度和特异性实现一套设备测定多种药物及其代谢产物，且每种被测物的检测时间短（<10分钟）探讨血药浓度的全自动HPLC分析2425PumpSamplerDetectorComputer

SingleHPLCSystemMobilePhaseColumn-----------

WasteDualHPLCSystemwithColumnSwitching2627柱切换转载方式—反向转载28阿立哌唑与脱氢阿立哌唑2955种被分析物的色谱图

30药物浓度检测的

质量控制技术及规程研究质控品的配制基质药物种类浓度水平稳定性考察室内质量控制测定频次质控规则室间质量评价国内：品种过少，极不普及国际：英国LGC(LaboratoryoftheGovernmentChemist)

德国Instande.V.31浓效关系的研究浓度血清浓度、血浆浓度、全血浓度、红细胞浓度游离浓度-总浓度活性旋光异构体浓度代谢产物浓度代谢产物/原药浓度/剂量（C/Dratio）效应临床疗效副作用不良反应毒性反应受体结合率心电图脑电图32常用抗抑郁药的参考治疗浓度及警戒浓度（1）中文名英文名血浆半衰期参考治疗浓度警戒浓度阿米替林+去甲替林Amitriptyline+nortriptyline10–28h30h80–200ng/mL300ng/mL多塞平+去甲多赛平Doxepin+nordoxepin15–20h50–150ng/mL300ng/mL米帕明+地西帕明Imipramine+desipramine11–25h15–18h175–300ng/mL300ng/mL氯米帕明+去甲氯米帕明Clomipramine+norclomipramine16–60h36h230–450ng/mL450ng/mL马普替林Maprotiline20–58h75–130ng/mL220ng/mL氟西汀+去甲氟西汀Fluoxetine+norfluoxetine4–6days4–16days120–500ng/mL1000ng/mL帕罗西汀Paroxetine12–44h30–120ng/mL240ng/mL氟伏沙明Fluvoxamine20h60–230ng/mL500ng/mL西酞普兰Citalopram33h50–110ng/mL220ng/mL艾司西酞普兰Escitalopram30h15–80ng/mL160ng/mL33常用抗抑郁药的参考治疗浓度及警戒浓度（2）中文名英文名血浆半衰期参考治疗浓度警戒浓度舍曲林Sertraline26h10–150ng/mL300ng/mL米氮平Mirtazapine20–40h30–80ng/mL160ng/mL文拉法辛+去甲文拉法辛Venlafaxine+O-desmethylvenlafaxine5h11h100–400ng/mL800ng/mL瑞波西汀Reboxetine13–30h60–350ng/mL700ng/mL度洛西汀Duloxetine9–19h30–120ng/mL240ng/mL安非他酮+羟基安非他酮Bupropion+hydroxybupropion8–26h17–47h225–1500ng/mL2000ng/mL吗氯贝胺Moclobemide2–7h300–1000ng/mL2000ng/mL米安舍林Mianserine14–33h15–70ng/mL140ng/mL曲唑酮Trazodone4–11h700–1000ng/mL1200ng/mL34常用抗精神病药的参考治疗浓度及警戒浓度中文名英文名血浆半衰期参考治疗浓度警戒浓度氯丙嗪Chlorpromazine15–30h30–300ng/mL600ng/mL奋乃静Perphenazine8–12h0.6–2.4ng/mL5ng/mL氟奋乃静Fluphenazine16h1–10ng/mL15ng/mL氟哌啶醇Haloperidol12–36h1–10ng/mL15ng/mL甲硫哒嗪Thioridazine30h100–200ng/mL400ng/mL舒必利Sulpiride8–14h200–1000ng/mL1000ng/mL氯氮平Clozapine12–16h350–600ng/mL1000ng/mL奥氮平Olanzapine30–60h20–80ng/mL150ng/mL喹硫平Quetiapine7h100–500ng/mL1000ng/mL利培酮+9-羟利培酮Risperidone+9-hydroxyrisperidone3h24h20–60ng/mL120ng/mL阿立哌唑Aripiprazole60–80h150–500ng/mL1000ng/mL齐拉西酮Ziprasidone6h50–200ng/mL400ng/mL舍吲哚Sertindole55–90h50–100ng/mL200ng/mL佐替平Zotepine13–16h10–150ng/mL300ng/mL35常用情感稳定剂及其它药物的

参考治疗浓度及警戒浓度中文名英文名血浆半衰期参考治疗浓度警戒浓度锂Lithium24h0.5–1.2mmol/l（4–8μg/mL）1.2mmol/l（8μg/mL）丙戊酸Valproicacid18h50–100μg/mL120μg/mL卡马西平Carbamazepine10–20h4–10μg/mL20μg/mL拉莫三嗪Lamotrigine7–23h3–14μg/mL30μg/mL苯巴比妥Phenobarbital80–120h10–40μg/mL50μg/mL苯妥英Phenytoin20–60h10–20μg/mL25μg/mL美沙酮Methadone24–48h400–600ng/mL600ng/mL300ng/mL丁螺环酮Buspirone2–3h1–4ng/mL8ng/mL36原型药与活性代谢产物(1)DrugMetaboliteRatiosofmetabolite/parentdrug(Mean±SD)AmitriptylineNortriptyline0.2–1.8AripiprazoleDehydroaripirazole0.3–0.5PMofCYP2D6:0.2BupropionHydroxybupropion5–47(24h);6–30(12h)Buspirone6-Hydroxybuspirone25–53CarbamazepineCarbamazepine-10,11-epoxide0.07–0.25CitalopramN-esmethylcitalopram0.31–0.60ClomipramineNorclomipramine0.8–2.6ClozapineNorclozapineNonsmokers0.5–0.6;Smokers0.4–0.7DoxepinNordoxepin0.6.–1.6PMCYP2C19:1.8PMCYP2D6:0.8EscitalopramN-Demethylescitalopram0.3–1.037原型药与活性代谢产物(2)DrugMetaboliteRatiosofmetabolite/parentdrug(Mean±SD)FluoxetineNorfluoxetine0.7–1.9FluvoxamineFluvoxaminoacid0–1.2HaloperidolReducedhaloperidolmean0.6ImipramineDesipramine0.6–3.2PMCYP2D64.1MaprotilineDesmethylmaprotiline1.1–3.7PMCYP2D64.9MianserinN-Desmethylmianserin0.5–0.8MirtazapineN-Desmethylmirtazapine0.2–1.2MoclobemideMoclobemideN-oxide0.8.–2.5OlanzapineN-Demethylolanzapinenonsmokers:0.1–0.3smokers:0.2–0.4PerphenazineN-Dealkylperphenazine0.6.–2.838原型药与活性代谢产物(3)DrugMetaboliteRatiosofmetabolite/parentdrug(Mean±SD)QuetiapineNorquetiapine0.1–3.8ReboxetineO-Desethylreboxetine<0.1Risperidone9-HydroxyrisperidoneEMorIMCYP2D6:1.5–10.0SertindoleDehydrosertindole1.1–2.7;1.0inPMofCYP2D6SertralineNorsertraline1.7–3.4Trazodonem-Chlorophenylpiperazine(mCPP)0.04–0.22VenlafaxineO-DesmethylvenlafaxineEMorIMCYP2D6:0.3–5.2PMCYP2D6:0.3UMCYP2D6:>5.2N-Desmethylvenlafaxine0.46–1.4839计算剂量相关血浆药物浓度的有关参数（1）DrugsnClt-SD-Clt+SD[mL/min]Fτ[h]C/Dlow[ng/mL/mg]C/Dhigh[ng/mL/mg]AntidepressantdrugsAmitriptyline8198–3730.5241.031.68Bupropion172500–113001240.060.28Citalopram8367–5450.8241.021.51Clomipramine9583–9330.5240.370.6Doxepin85769–26441240.180.27Duloxetine12610–17330.5240.20.57Escitalopram24360–9600.8240.581.54Fluoxetinen.r.600–8330.7240.60.83Fluvoxamine6807–19601240.350.86Maprotiline6503–17470.8240.321.1Mianserinn.r.843–19480.3240.110.25Mirtazapine10455–9450.5240.370.85Paroxetine301561–108561240.060.44Reboxetinen.r.22–5112412.5531.1Trazodone873–1031246.729.47Venlafaxine18747–15401240.450.9340计算剂量相关血浆药物浓度的有关参数（2）DrugsnClt-SD-Clt+SD[mL/min]Fτ[h]C/Dlow[ng/mL/mg]C/Dhigh[ng/mL/mg]AntipsychoticdrugsAmisulpride78520–6930.5240.50.67Aripiprazole647–700.9248.6312.85Chlorpromazine111043–15100.1240.050.07Clozapine16258–7280.5240.40.8Flupentixol3440–4900.6240.780.87Fluphenazinedecanoate122380–39401240.180.29Haloperidol6420–6800.6240.610.99Olanzapine491233–6370.8240.872.38Paliperidonen.r.31–980.3241.996.31Perphenazine81009–25660.4240.110.28Pimozide721–5530.5240.6416.53Quetiapine101146–24211240.130.21Risperidone891–1710.7243.514Sertindole6133–6001241.165.22Supiride6331–4990.25240.350.52Thiordazine11404–9820.6240.421.03Zotepine14467–102671240.071.49Ziprasidone12303–3970.6241.051.3641计算剂量相关血浆药物浓度的有关参数（3）DrugsnClt-SD-Clt+SD[mL/min]Fτ[h]C/Dlow[ng/mL/mg]C/Dhigh[ng/mL/mg]AnticonvulsantdrugsMoodstabilizersCarbamazepinen.r.58–741249.411.93Lamotrigine12922–4912414.0931.28Lithiumn.r.10–4012417.3669.44Oxcarbazepine71703–50631240.140.41Primidone830–4712414.782