精神科治療藥物監(jiān)測(cè)的現(xiàn)狀及發(fā)展方向

中國(guó)精神科治療藥物監(jiān)測(cè)的

現(xiàn)狀及發(fā)展方向2前言自氯丙嗪的抗精神病作用被發(fā)現(xiàn)60年來(lái)，已經(jīng)上市的精神藥物已經(jīng)達(dá)到130余種。這些藥物在精神疾病或癥候群的治療或緩解方面正在發(fā)揮愈來(lái)愈重要的作用。如何選好、用好精神藥物，保證精神疾病藥物治療的有效性和安全性是精神科面臨的一個(gè)重要問(wèn)題。治療藥物監(jiān)測(cè)是實(shí)現(xiàn)精神疾病的個(gè)體化精準(zhǔn)藥物治療的重要手段。3對(duì)精神藥物實(shí)施TDM的必要性精神疾病多屬慢性病，需要長(zhǎng)期用藥，而且精神藥物的不良反應(yīng)較多；精神藥物在藥動(dòng)學(xué)上的個(gè)體差異明顯，相同劑量的血濃度可相差幾倍到幾十倍；起效時(shí)間長(zhǎng)，通常給藥2~4周后起效；療效指標(biāo)不夠簡(jiǎn)明，且受醫(yī)生主觀因素影響；精神病患者的服藥依從性差；中毒反應(yīng)可隱匿性出現(xiàn)，且不易與疾病本身癥狀的加重相區(qū)別；血藥濃度與療效和毒副作用相關(guān)，過(guò)高或過(guò)低療效均不好。BenefitsofTDMinPsychiatrydosagetitrationadversereactionandintoxication(overdose)identificationpharmacogeneticparticularityevaluationdruginteractionevaluationrelapsepreventionpatient’scomplianceassessment45需要進(jìn)行TDM的藥物種類(lèi)抗抑郁藥物三環(huán)類(lèi)抗抑郁藥新型抗抑郁藥抗精神病藥傳統(tǒng)抗精神病藥非典型抗精神病藥情感穩(wěn)定劑碳酸鋰、丙戊酸、卡馬西平、拉莫三嗪戒毒藥及其它6精神藥物TDM必要性的等級(jí)劃分最應(yīng)該監(jiān)測(cè)的藥物（15種）鋰鹽、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、奮乃靜、氟奮乃靜、甲硫噠嗪、甲哌丙嗪、氨磺必利、氯氮平（去甲氯氮平）、奧氮平、苯巴比妥、苯妥英鈉應(yīng)該監(jiān)測(cè)的藥物（52種）多慮平（去甲多慮平）、麥普替林、西酞普蘭、氟西汀（去甲氟西?。?、舍曲林、文拉法辛（o-去甲文拉法辛）、曲唑酮、度洛西汀、米氮平、依他普侖、米那普侖、氯丙嗪、舒必利、利培酮（9-羥利培酮）、喹硫平、舍吲哚、溴哌利多、阿立哌唑、齊拉西酮、氟哌噻噸、卡馬西平、拉莫三嗪、丙戊酸、美沙酮等監(jiān)測(cè)有用的藥物（44種）潛在有用的藥物（19種）HistoryofTDMinChinavd.HELMHJ,ANDRIESSED.ClinChimActa.1961;6:747-748.王見(jiàn)義;吳貞喜;葛志榮.

神經(jīng)精神疾病雜志1980(05):

276-278陳剛;卓海通.中國(guó)醫(yī)院藥學(xué),1983(2):12-14吳萊文.中國(guó)臨床藥理學(xué)雜志,19862(3):151-157196119801983中國(guó)大陸精神科TDM現(xiàn)狀調(diào)查調(diào)查范圍：中國(guó)大陸地區(qū)三級(jí)精神病專(zhuān)科醫(yī)院、?。ㄊ校┘?jí)精神衛(wèi)生中心調(diào)查時(shí)間：2010年6月-12月數(shù)據(jù)采集時(shí)間：2009年調(diào)查者：北京安定醫(yī)院臨床精神藥理實(shí)驗(yàn)室論文發(fā)表：中國(guó)新藥雜志，2013年，22(11):1347-1352TherDrugMonit,December2013,35(6):816-8228910主要調(diào)查內(nèi)容basicinformationofthefacilityTDMrequestformsresultinterpretationtypesofpsychotropicdrugsmonitoredandannualworkloadsanalyticalmethodsinternalqualitycontrolandexternalqualityassessment11問(wèn)卷發(fā)放及回收情況12有效問(wèn)卷的地理分布圖13監(jiān)測(cè)項(xiàng)目及年樣本檢測(cè)量14ThestatusofanalyticalmethodsLithium32ionselectiveelectrode(ISE)25theatomicabsorptionspectrometry(AAS)2atomicemissionspectrometry(AES)2flamephotometryassay(FPA)2ValproicAcid7fluorescencepolarizationimmunoassay2enzymeimmunoassay2chemiluminescence2reversedphaseliquidchromatographymethod115ThestatusofanalyticalmethodsOtherPsychotropicDrugsHighperformanceliquidchromatography(HPLC)withdifferentdetectorssingle-wavelengthUVdetector20diodearraydetector4fluorescencedetector2Amperometricelectrochemicaldetector2Coulometricelectrochemicaldetector3Evaporativelight-scatteringdetector1HPLC-MS/MS31617我國(guó)精神科開(kāi)展TDM的質(zhì)控情況2009-2015年北京安定醫(yī)院

TDM項(xiàng)目樣本檢測(cè)量18年度2009201020112012201320142015氯氮平3018376033472661260233113198去甲氯氮平3018376033472661260233113198利培酮34784151458639924180491052009-羥利培酮3509423147554337466562336729氯丙嗪269249329246202224188阿米替林8212000去甲替林8213000多慮平1422000去甲多慮平1421000卡馬西平216962757511569丙戊酸3935548769626970713989639829血鋰全項(xiàng)3696386770575467575373847921合計(jì)（例次）20962255863045126417272183445136332精神科TDM的發(fā)展方向精神藥物血藥濃度測(cè)定技術(shù)的研究精神藥物血藥濃度測(cè)定的質(zhì)量控制濃-效關(guān)系研究遺傳藥理學(xué)檢測(cè)與TDM相結(jié)合群體藥代動(dòng)力學(xué)研究實(shí)驗(yàn)室建設(shè)與管理精神科TDM服務(wù)體系建設(shè)19精神藥物血藥濃度測(cè)定技術(shù)的研究血清鋰濃度測(cè)定生化試劑盒的開(kāi)發(fā)丙戊酸的HPLC-UV檢測(cè)技術(shù)蛋白沉淀-在線富集-柱切換-HPLC技術(shù)的研發(fā)液-質(zhì)聯(lián)用技術(shù)在精神科TDM中的應(yīng)用游離藥物濃度測(cè)定技術(shù)的開(kāi)發(fā)研究2021血鋰濃度的酶動(dòng)力學(xué)檢測(cè)法磷酸酶法的原理磷酸酶的活性依賴(lài)鋰離子的濃度，鋰離子的濃度越高，磷酸酶的活性越低。通過(guò)選用特定的磷酸酶底物（腺苷雙磷酸，PAP），并經(jīng)過(guò)一系列的酶促反應(yīng)偶聯(lián)，產(chǎn)生過(guò)氧化氫（H2O2）過(guò)氧化氫與顯色的Trinder反應(yīng)偶聯(lián)，可以產(chǎn)生有顏色的醌式化合物，在556nm波長(zhǎng)下檢測(cè)醌式化合物的生成速率，即可反映磷酸酶的活性高低和鋰離子的濃度大小在一定范圍內(nèi)，醌式化合物的生成速率與鋰離子的濃度成反比。22鋰測(cè)定試劑盒（磷酸酶法）國(guó)內(nèi)首家采用生化-磷酸酶法檢測(cè)血鋰濃度試劑盒；液體雙試劑，全自動(dòng)生化分析儀上機(jī)即用，操作方法簡(jiǎn)便；檢測(cè)結(jié)果準(zhǔn)確，與原子吸收光譜法和離子選擇電極法相關(guān)性良好，適合臨床實(shí)驗(yàn)室常規(guī)使用；丙戊酸的HPLC-UV檢測(cè)技術(shù)免疫學(xué)測(cè)定方法靈敏度高，方法成熟，自動(dòng)化程度高，檢測(cè)通量高；試劑價(jià)格貴，成本高；特異性差HPLC-UV檢測(cè)法方法尚不成熟，需要前處理，檢測(cè)通量較低；自配試劑，成本低特異性高23蛋白沉淀-在線富集-柱切換

-HPLC技術(shù)的研發(fā)簡(jiǎn)化樣本前處理，減少手工操作提高方法的準(zhǔn)確度、精密度、靈敏度和特異性實(shí)現(xiàn)一套設(shè)備測(cè)定多種藥物及其代謝產(chǎn)物，且每種被測(cè)物的檢測(cè)時(shí)間短（<10分鐘）探討血藥濃度的全自動(dòng)HPLC分析2425PumpSamplerDetectorComputer

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

WasteDualHPLCSystemwithColumnSwitching2627柱切換轉(zhuǎn)載方式—反向轉(zhuǎn)載28阿立哌唑與脫氫阿立哌唑2955種被分析物的色譜圖

30藥物濃度檢測(cè)的

質(zhì)量控制技術(shù)及規(guī)程研究質(zhì)控品的配制基質(zhì)藥物種類(lèi)濃度水平穩(wěn)定性考察室內(nèi)質(zhì)量控制測(cè)定頻次質(zhì)控規(guī)則室間質(zhì)量評(píng)價(jià)國(guó)內(nèi)：品種過(guò)少，極不普及國(guó)際：英國(guó)LGC(LaboratoryoftheGovernmentChemist)

德國(guó)Instande.V.31濃效關(guān)系的研究濃度血清濃度、血漿濃度、全血濃度、紅細(xì)胞濃度游離濃度-總濃度活性旋光異構(gòu)體濃度代謝產(chǎn)物濃度代謝產(chǎn)物/原藥濃度/劑量（C/Dratio）效應(yīng)臨床療效副作用不良反應(yīng)毒性反應(yīng)受體結(jié)合率心電圖腦電圖32常用抗抑郁藥的參考治療濃度及警戒濃度（1）中文名英文名血漿半衰期參考治療濃度警戒濃度阿米替林+去甲替林Amitriptyline+nortriptyline10–28h30h80–200ng/mL300ng/mL多塞平+去甲多賽平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馬普替林Maprotiline20–58h75–130ng/mL220ng/mL氟西汀+去甲氟西汀Fluoxetine+norfluoxetine4–6days4–16days120–500ng/mL1000ng/mL帕羅西汀Paroxetine12–44h30–120ng/mL240ng/mL氟伏沙明Fluvoxamine20h60–230ng/mL500ng/mL西酞普蘭Citalopram33h50–110ng/mL220ng/mL艾司西酞普蘭Escitalopram30h15–80ng/mL160ng/mL33常用抗抑郁藥的參考治療濃度及警戒濃度（2）中文名英文名血漿半衰期參考治療濃度警戒濃度舍曲林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+羥基安非他酮Bupropion+hydroxybupropion8–26h17–47h225–1500ng/mL2000ng/mL嗎氯貝胺Moclobemide2–7h300–1000ng/mL2000ng/mL米安舍林Mianserine14–33h15–70ng/mL140ng/mL曲唑酮Trazodone4–11h700–1000ng/mL1200ng/mL34常用抗精神病藥的參考治療濃度及警戒濃度中文名英文名血漿半衰期參考治療濃度警戒濃度氯丙嗪Chlorpromazine15–30h30–300ng/mL600ng/mL奮乃靜Perphenazine8–12h0.6–2.4ng/mL5ng/mL氟奮乃靜Fluphenazine16h1–10ng/mL15ng/mL氟哌啶醇Haloperidol12–36h1–10ng/mL15ng/mL甲硫噠嗪Thioridazine30h100–200ng/mL400ng/mL舒必利Sulpiride8–14h200–1000ng/mL1000ng/mL氯氮平Clozapine12–16h350–600ng/mL1000ng/mL奧氮平Olanzapine30–60h20–80ng/mL150ng/mL喹硫平Quetiapine7h100–500ng/mL1000ng/mL利培酮+9-羥利培酮Risperidone+9-hydroxyrisperidone3h24h20–60ng/mL120ng/mL阿立哌唑Aripiprazole60–80h150–500ng/mL1000ng/mL齊拉西酮Ziprasidone6h50–200ng/mL400ng/mL舍吲哚Sertindole55–90h50–100ng/mL200ng/mL佐替平Zotepine13–16h10–150ng/mL300ng/mL35常用情感穩(wěn)定劑及其它藥物的

參考治療濃度及警戒濃度中文名英文名血漿半衰期參考治療濃度警戒濃度鋰Lithium24h0.5–1.2mmol/l（4–8μg/mL）1.2mmol/l（8μg/mL）丙戊酸Valproicacid18h50–100μg/mL120μg/mL卡馬西平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丁螺環(huán)酮Buspirone2–3h1–4ng/mL8ng/mL36原型藥與活性代謝產(chǎn)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原型藥與活性代謝產(chǎn)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原型藥與活性代謝產(chǎn)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計(jì)算劑量相關(guān)血漿藥物濃度的有關(guān)參數(shù)（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計(jì)算劑量相關(guān)血漿藥物濃度的有關(guān)參數(shù)（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計(jì)算劑量相關(guān)血漿藥物濃度的有關(guān)參數(shù)（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